Antidepressant use during pregnancy does not raise the risk of autism spectrum disorder (ASD), according to two large observational studies published online today in JAMA.

Previous studies suggested increased risk for ASD in children with in utero exposure to antidepressants. However, evidence supporting such a link remains inconclusive, and prior studies may not have adequately accounted for potential confounding, researchers say.

For their study, Dr. Brian D'Onofrio, Indiana University, Bloomington, and colleagues examined associations between first–trimester antidepressant exposure and neurodevelopmental outcomes in nearly 1.6 million Swedish children and found that first–trimester maternal antidepressant use was associated with a small increased risk of preterm birth (odds ratio 1.34) but not with risk of ASD (hazard ratio 0.83), attention–deficit/hyperactivity disorder (HR 0.99) or small for gestational age (OR 1.01).

Unexposed siblings were at equal risk for poor fetal growth, ASD and ADHD as their exposed siblings.

“These results are consistent with the hypothesis that genetic factors, familial environmental factors, or both account for the population–wide association between first–trimester antidepressant exposure and these outcomes,” Dr. D'Onofrio and colleagues write in their paper.

“The information can help physicians collaboratively work their depressed patients to decide the best course of action. Deciding on the best course of treatment should be based on multiple factors, including the severity of the depression, the woman’s history of previous treatment, and accessibility to services,” Dr. D'Onofrio noted in email to Reuters Health.

Dr. Simone Vigod, Women's College Hospital, Toronto, Canada and colleagues failed to find an association between ASD and in utero exposure to a serotonergic antidepressant based on data from nearly 36,000 singleton births. In this analysis, ASD incidence was not statistically significantly different between exposed and unexposed siblings (3.40 vs 2.05 per 1000 person–years, respectively; adjusted HR, 1.60).

Dr. Vigod added in email to Reuters Health, “It is very difficult to have certainty on this question because the causes of autism are so multifaceted, and there are limitations to any research analysis. However, I believe that clinicians can take away the message from our study, combined with other rigorously conducted studies in this field, that it appears unlikely that antidepressant exposure in pregnancy is causally related to autism. These results should be reassuring for women who are required to take these medications to maintain their mental health in pregnancy.”

The co–authors of a linked editorial say, “An important methodological extension in this study was the use of a high–dimensional propensity score to adjust for 500 covariates that might collectively contribute to confounding.”

A meta–analytic review online April 17 in JAMA Pediatrics hints that the timing of prenatal antidepressant exposure may be a factor in ASD risk.

Dr. Florence Gressier from Bicetre University Hospital in France and colleagues identified 10 relevant studies, albeit with “inconsistent results.”

In their analysis of prenatal exposure, they found evidence of a positive association between antidepressant exposure and ASD (odds ratio 1.81) but the association was weaker when controlled for past maternal mental illness (OR 1.52). However, preconception exposure to antidepressants was significantly associated with an increased risk for ASD after controlling for past maternal illness (OR 1.77).

They conclude: “Maternal psychiatric disorders in treatment before pregnancy rather than antenatal exposure to antidepressants could have a major role in the risk for ASDs. Future studies should address the problem of this potential confounder.”

—Megan Brooks