Timing of selective serotonin reuptake inhibitor use and risk for preterm birth and related adverse events

Purpose There is uncertainty around the safety of SSRIs for treating depression during pregnancy. We aimed 1) to address confounding by indication, as well as socioeconomic and environmental factors associated with depression and 2) evaluate associations of timing of SSRI exposure in pregnancy with the risk of preterm birth and related outcomes (small for gestational age and low birthweight) among women with depression before pregnancy. Methods We conducted propensity score-adjusted regression to calculate odds ratios (OR) of preterm birth, small for gestational age, and low birth weight. We accounted for maternal/pregnancy characteristics, pre-pregnancy comorbidity/depression severity, social vulnerability, rural health disparity, and pre-natal depression severity. We additionally conducted a drug-specific analysis and assessed the impact of other classes of antidepressants within our cohort of interest. Results Among women with a history of depression, we identified women with indication of depression ≤ 180 days before pregnancy (n=6,408). Women with no SSRI order during pregnancy (n=3,122) constituted the unexposed group (no SSRI exposure group). The late SSRI exposure group consisted of women with an SSRI order after the first trimester (n=2,596). The early-only SSRI exposure group consisted of women with SSRI orders only in the first trimester (n=691). Late SSRI exposure group had an increased risk of preterm birth of OR=1.7 ([1.3,2.2], p<0.0001), and low birth weight of OR = 1.7 ([1.3,2.4], p<0.001), relative to the no SSRI exposure group. Conclusions These findings suggest associations between preterm birth/low birthweight and SSRI exposure is dependent on exposure timing during pregnancy. Small for gestational age is not associated with SSRI exposure. ### Competing Interest Statement YH, RTR, SNP, DAE, MFH, AGP, and PB declare no conflict of interest. JJH has received grant funding from Pfizer Inc. and Novartis Pharmaceutical Corporation for research unrelated to this study or any of its findings. LH and NDP are scientific advisors for Sera Prognostics, a pregnancy diagnostics company, and hold stock options. Sera Prognostics is not associated with this study or any of the findings. ### Funding Statement United States National Institute of Child Health and Human Development HD091527 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board at Providence St. Joseph Health reviewed all procedures and gave ethical approval through expedited review (study number STUDY2020000196). Consent was waived because disclosure of protected health information for the study was determined to involve no more than a minimal risk to the privacy of individuals. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Results have been aggregated and reported within this paper to the extent possible while maintaining privacy from personal health information as required by law. Data are archived within Providence St Joseph Health systems in a HIPAA-secure audited compute environment.