peri conceptional period & nutrition : biomarkers ... · désir d’enfant conception grossesse...
TRANSCRIPT
Peri conceptional period amp nutrition Biomarkers amp clinical stakes
Pr Dominique Luton MDPhD Dr Heacutelegravene Peacutejoan MD
Dr Pierre Franccedilois Ceccaldi MD Pr Jean Guibourdenche PhD
Deacutepartement Bichat Beaujon Gyneacutecologie Obsteacutetrique
APHP
UNIVERSITE PARIS VII DENIS DIDEROT
Periconceptionnal care period begins since the desire of
pregnancy an last two or three month after conception
deacutesir drsquoenfant
Conception
Grossesse
Peacuterinataliteacute
Accouchement
Peacutericonception
(Arrecirct de contraception)
foetus nouveau-neacute nourrisson
Allaitement
Consultation
preacuteconceptionnelle
1e consultation
preacutenatale
embryon
This period deserves our attention because many medical and
behavioral intervention can help to optimize further outcome of
pregnancy Evidence based medecine has clearly demonstrated the
effectiveness of these measures
bull Supplementation
bull Various vaccination
bull Obesity and Diabetes
bull Thyroid desease
bull HIV
bull Various treatment
bull Any addiction
bull helliphellip
Nutrition is one of these paradigm dealing mainly with the
folate (prevention of neural tube defect) and iodine status
(prevention of neurological defect) among women of
childbearing age
Other vitamin such as pyridoxin (B6) and
cobalamin (B12) could also participate in the
improvement of the conceptus
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Periconceptionnal care period begins since the desire of
pregnancy an last two or three month after conception
deacutesir drsquoenfant
Conception
Grossesse
Peacuterinataliteacute
Accouchement
Peacutericonception
(Arrecirct de contraception)
foetus nouveau-neacute nourrisson
Allaitement
Consultation
preacuteconceptionnelle
1e consultation
preacutenatale
embryon
This period deserves our attention because many medical and
behavioral intervention can help to optimize further outcome of
pregnancy Evidence based medecine has clearly demonstrated the
effectiveness of these measures
bull Supplementation
bull Various vaccination
bull Obesity and Diabetes
bull Thyroid desease
bull HIV
bull Various treatment
bull Any addiction
bull helliphellip
Nutrition is one of these paradigm dealing mainly with the
folate (prevention of neural tube defect) and iodine status
(prevention of neurological defect) among women of
childbearing age
Other vitamin such as pyridoxin (B6) and
cobalamin (B12) could also participate in the
improvement of the conceptus
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
deacutesir drsquoenfant
Conception
Grossesse
Peacuterinataliteacute
Accouchement
Peacutericonception
(Arrecirct de contraception)
foetus nouveau-neacute nourrisson
Allaitement
Consultation
preacuteconceptionnelle
1e consultation
preacutenatale
embryon
This period deserves our attention because many medical and
behavioral intervention can help to optimize further outcome of
pregnancy Evidence based medecine has clearly demonstrated the
effectiveness of these measures
bull Supplementation
bull Various vaccination
bull Obesity and Diabetes
bull Thyroid desease
bull HIV
bull Various treatment
bull Any addiction
bull helliphellip
Nutrition is one of these paradigm dealing mainly with the
folate (prevention of neural tube defect) and iodine status
(prevention of neurological defect) among women of
childbearing age
Other vitamin such as pyridoxin (B6) and
cobalamin (B12) could also participate in the
improvement of the conceptus
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
This period deserves our attention because many medical and
behavioral intervention can help to optimize further outcome of
pregnancy Evidence based medecine has clearly demonstrated the
effectiveness of these measures
bull Supplementation
bull Various vaccination
bull Obesity and Diabetes
bull Thyroid desease
bull HIV
bull Various treatment
bull Any addiction
bull helliphellip
Nutrition is one of these paradigm dealing mainly with the
