Concerns regarding a link between antidepressant use during pregnancy and autism emerged when two epidemiologic studies demonstrated an association between prenatal exposure to selective serotonin reuptake inhibitor antidepressants (SSRIs) with an increased risk of autism spectrum disorders in the offspring (ASD; Croen et al 2011, Rai et al, 2013). One important limitation of these earlier 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.
Since that time, there have been a series of studies which have demonstrated no association between prenatal exposure to SSRIs and risk for ASD. A new study published in JAMA Psychiatry takes another look at the prevalence of ASD among children exposed not only to SSRIs, but to other psychotropic medications which modulate neurotransmitter systems.
In this case-control study, researchers analyzed data from an Israeli health maintenance organization which included children born between January 1, 1997 and December 31, 2007. Rather than focusing on the type of medication used (e.g., antidepressants, antipsychotics) the researchers defined 34 groups of medications affecting different neurotransmitter systems (e.g., opioid receptor kappa agonists, muscarinic receptor 2 agonists) which had been prescribed to pregnant women in this sample. Children prenatally exposed to medications were compared with non-exposed children. Hazard ratios (HRs) and 95% CIs of ASD risk associated with prenatal exposure were calculated and adjusted for various confounding variables (e.g., birth year, maternal age, maternal history of psychiatric and neurologic disorders).
The analytic sample included 96,249 children (1405 with a diagnosis of ASD and 94,844 controls; mean [SD] age at follow-up, 11.6 [3.1] years; 48.8% female).
For most of the 34 groups of medications analyzed in this study, including SSRIs, other types of antidepressants, and antipsychotics, the researchers did not observe an association between prenatal exposure to medication and risk for ASD. One medication group in this sample was associated with a statistically significant increase in estimates of ASD risk. Exposure to antagonists of neuronal nicotinic acetylcholine receptor ? was associated with higher estimates of ASD risk (HR,?12.94; 95% CI, 1.35-124.25; P?=?.03). This category of medications includes anticonvulsants (primidone, biperiden, phenobarbital) and methadone.
Another interesting finding was that mothers with a higher number of diagnoses (medical and psychiatric) had a higher risk of having a child with ASD. While we cannot make conclusions regarding the nature of this association, it highlights the challenges we face with regard to disentangling the contributions of genetic vulnerability, environmental exposures, medication, and maternal illness to the development of ASD.
This study takes a novel approach to measuring the risks associated with prenatal exposure to medications. By focusing on the medications’ mechanisms of action, rather than on the types or classes of medications, the researchers attempt to minimize confounding by the underlying indication for the use of a particular medication. This is particularly important in understanding the risks associated with antidepressant exposure as the genetic factors which confer vulnerability to depressive illness (and thus may be associated with use of an antidepressant) appear to overlap to some degree with genetic factors which confer vulnerability to ASD.
There is no such thing as a perfect study when it comes to addressing the reproductive safety of medications. In such a study, we would randomize pregnant women to receive treatment with medication or placebo and assess the outcomes. Obviously this is not possible, and we are thus left to interpret data form imperfect studies with disparate methodologies in order to evaluate the reproductive safety of various medications.
This is by no means a stand alone study; however, it does add to a growing body of literature which does not support an association between prenatal exposure to antidepressants and increased risk for ASD in the offspring.
Ruta Nonacs, MD PhD
Janecka M, Kodesh A, Levine SZ, Lusskin SI, Viktorin A, Rahman R, Buxbaum JD, Schlessinger A, Sandin S, Reichenberg A. JAMA Psychiatry. 2018 Oct 31.