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INTRODUCTION

Orofacial clefts occur when the lips and/orthe roof of the mouth do not fuse properly

during development, leaving an opening;this occurs between 6 and 9 weeks ofpregnancy. Treatment involves plasticsurgery, beginning approximately 3 monthsafter birth and continuing into adolescence.The effects on an individuals speech,hearing, appearance, and psychology canlead to long-lasting adverse outcomes forhealth and wellbeing. Even when repaired,complications such as persistent earinfections, speech impairments, facialdeformities, and dental problems oftenremain.1

A cleft lip and palate occurs inapproximately one in 700 live births.2 Cleftlip, with or without cleft palate, is mostfrequent in males and isolated cleft palate ismost common in females. Prevalencevaries according to geography andethnicity.1

The cause of cleft lip and palate iscomplex but involves both genetic andenvironmental factors. Geneticstudieshavedemonstrated higher prevalence of cleft lipand palate in monozygotic twin pairs than intwins who are dizygotic, and in siblings inwhom congenital anomalies exist.1

Environmental factors havebeen implicatedas contributors to cleft lip and palate1 andinclude maternal exposure to: tobaccosmoke;3 alcohol; medicines such asanticonvulsant drugs, notably diazepam,phenytoin, and phenobarbital;4 illicit drugs;

viral infection; and nutritional deficiencies.A recent Cochrane review found that folic

acid intake before and during early

pregnancy can prevent the occurrence ofneural tube defects.5 There has been hugeinterest in the potential benefits of folic acidinotherareas suchascardiovascular andurinary tract congenital anomalies6 andcleft lip and palate7 although, to date,there has been insufficient evidence toevaluate this. Although the exactmechanism of folic acidin facilitating neuraltube closureis unknown, it is estimated that>70% of neural tube defects can beprevented by maternal folic acidsupplementation.8

Women of childbearing age are advisedto take an additional 400 g of folic aciddaily if there is any possibility of thembecoming pregnant, and to continue this forthe first 12 weeks of pregnancy.9 Inpractice, the consumption of preventivefolic acid has had mixed uptake; it issuggested that unplanned pregnanciesmay play a pivotal role in hamperingsuccess.10 Globally, some policy makershave introduced mandatory folic acidfortification of foods due to the benefits topopulation health;9 however, as previousstudies have shown that low

socioeconomic status (measured byoccupation), being a smoker, andunplanned pregnanciesareassociated withnot taking the recommended folic acidsupplements,11,12 there is still considerablescope for improving folic acid uptake.

D Kelly, BSc, MPSI, postgraduate researchstudent; T ODowd, MD, FRCGP, professor ofgeneral practice; U Reulbach, MSc, FRSPH,clinical research fellow, Department of PublicHealth and Primary Care, Trinity College Dublin,Dublin, Ireland.

Addressfor correspondence

Tom C ODowd, Department of Public Health andPrimary Care, Trinity College Centre for HealthSciences, Trinity College Dublin, Adelaide & Meath

Hospital, incorporating the National ChildrensHospital, Tallaght, Dublin 24, Ireland.

E-mail: [email protected]

Submitted: 29 November 2011; Editorsresponse:3 January 2012; final acceptance: 10 April 2012.

British Journal of GeneralPractice

This is the full-length article (published online25 June 2012) of an abridged version published inprint. Cite this article as: BrJ Gen Pract 2012;DOI: 10.3399/bjgp12X652328.

Use of folic acid supplements and risk ofcleft lip and palate in infants:a population-based cohort study

Dervla Kelly, Tom ODowd and Udo Reulbach

Research

Abstract

BackgroundOrofacial clefts occur when the lipsor the roofofthe mouth donotfuseproperly during the earlyweeks of pregnancy. Thereis strong evidence thatpericonceptional use of folic acid canpreventneuraltube defects but itseffect on oral cleftshas generated debate.

AimTo identify factors associated withsuboptimal

periconceptional use of folic acid and itspotentialeffect on oral clefts.

Designand settingThepopulation-based infant cohort of thenational Growing Up in Ireland study,whichconsists of 11 1349-month-old infants.

MethodData collectioncomprised questionnairesconductedby interviewerswith parents inparents homes.Characteristicsof mothers whodid or did not takefolic acid beforeand duringpregnancy, as well as the effect of folic acid useon theprevalenceof cleft lip andpalatewererecorded.

