From The September 2001 Issue of Nutrition Science News
David Wolfson, N.D.
The connection is well known between folic acid deficiency and birth defects, especially neural-tube defects, yet most people do not attribute the nutrient deficiency to pharmaceutical drugs.
In a New England Journal of Medicine study, researchers at Boston University School of Public Health and the Harvard School of Public Health raised concern over the use of drugs that interfere with folate metabolism during pregnancy, suggesting that such drug use may increase the risk of birth defects.  They asked the mothers of more than 15,000 infants with birth defects whether they had taken certain drugs, known by researchers to inhibit folate activity, during their pregnancies.
The researchers were interested in a class of folate antagonists known as dihydrofolate reductase inhibitors (DFRIs), which block folate activation. Examples of DFRI drugs include commonly used medications such as the anti-inflammatory sulfasalazine, the blood-pressure regulator triamterene, and the antibiotic trimethoprim (Bactrim). Researchers examined whether using these drugs during pregnancy increased the risk of birth defects other than neural-tube defects, since these have been well studied.
They learned that infants of mothers who used DFRIs during their first trimester were 3.4 times more likely to have cardiovascular defects, and 2.6 times more likely to have oral clefts (cleft palate or cleft lip), than infants of mothers who did not use DFRIs during the same stage of pregnancy. Women who used DFRIs either prior to conception or after their first trimester were not at higher risk, possibly because most developmental defects occur within the first three months of gestation.
Researchers then stratified the results according to whether mothers had taken multivitamin supplements containing folic acid during their pregnancies. Infants of mothers who used DFRIs and no folate supplement were 7.7 times more likely to have cardiovascular defects than infants of mothers who didn't use DFRIs. Infants whose mothers used a DFRI plus a folate supplement were only 1.5 times more likely to have cardiovascular defects than infants of mothers who didn't use DFRIs and who supplemented. Data on oral clefts in this part of the study were not reported because there was an insufficient number of cases.
The results of this study suggest not only that folate-inhibiting drugs increase birth defect risk but also confirm that folate supplementation can dramatically reduce that risk. These findings support the volume of evidence connecting folic acid deficiency and neural-tube defects.
It is also timely information in light of recent studies indicating that while there is increased awareness of the need for folic acid intake during pregnancy, most women in their childbearing years do not take folic acid supplements. For example, a recent March of Dimes poll of 1,000 women revealed only 32.2 percent take a daily folate supplement (another 12.2 percent take folic acid, but not every day).  Another study's researchers found that only 31.5 percent of 963 pregnant women had taken a folic acid supplement prior to conception, with that number increasing to only 38.1 percent during pregnancy. 
The NEJM study also suggests that while folate may help reduce the risk of birth defects, the levels found in most multivitamins (400 mcg) may be insufficient to offset the adverse effects of DFRIs. This is because, as mentioned earlier, women on DFRIs who supplemented with folic acid still had a greater incidence of birth defects than those who supplemented and were not on DFRIs. For this reason, and because adequate amounts of dietary folate are difficult to obtain, I recommend that sexually active women in their childbearing years take a higher-potency multivitamin/mineral supplement that provides 800 to 1,000 mcg folic acid per day.
Supplementing is most important during the first trimester, but ideally should begin prior to conception and continue throughout pregnancy. If a DFRI must be used during pregnancy, women should take 1,000 mcg folate per day. For women who have already had a neural-tube defect pregnancy, the U.S. Food and Drug Administration recommends 4 mg (i.e., 4,000 mcg) of folate daily. 
Because folic acid is most effective when taken with other nutrients, the most convenient supplement is a folate-containing multivitamin/mineral product. I recommend one that also has 50 to 100 mcg vitamin B12 and 15 mg zinc, because folic acid can sometimes exacerbate deficiencies of these nutrients.
David Wolfson, N.D., is a naturopathic physician, nutrition educator and consultant to the natural products industry.
1. Hernandez-Diaz S, et al. Folic acid antagonists during pregnancy and the risk of birth defects. NEJM 2000;343:1608-14.
2. No author listed. Many women remiss in taking folic acid. Clinician News 1997 Mar/Apr:18.
3. Mathews F, et al. Folates in the periconceptional period: are women getting enough? Br J Obstet Gynaecol 1998;105:954-9.
4. Combs GF, Jr. The vitamins, 2nd ed. San Diego: Academic Press; 1998. p. 398
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