hyperhomocystienemia in pregnancy and lactation and role of vitamin b12, d3 and calcium by dr...

Hyperhomocysteinemia in

Pregnancy and Lactation

Dr Shashwat K. Jani.m.s. ( gynec )

Diploma in Advanced Endoscopy.

Assist. Prof., Smt. N.H.L. Mun. Medical College.Sheth V. S. Hospital , Ahmedabad.

Mobile : +91 99099 44160.E- mail : [email protected]

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Outline Introduction to vitamin B12 its importance in pregnancy and

lactation

Introduction to Homocysteine

Hyperhomocysteinemia and its epidemiology

Homocysteine and pregnancy

Complication of hyperhomocysteinemia

Folate or vitamin B12 and Folate trap

Cynocobalamin vs. Methylcobalamin

Absorption of vitamin B12

Calcium and its role in pregnancy outcome

Vitamin D3 in pregnancy and lactation

Link between Calcium, vitamin D3 and vitamin B12

Summary

2Dr Shashwat Jani. 9909944160.

Dr Shashwat Jani. 9909944160. 3

Introduction to Vitamin B12Part of the complex of B vitamins, vitamin B12 is

one of the most intricate vitamins.

Vitamin B12 (Cobalamin) is a Water-soluble vitamin.


Sources of Vit. B12

• Naturally present only in Meats and Foods of animal origin.


Functions Crucial to normal neurologic function.

Red blood cell production.

DNA synthesis.


Vitamin B12 and Pregnancy Vitamin B12 and folate play an important

role in…

- Nucleic acid metabolism,

- cell growth and proliferation ,

- important determinants of fetal growth.

Deficient or inadequate maternal vitamin B12 status is associated with a significantly increased risk for neural tube defects.


Low maternal vitamin B12 status reduces the amount of vitamin B12 transported to the fetus.

Maternal vitamin B12 status in pregnancy influences cognitive function in offspring.

Linked with poor fetal growth with increased risk of cardiovascular disease in later life….!!!


Pediatrics. 2009;123(3):917-23Food Nutr Bull. 2008; 29(4): 249–254

Asia Pac J Clin Nutr 2005;14 (2):179-181

Vitamin B12 and Lactation• Pregnant women <14 wk of gestation in Bangalore, India,

supplemented with oral vitamin B-12 (50 mcg/day) had improved vitamin B12 status during pregnancy and post-partum.

• Supplementation led to improvement in breast-milk vitamin B12 level compared to placebo group (iron + folic acid)

• Infant plasma methylmalonic acid and homocysteine concentrations were significantly lower in the vitamin B-12 group as well.

11J Nutr. 2014;144(5):758-64

Oral supplementation of urban Indian women with Vitamin B-12 throughout pregnancy and early lactation significantly increases vitamin B-12 status of mothers and infants.

Dr Shashwat Jani. 9909944160.

Prevalence of Vitamin B12 Deficiency

An Indian study showed that… 60% of vegetarians and 29% of non-vegetarians were B12 deficient

Can Fam Physician 2004;50:743-747.

In developing countries often have a vitamin B-12 status that is only marginally better than that of lactoovovegetarians.

Am J Clin Nutr.2003 Jul;78(1):3-6.

17-39% deficiency among pregnant women dependent on the trimester.

Eur J Clin Nutr. 2014;68(5):541-812Dr Shashwat Jani. 9909944160.

Effect of Vitamin B12 deficiency • Pregnant women with low B12 levels are unable to

provide the necessary amount of this vitamin to their fetuses.

The mothers are usually NOT anemic.

Infants usually suffers from

Failure to thrive

Neurologic deficits

13

J Pediatr Hematol Oncol. 2009 Oct;31(10):763-5.


Consequences of low vitamin B12

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↓ Vitamin B12 levels

↑ Homocysteinemia

Osteoporotic fractures

Birth Defects

Smooth muscleproliferation2

Progressive arterial stenosis

HaemostaticchangesNephritic

syndrome

Placental vasculopathy

Diabetes

Hypertension

Impaired cognitivefunctions

DementiaDepression

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J Nutr 2009; 139(11):2119-2123 2. Asia Pac J Clin Nutr 2008; 17(1):8-16 3.

Am J Epidemiol 2002; 156(12):1105-13 Semin Cell Dev Biol 2011;22(6):619-23


Homocysteine Homocysteine is a non-protein forming, sulfur

containing amino acid

It is an intermediary amino acid, which is formed exclusively by demethylation of methionine, during conversion of methionine to cysteine

Vitamin B12 as a co-factor facilitates the methylation of homocysteine to methionine which is later activated into S-adenosyl-methionine.

