Summary: A large, population-based study provides reassuring evidence for pregnant women: taking nonsteroidal anti-inflammatory drugs (NSAIDs) in the first trimester does not appear to increase the risk of major birth defects.
Researchers examined 264,858 singleton pregnancies recorded in the Southern Israeli Pregnancy Registry (SiPREG) from 1998 to 2018. Of these, 20,202 pregnancies (7.6%) had documented first-trimester exposure to NSAIDs—most commonly ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%). After adjusting for maternal and pregnancy factors, the study found no meaningful association between first‑trimester NSAID exposure and major congenital malformations overall or within specific organ systems.
Key Facts
- No increased overall risk: Major congenital malformation rates were similar between exposed and unexposed pregnancies (8.2% vs. 7.0%), yielding a matched adjusted relative risk of 0.99.
- No organ‑system signal: Analyses showed no significant association with cardiovascular, musculoskeletal, central nervous system, gastrointestinal, or genitourinary malformations.
- Individual agents: Common NSAIDs—ibuprofen, diclofenac, and naproxen—were not individually linked to higher risk in this cohort.
- No dose–response effect: Cumulative exposure categories (short, medium, long duration) did not show a consistent increase in malformation risk.
Source: PLOS Medicine (study published May 14)
Pain and fever occur frequently in early pregnancy, but treatment choices have been limited by concern about fetal safety. While some prior studies raised questions about acetaminophen, evidence about NSAID safety in the first trimester remained unclear. This retrospective register-based cohort study addressed that gap by leveraging detailed registry records that link pharmacy dispensations, clinical and hospital records, pregnancy terminations, and diagnoses during the first postnatal year.
Major congenital malformations (MCMs) were identified from linked clinical, hospitalization, and termination records. The investigators adjusted analyses for multiple potential confounders, including maternal age, ethnicity, diabetes, obesity, smoking, folic acid use, gravidity, perinatal care level, calendar year, and the clinical indication for NSAID use. To reduce bias from differences between exposed and unexposed pregnancies, the study used propensity scores and generalized full matching, followed by weighted Poisson regression with robust standard errors.
Overall, NSAID exposure during the first trimester was not associated with an increased risk of MCMs (matched adjusted relative risk = 0.99; 95% CI [0.90, 1.10]). Organ‑system specific analyses similarly found no elevated risks: cardiovascular (matched-aRR = 1.05), musculoskeletal (matched-aRR = 1.03), central nervous system (matched-aRR = 0.77), cleft palate (matched-aRR = 0.95), gastrointestinal (matched-aRR = 1.03), and genitourinary (matched-aRR = 0.99). Dose–response assessments across defined daily dose categories also did not demonstrate a clear link between cumulative NSAID use and malformation risk.
The authors note a key limitation: over-the-counter availability of some NSAIDs, especially ibuprofen, could cause minor exposure misclassification if use was not recorded in pharmacy dispensation data. The study included sensitivity and tipping‑point analyses to assess how unrecorded use might affect results; these analyses suggested that modest levels of unrecorded use would not meaningfully change the conclusions.
Lead author Sharon Daniel and colleagues conclude that their findings offer reassuring evidence that first‑trimester NSAID use is not associated with major congenital malformations. They emphasize that these results can support informed decision‑making between pregnant women and their clinicians when managing pain and fever in early pregnancy. The registry’s comprehensive tracking of outcomes—covering births, pregnancy terminations, and the first postnatal year—strengthens confidence in the findings.
Frequently Asked Questions
A: This study provides reassuring evidence that common NSAIDs such as ibuprofen were not associated with an increased risk of major birth defects when used in the first trimester. However, pregnant women should always consult their healthcare provider before taking any medication.
A: Prior evidence about NSAID safety in early pregnancy was limited and sometimes conflicting. Large, well‑controlled population studies help clarify whether commonly used medications pose fetal risks and guide safer clinical practice.
A: Researchers used sensitivity and tipping‑point analyses to model the possible effects of unrecorded over‑the‑counter NSAID use, finding that such misclassification would have to be substantial to change the main findings.
Editorial Notes
- Edited by a Neuroscience News editor.
- Journal paper reviewed in full by the editorial team.
- Additional context and explanation provided by staff.
About this research
Author: Claire Turner (reporting for PLOS)
Source: PLOS Medicine
Contact: Claire Turner – PLOS
Image: Image credit: Neuroscience News
Abstract
Title: First‑trimester nonsteroidal anti‑inflammatory drugs exposure and risk of major congenital malformations: A retrospective register‑based cohort study
Background
Pain and fever in early pregnancy present common clinical challenges. While concerns have been raised about certain analgesics, the safety profile of NSAIDs during the first trimester was not definitively established. This study assessed whether first‑trimester NSAID exposure is associated with major congenital malformations in a large, population‑based cohort.
Methods and findings
Using the SiPREG registry, the investigators included 264,858 singleton pregnancies resulting in live births, stillbirths, or terminations for fetal anomalies between 1998 and 2018. Pregnancies with exposure to known teratogens, multiple gestations, or documented genetic anomalies were excluded. First‑trimester NSAID exposure was defined by pharmacy dispensations and categorized by specific agents and cumulative defined daily doses (DDD).
Propensity score methods and generalized full matching balanced covariates such as maternal age, ethnicity, medical indications for NSAID use, exposure to other antipyretics, obesity, smoking, folic acid use, gravidity, perinatal care, and year of pregnancy. Adjusted risk ratios were estimated using weighted Poisson regression with cluster‑robust standard errors. Sensitivity analyses addressed dose–response relationships and the potential impact of unrecorded over‑the‑counter NSAID use.
Results showed no association between first‑trimester NSAID exposure and major congenital malformations overall (matched‑aRR = 0.99; 95% CI [0.90, 1.10]) or for specific organ systems. Dose–response analyses across cumulative exposure categories did not demonstrate significant increases in risk. Sensitivity analyses suggested that modest misclassification from unrecorded NSAID use would not substantially alter the conclusions.
Conclusion
In this extensive, population‑based cohort, first‑trimester exposure to NSAIDs was not associated with major congenital malformations, offering reassuring evidence about the fetal safety of common NSAIDs in early pregnancy when evaluated across a broad range of clinical and methodological scenarios.