BY LIZETTE BORRELI
Does prenatal exposure to drugs that target neurotransmitter systems increase the risk of adverse neurodevelopmental outcomes, including autism spectrum disorder? A new analysis of drugs in these categories suggests it does not.
Prior studies have suggested that early interference with serotonergic, gamma-aminobutyric acid GABAergic, or glutaminergic systems could underlie some neurodevelopmental disorders. But in the population-based, case control study published online on October 31 in JAMA Psychiatry, researchers found that among 34 medication groups prescribed to pregnant women, the only two drugs that conferred a higher probability of risk for autism spectrum disorder were valproate, which inhibits GABA, (p = .09), and antagonists of neuronal acetylcholine alpha receptor (p = .03), both used to treat epilepsy.
The research team said maternal health and the conditions for which a mother takes the medication, may play a more critical role in child neurodevelopment. An increase in the number of maternal medical diagnoses during pregnancy was strongly associated with the risk of autism in children.
"Our study sheds new light on the role of maternal general health and its potentially confounding effects in pharmacoepidemiologic studies on [autism]," the researchers, led by Magdalena Janecka, PhD, of the Seaver Autism Center for Research and Treatment at the Icahn School of Medicine at Mount Sinai in New York City, wrote.
Unlike previous studies, the current study adjusted for prenatal maternal diagnoses, or the total number of reported health issues from one year before pregnancy until giving birth.
Adjusting for these factors, the researchers found medications associated with lower estimates of autism risk were cannabinoid receptor agonists (p = .02), muscarinic receptor 2 agonists (p = .04), opioid receptor κ and ε agonists (p = .045), and alpha2C-adrenergic receptor agonists (p = .04).
For their the analysis, the researchers reviewed data on children in an Israeli health maintenance organization who were born between January 1997 and December 2007 and monitored for autism until January 2015. In total, the sample size consisted of 96,249 individuals; 1,405 children with autism and 94,844 controls. The average age at the end of follow-up was 11.6 years and 48.8 percent were female.
They grouped drug-exposure categories based on their biological target, and not the conditions the drugs were designated to treat. They reasoned that if certain types of pharmaceuticals affect autism risk by interfering with neurodevelopment, they would exert their effects regardless of the maternal indication.
The outcomes in children who were prenatally exposed to these medications were compared to outcomes in children who were not exposed.
Participants suspected of autism underwent evaluation by a panel of by a group of social workers, a psychologist, and either a trained psychiatrist, a developmental behavioral pediatrician, or a child neurologist. The final diagnosis was made by a board-certified developmental behavioral pediatrician.
The researchers observed evidence of confounding effects of the number of maternal diagnoses on the associations between prenatal medication exposure and autism.
The data provided no support for the role of serotonin transporter in autism risk after adjusting the maternal number of diagnoses (HR 1.06, 95% CI 0.76-1.48; p = 0.73).
"The study remains exploratory in nature, and we acknowledge the limitations associated with our approach and the need to validate our findings through other epidemiologic (because the rates of ASD in Israel are low, the generalizability of our findings remains to be verified) and experimental studies," the study authors wrote.
This study received support from the Seaver Foundation, the National Institutes of Health, the Fredrik and Ingrid Thuring Foundation, the Swedish Society of Medicine, and the Swedish Brain Foundation.
Researchers disclosed relationships with Shire Pharmaceuticals, Forest Laboratories, Pfizer, the Reproductive Toxicology Foundation, and UpToDate. Editorialists reported relationships with Union Chimique Belge Nordic, Eisai AB, the Lundbeck Foundation, and the Novo Nordisk Foundation.
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Janecka M, Kodesh A, Levine SZ, et al. Association of autism spectrum disorder with prenatal exposure to medication affecting neurotransmitter systems. JAMA Psych 2018; Epub 2018 Oct 31.