Exposure to Systemic Antimicrobials During Pregnancy and Risk of Miscarriage: A Population‐Based Registry Study

ABSTRACT

Objective

To estimate miscarriage risk following gestational antimicrobial exposure while addressing biases that have affected previous studies.

Design

Population-based cohort study.

Setting

Linkage of four nationwide registries: Medical Birth Registry of Norway (MBRN), Norwegian Prescribed Drug Registry (NorPD), Norwegian Patient Registry (NPR) and Norwegian Control and Payment of Health Reimbursements Database (KUHR).

Population or Sample

A total of 704 082 pregnancies (2009–2018), with 91 836 (13.0%) exposed to systemic antimicrobials in early pregnancy.

Methods

Time-stratified Cox regression models with overlap weights were used, considering time-varying exposures and a 14-day lag to prevent reverse causation. Elective terminations were right-censored to address competing risks, with adjustment for common infections and probabilistic bias analysis for confounding by indication.

Main Outcome Measures

Miscarriage and gestational age at miscarriage, captured from NPR, KUHR and MBRN, using the UiO pregnancy algorithm.

Results

Nitrofurantoin, pivmecillinam and amoxicillin were not associated with increased miscarriage risk. Metronidazole (HR = 2.00; 95% CI: 1.82–2.21), ciprofloxacin (HR = 1.89; 95% CI: 1.62–2.20), cephalexin (HR = 1.87; 95% CI: 1.57–2.22), fluconazole (HR = 1.61; 95% CI: 1.45–1.78), trimethoprim-sulfas (HR = 1.49; 95% CI: 1.36–1.63) and others showed associations with miscarriage. Probabilistic bias analysis indicated that associations for common antimicrobials may be driven by the underlying infections.

Conclusions

Nitrofurantoin, pivmecillinam and amoxicillin did not increase miscarriage risk, but other less commonly used antimicrobials may carry higher risks. By addressing key biases, this study provided a more reliable assessment of miscarriage risks associated with antimicrobial use in early pregnancy.