title: Maternal exposure to folic acid antagonists and placenta-mediated adverse pregnancy outcomes.
abstract: 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.
  
  
  CONCLUSIONS
  Maternal exposure to folic acid antagonists appears to increase the risk of placenta-mediated adverse outcomes of pregnancy.
authors.affiliation: University of Ottawa, Ont., Canada. swwen@ohri.ca
authors.forename: Shi Wu
authors.initials: SW
authors.lastname: Wen
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Yang
authors.forename: William
authors.initials: W
authors.lastname: Fraser
authors.forename: Olufemi
authors.initials: O
authors.lastname: Olatunbosun
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
mesh_terms: D000037:Abruptio Placentae / Q000139:chemically induced; D000328:Adult; D015331:Cohort Studies; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D005317:Fetal Growth Retardation / Q000139:chemically induced; D005493:Folic Acid Antagonists / Q000009:adverse effects*; D006801:Humans; D018811:Maternal Exposure / Q000009:adverse effects; D010634:Phenobarbital / Q000009:adverse effects; D010920:Placenta / Q000187:drug effects*; D011225:Pre-Eclampsia / Q000139:chemically induced; D011247:Pregnancy; D011256:Pregnancy Outcome / Q000453:epidemiology*; D012189:Retrospective Studies; D012525:Saskatchewan / Q000453:epidemiology; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects; D055815:Young Adult
chemical_list: D005493:Folic Acid Antagonists; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D010634:Phenobarbital