Folic Acid During Pregnancy Reduces Risk of Cleft Lip

DURHAM, N.C., Jan. 26 -- Folic acid supplements during pregnancy apparently reduce the risk of a cleft lip in addition to neural tube defects, according to a study in Norway.

The findings reinforce recommendations for all women of childbearing age to take folic acid supplements, said Allen J. Wilcox, M.D., Ph.D., of the National Institute of Environmental Health Sciences here, and colleagues, in a study published online in the BMJ.

Daily folic acid supplementation for women starting before conception is recommended in the United States and many other countries to prevent neural tube birth defects, such as spinal bifida.

"Our study isn't going to change those recommendations," Dr. Wilcox said. "If anything it just makes them more relevant because it appears that women taking folic acid can help prevent two types of birth defects, not just one."

Previous studies had found some evidence for a reduction in orofacial clefts with folic acid intake but had been inconclusive because of study design and size.

So the researchers conducted an observational study of infants born in Norway, which has one of the highest rates of cleft lip and palate in Europe at one per 500 births compared with one per 750 in the United States. Norway also does not fortify grain products with folic acid as is done in the U.S.

However, Dr. Wilcox said American women are not off the hook because U.S. serum folate levels have significantly dropped in recent years despite fortification, as reported earlier this month.

"Fortification was designed to [provide the full 400 ?g recommended daily] for most women assuming certain patterns of diet, but it is clearly not succeeding because there are many women in the U.S. that are not getting enough," Dr. Wilcox said.

He added that the findings give physicians another reason to recommend folic acid supplements for all women of childbearing age because waiting until pregnancy is discovered may miss the stage when these birth defects occur.

The facial structures that form the embryonic lip fuse during the fifth and sixth weeks of life and the palatal shelves fuse during weeks seven to 10.

The study included most infants born in Norway from 1996 to 2001 with an orofacial cleft (377 with cleft lip with or without cleft palate and 196 with cleft palate alone) as well as 763 randomly selected controls.

Mothers of these infants were sent an initial questionnaire within three months of the birth regarding demographics, reproductive history, and early pregnancy smoking, alcohol, drugs, and other exposures.

Then the women were sent a second questionnaire on nutrition and supplement use during the month prior to and the first two months of pregnancy. For folic acid and multivitamin supplements, they were asked the specific product name and were contacted to send the empty pill bottle or label to the study office to confirm contents and dosage.

Controls were slightly more likely than women whose child had cleft palate alone or cleft lip (with or without cleft palate) to have taken at least 400 ?g of folic acid supplements (19% versus 16% and 14%). The same pattern was seen with multivitamins (37% versus 36% and 33%, respectively).

About half of women who took folic acid supplements got an average of 400 to 500 ?g of folic acid a day and just 12% got a higher dose.

The researchers found that at least 400 ?g/day of folic acid supplementation during early pregnancy was significantly associated with reduced risk of cleft lip even after adjustment for multivitamins, smoking, and other potential confounding factors (odds ratio 0.61, 95% confidence interval 0.39 to 0.96).

Lower dose folic acid was not associated with clefting regardless of adjustment for confounding factors.

Likewise, there was no link between folic acid supplementation and cleft palate without cleft lip (adjusted OR 1.07, 95% CI 0.56 to 2.03).

"Separate findings for the two types of orofacial clefts are consistent with embryological and epidemiological data that show distinct causal mechanisms for these two types of defects," the researchers wrote.

Interestingly, they also found an independent effect from high-folate diets and multivitamins.

Even after adjusting for supplements and other factors, diets rich in fruits, vegetables, and other high-folate foods tended to reduce the risk of cleft lip (adjusted OR 0.75, 95% CI 0.50 to 1.11).

Multivitamins were also modestly linked to reduced risk of cleft lip (crude OR 0.77, 95% CI 0.57 to 1.03) with minimal change in the association after adjustment for folic acid and other factors (OR 0.75, 95% CI 0.50 to 1.11).

The lowest risk of cleft lip was among women with at least the recommended dose of folic acid, multivitamins and good diet (relative risk 0.36 versus lower measures in all three, 95% CI 0.17 to 0.77).

"The finding that the relatively low levels of dietary folates (which are less bioavailable than folic acid) seemed to be weakly protective against cleft lip with or without cleft palate, even though we saw no evidence for a protective effect of low dose folic acid supplements?is curious," the authors wrote.

"This suggests that other nutritional factors correlated in diet with the folates may have a role in preventing cleft lip with or without cleft palate," they added.

Despite possible recall bias, the study suggests a public health impact for folic acid supplementation and an additional benefit for fortifying foods with folic acid, Dr. Wilcox and colleagues said.

If all pregnant women took at least the recommended amount of folic acid daily, an additional 22% of cleft lip cases in Norway could be averted, they said.