Trimethoprim use before pregnancy and risk of congenital malformation: reanalyzed using a case-crossover design and a case-time-control design

Pharmacoepidemiol Drug Saf. 2014 Oct;23(10):1076-83. doi: 10.1002/pds.3691. Epub 2014 Aug 11.


Purpose: Studies on the safety of drugs used during pregnancy are necessary and important but prone to bias. Using cases as their own controls can reduce bias. We used a case-crossover design and a case-time-control design to estimate the risk of congenital malformation (CM) for children born to mothers who redeemed a trimethoprim prescription shortly before pregnancy.

Methods: The study was based on all live born singletons (N = 685 600) in Denmark whose mothers had available information on prescriptions in the Danish National Prescription Registry between 1996 and 2008. We defined 1-3 months before pregnancy as a potential risk period and 13-15 months before pregnancy as a reference period. Two other reference periods were used (7-9 months before pregnancy and months 4-6 of pregnancy). The case-crossover design is dependent on the assumption of a stable trimethoprim prescription over the study period in the source population. To estimate the trend of trimethoprim prescriptions, we used a control group comprising children without CMs.

Results: Both study designs showed children had a higher risk of overall CM [odds ratio of 1.66, 95% confidence interval (CI): 1.10-2.53 and 1.50, 95%CI: 0.66-3.38, respectively] if their mothers had a trimethoprim prescription in the 3 months before pregnancy and subtypes of CM for example in the musculoskeletal system, which were consistent to the previous findings from a cohort study.

Conclusions: This study corroborates that trimethoprim is a potential teratogen when used 3 months before pregnancy and demonstrates the value of case-only approaches for studying, for example, adverse effects of antibiotics in reproductive epidemiology.

Keywords: antibiotics; case-crossover design; case-time-control design; congenital malformation; pharmacoepidemiology; trimethoprim.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced* / epidemiology
  • Abnormalities, Drug-Induced* / etiology
  • Case-Control Studies
  • Cross-Over Studies
  • Denmark / epidemiology
  • Electronic Health Records
  • Female
  • Humans
  • Infant, Newborn
  • Pregnancy
  • Prenatal Exposure Delayed Effects* / chemically induced
  • Prenatal Exposure Delayed Effects* / epidemiology
  • Trimethoprim / administration & dosage
  • Trimethoprim / adverse effects*
  • Trimethoprim / therapeutic use


  • Trimethoprim