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Folic-Acid Antagonists Are Associated with Neural-Tube Defects

Maternal folic-acid supplementation before and during early pregnancy can reduce the risk for having a child with a neural-tube defect (NTD). To determine whether periconceptional exposure to folic-acid antagonists (FAAs) increases the risk for NTDs, these U.S. authors performed a case-control study that compared data on infants and fetuses with NTDs (n=1242) with data on a control group of infants with malformations other than NTDs (n=6660). Within 6 months of delivery, nurses interviewed mothers in their homes regarding demographics, medical and obstetric histories, occupation, and tobacco, alcohol, and medication use from 2 months before conception and throughout pregnancy. Mothers were specifically queried about the ingestion of FAAs, including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim.

Twenty-seven (2.2 percent) of the infants with NTDs had been exposed to FAAs compared with 67 (1.0 percent) of the controls, a significantly higher risk (adjusted odds ratio, 2.8; 95 percent CI, 1.7-4.6). Controlling for other factors (e.g., smoking, alcohol intake, and family history) did not influence the difference in risk. Trimethoprim, the most commonly prescribed FAA, was used around the time of conception by 0.4 percent of cases and 0.1 percent of controls (AOR, 4.8).

Compared with infants who were not exposed to trimethoprim, those who were exposed during the first month after the last menstrual period had an OR of 7.8 for having an NTD; those exposed during the second month had an OR of 6.4; and those exposed during the third month had an OR of 0.9. When women exposed to either trimethoprim or carbamazepine took a folic acid supplement daily, the OR of having an infant with an NTD decreased from 13.3 to 1.2.

Comment: This study was designed well: The use of mothers with malformed infants as controls served to balance recall-bias effects between the study and control groups. Thus, women attempting pregnancy and those in early pregnancy should not be treated with FAAs unless it is not possible to use alternative drugs.

— SA Carson

Published in Journal Watch Women's Health August 14, 2001

Citation(s):

Hernandez-Diaz S et al. Neural tube defects in relation to use of folic acid antagonists during pregnancy. Am J Epidemiol 2001 May 15 153 961-968.

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