S-adenosyl-methionine. that donates its methyl group to methyl acceptors such as myelin, neurotransmitters and membrane phospholipids.

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J Diabetes Metab Disord. 2013;12(1):17


HyperhomocysteinemiaThe Classification Hyperhomocysteinemia …

16World Clinics Obstetrics and Gynecology: Recurrent Miscarriage by Mala Arora.

2011. Jaypee Publication

Test results Diagnosis

Normal 5-15mmol/l

Mild 15-30 mmol/l

Moderate 30-100mmol/l

Severe > 100mmol/l


Epidemiology in India

India predominantly follows vegetarian food habits

Higher levels of homocysteine due to Vitamin B12 deficiency

17www.veganhealth.org Homocysteine LevelsDr Shashwat Jani. 9909944160.

Homocysteine and PregnancyHomocysteine concentration decreased in pregnancy due to

Hemodilution

Raised glomerular filtration rate

Hormonal changes of pregnancy

Increased fetal uptake

18Best Pract Res Clin Obstet Gynaecol. 2003;17(3):459-69


Homocysteine and Pregnancy• In an Indian maternal nutrition study, two thirds of

pregnant mothers had low levels of vitamin B12 …!!!

• Very few mothers had low folate concentration.

• Vitamin B12 and folate play vital role in one carbon (1-C) metabolism, crucial for fetal growth.

19Asia Pac J Clin Nutr 2010;19 (3):335-343

The study showed that the plasma tHcy concentration at 34 weeks gestation was lower in those supplemented with vitamin B12 compared those who received only folic acid or no supplementation


Hyperhomocysteinemia – A risk factor

4 fold increased risk for development of non-severe preeclampsia in women with higher Hcy in early pregnancy.

7.7 fold higher risk for pre-eclampsia for pregnant women.

Increased risk of recurrent pregnancy loss.

Increased homocysteine increases incidences of IUGR, IUD and cesarean section.

Am J Obstet Gynecol. 2003 ;189(2):391-4; discussion 394-6Eur J Obstet Gynecol Reprod Biol.2003;108(1):45-9

J South Asian Fed Obs Gynec. 2011;3(2):71-7420Dr Shashwat Jani. 9909944160.

Complications of Hyperhomocysteinemia

21Food Nutr Bulletin. 2008;29(2):S238-241


How does hyperhomocysteinemia leads to

PIH ?

Homocysteine is primarily responsible for endothelial cell damage leading to pro-atherogenic effects, thromboembolic effects and hypoperfusion of placenta.

It also has been implicated in the overproduction of free radicals.

Suboptimal methylation

Increased levels of homocysteine

Excessive generation of free radicals leading to oxidative damage

Leads to DNA oxidation and endothelial dysfunction.

Placental Abruption

• Premature seperation of normally situated placenta

• Hyperhomocysteinemia --- Independent risk factor

• 2.5X increased risk in MHTFR mutation.

Complications of Hyperhomocysteinemia

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Cobalamin deficiency

Pre-eclampsia

IUGR

Placental abruption

Neural Tube defectsPre-term labor

Low birth weight

HELLP syndrome

Intrauterine fetal death

HELLP - hemolysis, elevated liver enzyme levels, and low platelet levelsDr Shashwat Jani. 9909944160.

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The Hordaland Homocysteine Study• Women with raised total homocysteine levels also have

an increased risk of having suffered from pregnancy complications and an adverse pregnancy outcome

J Nutr. 2006;136(6S):1731S-1740S.

The Generation R Study• High homocysteine concentrations were associated with

lower placental weight and birth weight and increased risk of small for gestational age (SGA)

BJOG. 2012;119(6):739-51

Clinical Evidence of Hyperhomocysteinemia and adverse pregnancy outcome


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Systemic Review and Meta-analysis

• Women with a history of hypertensive pregnancy disorders had a higher homocysteine level compared with women with a history of uncomplicated pregnancies.

Am J Obstet Gynecol. 2014 Mar 15.

Indian Study• Hyperhomocysteinemia and deficiency of folic acid and

vitamin B12 along with increased blood pressure is a risk factor for cardiovascular disease (CVD) in preeclampsia.

Indian J Clin Biochem. 2011 Jul;26(3):257-60

Clinical Evidence of Hyperhomocysteinemia and adverse pregnancy outcome


Folate or Vitamin B12• Study conducted in antenatal clinics of the Holdsworth

Memorial Hospital, Mysore, India.

