Two recent epidemiologic studies have demonstrated an association between prenatal exposure to selective serotonin reuptake inhibitor antidepressants (SSRIs) with autism spectrum disorders (ASD; Croen et al 2011, Rai et al, 2013).  One important limitation of these two studies is that parental psychiatric disorder in itself is associated with an increased risk of ASD in the offspring, and these studies could not distinguish between the effects of drug exposure and the consequences of the underlying maternal psychiatric illness.  Two new studies shed light on the association between prenatal antidepressant exposure and risk of autism spectrum disorder in the offspring.

In the first study, Danish researchers conducted a large population-based cohort study to investigate the association between maternal use of antidepressant medication during pregnancy and ASD in the offspring, adjusting for potential confounding factors.  They identified all children born in Denmark from 1996-2006 (n=668,468) and their parents using the Danish Civil Registration System. They obtained information on the mother’s prescriptions filled during pregnancy from the Danish National Prescription Registry, and on diagnoses of autism spectrum disorders in the children and diagnoses of psychiatric disorders in the parents from the Danish Psychiatric Central Register.

They observed that children exposed to antidepressants during pregnancy had an adjusted hazard ratio of 1.5 (95% confidence interval [CI] 1.2-1.9) of being diagnosed with an ASD compared with unexposed children.  The association was found for high as well as for low doses of antidepressants, and the risk estimates were similar regardless of the type of antidepressant or the timing of exposure.

Because parental psychiatric disorder carries a risk for ASD in the offspring, the researchers attempted to separate the effect of medication from that of the underlying indication for treatment.  When the researchers included only the children of women with a diagnosis of mood disorder, the adjusted hazard ratio (aHR) decreased to 1.2 (95% CI 0.7-2.1).  The risk was further reduced when exposed children were compared to their unexposed siblings (aHR = 1.1; 95% CI 0.5-2.3).

The second study, also from Danish researchers, was a population-based cohort study using the same database. In this analysis, the authors identified 3892 cases of ASD among 626,875 births in Denmark. A total of 52 cases of ASD were identified among the offspring of women using SSRIs during their pregnancy.

Compared to offspring with no exposure to SSRIs before or during pregnancy, the odds ratio (OR) of an ASD diagnosis was 1.62 (95% confidence interval [CI], 1.23 to 2.13). After controlling for various confounding factors, including maternal psychiatric diagnosis and exposure to other medications, the use of SSRIs during pregnancy was no longer associated with a significantly increased risk of ASD in the offspring (OR 1.20; 95% CI, 0.90 to 1.61).

The risk of having a child with ASD was also elevated among women who received SSRIs before – but not during — pregnancy (aOR = 1.46; 95% CI, 1.17 to 1.81).  This increased risk associated with SSRI use before pregnancy suggests that any risk associated with SSRI exposure during pregnancy may be related to genetic and/or environmental factors.

The Take Home Message

It is estimated that autism spectrum disorders affect about 1% to 2% of children.  Research carried out in twins and families indicate that ASD is highly heritable; however, it is generally believed that while genetic factors play an important role, there is an interplay between genetic and environmental factors in the etiology of this disorder.  Various environmental exposures have been implicated; however, there is no clear consensus here, and we have seen autism experts point to certain exposures (i.e., vaccines) without clear scientific evidence supporting a link to risk for autism.

Given the number of factors that may influence risk for autism spectrum disorders, it is difficult to differentiate the impact of prenatal exposure to antidepressants from other prenatal exposures and genetic factors.  Based on these studies, it appears that the association between prenatal antidepressant exposure and ASD in the offspring observed in previous studies may, all or in part, be the result of confounding factors, specifically the underlying indication for antidepressant use or other unmeasured factors related to maternal illness during pregnancy.

Ruta Nonacs, MD PhD

Hviid A, Melbye M, Pasternak B.  Use of selective serotonin reuptake inhibitors during pregnancy and risk ofautism.  N Engl J Med. 2013; 369(25):2406-15.

Sørensen MJ, Grønborg TK, Christensen J, et al.  Antidepressant exposure in pregnancy and risk of autism spectrum disorders.  Clin Epidemiol. 2013; 5:449-459.

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