Summary: A large, population-based study finds reassuring evidence for pregnant women: taking nonsteroidal anti-inflammatory drugs (NSAIDs) during the first trimester is not linked to an increased risk of major birth defects.
Researchers examined data from more than 260,000 singleton pregnancies and found no meaningful association between first-trimester exposure to common NSAIDs—such as ibuprofen, diclofenac, or naproxen—and major congenital malformations. These results help fill an important gap in prenatal care guidance for managing pain and fever in early pregnancy.
Key Facts
- No Increased Risk: First-trimester NSAID exposure was not associated with a higher overall risk of major congenital malformations (matched adjusted relative risk = 0.99).
- System-Specific Findings: No increased risk was observed for malformations of the cardiovascular, musculoskeletal, central nervous, gastrointestinal, or genitourinary systems.
- Individual Drug Findings: No specific association emerged for the most commonly used NSAIDs in the cohort: ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%).
- Dose-Response Analysis: Cumulative NSAID exposure showed no clear dose-response relationship with the risk of birth defects.
Source: PLOS Medicine
Nonsteroidal anti-inflammatory drugs (NSAIDs) taken in the first trimester—examples include ibuprofen and naproxen—were not associated with an increased risk of major birth defects, according to a study published in PLOS Medicine. The research was led by Sharon Daniel of Ben-Gurion University of the Negev and Clalit Health Services, Beer-Sheva, Israel, together with colleagues using the Southern Israeli Pregnancy Registry (SiPREG).
Pain and fever are common during early pregnancy, and safe treatment options have been limited. While some studies have raised concerns about acetaminophen, evidence around NSAIDs has been inconsistent. This large retrospective cohort study provides stronger evidence to guide clinicians and pregnant people weighing the risks and benefits of short-term NSAID use in early pregnancy.
The researchers analyzed 264,858 singleton pregnancies recorded in SiPREG between 1998 and 2018. Of these, 20,202 pregnancies (7.6%) had pharmacy-documented exposure to NSAIDs during the first trimester, with ibuprofen, diclofenac, and naproxen the most frequently dispensed agents. Major congenital malformations (MCMs) were identified through linked clinical, hospitalization, and termination records and were tracked through the first year of life.
To reduce confounding, the analysis adjusted for a comprehensive set of maternal and pregnancy characteristics: maternal age, ethnicity, diabetes, obesity, smoking, folic acid use, number of previous pregnancies (gravidity), the medical indication for NSAID use, exposure to other antipyretics, perinatal care, and year of pregnancy. Propensity score matching and generalized full matching techniques balanced covariates between exposed and unexposed groups, and weighted Poisson regression with G-computation produced adjusted risk ratios.
Overall rates of major congenital malformations were similar between exposed and unexposed pregnancies (8.2% vs. 7.0%). The matched-adjusted relative risk for any major malformation after first-trimester NSAID exposure was 0.99 (95% CI 0.90–1.10), indicating no meaningful increase in risk. Organ-system specific analyses likewise showed no significant associations for cardiovascular, musculoskeletal, central nervous system, cleft palate, gastrointestinal, or genitourinary malformations.
Dose–response analyses that categorized cumulative exposure by defined daily doses (DDDs) — short-term (1–7 DDD), medium-term (8–21 DDD), and long-term (>21 DDD) — revealed no statistically significant link to increased MCM risk, although confidence intervals were wider for longer exposures. The authors acknowledge a limitation: over-the-counter availability of some NSAIDs (especially ibuprofen) could lead to minor exposure misclassification. They conducted sensitivity and tipping-point analyses to evaluate the potential impact of unrecorded OTC use and found it unlikely to meaningfully change the conclusions.
Lead author Sharon Daniel emphasized that the study benefits from the comprehensive SiPREG registry, which captures medication dispensations and tracks congenital anomalies identified at birth, in pregnancy terminations, and during the first postnatal year. Co-author Ariel Hasidim highlighted the study’s careful handling of incomplete real-world data, including sensitivity analyses designed to assess the influence of potentially missing medication records.
Frequently Asked Questions
Q: Can I take ibuprofen (Advil) for a fever in the first trimester?
A: The study offers reassuring evidence that common NSAIDs like ibuprofen used in early pregnancy were not linked to an increased risk of major birth defects. However, medication decisions during pregnancy should always be discussed with your clinician, who can consider your individual health needs and alternatives.
Q: Why was this large study necessary?
A: Previous research on NSAID safety in early pregnancy was limited or inconclusive. Given rising concerns about other pain relievers and the frequent need to treat fever and pain, a robust, population-level analysis helps clinicians and patients make more informed choices.
Q: How did researchers ensure reliable results?
A: The study used a large, linked registry (SiPREG) that documents pharmacy dispensations and tracks outcomes beyond birth. The authors applied advanced matching and regression methods and ran sensitivity analyses to address unrecorded over-the-counter medication use.
Editorial Notes
- This article was edited by a Neuroscience News editor.
- The underlying journal paper was reviewed in full by editorial staff.
- Additional context and explanation were added to help readers interpret the findings.
About this research report
Author: Claire Turner
Source: PLOS Medicine
Contact: Claire Turner – PLOS
Image: Image credit: Neuroscience News
Original Research: Open access. “First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study” by Ariel Avraham Hasidim, Itamar Ben Shitrit, Daphna Idan, Tal Michael, Amalia Levy, Gali Pariente, Eitan Lunenfeld, and Sharon Daniel. DOI: 10.1371/journal.pmed.1005063
Abstract (condensed)
Background
Pain and fever frequently occur in early pregnancy, yet safe management options are limited and evidence about NSAID safety has been inconclusive. This study evaluated whether first-trimester NSAID exposure is associated with major congenital malformations (MCMs) using a large population-based cohort.
Methods
The retrospective cohort included all singleton pregnancies of women aged 15–45 years recorded in the Southern Israeli Pregnancy Registry (SiPREG) from 1998–2018. Exposures were defined by pharmacy dispensations during the first trimester; outcomes were major congenital malformations identified through clinical, hospitalization, and termination records up to one year after birth. The analysis excluded pregnancies with known teratogen exposure, multiple gestations, or documented genetic anomalies. Advanced matching and regression techniques adjusted for multiple confounders, and sensitivity analyses examined dose-response and possible misclassification from unrecorded over-the-counter NSAID use.
Findings
Among 264,858 pregnancies, 20,202 (7.6%) had documented NSAID exposure in the first trimester. No association was found between NSAID exposure and MCMs overall (matched adjusted RR = 0.99, 95% CI 0.90–1.10) or for specific organ-system defects. Dose–response analyses did not reveal a clear link between cumulative exposure and MCMs. Sensitivity checks suggested that unrecorded over-the-counter use would be unlikely to materially change the results.
Conclusion
In this extensive, population-based cohort, first-trimester NSAID exposure was not associated with major congenital malformations. These findings provide reassuring evidence about the fetal safety of short-term NSAID use in early pregnancy, while underscoring the importance of individualized clinical advice.