and a statistically significant dose-response relationship in which the risk increased at a greater duration of exposure was established in a case-control study published in the American Journal of Obstetrics and Gynecology .
The cohorts in the study were NSAID users, acetaminophen-only users, and controls exposed to neither NSAIDs or acetaminophen. The reasoning for including the acetaminophen cohort is that the drug has a similar indication but does not inhibit prostaglandin biosynthesis, as NSAIDs do. Prostaglandin is important for implantation in early pregnancy. The basic facts of what NSAIDs do and how implantation works have led to theories about miscarriage risk, but previous studies have not been conclusive, said De-Kun Li, MD, PhD, of Kaiser Permanente, and his coauthors.
Denise Fulton/MDedge News
Participants were women in the Kaiser Permanente Northern California database with positive pregnancy test results, questioned by interviewers and compared with pharmacy records when available. The total was 241 women exposed to NSAIDs, 391 exposed to acetaminophen, and 465 unexposed controls.
The adjusted hazard ratio for miscarriage was 1.59 for NSAID users of any timing and any duration, compared with 1.10 for acetaminophen users. If the NSAID exposure first occurred within the first 2 weeks of gestational age, that risk was a 1.89 hazard ratio, and increased to 2.10 when the duration of the near-conception exposure was greater than 14 days. The risk of miscarriage associated with NSAIDs had statistical significance within the first 8 weeks of gestational age, but not later.
“The timing of NSAID use (around conception) and the timing of miscarriage (early miscarriage only) are consistent with the underlying mechanism of the association,” wrote Dr. Li and his associates. The results “provide consistent findings as well as a coherent biological mechanism for the observation.”
The authors warned that the risk “remains largely ignored by both pregnant women and clinicians,” as NSAIDs are still widely prescribed and used .
“The risk was largely confined to women who were not overweight (body mass index less than 25). In contrast, there was little evidence of increased risk of miscarriage due to NSAID use among women who were overweight (body mass index greater than or equal to 25), thus indicating a potential mitigating effect of being overweight,” although this findings requires confirmation, Dr. Li and his associates said.
The study was funded by the National Institute of Child Health and Human Development. The authors reported no conflicts of interest.
SOURCE: Li DK et al. Am J Obstet Gynecol. 2018 Jun. doi: 10.1016/j.ajog.2018.06.002 .