Use of trimethoprim-sulfamethoxazole during pregnancy and risk of spontaneous abortion: a nested case control study

Br J Clin Pharmacol. 2018 Jun;84(6):1198-1205. doi: 10.1111/bcp.13542. Epub 2018 Mar 25.


Aims: Data available on the fetal safety of trimethoprim-sulfamethoxazole (TMP-SMX) exposure during pregnancy remains scarce and inconclusive. A previous study assessing the link between TMP-SMX exposure during pregnancy and the risk of spontaneous abortion (SA) did not control for protopathic bias and indication bias.

Methods: We conducted a nested control study (n = 77 429 pregnancies including 7039 cases of SA and 70 390 controls) within the Quebec Pregnancy Cohort. For each case of SA, we selected 10 controls at the index date that were matched on gestational age and year of pregnancy. TMP-SMX exposure was defined as either having filled at least one prescription between the first day of gestation (1DG) and the index date, or as having filled a prescription before pregnancy but with a duration overlapping the 1DG (102 pregnancies exposed to TMP-SMX, including 25 cases of SA and 77 controls).

Results: Adjusting for potential confounders, TMP-SMX exposure was associated with an increased risk of SA (AOR 2.94, 95% C 1.89-4.57, 25 exposed cases). Similar results were found after controlling for indication bias and protopathic bias.

Conclusion: Given that this drug is widely use in HIV patients to prevent opportunistic infections and malaria, there is an urgent need to identify potential data sources in Africa for analysis of early pregnancy exposure to TMP-SMX.

Keywords: indication bias; pregnancy; protopathic bias; spontaneous abortion; trimethoprim-sulfamethoxazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abortion, Spontaneous / chemically induced*
  • Adolescent
  • Adult
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / adverse effects*
  • Case-Control Studies
  • Drug Combinations
  • Female
  • Gestational Age
  • Humans
  • Middle Aged
  • Pregnancy
  • Pregnancy Complications, Infectious / diagnosis
  • Pregnancy Complications, Infectious / drug therapy*
  • Pregnancy Complications, Infectious / microbiology
  • Quebec
  • Risk Assessment
  • Risk Factors
  • Sulfadoxine / administration & dosage
  • Sulfadoxine / adverse effects*
  • Treatment Outcome
  • Trimethoprim / administration & dosage
  • Trimethoprim / adverse effects*
  • Young Adult


  • Anti-Bacterial Agents
  • Drug Combinations
  • trimethoprim, sulfadoxine drug combination
  • Sulfadoxine
  • Trimethoprim