A comprehensive new study published in the open-access journal PLOS Medicine offers reassuring evidence regarding the safety of nonsteroidal anti-inflammatory drugs (NSAIDs) during early pregnancy. Contrary to prior uncertainties, researchers from Ben-Gurion University of the Negev and Clalit Health Services in Israel found no association between first-trimester use of NSAIDs—such as ibuprofen, naproxen, and diclofenac—and an increased risk of major congenital malformations. This study, led by Dr. Sharon Daniel and her team, represents one of the largest observational investigations to date focusing on real-world medication exposure during a critical window of fetal development.
Pain management in early pregnancy is a challenging clinical issue, given the limited pharmacological options available that are both safe and effective. Pregnant women frequently encounter symptoms such as headache, muscle pain, and fever, conditions typically treated with over-the-counter NSAIDs. Despite their widespread use, prior studies have been inconclusive or raised concerns due to methodological limitations or incomplete data recording. Acetaminophen, another common analgesic, has also been scrutinized for potential risks, further complicating therapeutic decisions for clinicians and expectant mothers alike.
The research harnessed an extensive data set from the Southern Israeli Pregnancy Registry (SiPREG), a robust database that includes medical information on over 260,000 singleton pregnancies recorded between 1998 and 2018. In this cohort, approximately 7.6% of pregnancies involved NSAID exposure during the first trimester. The investigators meticulously identified medications used, focusing primarily on ibuprofen (5.1% exposure), diclofenac (1.6%), and naproxen (1.2%). To ensure analytical rigor, the study adjusted for confounding factors such as maternal age, ethnicity, presence of diabetes or obesity, folic acid intake, and the medical reason for NSAID use.
Major congenital malformations were monitored via integrated clinical records, hospitalization databases, and records from pregnancy terminations, allowing for detection beyond live births. The statistical analysis revealed that the prevalence of major birth defects among NSAID-exposed pregnancies was not significantly different from that in unexposed pregnancies—8.2% versus 7.0%, respectively. The adjusted relative risk was effectively neutral at 0.99, indicating no increased risk attributable to NSAID exposure. Furthermore, no elevated risk was identified for specific organ system malformations encompassing the cardiovascular, musculoskeletal, central nervous system, gastrointestinal, or genitourinary systems.
Delving deeper into drug-specific effects, the study found no evidence linking individual NSAIDs to increased teratogenicity. Dose-response analyses also failed to identify any relationship between cumulative NSAID exposure and congenital anomalies, further reinforcing the overall safety profile. This comprehensive epidemiological evidence thus challenges prior concerns and supports the therapeutic use of NSAIDs in early pregnancy when clinically indicated.
The authors situate these findings within the context of clinical decision-making, emphasizing how the absence of an observed association between NSAIDs and birth defects provides crucial information for health care providers and pregnant women. Dr. Daniel underscores the importance of reliable registry data that captures medication use comprehensively, including use recorded during pregnancy terminations and during the first year of life post-delivery, to avoid underestimation of risks. This study’s design addresses previous gaps in real-world data, a pivotal advance in perinatal pharmacoepidemiology.
Addressing methodological challenges inherent in observational registry-based research, co-author Dr. Ariel Hasidim highlights the innovative strategies employed to account for unrecorded over-the-counter NSAID use. Such unmeasured exposures might otherwise bias results and lead to misclassification. By applying sensitivity analyses and other robustness checks, the researchers ensured that their findings remain valid even in the presence of incomplete exposure data, lending further credibility to the conclusions.
This work arrives at a time when discussions about medication safety in pregnancy are particularly pertinent. With escalating concerns over the safety profiles of analgesics such as acetaminophen and widespread NSAID use globally, this study brings clarity to a critical clinical dilemma. The data suggest that when pregnant women require pharmacological intervention for pain or fever during the first trimester, commonly used NSAIDs may be considered without heightened fear of major birth defects.
Moreover, the study’s scale and comprehensive approach set a benchmark for future research in this domain. The large sample size, rigorous adjustment for confounders, and reliance on linked clinical data enhance confidence in the findings. These data not only affirm NSAIDs’ safety but also demonstrate the value of pregnancy registries that capture longitudinal medication exposure and outcomes comprehensively.
In summary, the research conducted by Daniel and colleagues represents a major contribution to our understanding of medication safety in early pregnancy. It paves the way for evidence-based recommendations around analgesic use, alleviating long-standing concerns that have left many clinicians and patients uncertain. As such, these findings will likely influence guidelines and clinical practice, empowering more informed and confident management of pain and fever in early gestation.
The absence of a significant association between NSAIDs and congenital anomalies underscores the need for healthcare professionals to weigh risks and benefits based on robust data. Rather than avoiding NSAIDs outright out of precaution, physicians can consider these agents a viable option when necessary. Continued surveillance and research will remain crucial, but for now, this study provides much-needed reassurance grounded in rigorous, real-world evidence.
This breakthrough also exemplifies the power of large-scale real-world data registries in resolving complex questions at the intersection of pharmacology, obstetrics, and public health. By leveraging diverse data sources including clinical records and birth defect registries, the authors have set a new gold standard for studying drug safety during pregnancy—an area where randomized controlled trials are often unfeasible or ethically challenging.
With widespread NSAID use and millions of pregnancies occurring worldwide annually, these findings have significant implications. They help demystify the risks of a common and important class of medications, ultimately supporting safer and more effective clinical decision-making in a vulnerable population. The publication of this exhaustive study in a high-impact journal like PLOS Medicine ensures its findings will reach a wide research and clinical audience, contributing substantially to maternal and fetal health knowledge.
Subject of Research: People
Article Title: First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study
News Publication Date: May 14, 2026
Web References: http://dx.doi.org/10.1371/journal.pmed.1005063
References: 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.
Image Credits: Dr. Sharon Daniel and colleagues (CC-BY 4.0)
Keywords: NSAIDs, pregnancy, birth defects, ibuprofen, first trimester, congenital malformations, safety, pharmacoepidemiology, observational study