folate (prevention of neural tube defect) and iodine status
(prevention of neurological defect) among women of
childbearing age
Other vitamin such as pyridoxin (B6) and
cobalamin (B12) could also participate in the
improvement of the conceptus
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
bull Supplementation
bull Various vaccination
bull Obesity and Diabetes
bull Thyroid desease
bull HIV
bull Various treatment
bull Any addiction
bull helliphellip
Nutrition is one of these paradigm dealing mainly with the
folate (prevention of neural tube defect) and iodine status
(prevention of neurological defect) among women of
childbearing age
Other vitamin such as pyridoxin (B6) and
cobalamin (B12) could also participate in the
improvement of the conceptus
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Nutrition is one of these paradigm dealing mainly with the
folate (prevention of neural tube defect) and iodine status
(prevention of neurological defect) among women of
childbearing age
Other vitamin such as pyridoxin (B6) and
cobalamin (B12) could also participate in the
improvement of the conceptus
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Other vitamin such as pyridoxin (B6) and
cobalamin (B12) could also participate in the
improvement of the conceptus
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
What about Vitamins and pregnancy bull Fundamental role bull Non synthetized by the organism bull Mandatory cofactor for various reactions
(oxydative stress E C β carotegravenes) bull Overall needs of vitamins during pregnancy bull Increase of oxydative stress during pregnancy bull Typical situations well known bull In between situations less known
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Clinical Manifestation
Vitamine A Eyes
Skin
- Ceacuteciteacute nocturne
- Xeacuterosis (seacutecheresse de la conjonctive bulbaire)
- Taches de Bitot (plaques conjonctivales)
- Keacuteratomalacie (ulceacuteration de la corneacutee)
- Hyperkeacuteratose
Vitamine B12 Hematopoietic and Neurological
system
Digestive system
- Aneacutemie macrocytaire
- Perte irreacuteversible du sens vibratoire et proprioceptif
- Parestheacutesies
- Diarrheacutee
Vitamine C Skin and mucosae - Papules peacuterifolliculaires (cheveux cassants)
- Heacutemorragies peacuterifolliculaires
- Saignements gingivaux
- Purpura ecchymoses
Vitamine D Bone - Douleurs osteacuteo-articulaires
- Deacutemineacuteralisation osseuse
- Rachitisme
- Myopathie proximale
Vitamine K Coagulation - Ecchymoses
- Heacutemorragies
Vitamine B6
(Pyridoxine)
Skin and mucosae - Dermatite seacuteborrheacuteique
- Cheacuteilite
- Glossite
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
Tableau II Clinical Manifestation
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Manifestations cliniques
Vitamine PP
(Niacine)
Skin
Digestive system
Neurological system
- Dermatite
- Diarrheacutee
- Deacutemence
Vitamine B1
(Thiamine)
Cardiovascular system
Neurological system
- Insuffisance cardiaque congestive
- Enceacutephalopathie de Wernicke
- Syndrome de Korsakoff
Zinc Skin
Taste
- Acrodermatite enteacuteropathique
- Alopeacutecie
- Hypogueusie
Vitamine B9
(Folates)
Hematopoietic and Neurological system
- Aneacutemie macrocytaire
- Perte reacuteversible du sens vibratoire et proprioceptif
Fer Hematopoiumletic system
Skin
Digestive system
- Aneacutemie microcytaire
- Troubles des phanegraveres (cheveux et ongles)
- Prurit seacutecheresse cutaneacutee
- Glossite perlegraveche
CV = appareil cardiovasculaire SNC = systegraveme nerveux central
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
What about preconceptionnal behaviour
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Table 1 overwiew of effective preconceptionnal behavior
100 of
the
women
21
Nutrionnal
complement
14
hellipfor more
than two
month
17
hellipknowing
it contained
folic acid
Expecting
their
pregnancy
88
45
considered
they had
prepared it
correctly
13
hellip had a
supplementation
Preconceptionnal care in France evaluation by a retrospective
study Dominique Luton Anne Forestier Steacutephanie Coureau
