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research

Eleanor Sharland

Brett Montgomery

Raquel Granell

Folate is a water soluble B vitamin that

must be obtained in the diet or through

supplementation. For more than 50 years

it has been known that folate plays an

integral role in embryonic development.1

Periconceptional folic acid in doses

of at least 0.36 mg has been shown to

prevent approximately 72% of neural tubedefects,2,3 and therefore a daily dose of 0.4

mg is widely recommended for all women

at average risk from at least 1 month

preconception to 12 weeks pregnancy.4

Despite this, many Australian women

do not have sufficient folate intake in

pregnancy,5 thus mandatory folic acid

fortification of flour was introduced in

Australia in September 2009.6

The Generation 1 Cohort Std,7 pblished in 2009,

fond that the se of folic acid in late pregnanc

was associated with an increased risk of childhood

asthma. This was widel reported in the poplar

media, both in Astralia8 and overseas,9 leading

to concern abot the safet of folic acid in

late pregnanc. Man women take pregnanc

mltivitamins throghot pregnanc to achieve the

recommended intake of microntrients.10,11 As all

sch mltivitamins seem to inclde folic acid, their

se in late pregnanc wold present a dilemma if

folic acid were nsafe.

There is a plasible explanation for theassociation between folate intake and childhood

asthma. A laborator std in mice showed that

maternal exposre to a high methl donor diet,

which inclded folic acid, increased the severit

of inherited allergic airwa disease in offspring

throgh increased DNA methlation. This

predisposition appeared to be partiall transmitted

into sbseqent generations.12 However, findings

in animal models are not necessaril applicable to

hmans. Folic acid, which is the snthetic form of

the B vitamin, is a potentiall more potent methl

donor than natrall occrring folate and so ma

have different effects.7

Method

We condcted a narrative review of stdies

that investigate the association betweenmaternal dietar folate intake and/or folic acid

spplementation exposre and childhood asthma

or wheeze. We considered performing a meta-

analsis, bt decided this was inappropriate de

to heterogeneit of poplations stdied, exposre

measrements, and otcome measre reporting.

The first athor (ES) searched MEDLINE (Ovid and

PbMed) and CinAHL, sing the strateg (Folic

Acid OR Folate) AND pregnanc AND (asthma

OR respirator health), as well as (Folate OR

Folic Acid) AND late pregnanc. Frther citation

searches were ndertaken sing Web of Science.

The second athor (BM) independentl searched

PbMed sing the strateg (asthma OR wheeze

OR respirator) AND (folate OR folic) AND

pregnanc. We identified for relevant stdies,

all of which were observational cohort stdies.

Results

The main reslts from the different stdies

inclded in this review are smmarised in Table 1

Norwegian Mother and Child study

Hberg et al reported the Norwegian Mother

and Child Cohort Std that involved 32 077

children.13 This std measred maternal se of

folic acid spplements in earl and late pregnanc

and child lower respirator tract infections

and wheeze p to the age of 18 months. Data

were collected sing qestionnaires that were

completed b participating mothers at 17 weeks

and 30 weeks gestation as well as 6 months and

Folic acid in pregnancyIs there a linkwith childhood asthma or wheeze?

Background

Folic acid supplementation has an

established role in early pregnancy

for preventing neural tube defects.

However, there is controversy over a

possible link between late pregnancy

folic acid supplementation and

childhood asthma.

Objective

To review the evidence exploring the

association between maternal folate

exposure in pregnancy and childhood

asthma or wheeze.

Results

Four relevant observational studies

were identified. Two found statistically

significant associations between

childhood asthma and late (but not

early) pregnancy maternal folic acid

exposure. Another found a statisticallysignificant association between

childhood wheeze and early (but not

late) pregnancy maternal folic acid

exposure. A fourth study found little

association between maternal dietary

folate in pregnancy and infantile

wheeze.

Discussion

The currently available evidence

regarding an association between

folate in pregnancy and childhood

asthma or wheeze is conflicting.We offer suggestions for discussing

the potential risk with patients and

recommend further research on this

subject be conducted.

