title: NSAIDs and spontaneous abortions - true effect or an indication bias?
abstract: OBJECTIVE
  The aim of the study was to characterize the extent of indication bias resulting from the excessive use of NSAIDs on the days preceding a spontaneous abortion to relieve pain.
  
  
  METHODS
  We used data from a retrospective cohort study assessing the risk for spontaneous abortions following exposure to NSAIDs. Three definitions of exposure for cases of spontaneous abortions were compared, from the first day of pregnancy until the day of spontaneous abortion and until 3 and 2 days before a spontaneous abortion. Statistical analysis was performed using multivariate time programmed Cox regression.
  
  
  RESULTS
  A sharp increase was observed in the dispensation of indomethacin, diclofenac and naproxen, and a milder increase was found in the use of ibuprofen during the week before a spontaneous abortion. Non- selective COX inhibitors in general and specifically diclofenac and indomethacin were found to be associated with spontaneous abortions when the exposure period was defined until the day of spontaneous abortion (hazard ratio (HR) 1.15, 95% confidence interval (CI) 1.04, 1.28; HR 1.31, 95% CI 1.08, 1.59 and HR 3.33, 95% CI 2.09, 5.29, respectively). The effect disappears by excluding exposures occurring on the day before the spontaneous abortion for non-selective COX inhibitors and on the last week before the spontaneous abortion for indomethacin. In general, decreasing HRs were found with the exclusion of exposures occurring on the days immediately before the spontaneous abortion.
  
  
  CONCLUSIONS
  The increased use of NSAIDs during the last few days that preceded a spontaneous abortion to relieve pain associated with the miscarriage could bias studies assessing the association between exposure to NSAIDs and spontaneous abortions.
authors: Departments of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel.|Departments of Pediatrics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel.
authors: Sharon
authors: S
authors: Daniel
authors: The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada.
authors: Gideon
authors: G
authors: Koren
authors: Department of Obstetrics and Gynecology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel.
authors: Eitan
authors: E
authors: Lunenfeld
authors: Departments of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel.
authors: Amalia
authors: A
authors: Levy
mesh_terms: D000022:Abortion, Spontaneous / Q000139:chemically induced* / Q000453:epidemiology*; D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D004008:Diclofenac / Q000009:adverse effects; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects; D007213:Indomethacin / Q000009:adverse effects; D007557:Israel / Q000453:epidemiology; D008875:Middle Aged; D009288:Naproxen / Q000009:adverse effects; D011247:Pregnancy; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D009288:Naproxen; D007052:Ibuprofen; D007213:Indomethacin
keywords: NSAIDs; ibuprofen; indication bias; miscarriage; reverse causality bias; spontaneous abortions