Exposure to folic acid antagonists during the first trimester of pregnancy and the risk of major malformations

Br J Clin Pharmacol. 2009 Dec;68(6):956-62. doi: 10.1111/j.1365-2125.2009.03544.x.


What is already known about this subject: * Previous studies have suggested a tendency of antifolate drugs to be associated with higher rates of neural tube defects.

What this study adds: * This study makes use of the data on abortuses, which is missed in many other studies. In this case, the abortion data were critical. * The study documents that clinicians should avoid, as much as possible, the use of folic acid antagonists during the first trimester of pregnancy, when embryogenesis takes place.

Aim: To investigate the safety of folic acid antagonists during the first trimester of pregnancy in a large cohort.

Methods: Computerized databases for medications dispensed from 1998 to 2007 to women registered in 'Clalit' HMO, Israel southern district, was linked with maternal and infant hospitalization records, and to therapeutics abortions data. The risk for adverse pregnancy outcomes of folic acid antagonists exposure was assessed by adjusting for known confounders.

Results: Eighty-four thousand, eight hundred and twenty-three infants were born and 998 therapeutic abortions took place; 571 fetuses and infants were exposed to one or more folic acid antagonists in the first trimester of pregnancy. Exposure was associated with an overall increased risk of congenital malformations [odds ratio (OR) 2.43, 95% confidence interval (CI) 1.92, 3.08], due mainly to increased risk for neural tube (adjusted OR 6.5, 95% CI 4.34, 9.15) and cardiovascular defects (OR 1.76, CI 1.05, 2.95).

Conclusion: First-trimester exposure to folic acid antagonists is associated with increased risk of congenital malformations.

MeSH terms

  • Abnormalities, Drug-Induced / etiology*
  • Adolescent
  • Adult
  • Cohort Studies
  • Databases as Topic
  • Female
  • Folic Acid Antagonists / adverse effects*
  • Humans
  • Infant, Newborn
  • Israel
  • Middle Aged
  • Pregnancy
  • Pregnancy Outcome
  • Pregnancy Trimester, First
  • Regression Analysis
  • Retrospective Studies
  • Risk Factors
  • Young Adult


  • Folic Acid Antagonists