Keywords: folic acid; pregnancy; dietary

supplements; asthma

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Folic acid in pregnancy is there a link with childhood asthma or wheeze?research

be noted that the relative r isks were expressed

per 1 mg/da dose of folate, whereas the

recommended dose for low risk women is 400 g/

da.6 This means that the increase in childhood

asthma risk for women on a tpical dose of folic

acid wold be mch smaller than these relative

risks impl.

Osaka Maternal and Child HealthStudy

A recent Japanese std14 involving 763 mother

and child pairs from the Osaka Maternal and

Child Health Std measred dietar intake

of B vitamins, inclding folate, and examined

associations with childhood atop inclding

wheeze and eczema as defined b responses to a

standardised maternal qestionnaire.

Folate intake was qantified sing a detailed

dietar qestionnaire, and mothers were thenfollowed p with a srve at 29 months and

1624 months postpartm. Folate intake was

divided into qartiles of amont consmed

(qartile medians: Q1=206.8 g/da; Q=255.1 g/

da; Q3=291.2 g/da; Q4=370.6 g/da), and

there were no data on timing in pregnanc. Even

in the highest qartile, intake was still below the

World Health Organization recommended dail

intake of 400 g/da.4 The std athors did not

inclde spplemental folic acid intake as this was

ncommon among the cohort (

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researchFolic acid in pregnancy is there a link with childhood asthma or wheeze?

sggested to be netral or beneficial for a

nmber of other pregnanc otcomes inclding

gestational hpertension, pre-eclampsia, birth

weight, nerodevelopment, preterm birth,

placenta praevia1 and paediatric malignanc.17

The vast majorit of this evidence comes

from observational stdies, as there are few

randomised controlled trials of folic acid

spplementation in late pregnanc.

Conclusion

The crrent available evidence of an association

between late pregnanc folate intake and

childhood asthma or wheeze is conflicting. The

Norwegian std sggested a risk for wheeze

from earl, bt not late pregnanc folic acid

intake. In contrast, the Astralian and English

stdies sggested a risk for asthma from late,

bt not earl pregnanc folic acid intake. TheJapanese std fond no significant risk of

wheeze with dietar folate, bt did not std folic

acid spplementation. We are naware of an

other relevant research.

We feel that an association between

childhood asthma and late pregnanc folic

acid spplementation at standard doses is

possible. However, given the evidence at

present is drawn from cohort stdies, it has

limitations. A randomised controlled trial of

Limitations of the studies

As the inclded articles were all cohort stdies,

a shared limitation is that, despite attempting

to adjst for plasible measrable confonders,

some confonding factors ma exist. Several of the

stdies did not adjst for paternal atop, asthma

and smoking.7,13,15 Some confonders ma not be

easil measred. For example, we speclate that

a health conscios mother might be more likel

to take folic acid, attend a doctor for concerns

regarding child respirator health (increasing the

chance of a diagnosis), and emphasise childhood

hgiene, a ptative risk factor for asthma.16 Neither

the Norwegian nor the ALSPAC stdies qantified

folic acid spplement intake beond a es/no

measre, and the Norwegian std did not measre

dietar folate intake. The Japanese std ma

have been nderpowered, and it did not measre

spplemental folic acid intake. The for stdiesmeasred respirator otcomes at different ages,

and ascertained otcomes differentl, making

direct comparison difficlt. In addition, children

with infantile wheeze do not necessaril develop

asthma. The reslts from the ALSPAC are post hoc,

and therefore shold be interpreted with cation.

Folate in late pregnancy in context

Althogh otside the scope of this review,

folic acid intake in late pregnanc has been

between folate metabolism genotpe and allerg.

(The athors of this ALSPAC sb-std did not aim

to std associations between maternal folate

intake and childhood asthma, bt as we noted

that data had been collected on these factors, the

ALSPAC std athors were approached for more

information.)

