Antidepressants in pregnancy: applying causal epidemiological methods to understand service-use outcomes in women and long-term neurodevelopmental outcomes in exposed children
Authors: Heuvelman Hein , Davies Neil M , Ben-Shlomo Yoav , Emond Alan , Evans Jonathan , Gunnell David , Liebling Rachel , Morris Richard , Payne Rupert , Storey Claire , Viner Maria , Rai Dheeraj 
Published: May 2023

BackgroundAntidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear.ObjectivesTo study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference.DesignThis was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis.SettingThis took place in UK general practice.ParticipantsParticipants were pregnant women with depression.InterventionsThe interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation.Main outcome measuresThe maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability.Data sourcesUK Clinical Practice Research Datalink.ResultsData on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratioinitiation2.16, 95% confidence interval 1.95 to 2.39; odds ratiocontinuation2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratiomultivariableregression1.10, 95% confidence interval 0.90 to 1.35; odds ratiopropensityscore1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratiomultivariableregression1.02, 95% confidence interval 0.80 to 1.29; odds ratiopropensityscore0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratiomultivariableregression0.81, 95% confidence interval 0.55 to 1.19; odds ratiopropensityscore0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratiomultivariableregression1.23, 95% confidence interval 0.85 to 1.78; odds ratiopropensityscore1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers.LimitationsSeveral causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured.ConclusionsWomen prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation.Future workFurther research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full inHealth Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.