Results

Theprevalenceof cleft lip andpalatewas1.98(95% confidence interval [CI] = 1.31 to 2.99) per1000 9-month-olds. Theodds ratio forcleftlipwas 4.36-fold higher (95% CI= 1.55to 12.30,P=0.005) for infants of mothers who did not takefolic acid duringthefirst 3 monthsof pregnancy,when compared with those who did have a folateintakeduringthe first trimester. Folicacid usewas suboptimal in 36.3% (95% CI= 35.4 to37.2)of thesample.

ConclusionThese findings support the hypothesisthat takingfolic acid maypartiallyprevent cleft lipand palate.They are particularly relevant forGPs, becausethey are usually the first port of call for womenbefore and during earlypregnancy.

Keywordscleft lip; epidemiology; folic acid; generalpractice; infant.

e466 British Journalof GeneralPractice, July 2012


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The potential effect of folic acidsupplements on preventing oral clefts has

generated considerable debate. A recentmeta-analysis concluded that maternalmultivitamin supplements taken duringearly pregnancywere associatedwitha 25%decreased risk of orofacial clefts; the role offolic acid, however, was far lessconvincing.13 In contrast, Badovinac et alreviewed five prospective studies and 12casecontrol studies and concluded thattaking a folic acid-containing supplementduring pregnancy did have a protectiveeffect against the risk of developing oralclefts.14

Further research is necessary toestablish the benefits of folic acidsupplements in preventing birth defects,other than neural tube defects. The aim ofthis study was to estimate the prevalence ofcleft lip and palate in the 9-month-old Irishpopulation and to assess the effect of folicacid supplement in preventing it.

METHOD

Study populationThe study involved a cross-sectionalanalysis of the first wave of data from theinfant cohort of the Growing Up in Ireland

study. Infants were randomly selected fromthe Child Benefit Register. A systematicselection procedure, based on a randomstart and constant sampling fraction, wasused.15 The 11 134 infants representing the9-month cohort were born between 1December 2007 and the 30 June 2008.

Data collection and analysisData were collected between September2008 and April 2009 via questionnaires,conducted by interviewers, that wereundertaken with parents in their homes.Inclusion in the study was on an opt-out

basis; consent forms were signed by theparent(s)/guardian(s) before the start of theinterview: 17 264 families were asked toparticipate in the study.

Analyses were based on statistically re-weighted data to ensure they wererepresentative of all 9-month-olds in

Ireland. The weighting system aims tocompensate for any imbalances in thepopulation recruited. Eleven maincharacteristics of the infant and his or herfamily were used in the generation of theweights: family structure; mothers age;mothers principal economic status;fathersprincipal economic status; familys socialclass; mothers education; householdtenure; region; mothers marital status;mothers nationality; and mothersresidency status. This method of weightingused is a minimum information algorithmthat fits population marginals in a

regression framework and adjusts thesample estimates to ensure that theyproduce estimates that match humanpopulation parameters.16

The power analysis for the present studywas based on thea prioriassumption of a2.5-fold increase of cleft lip and palate inchildren as threshold when users and non-users of folate were compared. Thea prioriestimates of cleft lip and palatewas 1 in 700births and one-third of the population innon-users of folates. Using a type-1 errorestimate of 0.05 and a power of 80%, thesample size calculation yields a requirednumber of 3362 in each group(users versusnon-users of folates). Based on 11 000infants in the cohort, a third (equating to3666 infants) would be the offspring of non-users. Therefore, it was concluded that thepresent study has enough power to detectdifferences between users and non-usersof folates regarding cleft lip and palate.

Cleft lip and palate prevalence wasestimated based on the following question,as answered by the primary caregiver:

Has a medical professional ever told you

that the baby has cleft lip and palate?Thequestionnaire included two questions

to determine use of folic acid; the biologicalmother was asked:

Did you take folic acid/folate prior tobecoming pregnant with the baby?; and

Did you take folic acid/folate during thefirst 3 months of pregnancy with thebaby?

In addition, information on maternal andfamily characteristics was collected,including details of household composition;

infants development; parenting andrelationships; the infants habits; childcarearrangements; siblings and twins; prenatalcare; the infants health; the health of the

How this fits in

Taking folic acid 4 weeks before, and forthe first 12 weeks during, pregnancy canprevent neural tube defects. A recentCochrane review concluded that there wasno statistically significant evidence of anyeffect of folic acid in the prevention of oralclefts. However, this study supports thehypothesis that folic acid taken in the first12 weeks of pregnancy may significantlyreduce the prevalence of cleft lip andpalate.

BritishJournalof GeneralPractice, July 2012 e467


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parent being interviewed; family context;sociodemographics; household income;and neighbourhood.