(Submitted)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
bull Promising results but still inadequate
bull Most women expect their pregnancy and
half of them prepare it
ndash Huge work of knowledge transmission
ndash Pregnancy (or planning a pregnancy) is a
potent trigger for modifying periconceptionnal
behaviour
bull Half of the patient succeeded in stopping tobacco
bull 90 of the patient succeeded in stopping alcohol
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
More Insight
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Iron Deficiency
bull Very frequent (40)
bull How to diagnose it
ndash Ferritinemia in sera
ndash Widespread and automat
ndash All methods are not similar ( immunoenzymo immunoneacutepheacuteleacutemeacutetrie chimiluminsecence ) =gt
a patient should be followed by the same method
ndash Non specific (inflammation)
ndash Should be associated with red blood cell count VGM hellip
bull Direct Iron assesment is not appropriate
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
B9 deficiency
bull Folates = B9
bull Immunodosage widespread and automat
bull In sera instantaneous circulating form (alimentation)
bull In erythrocytes ( stock)
bull In case of deficiency decrease of seric then erythrocite form
bull Non specific ( neoplasia kidney desease alcohol consumptionhelliphellip)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
REVIEW
Economic burden of neural tube defects and impactof prevention with folic acid a literature review
Yunni Yi ampMarion Lindemann ampAntje Colligs amp
Claire Snowball
Received 23 March 2011 Accepted 4 May 2011 The Author(s) 2011 This article is published with open access at Springerlinkcom
Abstract Neural tube defects (NTDs) are the second most
common group of serious birth defects Although folic acid
has been shown to reduce effectively the risk of NTDs and
measures have been taken to increase the awareness
knowledge and consumption of folic acid the full potential
of folic acid to reduce the risk of NTDs has not been
realized in most countries To understand the economic
burden of NTDs and the economic impact of preventing
NTDs with folic acid a systematic review was performed
on relevant studies A total of 14 cost of illness studies and
10 economic evaluations on prevention of NTDs with folic
acid were identified Consistent findings were reported
across all of the cost of illness studies The lifetime direct
medical cost for patients with NTDs is significant with the
majority of cost being for inpatient care for treatment at
initial diagnosis in childhood and for comorbidities in adult
life The lifetime indirect cost for patients with spina bifida
is even greater due to increased morbidity and premature
mortali ty Caregiver time costs are also significant The
results from the economic evaluations demonstrate that
folic acid fortification in food and preconception folic acid
consumption are cost-effective ways to reduce the inci-
dence and prevalence of NTDs This review highlights the
significant cost burden that NTDs pose to healthcare
systems various healthcare payers and society and
concludes that the benefits of prevention of NTDs with
folic acid far outweigh the cost Further intervention with
folic acid is justified in countries where the full potential of
folic acid to reduce the risk of NTDs has not been realized
Keywords Neural tube defects Spina bifida Economic
burden Cost Folic acid Prevention
Introduction
Neural tube defects (NTDs) are the second most common
group of serious birth defects NTDs result from failure of
the neural tube to close properly approximately 28 days
postconception Typically this occurs before the woman
knows that she is pregnant [7 38] Despite the identified
association between the achievement of adequate folate
level at time of conception and a risk reduction of NTDs
NTDs have a complex and imperfectly understood aetiol-
ogy in which both genetic and environmental factors appear
to be involved [7]
Two of the most common NTDs are spina bifida and
