Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring

While antidepressant use during pregnancy has been associated with adverse birth and neurodevelopmental outcomes, these associations may be attributed to confounding factors, such as genetic influences, maternal stress, or poor health practices during pregnancy. This study used 4 observational designs to investigate these associations, including sibling and paternal information. The study used multiple national Swedish registries. First-trimester exposures, defined as at least 1 dispensation between 90 days before estimated conceptions and 90 days after estimated conception, to any antidepressants and selective serotonin reuptake inhibitors, reported through either maternal self-report or dispensation records, were the main exposures evaluated. The main outcomes were small for gestational age, defined as birth weight less than 2 SDs below the mean for gestational age; preterm birth, defined as less than 37 gestational weeks; and diagnosis of autism spectrum disorder or attention-deficit/hyperactivity disorder (ADHD). Maternal and paternal covariates included age of childbearing, highest level of completed education, history of criminal conviction, history of psychiatric illnesses, history of suicide attempts, and country of origin (Sweden or outside Sweden). Parity and year of birth were pregnancy covariates. Population-wide baseline models were assessed adjusting only for pregnancy covariates. Then, population-wide associations were adjusted for maternal and paternal covariates as well. A third model compared exposure-and outcome-discordant offspring within families. After exclusion of multiple births, missing father identifiers, or other missing information, a final cohort of 1,580,629 offspring born to 943,776 was used. Of these, 26,477 offspring had first-trimester maternal antidepressant dispensations, 22,125 of which were selective serotonin reuptake inhibitor dispensations. Preterm births accounted for 6.98% of exposed and 4.78% of unexposed offspring. In the baseline models, first-trimester exposure was associated with all 4 outcomes (preterm birth odds ratio [OR], 1.47; 95% confidence interval [CI], 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; ADHD HR, 2.21 [95% CI, 2.04-2.39]). After adjusting for pregnancy and maternal and paternal traits and comparing sibling data, first-trimester antidepressant exposure was associated with only a small increased risk of preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) and was not associated with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), ADHD (HR, 0.99 [95% CI, 0.79-1.25]), or autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]). Unexposed and exposed siblings were found to be at equal risk of small for gestational age, ADHD, and autism spectrum disorder as one another, whereas exposed siblings had a slightly increased risk of preterm birth. Both autism spectrum disorder and ADHD were associated with paternal first-trimester antidepressant dispensations, supporting the idea that familial confounding may explain associations between exposure and neurodevelopmental disorders.