Risk of Preterm Birth Following Late Pregnancy Exposure to NSAIDs or COX-2 Inhibitors

Anick Bérard; Odile Sheehy; Sylvie Girard; Jin-Ping Zhao; Sasha Bernatsky


Pain. 2018;159(5):948-955. 

In This Article

Abstract and Introduction


Pregnant women may take nonsteroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase (COX)-2 inhibitors, or biological agents to relieve symptoms or manage disease flares in late pregnancy. We aimed to quantify the risk of prematurity associated with late pregnancy exposure to nonselective NSAIDs, selective COX-2 inhibitors, and biological agents. Using data from Quebec Pregnancy Cohort, we performed a population-based cohort study. We included all women who were covered by the Quebec Drug Plan and had a singleton live birth between January 1, 1998 and December 31, 2009. Late pregnancy exposure was defined as having filled at least 1 prescription for nonselective NSAIDs, selective COX-2 inhibitors, or biological agents in the 3 months before delivery. Prematurity was defined as <37 weeks of gestation. Crude and adjusted odds ratios (OR) were obtained using generalized estimation equation models. Covariates included maternal autoimmune diseases, demographics, concomitant drug use, history of pregnancy complications, and other comorbidities. A total of 156,531 pregnancies met inclusion criteria and were considered for analyses. In the 3 months before delivery, 391 pregnancies were exposed to nonselective NSAIDs, 55 to COX-2 inhibitors, and 12 to biological agents. After adjustment for maternal autoimmune diseases, concomitant medication use, and other risk factors, COX-2 inhibitor use in late pregnancy was associated with a 2.46-fold increased risk of prematurity (adjusted OR, 2.46; 95% confidence interval, 1.28–4.72) compared to nonuse; only late pregnancy exposure to celecoxib was found to increase the risk (adjusted OR, 3.41; 95% confidence interval, 1.29–9.02). In conclusion, celecoxib use during late pregnancy may increase the risk of prematurity.


Over the past decades, with the increased average age of first-time mothers, more women are likely to have autoimmune inflammatory diseases before and during pregnancy.[22] Although some experience improvement in disease activity during pregnancy, many women with inflammatory diseases require some treatment during this time.[5,10] Biologics and some disease-modifying antirheumatic drugs (DMARDs), including antimalarial, sulfasalazine, azathioprine, and cyclosporine, are used to prevent or manage disease flares during pregnancy.[4,14,30,32] Nonsteroidal antiinflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors are also frequently used during pregnancy to improve joint pain and stiffness in those with inflammatory diseases such as rheumatoid arthritis.[4,11,14,20,27,30,32,33] Inflammatory conditions affecting the musculoskeletal system usually arise in late pregnancy.[11,12,20,21,27,33] Consequently, pregnant women may have to take NSAIDs to relieve their symptoms.[31] Taking NSAIDs after the 32nd week of gestation[30,35] is not recommended because of the risk of premature closure or constriction of the ductus arteriosus, which may result in persistent pulmonary hypertension in the newborn (PPHN)[3,23,37,38] as well as fetal renal impairment.[18] Despite contraindications, a study from Norway found that 1.3% of pregnant women used NSAIDs during the third trimester, and more than half of them initiated NSAID therapy during this period.[25] Higher rates of NSAID exposure have been reported in France (3.6% after the sixth month of pregnancy)[9] and in the United States (third-trimester ibuprofen exposure: 5.7%[13] and 8.6%[42]). In Canada, NSAIDs are the most commonly used medications during pregnancy,[41] and in Quebec approximately 4.5% of women used NSAIDs during their pregnancy,[8] whereas only 0.2% of women in Saskatchewan used ibuprofen or naproxen in their third trimester.[41]

Thus far, studies on the safety of NSAID use during pregnancy have mainly focused on early exposure and the risk of miscarriage[24] and birth defects[28] or late exposure and the risk of PPHN.[3,37,38] Only a handful of studies examined a possible relationship between NSAID use and the duration of gestation[6,17,25,26,28] and their specific association with preterm birth.[17] However, these studies mainly evaluated NSAIDs as a group[6,17,26,28] and studied the exposure dichotomously throughout pregnancy. Preterm birth is a major risk factor for morbidity and mortality among infants worldwide and imposes considerable burden on health, education, and social services, as well as on families and caregivers.[16] The Canadian in-hospital preterm birth rate is approximately 8%.[1] Therefore, the primary purpose of our study was to quantify the risk of premature birth associated with NSAIDs, COX-2 inhibitors, and biological agent exposure 3 months before delivery.