Periconceptional folate intake by supplement and food reduces the risk of nonsyndromic cleft lip with or without cleft palate

Abstract

Background. Inadequate maternal vitamin intake during pregnancy has been suggested as a risk factor for cleft lip with or without cleft palate (CLP). The independent role of folate has not been clarified.

Methods. To investigate the association between maternal folate intake by supplement and food and the risk of CLP offspring, a case-control study was conducted in the Netherlands (1998–2000) among 174 mothers of a child with nonsyndromic CLP and 203 mothers of a child without congenital malformations.

Results. Daily use of a folic acid supplement by mothers starting from 4 weeks before until 8 weeks after conception gave a 47% CLP risk reduction compared to mothers who did not use these supplements [odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33, 0.85]. Ninety-three percent of the users took a supplement containing folic acid only. Dietary folate intake reduced CLP risk independently in a dose–response manner. The largest risk reductions were found on those mothers who had a diet of more than 200 μg folate per day in combination with a folic acid supplement (OR: 0.26, 95% CI: 0.09, 0.72).

Conclusions. We demonstrated that periconceptional maternal folic acid supplement use was beneficial to reduce the risk for CLP. An additional effect of food folate was shown.

Introduction

Cleft lip with or without cleft palate (CLP) is a congenital closure defect that can have serious medical, psychological, and social consequences. The multifactorial etiology of most nonsyndromic cleft lip with or without cleft palate is still not understood. Evidence is accumulating that inadequate maternal nutrition during early pregnancy, particularly of vitamins such as folate, is a cause of cleft lip with or without cleft palate in humans. The only randomized control trial with multivitamins, focussed on the occurrence of neural tube defects but evaluated orofacial clefts as well, failed to show a preventive effect on the occurrence of cleft lip with or without cleft palate [1]. Several other intervention and case-control studies, however, did show an association between multivitamins and orofacial cleft risk [2], [3], [4], [5], [6]. The independent role of folate in the pathogenesis of this congenital malformation remains to be clarified.

Folate, as a one-carbon donor, is involved in the biosynthesis of purines and pyrimidines and in homocysteine remethylation producing methyl groups for, for example, methylation of DNA, which is important for genetic expression. Thus, folate is essential for cellular multiplication and differentiation in the development of lip, alveolus, and palate.

Humans are dependent on dietary sources of folate. Major contributors are bread, cereals, fruits, vegetables, and liver. For most women, it is difficult to reach the recommended daily dose of 400 μg folate during pregnancy [7]. Therefore, in the Netherlands, like in most other countries, all women who want to get pregnant are recommended to take a tablet containing 400 μg of folic acid each day from at least 4 weeks before pregnancy until at least the eighth week of pregnancy [8]. Unlike many countries, in the Netherlands most women take a tablet containing only folic acid instead of a multivitamin.

In this case-control study, we investigated the independent effect of folate separate from other vitamins on the risk of cleft lip with or without cleft palate in offspring. Moreover, we obtained unique data on dietary folate intake to unravel the contribution of periconceptional supplement and dietary intake of folate in the pathogenesis of cleft lip with or without cleft palate. Therefore, this study provides important information for possible prevention of cleft lip with or without cleft palate.