Elizabeth Wall-Wieler1, Thalia K Robakis2, Deirdre J Lyell3, Reem Masarwa4, Robert W Platt4,5, Suzan L Carmichael1,3. 1. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. 2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3. Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA. 4. Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada. 5. Departments of Pediatrics, McGill University, Montreal, Canada.
Abstract
STUDY QUESTION: Are women who fill a benzodiazepine prescription before conception at increased risk of ectopic pregnancy? SUMMARY ANSWER: Risk of ectopic pregnancy is 50% higher among women who fill a benzodiazepine prescription before conception. WHAT IS KNOWN ALREADY: Benzodiazepine use in pregnancy increases the risk of miscarriage, adverse birth outcomes and adverse child development outcomes. STUDY DESIGN, SIZE, DURATION: Using data from US commercial insurance claims, we performed a cohort study of 1 691 366 pregnancies between 1 November 2008 and 30 September 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified ectopic pregnancies using diagnosis and procedure codes and used unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models to calculate relative risks (RR) of ectopic pregnancy for pregnant women who did and did not fill any prescriptions for benzodiazepines in the 90 days before conception. Two sub-groups of women with specific indications for benzodiazepine use were also examined-women who had a least one diagnosis for anxiety disorder and women who had at least one diagnosis of insomnia in the year before conception. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1 691 366 pregnancies, 1.06% filled at least two benzodiazepine prescriptions totaling at least 10 days supply in the 90 days before conception. Among women with a benzodiazepine prescription, there was an excess of 80 ectopic pregnancies per 10 000 pregnancies, and their IPT-weighted risk of ectopic pregnancies was 1.47 (95% CI 1.32 to 1.63) times greater relative to women without benzodiazepine prescriptions before conception. The IPT-weighted RR between ectopic pregnancy and benzodiazepine use was 1.34 (95% CI 1.18 to 1.53) among women with anxiety disorder diagnoses and 1.28 (95% CI 0.99 to 1.68) among women with an insomnia diagnosis. LIMITATIONS, REASONS FOR CAUTION: We relied on outpatient prescription data to identify benzodiazepine use before conception, which could result in over- or under-estimation of actual benzodiazepine consumption. We relied on medical claim codes to identify pregnancies and conception date, which may result in misclassification of pregnancy outcomes and gestational length. WIDER IMPLICATIONS OF THE FINDINGS: This study found that women who have a benzodiazepine prescription before conception are at an increased risk of ectopic pregnancy. This information can help women, and their healthcare providers make more fully informed decisions about benzodiazepine use in their reproductive years. STUDY FUNDING/COMPETING INTEREST(S): Funding for this project was provided by a Banting Postdoctoral Fellowship and a Stanford Maternal and Child Health Research Institute Postdoctoral Award. Data access for this project was provided by the Stanford Center for Population Health Sciences Data Core. The PHS Data Core is supported by a National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and internal Stanford funding. The authors have no competing interest. TRIAL REGISTRATION NUMBER: N/A.
STUDY QUESTION: Are women who fill a benzodiazepine prescription before conception at increased risk of ectopic pregnancy? SUMMARY ANSWER: Risk of ectopic pregnancy is 50% higher among women who fill a benzodiazepine prescription before conception. WHAT IS KNOWN ALREADY: Benzodiazepine use in pregnancy increases the risk of miscarriage, adverse birth outcomes and adverse child development outcomes. STUDY DESIGN, SIZE, DURATION: Using data from US commercial insurance claims, we performed a cohort study of 1 691 366 pregnancies between 1 November 2008 and 30 September 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified ectopic pregnancies using diagnosis and procedure codes and used unadjusted and inverse probability of treatment (IPT)-weighted log-binomial models to calculate relative risks (RR) of ectopic pregnancy for pregnant women who did and did not fill any prescriptions for benzodiazepines in the 90 days before conception. Two sub-groups of women with specific indications for benzodiazepine use were also examined-women who had a least one diagnosis for anxiety disorder and women who had at least one diagnosis of insomnia in the year before conception. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 1 691 366 pregnancies, 1.06% filled at least two benzodiazepine prescriptions totaling at least 10 days supply in the 90 days before conception. Among women with a benzodiazepine prescription, there was an excess of 80 ectopic pregnancies per 10 000 pregnancies, and their IPT-weighted risk of ectopic pregnancies was 1.47 (95% CI 1.32 to 1.63) times greater relative to women without benzodiazepine prescriptions before conception. The IPT-weighted RR between ectopic pregnancy and benzodiazepine use was 1.34 (95% CI 1.18 to 1.53) among women with anxiety disorder diagnoses and 1.28 (95% CI 0.99 to 1.68) among women with an insomnia diagnosis. LIMITATIONS, REASONS FOR CAUTION: We relied on outpatient prescription data to identify benzodiazepine use before conception, which could result in over- or under-estimation of actual benzodiazepine consumption. We relied on medical claim codes to identify pregnancies and conception date, which may result in misclassification of pregnancy outcomes and gestational length. WIDER IMPLICATIONS OF THE FINDINGS: This study found that women who have a benzodiazepine prescription before conception are at an increased risk of ectopic pregnancy. This information can help women, and their healthcare providers make more fully informed decisions about benzodiazepine use in their reproductive years. STUDY FUNDING/COMPETING INTEREST(S): Funding for this project was provided by a Banting Postdoctoral Fellowship and a Stanford Maternal and Child Health Research Institute Postdoctoral Award. Data access for this project was provided by the Stanford Center for Population Health Sciences Data Core. The PHS Data Core is supported by a National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and internal Stanford funding. The authors have no competing interest. TRIAL REGISTRATION NUMBER: N/A.
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