As well as univariate analyses (Pearsons2 test, Fishers exact test), multivariateanalyses considered factors associatedwith

non-use of folic acid and the effect of folicacid use on the rate of cleft lip and palate.The odds ratio (OR) was adjusted for:

maternal age (metric);

household composition (two variableswere included: lone parenthood andnumber of siblings of the study infant);

highest levelof education (five categories:less than lower secondary; lowersecondary; Leaving Certificate;subdegree; degree or higher);

equivalised annual income (quintiles);

occupational household class(professional/managerial; other non-manual/skilled, manual; semi-

skilled/unskilled; all others employed;and unknown/never worked at all);

urbanicity (urban or rural area);

smoking (smoking hazard duringpregnancy: how many members of thehousehold smoked including thebiological mother); and

at how many weeks the mother becameaware that she was pregnant.

Factors were included in themultivariablemodels if there was a biologically plausiblepotential for confounding. Results arereported as ORs and 95% confidenceintervals (CIs) derived from binary logisticregression analyses. The statistical softwareSPSS (version 19) was used, together with asignificance level of P= 0.05.

RESULTS

In total 17 264 families were approached,and a usable interview was completed with


Table 1. Factors associated with not taking folic acid during the first 3 months of pregnancy

Proportion of mothers who

did not take folic acid Mother not taking folic acidFactor % 95% CI AOR 95% CI P-value

Maternal age, years (n= 10 891), univariate P


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11 134 (64.5% response rate). Lone parentsandmothers in lower educational categorieswere under-represented in the unweighted

sample.

Prevalence of non-consumption of folicacidOver one-third of women (36.3%, 95% CI =35.4 to 37.2) did not take a folic acidsupplement before becoming pregnant.During the first trimester of pregnancy, aminority of women (6.7%, 95% CI = 6.3 to7.2) did not take a folic acid supplement. Asignificant association (z= 11.0; P


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and non-consumption was more commonin people with a low socioeconomic status.The prevalence of cleft lip and palate was

1.98 per 1000 births.

Strengths and limitationsThis study is based on self-reportedmeasures of folic acid consumption anddoes not contain information regardingformulation, dosage, or timing of initiation offolic acid. As the data were collected afterdelivery, it is possible that report bias hasoccurred; however, this bias will be, fromthe best of the authors knowledge, non-directional and will, therefore, not changethe direction of the findings. The bias mightaffect the power of the study: this has been

taken into account witha coherent samplingstrategy, resulting in a large sample size.Maternaldietary factorsandconsumption ofvitamins may also impact on the effect offolate on cleft lip and palate and women nottaking folic acid supplements may be lesslikely to have healthier habits duringpregnancy; these factors were not coveredin the initial questionnaire in detail.

In addition, the caseness of cleft lip andpalate was based on parental self-report.Based on the study governance of GrowingUp in Ireland, it was not possible to validateagainst medical records. It is not likely that

recall or report bias would change thedirection of the association; however, as apotential linkbetweenfolateandcleft lipandpalate is not discussed in the media, publicknowledge of it seems unlikely.

Difficulties in detecting populationchanges in rare conditions such ascongenital anomalies limit studies trying todetect protective behaviours. Furthermore,it is not possible to rule out the effect ofunknown confounders. The study designdoes allow an assessment of a statisticalassociation between folate intake and cleft

lip and palate, but no formal assessment ofcausality can be done. However, a majorstrength of this study is the large andrepresentative nature of the sample, whichequated to approximately one-seventh of allbirths in Ireland in 2007.15 This studysresults take cleft lip and palate and cleftpalate into account.

Comparison with existing literatureA study from England found that, although88.9% of women reported taking folic acidsupplements before their 18-weekantenatal clinicappointment,51.6% of those

surveyed did not take folic acid supplementbefore 4 weeks gestation.17 Internationally,in a systematic review of 52 studies, in some20 (mainly Western) countries between 1992

and 2001, the reported periconceptionalsupplement use ranged from 0.5% to 52%.18

Similar to previous studies, these findings

showed that not taking folic acid was morecommon in women of low socioeconomicstatus. An earlier Irish study using datacollected from 300 women attending amaternity hospital found professional classand planned pregnancy to be the mainpredictors of periconceptional use of folicacid.10 A recent study from New Zealandfound that youngermaternal age,increasingparity, minority ethnic group, lowereducation, and lower income predicted poorfolic acid intake in expectant mothers.19

The cleft lip and palate prevalence ofapproximately 1.98 per 1000 births was

similar tothat of a recentDutch study, whichreported a prevalence of 1.68 per 1000births.20 Although there is no nationalregistry of cleft lip and palate in Ireland, fourregional Irish cleft lip and palate registersreported prevalence estimates between1.17and 2.02 per 1000 birthsin 20082009.21 Thecurrent study is thought to be the firstformal estimate of the prevalence of cleft lipand palate in a nationally representativeIrish cohort.