anencephaly Spina bifida results from failure of fusion of
the posterior (caudal) neural tube whereas anencephaly
results from failure of fusion of the anterior (cranial) neural
tube Anencephaly is fatal many children with anencephaly
are stillborn or die shortly after birth Fifty percent have a
life expectancy of between a few minutes and 1 day and
25 only live up to 10 days [29] Children with spina
bifida have a high probabili ty of lifelong physical and
mental handicap and only a minority of these children are
able to function independently as adults [41] Due to
advances in medical technology the life expectancy of
patients with spina bifida is rising annually with 85 to
90 of children born with the disease surviving into
adulthood [46]
Patients with NTDs regularly have problems related to
hydrocephalus neurogenic bladder kidney involvement
Y Yi ( ) C Snowball
Mapi Values
Bollington Cheshire SK10 5JB UK
e-mail YunniYimapivaluescom
M Lindemann A Colligs
Bayer Schering Pharma AG
Berlin Germany
Eur J Pediatr
DOI 101007s00431-011-1492-8
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Cochrane
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis 11 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR 2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
206 No history of NTDsor
unknown
0 0 Risk Ratio (M-H Fixed 95 CI) Not estimable
Analysis11 Comparison 1 Supplementation with folic acid versusno treatmentother
micronutrientsplacebo Outcome 1 Neural tube defects (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 1 Neural tube defects(ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 02104 62052 144 008 [ 000 133 ]
ICMR2000 4137 10142 214 041 [ 013 129 ]
Kirke 1992 0172 4192 93 012 [ 001 229 ]
Laurence 1981 260 451 94 043 [ 008 223 ]
MRC 1991 6593 21602 455 029 [ 012 071 ]
Total (95 CI) 3066 3039 1000 028 [ 015 052 ]
Total events 12 (Folic acid) 45 (No treatother MNplacebo)
HeterogeneityChi2 = 179 df = 4 (P= 077) I2 =00
Test for overall effect Z = 405 (P= 0000051)
001 01 1 10 100
Favours experimental Favours control
55Effectsand safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
( Continued)Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
MRC 1991 1593 1602 296 102 [ 006 1619 ]
Subtotal (95 CI) 765 794 1000 046 [ 007 314 ]
Total events 1 (Folic acid) 3 (No treatother MNplacebo)
Heterogeneity Chi2 = 053 df = 1 (P= 046) I2 =00
Test for overall effect Z = 080 (P = 043)
6 No history of NTDs or unknown
Czeizel 1994 102104 172052 1000 057 [ 026 125 ]
Subtotal (95 CI) 2104 2052 1000 057 [ 026 125 ]
Total events 10 (Folic acid) 17 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 140 (P = 016)
001 01 1 10 100
Favours experimental Favours control
Analysis 19 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 9 Other birth defects (any) (ALL)
Review Effects and safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 9 Other birth defects (any) (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 212104 412052 726 050 [ 030 084 ]
Kirke 1992 3172 4192 66 084 [ 019 369 ]
MRC 1991 17593 12602 208 144 [ 069 298 ]
Total (95 CI) 2869 2846 1000 072 [ 048 107 ]
Total events 41 (Folic acid) 57 (No treatother MNplacebo)
Heterogeneity Chi2 = 537 df = 2 (P= 007) I2 =63
Test for overall effect Z = 164 (P = 010)
001 01 1 10 100
Favours experimental Favours control
64Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
( Continued)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Heterogeneity Chi2 = 143 df = 2 (P= 049) I2 =00
Test for overall effect Z = 134 (P= 018)
5 History of NTDs
ICMR2000 1137 3142 372 035 [ 004 328 ]
MRC 1991 7593 5600 628 142 [ 045 444 ]
Subtotal (95 CI) 730 742 1000 102 [ 038 270 ]
Total events 8 (Folic acid) 8 (No treatother MNplacebo)
Heterogeneity Chi2 = 121 df = 1 (P= 027) I2 =17
Test for overall effect Z = 004 (P= 097)
6 No history of NTDs or unknown
Czeizel 1994 462421 322346 1000 139 [ 089 218 ]
Subtotal (95 CI) 2421 2346 1000 139 [ 089 218 ]
Total events 46 (Folic acid) 32 (No treatother MNplacebo)
Heterogeneity not applicable
Test for overall effect Z = 145 (P= 015)
