title: Immortal time bias in drug safety cohort studies: spontaneous abortion following nonsteroidal antiinflammatory drug exposure.
abstract: OBJECTIVE
  Experimental research of drug safety in pregnancy is generally not feasible because of ethical issues. Therefore, most of the information about drug safety in general and teratogenicity in particular is obtained through observational studies, which require careful methodologic design to obtain unbiased results. Immortal time bias occurs when some cases do not "survive" sufficient time in the study, and as such, they have reduced chances of being defined as "exposed" simply because the durations of their follow-ups were shorter. For example, studies that examine the risk for spontaneous abortions in women exposed to a drug during pregnancy are susceptible to immortal time bias because the chance of drug exposure increases the longer a pregnancy lasts. Therefore, the drug tested may falsely be found protective against the outcome tested. The objective of the current study was to illustrate the extent of immortal time bias using a cohort study of pregnancies assessing the risk for spontaneous abortions following nonsteroidal antiinflammatory drug exposure.
  
  
  METHODS
  We assembled 3 databases containing data on spontaneous abortions, births and drug dispensions to create the present study's cohort. The risk for spontaneous abortion was assessed using 2 statistical analysis methods that were compared for 2 definitions of exposure (dichotomous, exposed vs unexposed, regular Cox regression vs Cox regression with time-varying exposure).
  
  
  RESULTS
  Significant differences were found in the risk for spontaneous abortions between the 2 statistical methods, both for groups and for most specific nonsteroidal antiinflammatory drugs (nonselective Cox inhibitors - hazard ratio, 0.70; 95% confidence interval, 0.61-0.94 vs hazard ratio, 1.10; 95% confidence interval, 0.99-1.22 for dichotomous vs time-varying exposure analyses, respectively). Furthermore, a significant correlation was found between the median misclassified immortal time for each drug and the extent of the bias.
  
  
  CONCLUSIONS
  Immortal time bias can easily occur in cohort studies assessing the risk for adverse pregnancy outcomes following exposure to drugs. One way to prevent such a bias is by defining exposure only from the time of exposure during follow-up onward using a time-varying exposure analysis.
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel; Department of Pediatrics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel; Ben-Gurion Motherisk Obstetric Registry of Exposure (BeMORE) collaboration, Beer-Sheva, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Daniel
authors.affiliation: Ben-Gurion Motherisk Obstetric Registry of Exposure (BeMORE) collaboration, Beer-Sheva, Israel; Motherisk Program, Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Lunenfeld
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Soroka Medical Center, Beer-Sheva, Israel; Ben-Gurion Motherisk Obstetric Registry of Exposure (BeMORE) collaboration, Beer-Sheva, Israel. Electronic address: lamalia@bgu.ac.il.
authors.forename: Amalia
authors.initials: A
authors.lastname: Levy
mesh_terms: D000022:Abortion, Spontaneous / Q000139:chemically induced*; D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D015982:Bias; D003627:Data Interpretation, Statistical; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D011247:Pregnancy; D016016:Proportional Hazards Models; D012107:Research Design; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal
keywords: NSAIDs; ibuprofen; immortal time bias; miscarriage; spontaneous abortions