CMAJ • December 2, 2008; 179 (12). doi:10.1503/cmaj.080859.
© 2008 Canadian Medical Association or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.
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Research

Maternal exposure to folic acid antagonists and placenta-mediated adverse pregnancy outcomes

Shi Wu Wen, MB PhD, Jia Zhou, MB MSc, Qiuying Yang, MD PhD, William Fraser, MD MSc, Olufemi Olatunbosun, MD and Mark Walker, MSc MD

From the OMNI (Obstetrics, Maternal, and Neonatal Investigation) Research Group (Wen, Zhou, Yang, Walker), Department of Obstetrics and Gynecology, and the Department of Epidemiology and Community Medicine (Wen, Walker), Faculty of Medicine, University of Ottawa, Ottawa, Ont.; the Clinical Epidemiology Program (Wen, Zhou, Yang, Walker), Ottawa Health Research Institute, Ottawa, Ont.; the School of Public Health (Zhou), Central South University, Changsha, Hunan, China; the Department of Obstetrics and Gynecology (Fraser), Faculty of Medicine, Université de Montréal, Montréal, Que.; and the Department of Obstetrics and Gynecology (Olatunbosun), Faculty of Medicine, University of Saskatchewan, Saskatoon, Sask.

Correspondence to: Dr. Shi Wu Wen, OMNI Research Group, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Ottawa, 501 Smyth Rd., Box 241, Ottawa ON K1H 8L6; fax 613 739-6266; swwen{at}ohri.ca

Background: In previous studies, maternal exposure to folic acid antagonists was associated with increased risks of neural tube defects, cardiovascular defects, oral clefts and urinary tract defects. The objective of the current study was to assess the possible effects of using folic acid antagonists in pregnancy on placenta-mediated adverse outcomes of pregnancy.

Methods: We used data from an administrative database to retrospectively compare the occurrence of placenta-mediated adverse pregnancy outcomes between pregnant women exposed to folic acid antagonists and women without exposure to these agents.

Results: We included in the analysis a total of 14 982 women who had been exposed to folic acid antagonists and 59 825 women who had not been exposed. Sulfamethoxazole–trimethoprim was the most frequently prescribed dihydrofolate reductase inhibitor (a total of 12 546 exposures during the preconception period and all 3 trimesters), and phenobarbital was the most frequently prescribed among the other folic acid antagonists (a total of 1565 exposures). The risks of preeclampsia (adjusted odds ratio [OR] 1.52, 95% confidence interval [CI] 1.39–1.66), severe preeclampsia (OR 1.77, 95% CI 1.38–2.28), placental abruption (OR 1.32, 95% CI 1.12–1.57), fetal growth restriction defined as less than the 10th percentile (OR 1.07, 95% CI 1.01–1.13), fetal growth restriction defined as less than the 3rd percentile (OR 1.22, 95% CI 1.11–1.34) and fetal death (OR 1.35, 95% CI 1.07–1.70) were greater among mothers with exposure to folic acid antagonists. In general, the risks associated with exposure to other folic acid antagonists were higher than those associated with exposure to dihydrofolate reductase inhibitors. Supplementary analyses involving tight matching with propensity score, restriction of the analysis to women with exposure during the first and second trimesters and restriction of the analysis to specific categories of folic acid antagonists yielded similar results.

Interpretation: Maternal exposure to folic acid antagonists appears to increase the risk of placenta-mediated adverse outcomes of pregnancy.


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