001 01 1 10 100
Favours experimental Favours control
Analysis 117 Comparison 1 Supplementation with folic acid versus no treatmentother
micronutrientsplacebo Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Review Effectsand safety of periconceptional folate supplementation for preventingbirth defects
Comparison 1 Supplementation with folic acid versusno treatmentother micronutrientsplacebo
Outcome 17 Pregnancy termination for fetal abnormality (ALL)
Study or subgroup Folic acid No treatother MNplacebo Risk Ratio Weight Risk Ratio
nN nN M-HFixed95CI M-HFixed95CI
Czeizel 1994 32104 132052 289 023 [ 006 079 ]
ICMR2000 3137 8142 173 039 [ 011 143 ]
Laurence 1981 060 151 36 028 [ 001 683 ]
MRC 1991 7677 23685 502 031 [ 013 071 ]
Total (95 CI) 2978 2930 1000 030 [ 016 054 ]
Total events 13 (Folic acid) 45 (No treatother MNplacebo)
Heterogeneity Chi2 = 036 df = 3 (P= 095) I2 =00
Test for overall effect Z = 395 (P= 0000078)
001 01 1 10 100
Favours experimental Favours control
73Effects and safety of periconceptional folate supplementation for preventing birth defects (Review)
Copyright copy 2010 The Cochrane Collaboration Published by John W iley amp Sons Ltd
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Limitation
1- Lack of systematic administration
2- 50 of french population is either homozygote or heterozygote for MTHFR gene (Chango et al Suvimax 2000 Botto 2000 et Gueacuteant-Rodriguez 2005)
00
50
100
150
200
250
300
350
400
450
Fre
qu
en
cy
in
US
poole
d
His
panic
s C
alif
orn
ia
Canada
Japan
Irela
nd
UK
Italy
C667T homozygous
MTHFR C677T polymorphism
C667T homozygous
C667T heterozygous
Botto L D et al Am J Epidemiol 151 No 9 862-877 (2000)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Homocystein excess
bull Non specific
bull Non widespread
bull HPLC on CAA (High performance Liquid Chromatography )
HOMOCYSTEINEMIE
INFLUENCE DE LA MUTATION MTHFR
7
8
9
10
11
12
13
14
H+F hommes femmes
non mutants CC
heacuteteacuterozygotes CT
homozygotes TT
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
B6 deficiency
bull Less widespread not easy (HPLC) non specific (kidney alcohol helliphellip)
bull Static assesment needs dynamic test
B12 deficiency
bull Chemiluminescence (competition) widespread automat few interferences (malabsoption
digestive or hepatic desesase)
bull Should be associated with red blood cell count
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
there are strong physiopathological arguments to support B12 and B6 association with B9
administration Until folic acid fortification becomes mandatory all women of reproductive
age should consume folic acid in a multivitamin that also contains B12 and B6
Nutritional and genetic determinants of vitamin B and homocysteine metabolisms in neural
tube defects a multicenter case-control study Candito et al Am J Med Genet A 2008
May 1146A(9)1128-33
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Vitamin D deficiency
bull calcidiol =25 OHD
bull quite widespread automat
bull calcitriol (125OHD2) non informative for deficiency
bull Deficiency incidence 50
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
AJOG 2010
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Deacuteficit lt 20 ngml
Carence lt 15 ngml
45 63
High prevalence of vitamin D deficiency in newborn a French cohort
Heacutelegravene Pejoan MD a Pierre Franccedilois Ceccaldi MD a Nicole Breau MD b Marie Claude Andre MD a Doufary Diallo
MD a Dario Franzone MD a Guillaume Ducarme MD a Carine Davitian MD a Dominique Luton MDPhD a
ngm
l
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
bull Vit D deficiency is still present
bull Huge matter of public health ( preeclampsia immunity
cancerhellip
bull Strengthen the message about supplementation and re
evaluate the modalities (single or multiple
administration dosagehellip)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Iodine deficiency
bull Ioduria (24h) not widespread applicable at group level (not individual)
