BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j2811 (Published 19 July 2017) Cite this as: BMJ 2017;358:j2811
Antidepressants during pregnancy and autism in offspring: population based cohort study

Abstract
Objectives To study the association between maternal use of antidepressants during pregnancy and autism spectrum disorder (ASD) in offspring.
Design Observational prospective cohort study with regression methods, propensity score matching, sibling controls, and negative control comparison.
Setting Stockholm County, Sweden.
Participants 254 610 individuals aged 4-17, including 5378 with autism, living in Stockholm County in 2001-11 who were born to mothers who did not take antidepressants and did not have any psychiatric disorder, mothers who took antidepressants during pregnancy, or mothers with psychiatric disorders who did not take antidepressants during pregnancy. Maternal antidepressant use was recorded during first antenatal interview or determined from prescription records.
Main outcome measure Offspring diagnosis of autism spectrum disorder, with and without intellectual disability.
Results Of the 3342 children exposed to antidepressants during pregnancy, 4.1% (n=136) had a diagnosis of autism compared with a 2.9% prevalence (n=353) in 12 325 children not exposed to antidepressants whose mothers had a history of a psychiatric disorder (adjusted odds ratio 1.45, 95% confidence interval 1.13 to 1.85). Propensity score analysis led to similar results. The results of a sibling control analysis were in the same direction, although with wider confidence intervals. In a negative control comparison, there was no evidence of any increased risk of autism in children whose fathers were prescribed antidepressants during the mothers’ pregnancy (1.13, 0.68 to 1.88). In all analyses, the risk increase concerned only autism without intellectual disability.
Conclusions The association between antidepressant use during pregnancy and autism, particularly autism without intellectual disability, might not solely be a byproduct of confounding. Study of the potential underlying biological mechanisms could help the understanding of modifiable mechanisms in the aetiology of autism. Importantly, the absolute risk of autism was small, and, hypothetically, if no pregnant women took antidepressants, the number of cases that could potentially be prevented would be small.

Introduction
Depression is common in women of childbearing age, and in Europe 3-8% of pregnant women are prescribed antidepressants during pregnancy.1 The fetal safety of antidepressant exposure during pregnancy has generated much debate after recent concerns of a possible association with autism in exposed offspring. In the past five years, several epidemiological studies234567891011 have assessed the relation between antidepressant use during pregnancy and autism in offspring, but robust conclusions have been elusive.1213Although most studies found evidence of unadjusted associations, conclusions differed because of concerns about “confounding by indication.” This was because depression or other psychiatric indications for antidepressant use could be associated with autism through genetic or non-genetic pathways, and thus the possibility of the observed associations representing the risk of autism from the underlying indication for prescription could not be ruled out.
All antidepressants cross the placental barrier and are available to the developing fetus.14 Most of the commonly used antidepressants such as selective serotonin reuptake inhibitors (SSRIs) increase the availability of serotonin in the synaptic cleft. The serotonergic system emerges early in embryogenesis and is critical for neurodevelopment.15 In utero exposure to serotonergic antidepressants in animal models have reported associations with autism-like behaviours in the offspring.16 It is therefore biologically plausible that similar effects could be seen in humans. Disentangling a potential causal association of antidepressants on the risk of autism from that observed from confounding by indication is crucial to reduce clinical uncertainty and help women make informed decisions regarding the risks and benefits of antidepressant use during pregnancy.
In the absence of randomised controlled trials,7 however, observational studies are the only available source of making risk:benefit decisions in relation to antidepressant use during pregnancy. It is well known that such studies are prone to confounding bias, which can persist even after adjustment for multiple confounders.171819Several approaches—such as propensity score matching, negative controls, and sibling control designs—have been suggested as strategies that could strengthen causal inference in observational studies18 but remain largely unused in investigations of this issue. To help to improve the understanding of the association between antidepressant use during pregnancy and autism in offspring, we applied a range of such causal analytical methods on data from a large total population cohort in Stockholm County. We hypothesised that if the association between antidepressant use during pregnancy and autism was likely to be causal, the results would be consistent across a range of analytical methods with different strengths and limitations and underlying assumptions.