This article is more than 5 years old. Information may no longer be current.

Prenatal exposure to drugs targeting neurotransmitters may not affect autism risk

Prenatal exposure to certain medications known to affect neurotransmitter systems may not affect the estimates of autism spectrum disorder risk in offspring, according to findings published in JAMA Psychiatry.

The results indicated that the higher estimates of autism risk among children born to mothers taking certain medications during pregnancy were most likely not due to the pharmacologic effects of those drugs.

“Pregnant women are exposed to a much wider range of drugs than those considered to date, including medications with potentially protective effects on the fetus,” Magdalena Janecka, PhD, from the psychiatry department, Icahn School of Medicine at Mount Sinai, and colleagues wrote.

“[We grouped] the drugs prescribed to pregnant women in our cohort and known to affect neurotransmitter systems based on their targets,” they continued. “The rationale behind our approach is that if certain types of pharmaceuticals affect the risk of the disorder by interfering with some facets of neurodevelopment, they will exert their effects regardless of maternal indication or the internal system on which they were designed to act.”

Researchers conducted a population-based case-control study of Israeli children to determine whether prenatal exposure to medications affecting neurotransmitter systems increased the risk for autism spectrum disorders in offspring.

Using data from a large health maintenance organization, the investigators identified 34 groups of medications affecting neurotransmitter systems prescribed to pregnant women in a sample of 95,978 individuals. They compared autism risk among children prenatally exposed to medications with nonexposed children, adjusting for birth year, maternal age, maternal history of psychiatric and neurologic disorders, or maternal number of all medical diagnoses 1 year prior to pregnancy.

The sample included 1,405 autism cases and 94,844 controls. In fully adjusted models, five of 34 medication groups showed nominally statistically significant associations with ASD. Janecka and colleagues found that the number of maternal diagnoses had confounding effects on the link between offspring exposure to medication and ASD. After adjusting for this, they observed lower estimates of autism risk among children exposed to:

• cannabinoid receptor agonists (HR = 0.72; 95% CI, 0.55-0.95);
• muscarinic receptor 2 agonists (HR = 0.49; 95% CI, 0.24-0.98);
• opioid receptor and agonists (HR = 0.67; 95% CI, 0.45-0.99); or
• 2C-adrenergic receptor agonists (HR = 0.43; 95% CI, 0.19-0.96).

“All groups of medications associated with reduced risk of ASD are used as anti-analgesic and/or anti-inflammatory agents, consistent with the previous reports of associations between maternal fever, inflammation, and immune-activation during pregnancy and ASD in her offspring,” the researchers wrote.

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).

“Our data indicate that, in the current sample, most of the medications known to affect the neurotransmitters and used by women during pregnancy may not themselves influence the estimates of offspring risk of ASD via effects on their known pharmacologic targets,” Janecka and colleagues wrote. “However, maternal number of diagnoses can confound associations between prenatal exposures and ASD and as such should be accounted for in the future studies.”

These study findings should be seen as exploratory, Diana Schendel, PhD, of the Lundbeck Foundation Initiative for Integrative Psychiatric Research and Aarhus University, Denmark, and colleagues wrote in a related editorial.

Future work could follow their example in suitably powered studies and with refinements ... to strengthen causal inference,” Schendel and colleagues wrote.

“In view of heterogeneous results by cognitive ability in autism, this could be best done by examining autism subgroups, which may differ in their susceptibility to a drug exposure,” they continued. “However, no single strategy may be enough to account for confounding by indication, and in the absence of randomized clinical trials, the above approach may be one of several tools in the epidemiologist’s toolbox to seek consistency or triangulation of findings across various methods with different strengths and limitations.” – by Savannah Demko

Disclosures: Janecka reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Schendel reports grant support from the Lundbeck Foundation and NIH. Please see the editorial for all other authors’ relevant financial disclosures.