bull Iodemia has no application (except for research and excess)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Iodine Deficiency in Northern Paris Area Impact on FetalThyroid Mensuration
Dominique Luton1 Corinne Albert i4 Edith Vuil lard2 Guillaume Ducarme1 Jean Francois Oury2 Jean
Guibourdenche3
1 Universite Paris VII AP-HP GHU nord Hopital Beaujon Service de Gynecologie Obstetrique Clichy France 2 Universite Paris VII AP-HP GHU nord Hopital Robert Debre
Service de Gynecologie Obstetrique Paris France 3 Universite Paris V AP-HP GHU ouest Hopital Cochin Port Royal Service de Biochimie Hormonologie Paris France
4 Universite Paris VII AP-HP Hopital Robert Debre Unite drsquoEpidemiologie Clinique Inserm CIE 5 Paris France
Abst ract
Introduction Iodine is essential for normal fetal and neonatal development We studied the prevalence and impact on fetalthyroid development of iodine deficiency in pregnant women in the northern part of the Paris conurbation
Materials and Methods 110 patients underwent several determinations of urinary iodine excretion (UIE) and of serum FT4FT3 and TSH Fetal thyroid gland size was assessed using ultrasonography
Results We found evidence of widespread iodine deficiency (mean UIE 498 mgL [standard deviation 211]) Iodinedeficiency did not correlate significantly with maternal thyroid parameters but showed a significant negative correlationwith fetal thyroid gland size (rho = 025 P= 002)
Conclusion Iodine deficiency during pregnancy is still a problem in our geographical area and affects the fetal thyroidgland Clinical Trialsgov NCT00162539
Citat ion Luton D Alberti C Vuillard E Ducarme G Oury JF et al (2011) Iodine Deficiency in Northern Paris Area Impact on Fetal Thyroid Mensuration PLoSONE 6(2) e14707 doi101371journalpone0014707
Editor Vincent Laudet Ecole Normale Superieure de Lyon France
Received July 18 2010 Accept ed January 10 2011 Published February 16 2011
Copyright szlig 2011 Luton et al This is an open-access article distributed under the terms of the Creative Commons Attribution License which permitsunrestricted use distribution and reproduction in any medium provided the original author and source are credited
Funding The project was funded by Development and Clinical Research Department Ile de France (CRC 04-106) of Assistance Publique - Hopitaux de Paris Thefunders had no role in study design data collection and analysis decision to publish or preparation of the manuscript
Compet ing Interests Dominique Luton did some remunerated counseling for Merck Medication Familiale during the years 2007 and 2008
E-mail dlutonfreefr
Int roduct ion
During pregnancy an appropriate supply of iodine is essential
to maintain homeostasis in both the mother and the fetus [1]
Compared with maternal hypothyroidism iodine deficiency may
have an even greater impact on fetal neurocognitive development
[234] probably because the area under the curve of fetal blood
thyroxine concentrations islower The prevention early detection
and immediate correction of iodine or thyroxine deficiency in
pregnant women are high priorities
Increased size of the neonatal thyroid gland measured using
ultrasonography just after delivery has been reported in infants
born to motherswith iodinedeficiency [5] Wehavemany yearsof
experience with ultrasonographic fetal thyroid gland measure-
ments Weuseboth our own unpublished reference curvesand the
curves established by Ranzini et al [6]
France is considered an area of moderate iodine deficiency
[789] To date no consensus has been developed regarding the
appropriateness of iodine supplementation before and during
pregnancy
The objective of the prospective observational study reported
here wasto assess the impact of maternal iodine statuson fetal and
neonatal thyroid gland size We studied pregnant women living in
the northern part of the Paris conurbation and their fetuses and
neonates
Materials and Methods
SubjectsWe planned to recruit 110 pregnant patients receiving routine
prenatal care at a single tertiary-level teaching hospital in northern
Paris France Inclusion criteria were normal pregnancy having
