folic acid supplementation in pregnancy and

8/17/2019 Folic Acid Supplementation in Pregnancy And

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Folic Acid Supplementation in Pregnancy and

Implications in Health and Disease

Subit Barua*, Salomon Kuizon and Mohammed A Junaid

ABSTRACT

Maternal exposure to dietary factors during pregnancy can influence embryonic development

and may modulate the phenotype of offspring through epigenetic programming !olate is

critical for nucleotide synthesis, and preconceptional inta"e of dietary folic acid #!A$ is

credited %ith reduced incidences of neural tube defects in infants &hile fortification of

grains %ith !A resulted in a positive public'health outcome, concern has been raised for the

need for further investigation of unintended conse(uences and potential health hazards

arising from excessive !A inta"es, especially follo%ing reports that !A may exert epigenetic

effects )he obective of this article is to discuss the role of !A in human health and to revie%

the benefits, concerns and epigenetic effects of maternal !A on the basis of recent findings

that are important to design future studies

Key%ords+ !olic acid, -A methylation, .pigenetic, /mprinting, 0renatal nutrition, -eural

tube defects, Autism


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REVIE

Introduction

)he emerging vie% of epidemiological studies indicates the importance of the

intrauterine environment in early fetal development &ith increased understanding of the

fundamental mechanism, appropriate -A methylation including the proper functioning of

the epigenetic machinery is highlighted to be essential for embryogenesis and adult health 12'

34 )hus, !A has gained considerable attention because of its promising role in modulating

diverse clinical conditions, %hereas folate deficiency has been lin"ed %ith a variety of

disorders including birth defects and defects in the development of neural tube closure 15'64

As stated by 7ippocrates nearly 8,9:: years ago+ ;

ng?ml, %hich is above the normal range of the serum folate concentrations in humans ie 8@'

2@ ng?ml 1@4 .pidemiological studies have sho%n that a significant number of %omen %ho

too" !A supplements during pregnancy exceeded the /nstitute of Medicines recommended

tolerable upper limit of 2,::: g?day /n addition, studies also reported consumption of 5::

g?day of natural food folate plus !A'containing prenatal supplements resulted in supra'

nutritional folate status %ith the greatest increases in pregnant %omen follo%ed by lactating

and non'pregnant %omen 1C,>4 Doncern has been raised if such exposure as a result of !A

fortification %ill have any detrimental effects in the general population if not overtly benefit

)his revie% summarizes the beneficial role of folate in human health, the metabolic path%ay,

epigenetic mechanism and potential concerns based on recent findings

Folic acid and neural tu!e de"ects

Birth defects are one of the maor burdens in the human public health %ith estimates

from Denters for isease Dontrol and 0revention #DD$ approaching 2 in every 33 ne%borns

in the ES and accounting for more than 8:F of all infant mortalities 12:,224 -eural tube

defects #-)s$ are common complex multifactorial disorders in the neurulation of the brain

and spinal cord that occurs bet%een 82 and 8C days after conception in humans 1284

&orld%ide depending on the ethnic grouping andgeographical location, the prevalence has

been reported to vary %idely bet%een 2and 2: in every 2::: births or established

pregnancies 1234 &hile %e are beginning to understand the underlying etiologies, evidence

gathered so far implicates both 'genetic and non'genetic factors such as maternal nutritional


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status or maternal obesity in the onset of -)s 125'264 Gver the years, numerous studies

including community'based trials often suggested -)s as vitamin deficiency disorders and

have sho%n that the exogenous or periconceptional supplementation of maternal !A can

reduce the ris" of -)s in offspring 12@4 /ndeed, research spanning decades suggests folate

deficiency as a ris" factor of -)sH ho%ever the involvement of %hole methylation

metabolism has also been lin"ed %ith the etiology of -)s 126,2C,2>4 Arguing against the

maternal folate deficiency model alone, some studies also reported normal concentrations of

folate in the mothers of human fetuses %ith -)s Supporting this, studies in cultured rat

embryos or !A deficient mice %ere reported not to be affected by -)s as a result of !A

deficiency 18:'854 /n contrast, studies also reported that exogenous !A and thymidine in the

homozygous splotch #0ax3$ mouse embryos prevented -)s and corrected biosynthetic

defects 1894 )herefore, no consensus has been reached based on the published data to date

