Background: Existing data on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during late pregnancy is well established, providing assurance. However, the use of NSAIDs during early pregnancy remains inconclusive owing to conflicting findings on adverse neonatal outcomes as well as the limited data on adverse maternal outcomes. Therefore, we sought to investigate whether early prenatal exposure to NSAIDs was associated with neonatal and maternal adverse outcomes.

Methods and findings: We conducted a nationwide, population-based cohort study using Korea's National Health Insurance Service (NHIS) database with a mother-offspring cohort constructed and validated by the NHIS to include all live births in women aged 18 to 44 years between 2010 and 2018. We defined exposure to NSAIDs as at least two records of NSAID prescriptions during early pregnancy (first 90 days of pregnancy for congenital malformations and first 19 weeks for nonmalformation outcomes) and compared against three distinct referent groups of (1) unexposed, no NSAID prescription during the 3 months before pregnancy start to end of early pregnancy; (2) acetaminophen-exposed, at least two acetaminophen prescriptions during early pregnancy (i.e., active comparator); and (3) past users, at least two NSAID prescriptions before the start of pregnancy but no relevant prescriptions during pregnancy. Outcomes of interest were adverse birth outcomes of major congenital malformations and low birth weight and adverse maternal outcomes of antepartum hemorrhage and oligohydramnios. We estimated relative risks (RRs) with 95% CIs using generalized linear models within a propensity score (PS) fine stratification weighted cohort that accounted for various potential confounders of maternal sociodemographic characteristics, comorbidities, co-medication use, and general markers of burden of illness. Of 1.8 million pregnancies in the PS weighted analyses, exposure to NSAIDs during early pregnancy was associated with slightly increased risks for neonatal outcomes of major congenital malformations (PS-adjusted RR, 1.14 [CI, 1.10 to 1.18]) and low birth weight (1.29 [1.25 to 1.33]), and for maternal outcome of oligohydramnios (1.09 [1.01 to 1.19]) but not antepartum hemorrhage (1.05 [0.99 to 1.12]). The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs against acetaminophen or past users. Risks of adverse neonatal and maternal outcomes were higher with cyclooxygenase-2 selective inhibitors or use of NSAIDs for more than 10 days, whereas generally similar effects were observed across the three most frequently used individual NSAIDs. Point estimates were largely consistent across all sensitivity analyses, including the sibling-matched analysis. Main limitations of this study are residual confounding by indication and from unmeasured factors.

Conclusions: This large-scale, nationwide cohort study found that exposure to NSAIDs during early pregnancy was associated with slightly higher risks of neonatal and maternal adverse outcomes. Clinicians should therefore carefully weigh the benefits of prescribing NSAIDs in early pregnancy against its modest, but possible, risk of neonatal and maternal outcomes, where if possible, consider prescribing nonselective NSAIDs for <10 days, along with continued careful monitoring for any safety signals.