Prenatal Exposure to Asthma Drugs May Boost Autism Risk

Liam Davenport

January 19, 2016

Prenatal exposure to commonly used asthma drugs may increase the risk for autism spectrum disorders (ASDs), new research shows.

Investigators found that exposure to beta-2-adrenergic receptor (B2AR) agonists during pregnancy is associated with an increased risk for ASD. The risk was similar in all trimesters.

However, lead author Nicole B. Gidaya, PhD, Drexel University School of Public Health, Philadelphia, Pennsylvania, warned that any concerns over ASD must be balanced against the risks posed by uncontrolled asthma.

"During an asthma exacerbation in pregnancy, the prenatal maternal stress response may be elevated, which would be harmful during a time when the fetal limbic system is considered to be the most vulnerable to such a stress response, especially before 32 weeks of gestation," Dr Gidaya told Medscape Medical News.

"Consequently, any ASD risk associated with maternal B2AR agonist drug use needs to be balanced against the benefits of indicated medication use by pregnant mothers."

The study was published online January 6 in Pediatrics.

More Research Needed

To examine associations between B2AR agonist exposure during pregnancy and ASD risk, the team examined data from the Danish Civil Registration System, the National Hospital Register, and the Danish Psychiatric Central Register. They identified 5200 patients with ASD and 52,000 individuals who did not have ASD. These latter persons were matched by month and year of birth and served as control participants. All participants were born between between 1997 and 2006.

Exposure to B2AR agonists was determined by use of data from the Drug Prescription Register. However, these data did not provide information on the use of B2AR agonists as tocolytic agents during the third trimester, and so it is likely that exposure was underestimated for the final trimester.

The frequency of exposure to B2AR agonists during pregnancy was 3.7% for ASD patients and 2.9% for control persons.

Conditional logistic regression analysis, which took into account maternal asthma and other potential confounders, revealed that use of a B2AR agonist was associated with an increased risk for ASD (odds ratio [OR], 1.3; P < .05).

The risk for ASD was elevated at all time points around pregnancy, including preconception (OR, 1.3) and the first, second, and third trimesters (OR, 1.3, 1.5, and 1.4, respectively). All associations were significant (P < .05), apart from associations during the first trimester.

Despite this, Dr Gidaya said that the risk for ASD associated with B2AR agonist exposure was similar throughout pregnancy.

"The trimester-specific effect estimates had confidence intervals with substantial overlap, indicating that results do not provide strong evidence suggesting a particular critical exposure window," she said.

Dr Gidaya noted that this is supported by the results of previous mechanistic studies.

"Given that B2ARs cross the placenta and have varied neurodevelopmental effects, it is biologically plausible that effects could be observed across multiple periods," she said.

In addition, the findings indicated that the risk for ASD increased with longer B2AR agonist exposure, defined as exposure of longer than 45 days.

"Prenatal pharmacologic exposures are one of the few known environmental risks factors for ASD. Although these drugs are now rarely prescribed during pregnancy, they provide proof of principal for associations between prenatal pharmacologic exposures and ASD," said Dr Gidaya.

"The fact is that the teratogenic risks, especially with respect to neurodevelopmental outcomes, of many other drugs are still undetermined."

Regarding the potential risks posed by B2AR agonist use, Dr Gidaya noted: "Additional studies need to replicate this present study before the implications of prenatal B2AR agonist drug exposure through maternal use of these agents for asthma control on ASD risk can be considered when making individual decisions about asthma control in pregnancy."

She added: "Further consideration of the biological mechanisms underlying these exposure effects could also lead to an improved understanding of common etiologic pathways in ASD that, in turn, might then inform potential prevention or treatment strategies that would affect larger number of ASD cases."

No Causality

Commenting on the findings for Medscape Medical News, Michael Rosanoff, MPH, director of public health at the advocacy organization Autism Speaks, said the current research represents "yet another study that hints at the complexity of autism and the sensitivity of child neurodevelopment during pregnancy.

"Its findings suggest a link between prenatal exposure to drugs used to treat asthma and increased risk of autism in children. However, the increased risk is very modest and certainly does not suggest asthma medication causes ASD."

Paul Wang, MD, a developmental/behavioral pediatrician and senior vice president and head of medical research at Autism Speaks, added that "all drugs have risks, and those risks have to be weighed against the risks of discontinuing the drugs.

"Asthma drugs are no exception. Leaving asthma untreated is dangerous for the mother and for her pregnancy."

Drexel University's Department of Epidemiology and Biostatistics provided fees to access data from Denmark's national registers. Dr Gidaya's travel to Denmark was supported by a Drexel University student travel subsidy grant. No other relevant financial relationships have been reported.

Pediatrics. Published online January 6, 2016. Abstract

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