The collected data inclded maternal dietar

folate intake (g/da) at 32 weeks of pregnanc,

as well as folic acid spplementation (es/no)

at 18 and 32 weeks. Childhood asthma was

measred at 7.5 ears of age and defined as

maternal recall of phsician diagnosis of asthma

together with wheeze within the previos

12 months. Analsis of these data ields the

previosl npblished reslts presented in

Table 2. Logistic regression models were sed

to evalate the association between childrens

asthma and maternal dietar/spplementalfolate intake. Reslts were adjsted for gender,

maternal histor of asthma or allerg, exposre

to prenatal and postnatal maternal smoking and

mothers edcation. There was no association

between childrens asthma and maternal dietar

folate intake at 32 weeks. However, there was

moderate evidence of a positive association

between childrens asthma and maternal

spplemental folic acid intake at 32 weeks (adj

OR 1.24, 95% CI: 1.021.51, p=0.03).15

Table 2. Association between asthma and maternal dietary folate intake or folic acid supplementation in the ALSPAC cohort15

OR (95% CI), pvalue for

childrens asthma at 7.5 years

Number of children

with asthma/no asthma

Mean (SD) for

asthmatics

Mean (SD) for

nonasthmatics

Crude Adjusted

Continuous variables

A) Maternal dietary folate intake

at 32 weeks (per 100 g/day)

599/5503 254.9 (68.2) 255.7 (7.07) 0.98 (0.87, 1.11)

p=0.77

0.97 (0.86, 1.10)

p=0.65

Binary variables

B) Maternal supplemental folic

acid intake at 18 weeks gestation

599/5491 NA NA 1.20 (0.94, 1.55)

p=0.14

1.17 (0.91, 1.51)

p=0.22

B) Maternal supplemental folic

acid intake at 32 weeks gestation

599/5503 NA NA 1.25 (1.04, 1.49)

p=0.02

1.25 (1.04, 1.49)

p=0.02

C) Maternal supplemental folic

acid intake at 32 weeks gestation

598/5480 NA NA 1.26 (1.05, 1.50)

p=0.01

1.24 (1.02, 1.51)

p=0.03

A) Adjusted for gender, maternal history of asthma or allergy, maternal supplemental folic acid at 32 weeks gestation, exposure to prenatal and

postnatal maternal smoking and mothers education

B) Adjusted for gender, maternal history of asthma or allergy, maternal dietary folate intake at 32 weeks gestation, exposure to prenatal and

postnatal maternal smoking and mothers education

C) Adjusted as in B, but also adjusted for maternal supplemental folic acid intake at 18 weeks gestation

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between mother and child MTHFR C677T polmor-phisms, dietar folate intake and childhood atop ina poplation-based, longitdinal birth cohort. ClinExp Allerg 2008;38:3208.

16. Bran-Fahrlnder C, Riedler J, Herz u, et al.Environmental exposre to endotoxin and its rela-tion to asthma in school-age children. New Engl JMed 2002;347:86977.

17. Goh yI, Koren G. Folic acid in pregnanc and fetalotcomes. J Obstet Gnaecol 2008;28:313.

18. Hpponen E, Bocher BJ. Avoidance of vitamin Ddeficienc in pregnanc in the united Kingdom: thecase for a nified approach in national polic. Br JNtr 2010;104:30914.

19. National Health and Medical Research Concil.Iodine spplementation for pregnant and breast-feeding women. Canberra: NHMRC, 2010. Availableat www.nhmrc.gov.a/pblications/snopses/new45_sn.htm.

20. Astralian Centre for Asthma Monitoring. Asthmain Astralia 2008. AIHW Asthma Series No. 3.Canberra: AIHW, 2008.

AcknowledgmentsWe thank Jon Emer and John Henderson for

helpfl comments on this article. Eleanor Sharland

is gratefl to General Practice Edcation and

Training for fnding her academic registrar post at

the universit of Western Astralia, dring which

mch of this research was ndertaken.

References1. Tamra T, Picciano MF. Folate and hman reprodc-

tion. Am J Clin Ntr 2006;83:9931016.

2. Lmle J, Watson L, Watson M, et al.Periconceptional spplementation with folate and/or mltivitamins for preventing neral tbe defects.Cochrane Database Sst Rev 2001;3:CD001056.Available at www.mrw.interscience.wile.com/

cochrane/clssrev/articles/CD001056/frame.html.3. Czeizel AE, Ddas I, Metneki J. Pregnanc

otcomes in a randomized controlled trial of peri-conceptional mltivitamin spplementation final

report. Arch Gnecol Obstet 1994;255:1319.4. Lincetto O. Prevention of neral tbe defects.

Department of Making Pregnanc Safer, WorldHealth Organization, 2007. Available at www.who.int/reprodctivehealth/pblications/maternal_peri-

natal_health/neral_tbe_defects.pdf.5. Hre A, yong A, Smith R, et al. Diet and pregnanc

stats in Astralian women. Pblic Health Ntr2009;12:85361.

