Maternal thyroid-hormone imbalances, particularly concurrent chronic and gestational hypothyroidism, were associated with a dose-dependent increased risk for autism spectrum disorder (ASD) in offspring, a new study found.

In contrast, chronic (prepregnancy) hypothyroidism alone — assumed to reflect adequate treatment during pregnancy — was not found to be associated with ASD in the offspring.

Previous studies have demonstrated an association between maternal thyroid dysfunction and adverse neurodevelopmental outcomes in offspring, “but it wasn’t known whether the timing of the thyroid condition was important,” said lead study author Idan Menashe, PhD, professor in the Department of Epidemiology, Biostatistics, and Community Health Sciences at Ben Gurion University of the Negev, Beersheba, Israel.

The current findings come from a retrospective cohort study of mothers who gave birth over a 6-year period at a single hospital in Israel. It was recently published in the Journal of Clinical Endocrinology and Metabolism.

The main takeaway, Menashe told Medscape Medical News, “is to test all pregnant women because it may make a difference in the risk of autism in their children. It’s very easy to test, and very easy to treat.”

Persistent Hormonal Imbalance, Duration Increase ASD Risk

A total of 4409 mothers (8.6%) with abnormal thyroid function were identified at the time of pregnancy screening from 51,296 singleton births at Soroka University Medical Center, Beersheba, Israel, during 2011-2017. Of those, 1161 had chronic hypothyroidism,1600 had gestational hypothyroidism, and 1054 had both. Another 100 women had chronic hyperthyroidism, 376 had gestational hyperthyroidism, and 15 had both. The chronic conditions were identified using International Classification of Diseases, Ninth Revision, codes, while gestational diagnoses were based on trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine 4 (FT4) levels.

Children with ASD were identified from a hospital database. There were no significant differences in cumulative incidence of ASD between the offspring of women with normal thyroid function and those with any thyroid dysfunction (P = .27). Cumulative ASD incidence among offspring also didn’t differ in those with either chronic thyroid dysfunction alone or gestational thyroid dysfunction alone compared with normal thyroid function.

However, the cumulative ASD risk was significantly higher among children born to mothers diagnosed with both chronic and gestational thyroid dysfunction than those born to mothers with normal thyroid function (P = .0002).

In adjusted models, no significant associations were found between “any thyroid dysfunction” (hypo- or hyper-, gestational, or chronic) and ASD risk, while hypothyroidism and hyperthyroidism showed opposite but nonsignificant associations.

Having both chronic and gestational thyroid dysfunction, however, was associated with more than a doubling of ASD risk (adjusted hazard ratio [aHR], 2.68), whereas chronic-only and gestational-only dysfunction were not associated with ASD.

A possible dose-response relationship in thyroid hormone levels was seen among those with gestational hypothyroidism, in that offspring of women with overt hypothyroidism had a higher ASD risk than those with subclinical hypothyroidism (aHR, 2.11 and aHR, 1.65, respectively, compared with normal thyroid function). Also, there was a significant 28%-39% increase in ASD risk for each additional trimester of thyroid dysfunction.

“Based on these data, we saw that the timing is important. The longer the hormonal imbalance during pregnancy, the higher the risk of autism,” Menashe said.

Similar analyses were not done in the women with hyperthyroidism due to the low numbers.

Universal Screening? Not Everyone Agrees

All pregnant women in Israel receive thyroid hormone screening, but that’s not the case everywhere, including the US. Guidelines from the American Thyroid Association (ATA) and the American College of Obstetrics and Gynecology advise screening only women with risk factors for thyroid disease.

“There’s a very good reason for that, and I don’t think this study changes that recommendation,” ATA guideline author Elizabeth N. Pearce, MD, an endocrinologist at Boston Medical Center, Boston, told Medscape Medical News.

Asked to comment on the study, Pearce said that this paper certainly adds to the current evidence base that overt maternal hypothyroidism (high TSH, low FT4) is associated with an increased risk for adverse neurodevelopmental outcomes in children and requires treatment.

But she added, “We knew that already. There is zero controversy about treating that when we find it, but that’s maybe half of 1% of pregnant women. It’s relatively uncommon.”

Universal screening would pick up those women but also would identify larger groups who have either mild hypothyroidism (high TSH and normal FT4) or isolated hypothyroxinemia (normal TSH and low FT4). In those individuals, “we do not have any evidence from randomized clinical trials that initiating levothyroxine improves outcomes. We have, in fact, trial data published in The New England Journal of Medicine in 2012 and in 2017 showing that it didn’t,” said Pearce, professor of medicine at Boston University Chobanian & Avedisian School of Medicine, Boston.

What’s more, she noted, data have also suggested that children of women who are overtreated with thyroid hormone may also be at a higher risk for ASD and attention-deficit/hyperactivity disorder, “so this may well be a U-shaped relationship, if this association is real. I think we’re going to need more studies that look at both ends of the spectrum.”

No Perfect Studies as Yet

Both Menashe and Pearce pointed to the lack of treatment data as a study limitation, although it was presumed given common clinical practice in Israel. “Unfortunately, we didn’t have information about treatment, but we believe that any woman who was tested and found to be imbalanced got treatment, while those who maintained thyroid hormone dysfunction may have [had] a specific condition that is hard to treat,” Menashe said.

But, Pearce pointed out, “If you look at studies looking at the longitudinal trajectory of hypothyroidism in pregnancy, in a remarkable number of cases when it’s mild it actually normalizes with no treatment. So we don’t know for sure whether the lack of persistence really meant that there was an intervention.”

She added that while this paper “does strengthen the evidence base,” at the same time “all of the observational studies that have looked at these questions to date are limited. The perfect studies probably have not been done yet.”

Menashe said that he and the first author, PhD student Leena Elbedour, are proceeding with further research into the possible role of other maternal autoimmune conditions and the risk for autism in offspring.

“We are designing a study like this one trying to pinpoint the mechanism that may explain this association, whether it’s genes that are causing autoimmune diseases in the mother and may also increase the risk for autism,” or if it’s “the actual immune system or immune cellular component that are transferred to the fetus,” which then causes abnormal neurodevelopment, said Menashe.

“We don’t really know, so we’re designing studies that try to answer these questions.”

The study authors had no disclosures. Pearce reported being on the ATA task force writing the upcoming ATA maternal thyroid disease guidelines.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.