28Asia Pac J Clin Nutr 2010;19 (3):335-343

Vitamin B12-deficient women had…•Increased adiposity (higher skinfold)•Higher incidence of gestatational diabetes mellitus increased with folate concentration

Lower prevalence of folic acid deficiency


Folate or Vitamin B12Indian studies

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• Cobalamin deficiency is 5 times more common than folate

Natl Med J India.2005;18(4):182-3.

• Cobalamin deficiency was 74.1% while folate was 26.3% in Indian women

Food Nutr Bull. 2007 Dec;28(4):435-8.

Thus, prevalence of vitamin B12 is more compared to folate deficiency…!!!


Folate Trap - Hypothesis• In vitamin B12 deficiency, blocking of the methylation

cycle causes the folate cofactors in the cell to become trapped as 5-methyltetrahydrofolate.

• This process in turn produces a pseudo folate deficiency in such cells.

30Proc Nutr Soc.1999 May;58(2):441-8.Clin Chem. 2000 ;46(8 Pt 2):1277-83.


Vitamin B12 in Folate “Trap”• In Vitamin B12 insufficient , folate replete pregnant women

vitamin b12 supplementation is associated with a reduction of plasma total homocysteine concentration in late pregnancy.

• Vitamin B12 releases “trapped” folate allowing homocysteine to be re-methylated to methionine, resulting in the reduction of plasma tHcy concentration

• Increasing supplementation dose of B12 was associated with progressively lower plasma tHcy concentration.

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Asia Pacific J Clin Nutr 2010;19(3):338

Pediatrics. 2009 ;123(3):917-23Dr Shashwat Jani. 9909944160.

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What is best for patients between cynocobalamin and methylcobalamin?


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• The form of cobalamin used in most supplements is cyanocobalamin, which readily converts to 5-deoxyadenosyl and methylcobalamin in the body.

• It plays a key role in the remethylation of Homocysteine to Methionine.

Vit.B12 Vs. Methylcobalamin


• There is no disease described in human body where conversion of inactive cobalamin to active methylcobalamin is impaired. So, there is absolutely no necessity to use methylcobalamin in place of cobalamin

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• There is no isolated disease of methylcobalamin deficiency.

• Methylcobalamin has little effect on neurological complications due to vitamin B12 deficiency.

• When cobalamin deficiency is diagnosed only cobalamin to be given so, that patient gets both methylcobalamin and adenosyl cobalamin, thereby both hematological and neurological abnormalities can be corrected simultaneously.

http://www.apiindia.org/medicine_update_2013/chap139.pdf

Vit.B12 ( cobalamin) Vs. Methylcobalamin


Vitamin B12 Supplementation

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• Vegetarians and older persons receiving oral vitamin B12 10-500 µg have been shown to have lower concentrations of MMA .

Dtsch Arztebl Int. 2008; 105(40): 680–685.

• Doubling of the vitamin B-12 intake increases vitamin B-12 concentrations by 11%

• A decrease in methylmalonic acid (MMA) of 7% for every doubling of the vitamin B-12 intake.

Am J Clin Nutr. 2013 ;97(2):390-402

• Strict vegetarians and women planning to become pregnant should take a multivitamin supplement daily a daily intake of 6 to 30 mcg of vitamin B12 in a form that is easily absorbed.

http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/


Vitamin B12 is bound to protein in food and primarily absorbed in the terminal ileum.

The absorption is mediated by the intrinsic factor (IF)

The IF - Cobalamin complex is absorbed by the distal ileum and requires calcium.

Vitamin B12 enters the circulation about 3–4 hours later bound to transport proteins transcobalamins I, II and III.

Excess vitamin B12 is stored in the liver, largely bound within a vitamin B12 protein complex.

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Nutrients. 2010;2(3):299-316Nutrition Science. 2nd Edition (2006) by B. Silakshmi. New Age International Publishers

Absorption of vitamin B12


Calcium - Halves risk in Pregnancy

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Meta-analysis of studies from Developing countries

• Pooled analysis showed that calcium supplementation during pregnancy reduces risk of • Gestational hypertension by 45%• Pre-eclampsia 59%

BMC Public Health 2011, 11(S3):S18

Cochrane Review

• Calcium supplementation (≥ 1 g/day) is associated with a significant reduction in the risk of pre-eclampsia, particularly for women with low calcium diets

Cochrane Database Syst Rev.2014 Jun 24;6:CD001059

Calcium - In Pregnancy and lactation There is an inverse relationship exists between calcium

intake and development of hypertension in pregnancy

Calcium supplementation reduces circulating lead levels, an important secondary prevention effort to reduce circulating maternal lead and, consequently, fetal exposure.

Fetus in utero and the neonate through breast-feeding are dependent on maternal sources for the total calcium load, adequate maternal calcium intake also can affect fetal bone health positively.

