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Folic Acid Antagonists and Risk of Birth Defects



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Am Fam Physician. 2001 May 1;63(9):1843-1844.

Results from two studies conducted previously showed that prenatal supplementation with folic acid reduces the risk of neural tube defects in infants. It is also believed that peri-conceptional supplementation with a multivi-tamin containing folic acid decreases the risk of other congenital malformations. Whether the lowered risk is attributable to folic acid alone or to another component of the multi-vitamin is not clear. One way to assess the role of folic acid in birth defect prevention is to determine whether antagonists of folate are associated with an increased risk of such defects. Two types of medicinal antagonists include dihydrofolate reductase inhibitors (e.g., trimethoprim) and drugs that impair folate metabolism and absorption (e.g., antiepileptics). Hernández-Díaz and colleagues analyzed data from a large multicen-ter, case-control program of surveillance for birth defects to assess the role of folate antagonists as well as folic acid supplementation in congenital malformations.

Data were collected about infants born at 80 hospitals in Boston, Philadelphia and Toronto, and in parts of Iowa, between 1976 and 1998. The mothers of infants born with oral clefts or abnormalities of the cardiovascular and genitourinary systems were interviewed. The interviews took place within six months of delivery, mostly in the parents' homes. Included in the interviews were detailed questions regarding the mothers' medical and obstetric history, the parents' occupations and the use of prescription and nonprescription medications from two months before conception until the end of the pregnancy. All of the women included in the case part of the study were taking at least one of the following folic acid antagonists: trimethoprim, triamterene, sulfasalazine, phenytoin, phenobarbital, primidone and carbamazepine. The control group included mothers whose infants had malformations other than oral clefts and cardiovascular, genitourinary or neural tube defects.

During the 22-year period, 3,870 infants were born with cardiovascular abnormalities, 1,962 with oral clefts and 1,100 with urinary tract defects. Of this group, 63 mothers who had infants born with a cardiovascular anomaly, 36 who had infants with an oral cleft and 16 who had infants with genitourinary abnormalities reported taking a folic acid antagonist during the second or third month after their last menstrual period. More specifically, the use of a dihydrofolate reductase inhibitor during this time was associated with a relative risk of 3.4 for a cardiovascular abnormality and a relative risk of 2.6 for oral cleft. In mothers who took an antiepileptic drug during this same time, the relative risk of their infant having a cardiovascular defect was 2.2, an oral cleft was 2.5 and a urinary tract defect was 2.5. The use of multivitamin supplementation with folic acid was found to reduce the relative risk associated with dihydrofolate reductase inhibitors but not the risk of congenital abnormalities associated with taking antiepileptic drugs.

The authors conclude from this data that folic acid antagonists taken early in pregnancy appear to increase the risk of neural tube defects, facial clefts and abnormalities of the cardiovascular and genitourinary systems. They suggest that the folic acid supplement contained in prenatal vitamins may help decrease the risk of these birth defects.

Hernández-Díaz S, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. November 30, 2000;343:1608–14.



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