signed thestudy informed consent document and being covered by
the French public healthcare insurance system Exclusion criteria
were the presence of chronic disease iodine supplementation
current or past thyroid disease fetal abnormalities multiple
pregnancy pregnancy induced using assisted reproductive technol-
ogy and abnormal thyroid hormone concentrationsat baseline
Of 129 patients who were invited to participate in the study 4
refused participation and 1 had abnormal serum thyroid hormone
concentrations Of the remaining 124 patients 108 (87)
attended all the study visits One patient had a miscarriage and
another fetus died in utero at 22 weeks gestational age (WGA)
Five additional patients asked to leave the study later during the
pregnancy usually at the request of the husband (Figure 1) None
of the study patients delivered prematurely Cord blood samples
were obtained at delivery from 72 fetuses
MethodsStudy data were collected at four time points 12 WGA 22
WGA 32 WGA and birth At the inclusion visit at 12 WGA a
PLoS ONE | wwwplosoneorg 1 February 2011 | Volume 6 | Issue 2 | e14707
maternal blood sample was obtained for assays of free triiodothy-
ronine (FT3) free thyroxine (F4) and TSH as well as a urine
sample or a 24 hours collection for determination of urinary
iodine excretion (UIE) At both 22 and 32 WGA ultrasonography
of the fetal thyroid gland was performed for measurement of
thyroid diameter and circumference In addition at 32 WGA a
maternal blood sample was collected for assays of serum FT3
FT4 TSH and iodine as well as a urinary sample or a 24 hours
collection for UIE measurement Finally at delivery maternal
blood and cord blood samples were used for assays of FT3 FT4
and TSH Ultrasonography of the thyroid gland was performed
and the results of the neonatal screening test for hypothyroidism
were collected
Ultrasonography was used to measure the diameter and
circumference of the fetal or neonatal thyroid gland aspreviously
described [101112] using an EVB 525 variable-focus ultrasound
machine (Hitachi Hialeah FL USA) with a 35-MHz sector
transducer To minimize variability in fetal thyroid gland diameter
measurements due to differences in fetal size we normalized fetal
thyroid gland diameter for fetal head circumference
All blood samples were tested after collection of all study data
was complete All sera were frozen at 2 80uC until use UIE and
serum iodine were assayed in Cerba laboratories using inductively
coupled plasma-mass spectroscopy (Agilent 7500ce Santa Clara
CA USA) The limits of detection were 5 mg L and 15 mg L for
serum and urine respectively Interassay variability was 78 in
serum and 35 in urine intraassay variability was always lower
than interassay variability UIE was expressed in mg 24 h when a
24-hour urine collection was obtained and in mg L when a single
urine sample wasused Single sampleswere alwayscollected in the
morning Serum iodine was expressed in nanomole per liter
Serum FT3 FT4 and TSH were assayed in our hospital
laboratory on an ACS-180SE automate using a chemiluminescentFigure 1 Flow-chart doi101371journalpone0014707g001
Figure 2 Urinary iodine excret ion in pregnant women at 12 GA in the northern part of the Paris conurbat ion in 2006-2007 (pooleddata) Mean ioduria is 498 mgl +2 21 among 165 samplesdoi101371journalpone0014707g002
Fetal Thyroid and Iodine Input
PLoS ONE | wwwplosoneorg 2 February 2011 | Volume 6 | Issue 2 | e14707
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Omega 3 deficiency
DHA deficiency
bull Not routine but lab research
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
DHA
Docosahexaeacutenoiumlque acid (acide 4Z7Z10Z13Z16Z19Z-docosahexaeacutenoiumlque acide C226 ω-3 or DHA) belongs to omega 3 fatty acid family Brain and typically need DHA for a correct work Involved in the develloping brain of prematurate babies Fish oil eggs milk of animals fed with DHA DHA (and EPA eicosapentaeacutenoiumlc acid) is synthetized by the liver alphalinolenic acid contained in vegetal (wheat soya)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