7o%ever, as !A deficiency may be a ris" factor for -)s additional studies %ill be re(uired

to determine the mechanistic role of the !A path%ay in the onset of neural tube defects

History and impact o" "olic acid on pu!lic health

A possible relationship bet%een apparent folate deficiency and increased incidence of

prematurity %as suggested as early as 2>55 by Dallender 1864 )his %as later confirmed by

Iatenby and 6:s, ichard Smithells and .lizabeth 7ibbard hypothesized

that the under nutrition or impaired folate status could be an important factor in the origin of

-) based on significant observations, that %omen %ho had given birth to the children %ith

birth defects ie anencephaly and spinabifida have an altered formiminoglutamic acid

compared to the %omen %ith unaffected children 18C4 )o test this hypothesis Smithells and

his group conducted an intervention trial %ith supplementation of a multivitamin containing

diet %ith !A :36 mg?day during the periconceptional period to the participating %omen %ho

previously had infants %ith -) /ncontrast, %omen %ho %ere already pregnant %ithout

vitamin supplementation %ere considered as controls /n the2>C:s, they published the results

of this multi'center intervention study that revealed about C3'>2F reduction in -)

recurrence in supplemented %omen compared to that of unsupplemented %omen 18>'384

)hese results first highlighted that multivitamin or !A supplementation may play a significant

role in gestation and may reduce the recurrence of -) >2, after a randomized

control trial #D)$ conducted at 33 centers in seven countries, the British Medical esearch

Douncil suggested, for %omen %ith a previous history of -)'affected 'pregnancies, the

daily supplementation of 5:: micrograms of !A is effective in preventing the recurrence of


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-)s by @:F 1334 )his %as further supported by the results of a 'D) conducted in

7ungary in 2>>8 that reported a daily inta"e of :C mg of !A during the periconceptional

period significantly reduced the incidence of a first occurrence of -) 1354 /n 2>>2, the

DD recommended a daily inta"e of 5::: g of !A before and throughout the period of

pregnancy for %omen %ith prior history of -)'affected pregnancy 1394 >C,

based on the evidence and recommendation from the %ider medical community, the ES

0ublic 7ealth Service and !ood and rug Administration recommended mandatory

fortifications of !A in flour and grains to prevent -) and birth defects 1364 /n 8::@, the

Danadian recommendations also included obesity #BM/ L39$ as a health ris", and

recommended ;the higher dose !A strategy #9 mg$= in patients %ith a history of poor

compliance %ith medications and additional lifestyle issues of variable diet, no consistent

birth control, alcohol, tobacco, and recreational non'prescription drugs use !urthermore, to

prevent the occurrence of -)s in epileptic and diabetic mothers the recommendation is to

ta"e a higher dose of !A, 59 mg?day 13@'3>4

Folate meta!olism

!A is central to folate're(uiring one'carbon metabolism %hich play "ey roles in

numerous cellular reactions )hese involve amino acid metabolism, biosynthesis of purine

and pyrimidineH #the building bloc"s for -A and -A synthesis$, and formation of primary

methylating agent S'adenosyl'methionine #SAM$, %hich is the universal methyl donor for

-A, histones, proteins and lipids 12:4 Mechanistically, the transport of transmembrane

folate is facilitated by both receptors and specific carriers active across cell membranes 15:4

