New research suggests that mothers of children with autism spectrum disorder (ASD) carrying the short allele variant of the serotonergic transporter gene were more likely to have experienced stress during pregnancy.
The analysis, which involved two separate datasets, linked a specific polymorphism in the serotonin transporter gene ― the short allele of 5-HTTLPR ― among mothers of children with ASD to a higher incidence of stress during the pregnancy.
The findings, published online in Autism Research, provide important evidence that a specific gene and environment interaction affects ASD risk and underline the importance of "optimal behavioral health" during pregnancy, said author David Q. Beversdorf, MD, William and Nancy Thompson Chair in Radiology, Department of Radiology, University of Missouri, in Columbia.
The research is still emerging, and experts do not yet know how to intervene biologically to reduce the risk for autism. Nevertheless, pregnant women under significant stress might want to seek counseling, explained Dr Beversdorf.
"We are not yet at the stage where we say we need to do genotyping on all people who are pregnant, but counseling is a safe intervention; it's a reasonable, conservative, do-no-harm-first measure."
The researchers gathered information from families with a child with ASD. All children were younger than 10 years; families provided samples for genetic analysis. The datasets came from the University of Missouri (59 families) and Queen's University, in Kingston, Ontario, Canada (99 families).
At the University of Missouri, mothers completed questionnaires about their child with ASD and the gestational period of that child. They were asked about the occurrence and subjective severity of major stressful events during or within a year of the pregnancy. Participants were provided with a list of common stressors to facilitate their recall of events.
Mothers at Queens University completed questionnaires about each of their children, including those with ASD as well as those without ASD. They were asked whether there were any stressful events during the pregnancies for all of their children and, if so, what happened, when, and for how long during the pregnancy the stressful event lasted. They were not given a list of common stressors. The severity of each stressor was also recorded.
The kind of stressors that were tracked were psychosocial, for example, divorce, a major move, death of a spouse, and change in health of a family member.
The average number of reported stressors was 2.03 in the University of Missouri dataset and 0.45 in the Queens University dataset. The difference, said Dr Beversdorf, may be due to methodology; more stressors were identified when responders were presented with a list of common stressors, as at the Missouri site.
The University of Missouri cohort had a greater proportion of participants who were homozygous for the short allele (23.7%) compared with the Queen's University cohort (13.1%). There were no significant differences in the racial/ethnic makeup that might account for this difference.
In previous research by Dr Beversdorf and his team, prenatal stress was found to be associated with increased risk for ASD, especially during the fifth and sixth month of gestation. The current analysis revealed a significantly greater number of stressors during this "critical period" of pregnancy among carriers of the short allele of the serotonin transporter in both the University of Missouri cohort (P = .043) and the Queen's Univeristy cohort (P = .017).
The severity of stressors during this period was significantly different between groups in the Queen's University sample (P = .021) with a trend found in the University of Missouri dataset (P = .073). In both datasets, the stressors throughout the pregnancy were more severe in short-allele carriers.
According to Dr Beversdorf, this suggests that the findings are "robust" even given the slightly different methodologies and that "any way you slice it, there's something interesting there."
Queen's University researchers also had information on the gestational period of 109 typically developing siblings. Mothers reported no significant stress exposure during these pregnancies regardless of genotype.
This, according to Dr Beversdorf, suggests that "this isn't some strange epiphenomenon" of mothers with this allele being better able to remember stressors. "They looked at unaffected siblings and found nothing there; there was no bump in stressors, no increased incidence, no temporal specificity, so it does mean something specific for autism, not for recall of stress."
Of the 99 children with ASD in the Queen's University group, 50.5% were first born; of the 109 typically developing siblings, 34.9% were first born. The increased rate of first-born children in the ASD group may simply be due to families choosing not to have more children after having a child with ASD, said Dr Beversdorf.
There was not enough available information to say whether the severity of stressors was linked to the severity on the autism spectrum. "We didn't have severity data in the study to track that," said Dr Beversdorf. "I would love to know more about that in subsequent studies, as it is an important question."
Interestingly, though, a post hoc analysis in his original study (J Autism Dev Dis. 2005;35:471-478) that investigated the impact of maternal prenatal stress on ASD risk (without genetic data) showed that a larger proportion of stress-exposed children with ASD failed to develop language than did children with ASD who were not exposed to stress.
Researchers are beginning to look at biological factors, such as the effects of the immune system and of gene expression, as potential biomarkers in mothers, said Dr Beresdorf.
"If it turns out that there is something phenotypically different about these affected children that results from this apparent etiology, that may impact treatment, but we have nothing to go on yet."
Medscape Medical News invited Eric Hollander, MD, director, Autism and Obsessive Compulsive Spectrum Program, and clinical professor of psychiatry and behavioral Sciences, Albert Einstein College of Medicine and Montefiore Medical Center, New York City, to comment on the study.
An advantage of the study, said Dr Hollander, is that it had an independent replication sample.
"They collected two different samples in two different locations and saw similar findings in both sites, so in a sense, it's an internal replication, and that strengthens the findings."
The study is "intriguing," but the sample size is "not overwhelming," said Dr Hollander.
"Although it's nice that they replicated it at two different sites, it would also be good to replicate it in larger existing samples."
He found it interesting that the authors focused on the timing of the stressors during pregnancy. Stressful events during the 5th and 6th month of gestation may have a critical impact on development of brain circuits and synaptic connections, said Dr Hollander.
Maternal stress might increase the risk of the offspring having a range of different disorders, not just ASD, according to Dr Hollander.
It may also be that other factors, in addition to maternal stress, increase the risk for ASD. Dr Hollander pointed out that researchers are investigating maternal inflammation.
There is evidence, he said, that exposure to the flu virus during pregnancy increases the risk of offspring having ASD. "In fact, some animal models show that if you expose mothers to the protein coat of the virus ― so they're not actually getting an infection, just triggering an inflammatory response ― there's an increased risk for the offspring."
The research was supported by the the Mizzou Advantage Initiative, the University of Missouri College of Medicine Mission Enhancement Fund, and the Ongwanada Fund.
Autism Res. Published online April 19, 2016. Abstract
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Cite this: Stress During Pregnancy Linked to Autism - Medscape - Jun 17, 2016.