Pre-Conception Benzodiazepine Use and Ectopic Pregnancy Risk
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.
Ectopic pregnancy occurs in 1 to 2% of the approximately 6.3 million recognized pregnancies in the USA every year, resulting in up to 126 000 ectopic pregnancies annually (Hoover et al., 2010; Curtin et al., 2013). Ectopic pregnancy is responsible for 6–13% of all pregnancy-related deaths, and hemorrhage from ectopic pregnancy is the leading cause of pregnancy-related death in the first trimester (Chang et al., 2003; Creanga et al., 2011). Additionally, around 11% of ectopic pregnancies result in serious complications, such as blood transfusion and sterilization (Stulberg et al., 2016). Most ectopic pregnancy implantations (>98%) occur in the fallopian tube; this occurs when changes to the tubal environment impair embryo-tubal transport (including smooth muscle contraction and ciliary beating) resulting in early implantation (Halbert et al., 1976; Walker, 2007; Shaw et al., 2010). Although several risk factors for ectopic pregnancy have been identified, such as pelvic infections, use of reproductive technology, intrauterine devices, smoking and increased age, approximately half of women who have an ectopic pregnancy do not have any known risk factors (Kamwendo et al., 2000; Bouyer 2003; Backman et al., 2004; Barnhart et al., 2006; Li et al., 2015; Du et al., 2017; Mikhail et al., 2018). A potential but unstudied risk factor for ectopic pregnancy is benzodiazepine use. Benzodiazepine use could affect muscle contraction in the fallopian tube through two mechanisms—through the central relaxation of smooth muscle and the direct effect on GABA receptors in the fallopian tube (French et al., 1989; László et al., 1989).
Benzodiazepine use has increased substantially in the USA in the past few decades and is commonly prescribed for indications such as anxiety disorder, insomnia, acute alcohol withdrawal and seizures (Lembke et al., 2018). Based on national data from 2008 in the USA, ~3.6% of women between ages 18 and 35 years had a prescription for benzodiazepine in a 1-year period (Olfson et al., 2015). While the use of benzodiazepines during pregnancy has been found to be associated with miscarriage, adverse birth outcomes and child development outcomes (Kieviet et al., 2013; Yonkers et al., 2017; Sheehy et al., 2019), it is unknown whether their use affects ectopic pregnancy. We conducted a cohort study using a large national database of privately insured women in the USA to assess whether women who are prescribed benzodiazepines before conception are at increased risk of ectopic pregnancy.
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