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Paediatr Perinat Epidemiol.2012 ;26 S1:138-52Environ Health Perspect. 2009; 117(1): 26–31

Am J Obstet Gynecol. 2006 ;194(4):937-45. Dr Shashwat Jani. 9909944160.

High prevalence of hypovitaminosis D among pregnant women and their newborns has been reported in Indian population

Vitamin D deficiency during pregnancy is the origin for a host of future perils for the child, especially effect on neurodevelopment and immune system.

Research indicates that adequate vitamin D intake in pregnancy is optimal for maternal, fetal and child health.

Adequate vitamin D concentrations during pregnancy are necessary to ensure appropriate maternal responses to the calcium demands of the fetus and neonatal handling of calcium.

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Vitamin D3 in Pregnancy and Lactation

Am J Clin Nutr.2005 ;81(5):1060-4Am J Clin Nutr .2004 ;80 (6): 1740S-

1747SIndian J Endocrinol Metab. 2013 ; 17(1):

76–82.


• Daily supplementation of 1000 IU vitamin D3 to pregnant women showed improvement in 25(OH)D levels

J Pediatr. 1986 ;109(2):328-34.76–82

• Vitamin D supplementation in a single or continued dose during pregnancy increases serum vitamin D concentrations

Cochrane Database Syst Rev.2012 Feb 15;2:CD008873

Poland -2009 Guideline

• In pregnant and lactating women 800-1000 IU vitamin D3 per day is recommended.

Med Wieku Rozwoj.2010;14(2):218-23

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Vitamin D3 in Pregnancy and Lactation


Recommendation for Indians

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Adults Calcium (mg/day)

Vitamin D3 (IU/day)

Vitamin B12 (mcg/day)

Males 600 400 1.0

Females 600 400 1.0

Pregnant 1200 400 1.2

Lactation 1200 400 1.5

ICMR, 2010

Nutrition recommendation for Indians. ICMR. 2010Dr Shashwat Jani. 9909944160.

Recommendations

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Adults Calcium (mg/day)

Vitamin D3 (IU/day)

Vitamin B12 (mcg/day)

Males 1000-1200 600-800 2.0

Females 1200 600-800 2.0

Pregnant 1000-1300 600-800 2.2

Lactation 1000-1300 600-800 2.4

RDA by Institute of Medicine. 2010

Vitamin D3 Recommendation

Adults Vitamin D3 (IU/day)

International Osteoporosis Foundation

800-1000

Endocrine Society Clinical Practice Guideline 1000http://www.iofbonehealth.org/vitamin-d-0J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30


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Is there a connecting link between Vit. D3, Calcium

and Vitamin B12 ???


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B12-intrinsic factor (IF) complex binds with ileal cell surface receptor in the ileum mucosa.

Intrinsic factor is split off and vitamin B12 is released in portal blood This process does not This process does not require energy but it is calcium dependent.require energy but it is calcium dependent.

Vitamin D3 is essential for adequate calcium absorption.

Insufficiency or deficiency of serum 25(OH)D may adversely affect calcium dependent processes.

Calcium – The vital link

J Diabetes Metab Disord. 2013 May 7;12(1):17Nutrients 2010; 2:299-316

J Nutr. 2004 Nov;134(11):3137-9Insights in Physiology by S V Khanorkar. Jaypee Publication


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Why combined palette Why combined palette of Vit. B12, Vit. D3 of Vit. B12, Vit. D3

and Calciumand Calcium is suitable? is suitable?


• Emerging studies suggest high prevalence of calcium, vitamin D and vitamin B12 in Indian pregnant and lactating women

• All three nutrients are involved in several cellular function.

• Combined deficiency of all three vital nutrient significantly affect the maternal health and pregnancy outcome

• Combination of calcium, vitamin D3 and vitamin B12 in adequate required amount in a single palette is rational choice for decreasing risk factors and better pregnancy outcome

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Importance of Calcium, Vit. D3 and Vit.B12


Hyperhomocysteinemia is responsible for various pregnancy related complications and adverse health outcomes

Vitamin B12 played important role in reducing elevated levels of homocysteine.

B12 deficiency impairs overall folate metabolism.

Calcium is critical nutrient in pregnancy and positively affects maternal and fetal health.

Vitamin D3 has pleiotropic effect and implicated in several diseases in all age group.

Combination of calcium, vitamin D3 and vitamin B12 in adequate required amount in a single palette is rational choice for decreasing risk factors and better pregnancy outcome.

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Summery


hyperhomocystienemia in pregnancy and lactation and role of vitamin b12, d3 and calcium by dr...

Health & Medicine

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