No Fetal Risks with First Trimester NSAID Use Save

PLoS Medicine has published a population-based retrospective cohort study from the Southern Israeli Pregnancy Registry (siPREG) project showing that 1st trimester exposure to NSAIDs was not associated with major congenital malformatoin (MCM) risk. 

Pain management during pregnancy is inevitable and safe analgesic options remain limited. Acetaminophen appears to be safe.  ACR Reproductive guidelines note that in the third trimester NSAIDs are to be avoided. 

This Israeli study looked at 264,858 singleton pregnancies were analyzed; 20,202 (7.6%) were exposed to NSAIDs in the first trimester. The most commonly used agents were ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%). Propensity score matching adjusted for maternal age, ethnicity, diabetes, obesity, smoking, folic acid use, and other key covariates. Major congenital malformations (MCMs) were tracked through the first year of life.

First-trimester NSAID exposure was not associated with increased MCM risk — overall or by organ system:

• Overall MCMs: 8.2% (exposed) vs. 7.0% (unexposed); adjusted RR = 0.99 (95% CI 0.90–1.10)
• Cardiovascular: aRR = 1.05 (0.92–1.20)
• Musculoskeletal: aRR = 1.03 (0.77–1.39)
• CNS: aRR = 0.77 (0.53–1.11)
• Cleft palate: aRR = 0.95 (0.47–1.91)
• Gastrointestinal: aRR = 1.03 (0.64–1.63)
• Genitourinary: aRR = 0.99 (0.72–1.35)

Dose-response analyses across cumulative NSAID exposure categories also showed no significant signal:

• Short-term (1–7 DDD): aRR = 1.06 (0.97–1.15)
• Medium-term (8–21 DDD): aRR = 1.10 (0.99–1.22)
• Long-term (>21 DDD): aRR = 1.24 (0.94–1.63)

Individual agents — ibuprofen, diclofenac, and naproxen — showed no association with MCMs when analyzed separately.

This large registry-based study shows that first-trimester NSAID use — at short, medium, and long-term exposures — was not associated with major congenital malformations. These findings provide clinically reassuring evidence for physicians managing pain or fever in early pregnancy.