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Prenatal Folic Acid Reduces Risk for Isolated Cleft Lip

Authors: News Author: Laurie Barclay, MD CME Author: Penny Murata, MDFaculty and Disclosures


January 31, 2007 — Folic acid supplements during early pregnancy were effective in reducing the risk for isolated cleft lip in infants by about one third, according to the results of a national population-based, case-control study reported in the January 26 Online First issue of the BMJ.

"The discovery that folic acid in early pregnancy reduces the risk of neural tube defects is one of the important public health advances of recent years," write Allen J. Wilcox, MD, PhD, of the National Institute of Environmental Health Sciences/National Institutes of Health in Durham, North Carolina, and colleagues. "Even before folic acid deficiency had been linked to neural tube defects, it was known to produce facial clefts in rodents. However, studies of an association with facial clefts in humans have provided inconsistent results, and the question remains unresolved."

From infants born between 1996 and 2001 in Norway, the investigators identified 377 infants with cleft lip with or without cleft palate, 196 infants with cleft palate alone, and 763 controls. The primary endpoints were associations of facial clefts with maternal intake of folic acid supplements, multivitamins, and dietary folates.

After adjustment for multivitamins, smoking, and other potential confounders, folic acid supplementation (≥ 400 µg/day) during early pregnancy was associated with a reduced risk for isolated cleft lip with or without cleft palate (adjusted odds ratio [OR], 0.61; 95% confidence interval [CI], 0.39 - 0.96).

Independent of supplements, high dietary intake of fruits, vegetables, and other foods rich in folate reduced the risk somewhat (adjusted OR, 0.75; 95% CI, 0.50 - 1.11). Women with folate-rich diets who also took folic acid supplements and multivitamins had infants with the lowest risk for cleft lip (adjusted OR, 0.36; 95% CI, 0.17 - 0.77). Folic acid provided no protection against cleft palate alone (adjusted OR, 1.07; 95% CI, 0.56 - 2.03).

"Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third," the authors write. "Other vitamins and dietary factors may provide additional benefit."

Study limitations include participation rate lower for controls (76%), inability to reconstruct the mothers′ complete exposure history retrospectively, possible errors in self-report, error in folate measurement, inexact nutritional assessment, recall bias, and confounding.

"This apparent effect of folic acid is relevant to ongoing discussions about food fortification," the authors conclude. "If folic acid is able to prevent a major birth defect in addition to neural tube defects, this benefit should be included among the risks and benefits of fortifying foods with folic acid, a matter of ongoing controversy in many countries."

The National Institutes of Health, National Institute of Environmental Health Sciences, the Johan Throne Holst Foundation for Nutrition Research, and the Thematic Area of Perinatal Nutrition at the Medical Faculty of the University of Oslo in Oslo, Norway, supported this study. The authors have disclosed no relevant financial relationships.

BMJ. Published online January 26, 2007.

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