- Background: Spontaneous abortion is the most common complication of pregnancy. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used during pregnancy. Published data are inconsistent regarding the risk of spontaneous abortion following exposure to NSAIDs. Methods: We performed a historical cohort study involving all women who conceived between January 2003 and December 2009 and who were admitted for delivery or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. We constructed time-varying Cox regression models and adjusted for maternal age, diabetes mellitus, hypothyroidism, obesity, hypercoagulation or inflammatory conditions, recurrent miscarriage, in vitro fertilization of the current pregnancy, intrauterine contraceptive device, ethnic background, tobacco use and year of admission. Results: The cohort included 65,457 women who conceived during the study period; of these, 58,949 (90.1%) were admitted for a birth and 6508 (9.9%) for spontaneous abortion. A total of 4495 (6.9%) pregnant women were exposed to NSAIDs during the study period. Exposure to NSAIDs was not an independent risk factor for spontaneous abortion (nonselective cyclooxygenase [COX] inhibitors: adjusted hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.99-1.22; selective COX-2 inhibitors: adjusted HR 1.43, 95% CI 0.79-2.59). There was no increased risk for specific NSAID drugs, except for a significantly increased risk with exposure to indomethacin (adjusted HR 2.8, 95% CI 1.70-4.69). We found no dose-response effect. Interpretation: We found no increased risk of spontaneous abortion following exposure to NSAIDs. Further research is needed to assess the risk following exposure to selective COX-2 inhibitors.