Association of Non-Steroidal Anti-Inflammatory Drug Use during Pregnancy and Miscarriage: A Norwegian Registry Linkage Study

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications to treat fever, pain, and inflammation. Multiple studies indicate that NSAID use during pregnancy might increase the risk of miscarriage, but it remains unclear whether risks vary by timing and type of NSAID use.

Objectives: To assess the association between NSAID use during pregnancy and the risk of miscarriage overall, and according to timing of use and chemical subgroup.

Methods: The study population included pregnancies in Norway in 2008-2018, identified by the recently developed UiO pregnancy algorithm using linked population-based data from the Medical Birth Registry of Norway (MBRN) and the Norwegian primary (KUHR) and secondary (NPR) healthcare registries. Information on NSAID prescription fills was obtained from the Norwegian Prescription Database (NorPD) with a grace period of 14 days. We estimated hazard ratios (HR) with 95% confidence intervals (CI) to account for time-varying exposure and outcome using cause-specific hazard models considering the competing risk of elective terminations. Overlap propensity score weighting was used to adjust for confounding.

Results: We identified 746,738 pregnancies, of which 23,899 (3.2%) had an NSAID prescription fill in the first 18 weeks of gestation. Among pregnancies with NSAID prescription fills, 4,091 (17.1%) ended in a miscarriage, whereas miscarriages occurred in 94,403 (12.8%) of unexposed pregnancies. Any use of NSAIDs in early pregnancy was associated with an increased rate of miscarriage (weighted HR 1.69, 95% CI 1.64-1.75). Rates were increased for all chemical subgroups, including acetic acid derivatives (weighted HR 1.94, 95% CI 1.85-2.03), coxibs (weighted HR 1.74, 95% CI 1.52-1.99), propionic acid derivatives (weighted HR 1.54, 95% CI 1.47-1.61), and oxicams (weighted HR 1.53, 95% CI 1.29-1.82). Risk estimates were highest for NSAID use in gestational weeks 7-10, reflecting to miscarriages in gestational week 9 onwards. We did not observe associations between NSAID use after gestational week 10 and miscarriages.

Conclusions: In this population-based study tackling multiple methodological challenges related to studying miscarriage as an outcome, NSAID use in early pregnancy was associated with an increased risk of miscarriages. These results may further improve benefit-risk assessment for pregnant persons who have an indication for NSAIDs.