Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, taken during the first trimester of pregnancy are not associated with an increased risk of major birth defects, according to a new study published May 14th in the open-access journal PLOS Medicine by Sharon Daniel of Ben-Gurion University of the Negev and Clalit Health Services, Beer-Sheva, Israel, and colleagues.
Pain and fever are common in early pregnancy and the options to manage them have been limited. Studies have raised safety concerns regarding acetaminophen while data on the safety of NSAIDs—which include widely used medications such as ibuprofen, diclofenac, and naproxen—has remained inconclusive.
The new study used data from the Southern Israeli Pregnancy Registry (SiPREG) to analyze 264,858 singleton pregnancies between 1998 and 2018, of which 20,202 (7.6%) were exposed to NSAIDs during the first trimester—most commonly ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%). Major congenital malformations were identified from linked clinical, hospitalization, and termination records. The researchers adjusted risks for maternal and pregnancy characteristics including maternal age, ethnicity, diabetes, obesity, folic acid use, and the reason for NSAID use.
NSAID exposure was not associated with major congenital malformations overall (8.2% vs. 7.0% in unexposed pregnancies; matched adjusted relative risk = 0.99), nor with malformations in specific organ systems including the cardiovascular, musculoskeletal, central nervous system, gastrointestinal, and genitourinary systems. No association was observed for any individual drug, and dose-response analyses found no significant link between cumulative NSAID exposure and birth defect risk.
"Our results provide reassuring evidence that NSAID use in early pregnancy is not associated with major birth defects," the authors say. "These findings can help both pregnant women and physicians make informed decisions about managing pain and fever in early pregnancy."
Dr. Daniel adds, "We used data from SiPREG, a large pregnancy registry in southern Israel that tracks medication use and pregnancy outcomes, including birth defects identified not only at birth, but also in pregnancy terminations and during the first year of life."
"We examined whether common pain relievers from the NSAID group, such as ibuprofen, are linked to birth defects. We found no increased risk overall or for specific types of birth defects."
Dr. Ariel Hasidim notes, "One of the most interesting parts of this research was finding a careful way to deal with gaps in real-world data. One key issue was that some people may have used common medicines like ibuprofen without it being recorded, which could affect the results. We tackled this head-on by using a special analysis to see whether and how this missing information might have influenced our findings."
In your coverage, please use this URL to provide access to the freely available paper in PLOS Medicine: https://plos.io/4mGgtZ9
Citation: Hasidim AA, Ben Shitrit I, Idan D, Michael T, Levy A, Pariente G, et al. (2026) First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study. PLoS Med 23(5): e1005063. https://doi.org/10.1371/journal.pmed.1005063
Author countries: Israel
Funding: The author(s) received no specific funding for this work.