Ender normal circumstances, natural dietary folate is absorbed in the intestine and?or liver

and metabolized primarily to 9'methyl tetrahydrofolate #9'methyl)7!$ and subse(uently gets

polyglutamated for cellular retention #!igure 2$ 7o%ever, !A consumed in fortified

foods?supplements is reduced primarly to dihydrofolate by the enzyme dihydrofolate

reductase in the liver and finally converted to the tetrahydrofolate #)7!$, the substrate for

polyglutamate synthetase )he polyglutamyl form of tetrahydrofolate #)7!$ formed either

from !A or normal dietary folate is the central folate acceptor molecule in the one'carbon

cycle -ext, )7! is converted to 9,2:'methylene)7! by vitamin B6 dependent serine

hydroxymethyltransferase and then reduced irreversibly to 9'methyl)7! by

methylenetetrahydrofolate reductase #M)7!$ 9'Methyl')7! acts as a primary methyl

donor for the remethylation of homocysteine to methionine Methonine is a "ey substrate for

S'adenosylmethionine #SAM$ %hich plays a central role in methylation reactions catalyzed


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by -A methyltransferases #-M)s$ forming 9'methylcytosine 152'534 )hus, the entire !A

metabolism is modulated by several folate coenzymes Mechanistically, the central role of

this coenzyme is to modulate the metabolic path%ay by accepting or donating one'carbon

units 1554 Key genes in this path%ay that are involved in transferring the methyl group to

homocysteine, and have been most extensively studied include methylenetetrahydrofolate

reductase #M)7!$, methionine synthase reductase #M)$, reduced folate carrier #!D$,

along %ith vitamin B28' dependent methionine synthase #M)$ 1594 /ntriguingly, the

etiology of -)s has long been genetically associated %ith the dysregulation of the maor

folate path%ay or methionine synthase genes, and single'nucleotide polymorphisms #S-0s$

such as 6@@D L ) in the M)7! gene in humans 189,564 )hus, further studies on !A

induced methylation and detailed analysis of the folate path%ay and its role in mammalian

neural tube closure could give us more insights in coming years

Implications o" FA in epigenetic regulation

)he possible impact of nutritional supplements, for example !A, on the mammalian

genome can have long lasting effects in human health %ithout any underlying genetic change

)he availability of many dietary components involved in one'carbon metabolism including

vitamin B6, choline, betanine, methionine, vitamin B28 and folate can result in alterations in

the -A methylation and histone modification Mechanistically, the modulation of

methylation patterns depends on the level of t%o metabolites of one'carbon metabolism+ S'

adenosylmethionine #SAM$, a methyl donor and S'adenosylhomocysteine #SA7$, a product

inhibitor of methyltranferases 15@'5>4 )hus, nutrient epigenetic factors such as !A, a


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cofactor in one'carbon metabolism during gestation can affect the fetal programming and

may modulate the genome'%ide methylation pattern of -A and cause dysregulation in the

expression of genes 19:4 )he epigenetic impact of !A along %ith other onecarbon

metabolites is best studied in the agouti mouse #Avy$ experiment that has sho%n that the

dietary methyl donors, including !A, has no affect on the Avy methylation in the mother but

clearly affected the Avy methylation and phenotype of developing offspring 1924 Similar to

the animal study, a study in young children from mothers having periconceptional !A of 5::

g per day %as sho%n to have enrichment in the methylation of maternally imprinted insulin'

li"e gro%th factor 8 gene #/I!8$ compared to those %ith no periconceptional maternal !A

1984 /n addition, several epidemiologic and molecular evidences also lin" folate

supplementation and epigenetic alteration by -A methylation %ith neural gro%th and

recovery, including the activation of folate receptor #!olr2$, in spinal cord regeneration

193,954 /n an attempt to understand the !A induced epigenetic mechanism to rescue neural

tube closure, a recent study in Splotch embryos #SpN?N$ has also sho%n that maternal inta"e

of folate prior to conception decreases the 73K8@ methylation mar"s and remodels the

chromatin on 7es2 and -eurog8 promoters, genes that are essential for neural tube

development 1994 ecently, our study has sho%n that !A supplementation dysregulates

expressions of several genes including !M2 in lymphoblastoid cells 1964, and a follo% up

study in a mouse model has also identified %idespread alteration in the methylation pattern of

the brain epigenome in offspring from high maternal !A during gestation 19@4 )he alterations

in the methylation pattern %ere exhibited both in DpI and non'DpI regions resulting in

differences in the expression of several "ey developmental and imprinted genes /n addition,

