Folic acid deficiency was linked with facial clefts in rodents even before its association with neural tube defects was established, but studies of facial clefts in humans have given inconsistent results. This issue is especially important in countries such as Norway where foods are not fortified with folic acid. As it happens, Norway has one of the highest rates of facial clefts in all of Europe. A national population-based case-control study was undertaken in Norway, enrolling infants born between 1996 and 2001. Participating were 377 infants having cleft lip with or without cleft palate, 196 with only cleft palate, and 763 control infants. Ten percent of control mothers took a daily folic acid supplement of 400 μg or more as well as multivitamins in early pregnancy. Another 9% took only folic acid, and 26% took only multivitamins. Other birth defects were found in 17% of infants with cleft lip, with or without cleft palate, and in 40% of those with cleft palate only.
With folic acid supplementation, the crude odds ratio (OR) for cleft lip with or without cleft palate was 0.66, with a 95% confidence interval (CI) of 0.47–0.95, and 0.81 (95% CI, 0.53–1.26) for cleft palate only. Adjusting for numerous potential confounding factors and excluding infants with other birth defects slightly lessened the association between supplementation and cleft lip and totally eliminated the association with cleft palate only. Supplementation with less than 400 μg of folic acid daily did not affect the risk of cleft formation. The relative risk of cleft lip (with or without cleft palate) was somewhat less in women taking multivitamins at about the time of conception (crude OR, 0.77; 95% CI, 0.57–1.03). The OR was very similar after adjusting for covariates. Risk levels were lowest for women who took at least 400 μg of folic acid daily and who, in addition, took multivitamins or consumed dietary folate. When all 3 sources were combined, the adjusted OR for cleft lip with or without cleft palate was 0.36 (95% CI, 0.17–0.77).
Taking a daily folic acid supplement in early pregnancy appears to lessen the risk of cleft lip, with or without cleft palate, by about one-third. Taking multivitamins and/or a folic acid-enriched diet as well may provide added benefit.
Epidemiology Branch, National Institute of Environmental Health Sciences/NIH, Durham, North Carolina; Department of Public Health and Primary Health Care, Section for Epidemiology and Medical Statistics, University of Bergen, Norway; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; WESTAT, Durham, North Carolina; Department of Plastic Surgery, Rikshospitalet, Oslo; and Department of Plastic Surgery, Haukeland University Hospital, Bergen