DHAhellip bull Preeclampsia laquo ex inuits raquo stress oxydatif et HTA
bull Gestational Diabete meacutetabolisme des lipides et glucides macrosomie et dyslipideacutemies
bull Lenght of pregnancy baisse de la synthegravese des PG taux de DHA au cordon EEG plus
matures agrave J2
bull Vision meilleure agrave 4 mois si suppleacutementation ou sang du cordon
bull Atopia cytokines au cordon
bull Weight at delivery cognitives functions
bull =gt some recommendation no increase in overall lipid administration but daily supply in DHA 200 mg (Koletzko Br
Journal of Nutrition 2007 Picone jgyn2008)
bull =gt mind equilibrium with Arachidonic Acid (AA) (Br J Nut 2010
Van Goor SA)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
bull In all studies DHA and EPA supplementation is typically well tolerated Further research is needed to determine optimal doses for efficacy at different developmental ages The potential long-term benefits of early LCPUFA supplementation also require consideration
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Polyvitamin
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Effect of maternal multiple micronutrient supplementation on fetal loss and infant death in Indonesia a double-blind cluster-randomised trial Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) Study Group Shankar AH Jahari AB Sebayang SK Aditiawarman Apriatni M Harefa B Muadz H Soesbandoro SD Tjiong R Fachry A Shankar AV Atmarita Prihatini S Sofia G
Lancet 2008 Jan 19371(9608)215-27 bull IFA contained 30 mg iron (ferrous fumarate) and 400 μg folic acid
bull MN IFA +
ndash 800 μg retinol (retinyl acetate) ndash 200 IU vitamin D (ergocalciferol) ndash 10 mg vitamin E (alpha tocopherol acetate) ndash 70 mg ascorbic acid ndash 1middot4 mg vitamin B1 (thiamine mononitrate) ndash 18 mg niacin (niacinanide) ndash 1middot9 mg vitamin B6 (pyridoxine) ndash 2middot6 μg vitamin B12 (cyanocobalamin) ndash 15 mg zinc (zinc gluconate) ndash 2 mg copper ndash 65 μg selenium ndash 150 μg iodine
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Probably more appropriate to better feed the population than to have a polyvitamin supplementation
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Conclusion
bull Very few individual markers in standard practice
care (ex ferritinemia)
bull Markors can be developped at the population level
with iterative assement (ex ioduria)
bull At clinical level most intervention of supplementation
are justified without personnal testing
bull
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Conclusion buthellip
bull Population must be correctly targeted
ndash Degree of nutrition
ndash Genetic background
ndash Food habits
bull Regular epidemiologic studies of various
biomarkers (ioduria)
bull Recommendation can evoluate quite fast with
scientific work (iodine vitamine Dhelliphellip)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Conclusion buthellipkeep in mind that
bull Intervention can also be deleterious
ndash Fish over consumption inducing various toxic
(vitamin A (liver) lead mercury (tuna shark
swordfishhellip)
ndash Folate administration has an effect on the
methylome and sanitary lookout is mandatory
ndash Iode overload can induce hypo or hyper thyroidia
ndash helliphellip
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
What is certain today bull Folate administration in periconceptional period
bull Iodine administration in periconceptional period
bull Iron quasi mandatory during pregnancy
bull Vitamin D mandatory during pregnancy
What could be added bull B6 and B12 in periconceptional period
bull Polyvitamin
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)
Conclusion (Last)
bull Although the rate remains weak there is an increase in
adequate preconceptionnal behavior There is therefore
a large progression margin which deserves to be
implemented
bull Health care network has a huge potential impact in
inducing preconceptionnal behaviour
bull This impact is under used
bull Institution and other relay can be used (Chemist
Education network media)