Previous research from the InternationalDatabase of Craniofacial Anomaliessuggests that Ireland has a high rate of cleft

lip and palate compared with the Europeanaverage, which is reported as 1.4 per 1000births (no CI available).22 Similarly, theprevalence of cleft lip and palate in the UKranges from 1.32 to 1.78 per 1000 births.17 Itis of interest that the prevalence of cleft lipand palate was higher in northern Europe(1.73 per 1000 births) compared with itsprevalence in southern Europe (0.87 per1000 births), although no explanation forthishas been suggested.22 Although promotionand awareness of the benefits of folic acidhave been ongoing in Ireland over the last

two decades, a concomitant reduction in theprevalence of neural tube defects has notbeen found.23

The potential protective effect of folic acidon cleftlipandpalate, as illustratedin Figure1, is consistent with findings from a numberof casecontrol studies, althoughsignificance levels vary considerably. A smallHungarian cohort control study found aninsignificant OR of 1.00 (95% CI = 0.20 to4.95),24 whereas another casecontrol studyfound an OR of 0.60 (95% CI = 0.39 to 0.92)with regard to the effect of folic acidsupplementation on the rate of cleft lip and

palate.25

Thecorresponding crude OR of 0.23in this study is in line with the findings fromthelatterstudy,andcomparable consideringthe CIs used (95% CI = 0.08 to 0.65).

Funding

We wish to acknowledge the funding of theproject by the Department of Health andChildren,throughthe OfficeoftheMinisterforChildren andYouth Affairs, in associationwiththe Department of Social and Family Affairsand the Central Statistics Office. UdoReulbach is supported by the HealthResearch Board (HRB) of Ireland throughtheHRB Centre for Primary Care Researchunder Grant HRC/2007/1. Dervla Kelly issupported by a research studentship throughthe Irish Lung Foundation.

Ethicalapproval

All material and procedures during datacollection were carried out under ethicalapproval granted by an independentResearch Ethics Committee: 'The NationalLongitudinal Study of Children in Ireland,Research Ethics Committee (REC)'.

Provenance

Freely submitted; externally peer reviewed.Competinginterests

The authors have declared no competinginterests.

Acknowledgements

In addition to the funders, the authors wouldlike to gratefully acknowledge the work ofProfessor James Williams, Professor SheilaGreen, and the entire Growing Up in Irelandproject andstudyteams.Wewouldalsoliketothank the children and families whoparticipatedin thestudyandprovidedthedataforthispaper.

Discuss this articleContribute and read comments aboutthis article on the Discussion Forum:http://www.rcgp.org.uk/bjgp-discuss


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In contrast to this study, a recentCochrane review of the effect of folic acid oncleft lip or cleft palate found insufficient

evidence to support the protective effect offolic acid. This was largely owing toinsufficient cases of the defect occurring inthe trials.5 The plausibility of folic acid inpreventingcleft lip is indirectly supported bythe higher prevalence of cleft lip and palateamong pregnant women taking drugs thatcan act as folic acid antagonists, such asphenytoin and phenobarbitone.7

Previous research addressedconfounding in several ways. Severalstudiesincluded an adjusted OR, controllingfor a wide range of variables includingsmoking, alcohol consumption, maternal

age, education, employment during earlypregnancy, sex of infant, year of infantsbirth, family history of cleft lip and palate,maternal epilepsy and diabetes, andwhether pregnancy was planned.13,14 The

adjusted OR in the present study did notdiffer significantly from the crude OR.

Implications for practiceThis study supports the hypothesis that folicacid supplements play a significant role inpreventing cleft lip and palate when taken inthe first 12 weeks of pregnancy. Healthcarepractitioners should be made aware of thegrowing benefits of folic acid and reinforcethe importance of folic acid supplementeducation as part of prenatal counselling.This information is particularly pertinent toGPs as they are usually the first point ofcontact for women who are trying toconceive or in the very early stages ofpregnancy. These findings suggest that folic

acid plays a major rolein preventing a majorbirth defect and, in addition, it is offersestablished protection against neural tubedefects.


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