In scientists’ search to understand the causes of autism, a spotlight has fallen on maternal health during pregnancy. Based partly on association studies, researchers have proposed that conditions including obesity and depression during pregnancy could lead to autism in a child by affecting fetal neurodevelopment.
But a study of more than 1 million Danish children and their families, published today in Nature Medicine, pushes back against this view. Researchers analyzed more than 200 health conditions that occurred in these children’s mothers before or during pregnancy. They conclude that many of the supposed links to a child’s autism diagnosis may not be causal, and instead reflect inherited genetic variants or environmental factors shared within families.
“It’s a very comprehensive and well-done study,” says Håkan Karlsson, a neuroscientist at the Karolinska Institute who was not involved in the work. It suggests “conditions [pregnant people] suffered from during pregnancy are probably not the cause of autism in their kid.” The findings dovetail with a growing view in the field that shared genetics could explain a lot of the apparent connections between maternal health and autism, adds Drexel University epidemiologist Brian Lee. However, he and others caution the study doesn’t rule out that some conditions during pregnancy could have a causative role, nor does it identify factors that do influence the likelihood of autism.
Previous research has linked conditions such as maternal obesity, psychiatric disorders, and pregnancy or birth complications to an increased likelihood of autism diagnoses in children. Such findings can lead some pregnant people to feel that “if they get this or that condition, their [child’s] chance of autism may increase,” says Magdalena Janecka, an epidemiologist at New York University’s Grossman School of Medicine and a co-author on the new paper.
Several recent studies have highlighted flaws in this reasoning, noting that observed links may actually reflect genetic predispositions to autism passed from parents to children, or shared environmental factors, such as household exposure to pollutants, that are also associated with the condition. For example, a 2022 study of thousands of Norwegian parents found that people carrying genetic variants linked to neurodevelopmental conditions including autism were also more likely to experience pregnancy-related health issues associated with those same neurodevelopmental conditions in children. This suggests inheritance of the genetic variants, rather than the maternal health problems themselves, partly explain the increased chance, the study authors note.
In the new research, Janecka and her colleagues set out to systematically test for this so-called familial confounding in an even larger group. They used records in the Danish national health registry from roughly 1 million children born between 1998 and 2015, more than 18,000 of whom had received diagnoses of autism spectrum disorder. The team then looked at health conditions documented in the children’s mothers. Thirty of these conditions, including depression and various pregnancy complications, showed a link to autism diagnosis even after the team had run statistical analyses to try to account for socioeconomic, demographic, and other known confounding factors.
Next came the hunt for familial confounding. First, Janecka’s team analyzed the incidence of autism in families with more than one child where the mother had a health condition during one pregnancy, but not another. For most of the 30 conditions, they found the likelihood of an autism diagnosis among siblings was relatively stable, regardless of which pregnancy had been affected, Janecka says. What’s more, health issues documented in the children’s fathers were associated with similar likelihoods of an autism diagnosis as the maternal conditions. (The team couldn’t run this paternal analysis for pregnancy-specific complications, such as preeclampsia and gestational diabetes.)
Those findings indicate familial confounding is widespread in the observed associations, weakening the argument that maternal health conditions directly cause autism by affecting development in utero, Janecka says. She adds that the evidence for confounding was stronger for some conditions, such as obesity and mental health disorders such as depression, than others, such as gestational diabetes.
Lee and others caution against interpreting the paper as meaning that autism isn’t affected at all by maternal health, or that it’s entirely genetically determined. The analyses used in the paper are a “blunt instrument” that can’t get at mechanisms underlying autism, he adds.
Some scientists also criticize the paper’s claim that “most of the observational associations are attributable to family-level factors.” The study didn’t use the specialized statistical methods needed to make claims about causation, says Peter Tennant, an epidemiologist at the University of Leeds, making it “difficult to draw definitive conclusions.” He adds that additional confounding factors, such as how often a pregnant person used health care—something that itself is likely linked to that person’s health—might have skewed the study results.
Janecka acknowledges that potential confounder, though she thinks it’s unlikely to have had a strong impact and stands by the team’s conclusions. For now, she says, her team is working to combine its findings with genetic data from Danish families to test whether shared genes can explain a lot of the associations between maternal health and child autism. Either way, she says, parents and families “deserve to know the true role of these [health] conditions in their child.”
