Folate intake, markers of folate status and oral clefts: An updated set of systematic reviews and meta‐analyses

Abstract

Background There has been a longstanding debate about the role of folate in the etiology of orofacial clefts (OFCs). Studies of different measures of nutritional intake or folate status have been done to investigate the possible role of folate in the prevention of OFC. Only one knowledge synthesis has attempted to bring together different types of evidence. The aim of the present work was to update it. Methods Evidence for associations between OFC and dietary folate, supplement use, folic acid fortification, biomarkers of folate status, and variants of MTHFR (C677T and A1298C) were included. Potentially eligible articles were systematically identified from PubMed, Medline, Embase, and Web of Science (2007–2020) and combined using random‐effects meta‐analysis when appropriate. Quality assessments were conducted using the Newcastle‐Ottawa scale and Cochrane's risk of bias tool. Results Sixty‐four studies published since the previous knowledge synthesis were identified, with eight of these identified through a supplementary search from October, 2018 to August, 2020. There was an inverse association between folic acid‐containing supplement use before or during pregnancy and cleft lip with or without cleft palate (CL/P) (OR 0.60, 95% CI 0.51–0.69), with considerable between‐study heterogeneity. The prevalence of CL/P showed a small decline post‐folic acid fortification in seven studies (OR 0.94, 95% CI 0.86–1.02). No association was found between OFC and genetic markers of folate status. The coronavirus‐19 pandemic has threatened food availability globally and therefore there is a need to maintain and even enhance surveillance concerning maternal intake of folate and related vitamins. Conclusions The risk of non‐syndromic OFC was reduced among pregnant women with folic acid‐containing supplements during the etiologically relevant period. However, high heterogeneity between included studies, incomplete reporting of population characteristics and variation in timing of exposure and supplement types mean that conclusions should be drawn with caution.

Maternal periconceptional folic acid supplementation reduced risks of non-syndromic oral clefts in offspring

“…Maternal folic acid supplementation (FAS) before and during early pregnancy is a well-established prevention approach for neural tube defects (NTDs). As facial mesenchyme is derived from neural crest, the protective effect of maternal FAS on oral clefts has been studied in various populations, but the findings are inconclusive 5 – 8 . Most observational studies conducted in Europe 9 – 14 , America 15 – 17 , and Asia 18 – 21 , have shown that maternal FAS during early pregnancy is associated with decreased risk of nonsyndromic CL/P (NsCL/P), while other investigations in these areas did not 22 – 27 .…”

The Prenatal High Risk Factors in Non-syndromic Cleft Lip or/and Palate Fetuses: A Nested Case-control Study Based on Maternal Health Care Records of a Population

“…Another review has reported that mandatory folic acid fortification of wheat and/or maize flour may have beneficial effects on non-syndromic CL/P [26]. A recent meta-analysis also has shown that the risk of non-syndromic orofacial clefts was reduced among pregnant women with folic acid-containing supplements during the etiologically relevant period [27]. In Zhongshan of China, every pregnant woman is recommended daily intake of 0.4 mg folic acid in 3 months before pregnancy and in first 3 moths of pregnancy.…”

Parental Risk Factors and Child Birth Data in a Matched Year and Sex Group Cleft Population: A Case-Control Study

“…Concerning environmental risk factors, previous researches, which have shown consistency, have proposed smoking consumption during pregnancy and gestational diabetes as maternal risk factors [ 4 , 9 , 10 ]. Other associations have been reported with less consistency, namely alcohol consumption during pregnancy, intrapartium interval, maternal and paternal age, and nutritional deficiencies (folic acid, vitamin A and B12, and zinc) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Furthermore, both extremes of maternal body mass index (BMI) have been associated with birth defects, but with controversial results in the literature [ 10 , 19 , 20 , 21 ].…”