Summary: A comprehensive study offers reassuring evidence for expectant mothers: the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during the first trimester is not associated with an increased risk of major birth defects.
Researchers analyzed over 260,000 pregnancies, finding no significant link between common medications like ibuprofen, diclofenac, or naproxen and congenital malformations. This research fills a critical gap in prenatal care, providing data-driven guidance for managing pain and fever during early pregnancy.
Key Facts
- No Increased Risk: Exposure to NSAIDs in the first trimester showed no association with major congenital malformations overall, with a matched adjusted relative risk of 0.99.
- System-Specific Safety: The study found no increased risk for defects in specific organ systems, including the cardiovascular, musculoskeletal, central nervous, gastrointestinal, or genitourinary systems.
- Individual Drug Safety: No specific association was found for the most commonly used NSAIDs: ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%).
- Dose-Response Findings: Analyses revealed no significant link between the cumulative dose of NSAID exposure and the likelihood of birth defects.
Source: PLOS
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.”
Key Questions Answered:
A: This study provides “reassuring evidence” that taking common NSAIDs like ibuprofen (Advil) in early pregnancy does not increase the risk of major birth defects. However, you should always consult your physician before starting any medication while pregnant.
A: Options for managing pain in early pregnancy have been limited; studies raised concerns about acetaminophen, while previous NSAID data remained inconclusive. This large-scale study provides the clarity needed for informed medical decisions.
A: They used a massive registry (SiPREG) that tracked outcomes not just at birth, but also in terminations and through the first year of life. They also used special “sensitivity analyses” to account for medications that might have been taken but not recorded.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this pharmacology and neurodevelopment research news
Author: Claire Turner
Source: PLOS
Contact: Claire Turner – PLOS
Image: The image is credited to 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. PLOS Medicine
DOI:10.1371/journal.pmed.1005063
Abstract
First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study
Background
Pain and fever are common in early pregnancy, yet their management poses a major clinical dilemma. Although not confirmed, recent studies have raised safety concerns regarding acetaminophen. Evidence on the use of nonsteroidal anti-inflammatory drugs (NSAID) in the first trimester remains inconclusive.
This uncertainty has left clinicians with limited evidence to guide treatment decisions. This study evaluated the association between first-trimester NSAID exposure and the risk of major congenital malformations (MCMs) in a large, population-based cohort of pregnancies.
Methods and findings
We conducted a population-based retrospective cohort study within the Southern Israeli Pregnancy Registry (siPREG) project, including all singleton pregnancies of women aged 15–45 years resulting in live births, stillbirths, or elective terminations for fetal malformations at a Soroka University Medical Center between 1998 and 2018. Pregnancies exposed to established teratogens, multiple gestations, and those with documented genetic or chromosomal anomalies were excluded.
First-trimester NSAID exposure was defined by pharmacy dispensations (overall and by specific agents). MCMs were identified from linked clinical, hospitalization, and termination records through the first postnatal year.
Propensity scores were estimated using covariates selected via a directed acyclic graph, including maternal age, ethnicity, diabetes, medical indication for NSAID use, exposure to other antipyretics, obesity, smoking, folic-acid use, gravidity, perinatal care, and year of pregnancy. Generalized full matching was used to balance covariates. Adjusted risk ratios were derived using weighted
Poisson regression with G-computation, and two-way cluster-robust standard errors, jointly clustering by maternal identifier and matching subclass. Sensitivity analyses included a dose–response assessment across defined-daily-dose (DDD) categories and a tipping-point analysis evaluating the impact of potential misclassification from unrecorded over-the-counter NSAID use.
A total of 264,858 singleton pregnancies were included in the final cohort; 20,202 (7.6%) were exposed to NSAID, most commonly ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%).
NSAID exposure, in total and as individual agents, was not associated with MCMs overall (8.2% versus 7.0%; matched-adjusted-Relative Risk (aRR) = 0.99 (95% CI [0.90,1.10])) or with organ-system-specific MCMs, including cardiovascular (matched-aRR = 1.05 (95% CI [0.92,1.20]), musculoskeletal (matched-aRR = 1.03 (95% CI [0.77,1.39])), central nervous system (matched-aRR = 0.77 (95% CI [0.53,1.11])), cleft palate (matched-aRR = 0.95 (95% CI [0.47–1.91])), gastrointestinal (matched-aRR = 1.03 (95% CI [0.64–1.63])), and genitourinary (matched-aRR = 0.99 (95% CI [0.72,1.35])) malformations.
Dose–response analyses showed no significant association with MCMs across cumulative NSAID exposure: short-term (1–7 DDD, matched-aRR = 1.06 (95% CI [0.97,1.15]), medium-term (8–21 DDD, matched-aRR = 1.10 (95% CI [0.99,1.22]), and long-term (>21 DDD, matched-aRR = 1.24 (95% CI [0.94,1.63])). The main limitation was the potential for minor exposure misclassification due to over-the-counter availability of ibuprofen, although sensitivity analyses simulating such misclassification suggested minimal impact on the risk estimates.
Conclusion
In this large, population-based cohort, we found no evidence supporting an association between first-trimester exposure to NSAID and MCMs, providing reassuring evidence regarding their fetal safety in early pregnancy.
