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.

Objective To examine associations between interpregnancy interval, the duration from the preceding birth to the conception of the next-born index child, and adverse birth outcomes using designs that adjust for measured and unmeasured factors. Methods In this prospective cohort study we used population-based Swedish registries from 1973 to 2009 to estimate the associations between interpregnancy interval (referent 18-23 months), and adverse birth outcomes [i.e., preterm birth (PTB, < 37 weeks), low birth weight (LBW, <2,500 g), small for gestational age (SGA, > 2 standard deviations below average weight for gestational age)]. Analyses included cousin- and sibling-comparisons, and postbirth intervals (ie, the interval between second- and third-born offspring predicting second-born outcomes), to address unmeasured familial confounding. Results Traditional cohort-wide analyses showed higher odds of PTB [adjusted odds ratio (aOR)=1.51, 99% CI=1.39-1.63, 5.99% PTBs)] and LBW (aOR=1.25, 99% CI=1.13-1.39, 3.32% LBW) after short interpregnancy interval (0-5 months) compared to offspring born after an interpregnancy interval of 18-23 months (3.21% PTBs, 1.92% LBW). For pregnancy intervals of 60 months or more, odds of PTB (aOR=1.51, 99% CI=1.43-1.60, 5.07% PTBs), LBW (a OR=1.61, 99% CI=1.50-1.73, 3.43% LBW births), and SGA (aOR=1.54, 99% CI=1.42-1.66, 2.49% SGA births) were also higher when compared with the reference interval (1.53% SGA). Except for PTB (aOR=1.72, 99% CI=1.26-2.35), associations were attenuated in cousin-comparisons. A small association between short interpregnancy interval and PTB remained in sibling-comparisons (aOR=1.22, 99% CI=1.11-1.35), but associations with LBW (aOR=0.83, 99% CI=0.74-0.94) and SGA (aOR=0.74, 99% CI=0.64-0.85) reversed direction. Associations between long interpregnancy interval and adverse birth outcomes remained through cousin- and sibling-comparisons. Post birth interval analyses showed familial confounding is present for short interpregnancy intervals, but supported independent associations for long interpregnancy intervals. Conclusion Familial confounding explains most of the association between short interpregnancy interval and adverse birth outcomes while associations with long interpregnancy intervals were independent of measured and unmeasured factors.

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%