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

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. Copyright © 2014 John Wiley & Sons, Ltd.