Maternal Health, Not Meds, May Play Bigger Role in Childhood ASD

Michael Vlessides

November 05, 2018

Prental exposure to most medications affecting neurotransmitter systems is not associated with the subsequent development of autism spectrum disorder (ASD) in children. However, maternal health may well play a role, a large population-based study suggests.

Among 34 medication groups, only two were associated with higher estimates of ASD risk: valproate (Depacon, AbbVie), which inhibits γ-aminobutyric acid (GABA) transaminase, and antagonists of neuronal nicotinic acetylcholine receptor α, both of which are used in the treatment of epilepsy.

By comparison, an increase in the number of medical diagnoses that expectant mothers had received was strongly associated with the development of childhood autism.

"We set out to study the role of medications, but what we really observed was that maternal health status seems to be a much more important factor for a child's neurodevelopment," principal investigator Magdalena Janecka, PhD, postdoctoral fellow, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.

"We observed that women with a higher number of medical diagnoses around pregnancy had higher rates of children with autism," Janecka added.

The study was published online October 31 in JAMA Psychiatry.

Research Challenges

For years, scientists have hypothesized that prenatal exposure to certain medications may influence the risk for ASD in children. However, the exclusion of pregnant women from clinical trials has made it difficult to determine the downstream effects of prenatal exposure to these agents.

Despite these challenges, some epidemiologic studies have uncovered associations between maternal use of antidepressants/anticonvulsants and subsequent adverse outcomes in children.

Investigators have used these trials to support the idea that early pharmacologic interference with various neurotransmitter systems may be the ultimate cause of some neurodevelopmental disorders.

However, the investigators note, most of these studies did not consider the full gamut of drugs that pregnant woman may be exposed to.

As such, drug-exposure categories were defined by grouping them according to their common physiologic targets. The investigators hypothesized that if certain drug types affect the risk for neurodevelopmental disorders, they would exert these effects regardless of either maternal indication or the internal system on which they were designed to act.

The researchers identified 55 initial groups of medications prescribed to the pregnant women that affect neurotransmitter systems. Of these, 34 were ultimately tested.

Outcomes in children who were prenatally exposed to these medications were compared with outcomes in children who were not exposed.

Participants suspected of having ASD underwent evaluation 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.

Hazard ratios (HRs) were calculated using Cox proportional hazards regression models and were adjusted for a variety of potential confounders, including birth year, maternal age, maternal history of psychiatric and neurologic disorders, and maternal number of medical diagnoses 1 year prior to pregnancy.

Risk Linked to Two Drug Groups

Only two drug groups were associated with subsequent ASD. The risk for ASD associated with neuronal nicotinic acetylcholine α receptors was found to increase after adjustments (HR, 12.94; 95% confidence interval [CI], 1.35 - 124.25; P = .03) and remained statistically significant in all sensitivity analyses.

HRs for ASD risk associated with the use of GABA transaminase inhibitors were high in both main and sensitivity analyses but were not found to be statistically significant after adjustments (HR, 3.15; 95% CI, 0.82 - 12.06; P = .09).

Interestingly, the study also identified medications associated with lower estimates of ASD risk. These were as follows:

  • cannabinoid receptor agonists (HR, 0.72; 95% CI, 0.55 - 0.95; P = .02),

  • muscarinic receptor 2 agonists (HR, 0.49; 95% CI, 0.24 - 0.98; P = .04),

  • opioid receptor κ and ε agonists (HR, 0.67; 95% CI, 0.45 - 0.99; P = .045), and

  • α2C-adrenergic receptor agonists (HR, 0.43; 95% CI, 0.19 - 0.96; P = .04).

Unlike previous research, the current study adjusted for the number of prenatal maternal diagnoses, which the investigators note may help shed new light on the role of maternal general health — and its potentially confounding effects — in the development of ASD in children.

"It's important to understand the possible consequences of this research for maternal medication use during pregnancy," Janecka said.

"Right now, many women choose to discontinue certain medications when they become pregnant. However, it seems like that may be unnecessary in certain situations and even has the potential for adverse consequences for both the mother and child if it changes the mother's health status," she added.

Caution Urged

Commenting on the study for Medscape Medical News, Diana Schendel, PhD, Aarhus University, Denmark, urged caution when interpreting the findings.

"Unfortunately, collapsing several drugs into a single mechanism category makes it difficult to tease out the effects on autism risk of individual drugs in a single category which, for example, may have been given in different doses, depending on the medical indication," she said.

Schendel, who was not involved in the research, was lead author of an accompanying editorial.

"There are other reasons why we need to be cautious before we draw a definite conclusion or rethink current clinical practice based on these results," she said.

"There can be more than one mechanism, apart from targeting a neurotransmitter, for example, by which a prenatal drug treatment could affect offspring development. Also, there is much we don't know about the pharmacological properties of many of the drugs considered in the study," Schendel added.

Janecka agreed that the study is just a first step in the research chain.

"We need robust evidence to know what medications really should and shouldn't be stopped," she said.

"But there is still a very long way to go, and this study doesn't conclusively answer these questions."

The study was supported in part by the Seaver Foundation, the National Institutes of Health, the Fredrik and Ingrid Thuring Foundation, the Swedish Society of Medicine, and the Swedish Brain Foundation. Disclosures of the authors' and editorialists' relevant financial relationships are listed in the original articles.

JAMA Psychiatry. Published online October 31, 2018. Abstract, Editorial

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