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

Abstract

Importance Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding. Objective To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems. Design, Setting, and Participants This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal, and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations. Exposures Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations. Main Outcomes and Measures Preterm birth (< 37 gestational weeks), small for gestation age (birth weight < 2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring. Results Among 1,580,629 offspring (mean gestational age 279 days; 48.6% female; 1.4% [n = 22,544] with maternal first-trimester self-reported antidepressant use) born to 943,776 mothers (mean age at childbirth 30 years), 7.0% of exposed vs. 4.8% of unexposed offspring were preterm, 2.5% of exposed vs. 2.2% of unexposed were small for gestational age, 5.3% of exposed vs. 2.1% of unexposed were diagnosed with autism spectrum disorder by age 15, and 12.6% of exposed vs. 5.5% of unexposed were diagnosed by attention-deficit/hyperactivity disorder by age 15. At the population level, first-trimester exposure was associated with all outcomes, compared with unexposed offspring (preterm birth: OR = 1.5, 95% CI, [1.4, 1.6]; small for gestational age: OR = 1.2, 95% CI, [1.1, 1.3]; autism spectrum disorder: HR = 2.0, 95% CI, [1.8, 2.3]; attention-deficit/hyperactivity disorder: HR = 2.2, 95% CI, [2.0, 2.4]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR = 1.3, 95% CI [1.2, 1.5]) but not with small for gestational age (OR = 1.0, 95% CI [0.8, 1.3]), autism spectrum disorder (HR = 0.8, 95% CI [0.6, 1.1]), or attention-deficit/hyperactivity disorder (HR = 1.0, 95% CI [0.8, 1.3]). Results from analyses assessing associations with maternal dispensations before pregnancy and paternal first-trimester dispensations were consistent with findings from the sibling comparisons. Conclusion and Relevance Among offspring born in Sweden, after accounting for confounding factors, first-trimester antidepressant exposure, compared to no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study

“…[6][7][8][9][10] Comparing standardised differences in the rate of antidepressant use between the current study and previous studies (see supplementary material 9), our rate is lower than one study only 7 and comparable with five other studies. [6][7][8][9][10][11] In a previous drug prevalence study in Hong Kong, the prescribing prevalence was generally lower than in Western countries. 24 This may be explained by the conservative approach in local practice.…”

“…[6][7][8][9][10][11] A systematic literature search identified six observational studies, including three cohort studies 6 9 11 and three case-control studies, 7 8 10 which investigated the association between antidepressant use in pregnancy and ADHD in children, with the study populations from Scandinavian countries or North America. However, findings were inconsistent.…”

Pharmacobiological Treatments in Autism Spectrum Disorders

“…However, two very recent studies have concluded that there is no significant relationship between prenatal exposure to SSRIs and ASD risk and suggest that the previously observed association may be due to other factors [22,23].…”

The safety of antidepressants in pregnancy

“…Overall they found consistent signs of confounding by indication, in accordance with a recent study from Sweden. 7 As the authors point out, however, the importance of maternal depression or related factors in these studies does not rule out a causal effect of antidepressants. For example, potential errors in the data such as non-differential misclassification of the exposure can bias results towards the null.…”