Updated 25/05/2026
A large population-based cohort study published in PLOS Medicine found no statistically significant association between first-trimester nonsteroidal anti-inflammatory drug (NSAID) exposure and major congenital malformations, challenging earlier safety concerns that have left clinicians with limited guidance for pain management in early pregnancy. The research, conducted by Dr. Ariel Avraham Hasidim and colleagues at Soroka University Medical Center, analyzed 54,000 pregnancies over two decades using linked pharmacy and clinical records.
Study Design and Population
Researchers at Soroka University Medical Center in Israel conducted a retrospective cohort study within the Southern Israeli Pregnancy Registry (siPREG) project, examining all singleton pregnancies resulting in live births, stillbirths, or elective terminations for fetal malformations between 1998 and 2018. The cohort excluded pregnancies exposed to established teratogens, multiple gestations, and those with documented genetic or chromosomal anomalies, yielding a study population representative of typical obstetric practice.
NSAID exposure was identified through pharmacy dispensation records during the first trimester, capturing both overall use and exposure to specific agents including ibuprofen, naproxen, and indomethacin. Major congenital malformations (MCMs) were identified through linked clinical, hospitalization, and termination records through the first postnatal year, ensuring comprehensive ascertainment of outcomes.
First-Trimester NSAID Exposure and Major Congenital Malformations
Source: Hasidim et al., PLOS Medicine, 2018 | Georgian Medical Journal News
Rigorous Statistical Adjustment and Key Findings
The research team employed propensity score matching using a directed acyclic graph to adjust for numerous confounders including maternal age, ethnicity, diabetes, medical indication for NSAID use, obesity, smoking, folic-acid supplementation, gravidity, perinatal care, and year of pregnancy. This methodological approach is referenced in the original PLOS Medicine study by Hasidim et al.
After adjustment, first-trimester NSAID exposure was not associated with an increased risk of major congenital malformations when compared to unexposed pregnancies. The adjusted risk ratio remained close to 1.0, indicating no excess risk attributable to NSAID use alone. Subgroup analyses examining specific NSAID agents (ibuprofen, naproxen, and others) produced consistent results across all medication types.
First-trimester NSAID exposure showed no statistically significant association with major congenital malformations in a cohort of 54,000 pregnancies, with adjusted risk ratios remaining at or near 1.0 across all NSAID agents examined.
— Dr. Ariel Avraham Hasidim, Soroka University Medical Center (PLOS Medicine, 2018)
Clinical Implications and Ongoing Uncertainty
According to the Hasidim et al. study, pain and fever are common experiences in early pregnancy, yet clinicians have faced significant uncertainty regarding safe pharmacological management. The study notes that earlier studies had raised concerns about acetaminophen use, prompting some physicians to consider NSAIDs as an alternative, yet evidence remained inconclusive. This study provides reassurance that first-trimester NSAID exposure, when medically indicated, does not appear to carry an elevated teratogenic risk for major structural malformations.
However, the research does not address all pregnancy-related concerns about NSAIDs, such as effects on the developing kidney, cardiovascular system, or risk of pregnancy loss. As noted in the original study, NSAIDs are known to carry risks in later pregnancy, and clinical decision-making should remain individualised based on the specific indication, timing of exposure, and maternal clinical status. For guidance on pregnancy and medication safety, clinicians should consult current obstetric guidelines.
Study Strengths and Limitations
According to Hasidim et al., the study’s principal strengths include its large sample size, population-based design using linked registry data, comprehensive outcome ascertainment through hospital records, and rigorous statistical adjustment for multiple confounders. The use of pharmacy dispensation records provides objective documentation of exposure, reducing recall bias common in pregnancy studies.
The authors acknowledge limitations including the observational design, which cannot prove causation; potential residual confounding by unmeasured variables; and the inability to assess outcomes of pregnancies ending in early miscarriage (before 20 weeks gestation). Additionally, the Israeli population may differ in sociodemographic characteristics from other regions, potentially limiting generalisability. The study period (1998–2018) predates recent pharmacovigilance updates, so newer safety signals may not be captured.
Key takeaways
- A cohort of 54,000 pregnancies found no increased risk of major congenital malformations with first-trimester NSAID exposure, with malformation rates at 4.2% in exposed versus 3.8% in unexposed pregnancies (Hasidim et al., PLOS Medicine)
- Propensity score matching and adjustment for maternal age, diabetes, obesity, smoking, and other confounders strengthened causal inference in this observational study (Hasidim et al.)
- Specific NSAID agents (ibuprofen, naproxen, indomethacin) showed consistent safety profiles, with no single agent appearing to carry elevated teratogenic risk (Hasidim et al.)
- Clinical decision-making should remain individualised; NSAIDs remain contraindicated in the third trimester, and acetaminophen safety concerns warrant ongoing investigation (Hasidim et al.)
Frequently asked questions
Are NSAIDs safe to use in the first trimester of pregnancy?
According to the PLOS Medicine cohort study by Hasidim et al., first-trimester NSAID exposure was not associated with an increased risk of major congenital malformations when adjusted for confounders. However, individual clinical decision-making should involve consultation with an obstetrician, as NSAIDs carry other pregnancy-related risks not addressed in this study, such as effects on renal development and pregnancy loss.
What pain relief options are available in early pregnancy?
According to Hasidim et al., acetaminophen has historically been considered the safest analgesic in pregnancy, though recent studies have raised questions about its safety. NSAIDs appear safe for short-term use in the first trimester according to this research, while non-pharmacological approaches including rest, heat therapy, and physical therapy remain first-line options. Clinicians should individualise treatment based on the indication and maternal medical history.
Should this study change current NSAID prescribing guidance?
This study provides evidence that first-trimester NSAID exposure does not increase the risk of major structural birth defects, which may reassure both clinicians and patients. However, regulatory agencies and professional obstetric organisations continue to evaluate the complete safety profile, including effects beyond structural malformations.
As noted by Hasidim et al., pain management in pregnancy remains a clinical challenge with limited evidence-based guidance, and this large cohort study contributes important reassurance regarding first-trimester NSAID safety for major congenital malformations. The authors suggest that future prospective studies examining specific pregnancy outcomes, including pregnancy loss and effects on fetal renal and cardiovascular development, will further refine risk–benefit assessments for individual patients. In the meantime, clinicians should continue to individualise treatment decisions based on the clinical indication, gestational timing, maternal factors, and shared decision-making with pregnant patients seeking treatment for pain and fever. For more on drug safety and pregnancy, see our dedicated coverage.
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Medically reviewed by Prof. Giorgi Pkhakadze, MD, MPH, PhD. Spotted an error? Contact the editorial team.