6. Food Standards Astralia New Zealand.Mandator folic acid fortification in Astralia,2009. Available at www.foodstandards.gov.a/scienceandedcation/factsheets/factsheets2009/

mandatorfolicacidfo4389.cfm.7. Whitrow MJ, Moore VM, Rmbold AR, et al. Effect

of spplemental folic acid in pregnanc on child-hood asthma: a prospective birth cohort std. Am JEpidemiol 2009;170:148693.

8. AAP. Folic acid in pregnanc linked to asthma.

Sdne Morning Herald, 5 November 2009.Available at www.smh.com.a/lifestle/wellbeing/folic-acid-in-pregnanc-linked-to-asthma-20091105-

hvs.html.9. Campbell D. Researchers link asthma risk to folic

acid dring pregnanc. Gardian, 4 November 2009.Available at www.gardian.co.k/science/2009/

nov/04/asthma-folic-acid-pregnanc-research.10. Forster DA, Wills G, Denning A, et al. The se of

folic acid and other vitamins before and dringpregnanc in a grop of women in Melborne,Astralia. Midwifer 2009;25:13446.

11. Maats FH, Crowther CA. Patterns of vitamin,mineral and herbal spplement se prior to anddring pregnanc. Ast N Z J Obstet Gnaecol2002;42:4946.

12. Hollingsworth J, Maroka S, Boon K, et al. In terospplementation with methl donors enhancesallergic airwa disease in mice. J Clin Invest2008;118:34629.

13. Haberg SE, London SJ, Stigm H, et al. Folic acid

spplements in pregnanc and earl childhood res-pirator health. Arch Dis Child 2009;94:1804.

14. Miake y, Sasaki S, Tanaka K, et al. Maternal Bvitamin intake dring pregnanc and wheeze and

eczema in Japanese infants aged 1624 months:The Osaka Maternal and Child Health Std. PediatrAllerg Immnol 2011;22(1 Pt 1):6974.

15. Granell R, Heron J, Lewis S, et al. The association

folic acid spplementation in late pregnanc

wold offer more reliable evidence. Considering

the range of possible benefits and risks from

folate spplementation, and the fact that sch

spplementation is commonl sed, sch a std

cold be considered bt wold face challenges of

adeqate power and ethical acceptabilit.

Implications for practice

We will contine to recommend

periconceptional and earl pregnanc folic acid

spplementation for the prevention of neral

tbe defects. Given the possible association

with asthma, we wold not recommend

spplements containing onl folic acid in late

pregnanc. However, given the ncertaint of

this risk, and the possible benefits of other

microntrients (which are otside the scope

of this article bt reviewed elsewhere18,19

) wewold not dissade a pregnant woman from

taking a standard pregnanc mltivitamin.

We wold remind women that respirator risks

from late pregnanc folic acid are nproven, bt

that even if the are real, the absolte increase

in risk to an individal child wold be fairl

small. Hpotheticall, if the relative risk increase

of asthma from standard dose late pregnanc

folic acid was 1020% (consistent with the

Astralian and English stdies), and assming

an Astralian childhood asthma prevalence of

20%,20 a pregnant woman taking folic acid in

late pregnanc wold increase her childs risk

of asthma b 24%. Coching the statistics in

these terms ma help patients make an informed

decision.

AuthorsEleanor Sharland MBBS(Hons), FRACGP, is a

former academic registrar, Discipline of General

Practice, School of Primar, Aboriginal and Rral

Health Care, universit of Western Astralia,

Perth, Western Astralia. aesharland@gmail.com

Brett David Montgomer MBBS, DCH, FRACGP,is Associate Professor, Discipline of General

Practice, School of Primar, Aboriginal and Rral

Health Care, universit of Western Astralia,

Perth, Western Astralia

Raqel Granell BSc(Valencia), MSc(Bristol),

PhD(Bristol), is Research Fellow, School of Social

and Commnit Medicine, universit of Bristol,

Oakfield, united Kingdom.

Conflict of interest: none declared.

424 Reprinted from AuSTRALIAN FAMILy PHySICIAN VOL. 40, NO. 6, JuNE 2011