title: Trimethoprim use before pregnancy and risk of congenital malformation: reanalyzed using a case-crossover design and a case-time-control design.
abstract: OBJECTIVE
  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.
authors.affiliation: Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Yuelian
authors.initials: Y
authors.lastname: Sun
authors.forename: Chun Sen
authors.initials: CS
authors.lastname: Wu
authors.forename: Jørn
authors.initials: J
authors.lastname: Olsen
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000453:epidemiology / Q000209:etiology; D016022:Case-Control Studies; D018592:Cross-Over Studies; D003718:Denmark / Q000453:epidemiology; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000453:epidemiology; D014295:Trimethoprim / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D014295:Trimethoprim
keywords: antibiotics; case-crossover design; case-time-control design; congenital malformation; pharmacoepidemiology; trimethoprim