%e also found that the methylation and expression of several genes are altered in a gender'

specific manner )hus, it is clear that folate plays a "ey role in epigenetic regulation of fetal

developmental programming /n the future, more studies on the role of folate deficiency or

over supplementation on epigenetic alterations %ill establish causality of the amount of !A

and -A methylation in diseases

Folate inta#e and concern a!out potential ad$erse e""ect

)he clinical significance of the chronic or high inta"e of !A is not %ell established

0ost fortification epidemiological studies have reported an increase of approximately t%ice

the amount in the inta"e of !A than previously proected Doncern has been raised regarding

the potential health effects, since in addition to the fortified products there is prevalence of

using %idespread supplementation including over'the counter prenatal vitamins as %ell as


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energy drin"s %hich are substantially enriched %ith various vitamins 19C,9>4 ecently, our

study in the mouse model has found that ten'fold increase in maternal !A supplementation

during gestation altered the expression of several genes in the frontal cortex of day old pups

16:4 Moreover, continuation of such higher amounts of !A throughout the post'%eaning

period exhibited alterations in behaviors compared to offspring from mothers having lo%er

doses of gestational !A supplementation Mechanistically, such changes of behavioral

outcomes may possibly result from alterations of gene expression as a result of aberrant

methylation

/ntriguingly, results from several studies also suggested that folate supplementation can

induce aberrant patterns of -A methylation, and mechanistically may play a dual role in

carcinogenesis !A supplementation may prevent the early lesions, or potentially harm by

enhancing the progression of established preneoplastic lesions 1624 Studies in rodent models

'have sho%n that supplementation of !A promotes the progression of mammary tumor, and

supporting this vie% a study in a genetically engineered mouse model of a human cancer has

sho%n that !A deficiency during the peri'gestational period protects or decreases

medulloblastoma formation 168,634 7o%ever, a meta'analysis of data conducted on 9:,:::

individuals to assess the effects of !A found that !A supplementation does not substantially

increase or decrease incidence of site'specific cancer during the first 9 years of treatment #

O 2:6, >9F D/ :>>'223$ in comparison to placebo 1654 Moreover, a study from children

participating in the -orthern Dalifornia Dhildhood


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during pregnancy may modulate pregnancy related outcomes 1@2'@94 including

developmental outcome of offspring #Additional file 2+ )able S2$

)he causal lin" bet%een the maternal !A supplementation and the development of

childhood asthma has been of interest as asthma is considered to be an interaction of both

genetic and environmental ris" factors, and concern has arisen as epidemiological studies

have also sho%n that increased folate in pregnancy may influence poor respiratory health in

children 1@6,@@4 Several studies, including D) and observational studies %ere conducted to

reveal such associations, ho%ever conflicting results %ere found in these studies &hile some

studies found positive association bet%een !A exposure and increase in ris" of childhood

asthma, other studies found no such association #Additional file 2+ )able S2$

/n addition, studies in humans, also reported to have found higher blood folate concentration

of unmetabolized !A and naturally occurring folates 1@C4

)o gain a better understanding if maternal supplementation of !A modulates pregnancy

related outcomes, much focus has been given to reveal the role of !A supplementation in the

increased incidence of dizygotic t%ining )his follo%ed after the report of a S%edish study

suggested a possible association of !A supplementation %ith the increase in the t%ining rate

1@>4 A meta' analysis using the !ood Standards Australia -e% Pealand #!SA-P$ frame%or"

by Muggli et al 1C:4 has suggested that the hypothesis of the increase in dizygotic t%ins is

still to be demonstrated #G O 286, >9F D/ :>2'2@3 for pre'conceptional supplementation

and dizygotic t%insH G O 2:8, >9F D/ :C9'285 for overall t%ins$, and, if true, it %ould

only cause a very limited increase 7o%ever, Berry et al reported that the association of !A

%ith an increase in dizygotic t%ining as reported by the S%edish study has probably led to

false findings based on the reported 5:F misclassification of the use of in vitro fertilization

