Study Offers Cautious Reassurance on First-Trimester NSAID Use and Congenital Malformation Risk
Key Insights
A large Israeli population-based cohort study found no statistically significant adjusted association between first-trimester NSAID exposure and major congenital malformations (search) overall or by organ system.
After propensity score matching and G-computation adjustment, the elevated unadjusted malformation rates in NSAID-exposed pregnancies (8%) versus unexposed (7%) were no longer significant.
Drug-specific analyses for ibuprofen, diclofenac, naproxen, etodolac, and indomethacin returned null results, though indomethacin data were limited by small sample size (287 pregnancies).
A large retrospective cohort study published in PLOS Medicine (search) has found no adjusted association between first-trimester exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) and major congenital malformations (search), providing cautious reassurance for clinicians managing pain, inflammation, and fever in early pregnancy at a time when analgesic counseling has grown increasingly complex.
The study, conducted by Hasidim and colleagues using data from the Southern Israeli Pregnancy Registry, analyzed 264,858 singleton pregnancies between 1998 and 2018. First-trimester NSAID exposure was defined using pharmacy dispensation records from the first day of the last menstrual period through the end of gestational week 13, with major congenital malformations (search) identified through linked clinical, hospitalization, and pregnancy-termination records through the child's first year of life.
Overall, approximately 8% (n = 20,202) of pregnancies had first-trimester NSAID exposure. Ibuprofen was the most commonly dispensed agent, identified in 5% (n = 13,627) of pregnancies, followed by diclofenac in 2% (n = 4,334) and naproxen in 1% (n = 3,105). Etodolac, indomethacin, piroxicam, and lornoxicam were less commonly dispensed.
Unadjusted Findings and Adjusted Results
In unadjusted analyses, major congenital malformations (search) were more common in NSAID-exposed pregnancies compared with unexposed pregnancies — approximately 8% (n = 1,651) versus 7% (n = 16,998). However, after generalized full matching and adjustment for maternal and pregnancy characteristics, including clinical indications for NSAID use, the association was no longer statistically significant.
Null findings were observed across all organ-system categories, including cardiovascular, musculoskeletal, central nervous system, gastrointestinal, and genitourinary malformations. Drug-specific analyses did not identify statistically significant associations between ibuprofen, diclofenac, naproxen, etodolac, or indomethacin and major congenital malformations (search). However, indomethacin exposure was identified in just 287 pregnancies, and the matched adjusted relative risk for any major congenital malformation was 1.76. The investigators could not reliably determine a clinically meaningful indomethacin-specific risk.
Dose-Response Analysis
The investigators also examined dose-response relationships. The prevalence of major congenital malformations (search) was 8.2% among short-term NSAID users (1 to 7 defined daily doses), 8.6% among medium-term users (8 to 21 defined daily doses), and 9.3% among long-term users (more than 21 defined daily doses), compared with 7.0% in the unexposed group. Adjusted analyses did not show a statistically significant association across these categories, though the long-term point estimate was 1.24, indicating greater uncertainty with higher cumulative dispensing.
Methodological Strengths
The study employed several methodological advances. Investigators used directed acyclic graphs to guide covariate selection, generalized full matching to improve balance between exposed and unexposed pregnancies, and G-computation to estimate adjusted relative risk. The inclusion of elective pregnancy terminations for fetal malformations was notable because birth-only cohorts may miss severe anomalies detected prenatally. Follow-up through the first year of life also increased the likelihood of identifying malformations diagnosed after birth. The analytical code was made publicly available on GitHub.
Limitations and Caveats
Several limitations warrant careful interpretation. NSAID exposure was based on drug dispensation rather than confirmed ingestion, and some over-the-counter ibuprofen use may not have been captured. Sensitivity analyses suggested that plausible levels of unrecorded exposure were unlikely to materially change the results. The study also did not capture spontaneous abortions — a clinically important gap given that data on early-pregnancy NSAID exposure and miscarriage remains mixed, with some studies reporting increased risks and others reporting elevated but statistically insignificant associations.
The study population included a large proportion of Bedouin women, comprising 77% of NSAID-exposed pregnancies and 53% of unexposed pregnancies. The investigators adjusted for ethnicity and noted that the Bedouin population has distinct demographic and social characteristics, including historically higher rates of consanguinity, which could be relevant when applying results to other populations.
Perspective and Clinical Implications
In an accompanying Perspective published in PLOS Medicine (search), authors Andrew S. C. Yuen and Kenneth K. C. Man described the findings as "clinically meaningful and reassuring, but not definitive." They emphasized a persistent challenge in perinatal pharmacoepidemiology: analgesic use during pregnancy is often intermittent, sequential, and tied to evolving symptoms.
The Perspective authors cautioned against extrapolating the results beyond the specific outcome studied. The study did not resolve questions about miscarriage, low birth weight, oligohydramnios, neurodevelopmental outcomes, or later-pregnancy NSAID risks. NSAID-related fetal renal and ductal risks later in pregnancy remain well recognized, particularly after 20 weeks' gestation.
They also noted that a previous nationwide South Korean cohort study reported modestly increased risks of major congenital malformations (search) associated with early-pregnancy NSAID exposure and higher risks of low birth weight and oligohydramnios — outcome domains the Israeli cohort did not examine.
For clinicians, the practical message is one of cautious reassurance, particularly for short-course first-trimester exposure. As the Perspective authors concluded: "NSAIDs are not the teratogenic villains some feared, but neither are they unambiguously safe; the honest answer to a pregnant patient asking which analgesic to take is that the evidence is improving but still incomplete."
The counseling challenge remains that untreated pain, inflammation, and fever may also carry risks. The findings support individualized, indication-specific counseling in early pregnancy, with decisions grounded in shared communication about the trade-offs between drug exposure and undertreated maternal disease rather than categorical reassurance or categorical avoidance.