1C24 )his %as further supported by a -or%egian study that found no evidence for an

association bet%een preconceptional folate supplements and t%inning after exclusion of

"no%n in vitro fertilization pregnancies, and accounting for underreporting of both in vitro

fertilization pregnancies and folate use 1C84

)hus it is clear that !A inta"e during pregnancy and during daily life plays a significant

role in modulating gene expression and disease related outcome Donsidering the important

role of !A in several cellular process, including epigenetic modulation and reducing the

incidence of -)s #Additional file 2+ )able S2$, the dose, timing #pre'conceptional?peri'

conceptional?in'pregnancy$, and source of folate intervention during pregnancy and

throughout the life time may be critical /n the future, more clinical and basic studies to


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decipher the lin" bet%een over supplementation and normal development %ill help us to

understand the discordances bet%een benefit and possible harm

%aternal "olate inta#e and health outcomes in children & a !rie" systemic re$ie' o"

recent cohorts study

!or a better understanding of the effect of maternal !A, %e systematically revie%ed

recent published literature #8:228:25$ in order to assess the outcome of maternal !A

supplementation on the health of ne%born infants 1C3'2354 #Additional file 2+ )able S2$

&hile results of several cohort and observational studies in ESA, Danada, Dhile, Australia,

several countries in .urope and Asia have reported the clinical significance of !A

supplementation, the direction of the beneficial effect %as not in favorable terms in all the

cases )herefore, several countries have mandatory regulated !A fortifications, and despite its

efficacy there is no universal agreement based on the published data to date 12394 )he

concern regarding the appropriate dose and potential side effects are still a matter of debate

126,2364 As maternal !A can induce potential epigenetic effects on the genome of the

offspring %hich may vary %ith the metabolic ability of individual race, sex, geographical

locations or interactions %ith other nutrients, one possible reason of inconsistency bet%een

studies may be due to differences in the design of the study /n the future there is definitely a

need of global collaboration to accumulate scientific evidence from a clinical perspective,

and to interpret these intervention studies and potential effect in large cohorts


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C()C*+SI()

)he clinical application of !A supplementation?inta"e to prevent -)s has been %ell

proven for the last 8:89 years #Additional file 2+ )able S2$ 7o%ever considering the

concern %ith the level of folate concentration follo%ing post'fortifications, it is of interest to

explore if !A exposure in significant sections of the population is influencing other normal

biological processes, such as the brains development #!igure 8$ etermining the level and

distribution of the methylation profile of the brain epigenome may reveal the mechanism and

do%nstream conse(uences of various neuropsychiatric and imprinted disorders including

autism Moreover as the level of folate status can influence methylation, in the future more

studies are needed to explore the systemic differences in the -A methylation profile in

relation to timing and dose bet%een different populations and bet%een genders Studies and

careful monitoring of the conse(uences of !A inta"e in global perspectives %ill help

clinicians to determine a proper therapeutic strategy and the best preventive measures to

improve the overall public health, moreover to precisely differentiate the evaluation of this

vitamin in nutrition, in fortification and in supplementation


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Additional "ile

Additional file 2+ )able S2 Studies of maternal folate inta"e and health outcomes in children

A!!re$iations

!A+ !olic acidH -)+ -eural tube defectH DD+ Denters for disease control and preventionH

D)+ andomized control trialH SAM+ S'adenosyl' methionineH SA7+ S'

adenosylhomocysteineH -M)s+ -A methyltransferaseH 9'methyl)7!+ 9'methyl

tetrahydrofolateH )7!+ )etrahydrofolateH M)7!+ Methylenetetrahydrofolate reductaseH

M)+ Methionine synthase reductaseH M)+ Methionine synthaseH !D+ educed folate

carrierH S-0s+ Single'nucleotide polymorphismsH /I!8+ /nsulin'li"e gro%th factor 8 geneH

BM/+ Body mass indexH )oDA+ )abriz registry of congenital anomaliesH


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polymorphism in dihydrofolatereductase #7!$ and prenatal folic acid inta"e

Dancer 8:28, 22C+9>289>2>

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