High Maternal Thyroid Function Affects Offspring Brain Development

Nancy A Melville

October 21, 2015

ORLANDO, Florida — While low maternal thyroid function during pregnancy has been linked to adverse effects on offspring brain development, new research suggests that high maternal thyroid function in early pregnancy is also linked to similar effects, including lower IQ, in offspring observed at age 6.

"We know that in nature, as is seen for instance for blood pressure, glucose levels, or iodine status, levels can be too low but also too high, and we now show that this is also the case for maternal thyroid hormone levels during pregnancy," first author Tim IM Korevaar, MD, of Erasmus Medical Center, in Rotterdam, the Netherlands, told Medscape Medical News.

The findings were presented here at the 2015 International Thyroid Congress and Annual Meeting of the American Thyroid Association (ITC/ATA) and published simultaneously in Lancet Diabetes & Endocrinology.

The data suggest the need for caution in treatment of low thyroid function in pregnancy in order to avoid overtreatment and pushing patients into higher thyroid hormone levels, said Dr Korevaar.

"Importantly, our data also suggest that in women receiving levothyroxine therapy for preexisting disease or subclinical gestational thyroid disease there is the potential of overtreatment when the dosage is high and/or titrated too fast," he stressed.

In an editorial accompanying the article, Erik K Alexander, MD, of the thyroid section, department of medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, says: "It is becoming increasingly apparent that the available data, now further supported by Korevaar and colleagues' findings, confirm the importance of normal maternal thyroid function during pregnancy.

"These data now provide increasing support to conclude that even mild to moderate perturbations in maternal thyroid status can have a long-term effect on the developing offspring.

"What we continue to seek, however, is just what 'normal' means and the best way to precisely identify, treat, and prevent what is abnormal."

U-Shaped Association of Thyroid Function and Neural Development

Using data from the Generation R Study, a population-based prospective cohort study from early fetal life onward in Rotterdam, the Netherlands, which included MRI, Dr Korevaar and his colleagues identified mother-child pairs and found that free thyroxine (free T4) levels in early pregnancy, measured between 9 to 18 weeks' gestation, had an inverted U-shaped association with total gray-matter volume (P = .006) and cortex volume (P = .001) in 646 offspring on MRI at a median age of 8 years.

Association between maternal free thyroxine and offspring brain morphology [©Lancet Diabetes & Endocrinology. Used with permission. For a larger view, click here]

Data on child IQ, assessed by nonverbal intelligence tests and available on 3839 mother-child pairs, also showed an inverted U-shaped association (P = .004).

Specifically, in the inverted U-shaped pattern, low as well as high levels of maternal free T4 concentrations each corresponded with a 1.4- to 3.8-point reduction in mean child IQ.

Association between maternal free thyroxine and offspring IQ [©Lancet Diabetes & Endocrinology. Used with permission. For a larger view, click here]

No association was seen between maternal thyroid-stimulating hormone (TSH) levels and child IQ or brain morphology.

The associations remained similar after exclusion of women with overt hypothyroidism and overt hyperthyroidism and after adjustment for concentrations of human chorionic gonadotropin (hCG), thyroid peroxidase antibodies, and child TSH and free thyroxine

"It was a surprise to us that neither the pregnancy hormone hCG nor the thyroid function of the child itself changed the association between free T4 and brain development," Dr Korevaar said.

The findings underscore the need for clinicians to monitor pregnant patients' free T4 levels, in addition to the more commonly monitored marker of thyroid function, TSH, he added.

"[Awareness of free T4 is important], because TSH levels are considered as the most important marker for thyroid hormone availability during pregnancy, while neither properly executed previous studies nor our study show an effect of maternal TSH levels on neurodevelopmental outcomes," he stressed.

Concern About Accuracy of Free T4 Assays

In his presentation, Dr Korevaar also addressed some concerns raised at the ITC meeting about questionable accuracy of free T4 assays.

"It has been observed that in the third trimester, most assays underestimate the role of free T4," likely due to various pregnancy changes, he said.

He noted that international guidelines recommend the use of trimester-specific, population-based reference ranges for free T4 and added that calculations of normal and abnormal ranges can be relatively simple to perform.

"In your own lab, you take the median 95th percentiles and determine what's low and high, and if you do this for your specific assay, you will catch women with high or low free T4, regardless of the measurement error your assay has."

In commenting on the findings, John Lazarus, MD, an emeritus professor of clinical endocrinology at Cardiff University School of Medicine, Wales, said the study contributes importantly to the growing focus on the role of free T4 in maternal thyroid function. "I think that free T4 is the relevant biomarker in the mother as it is the moiety that is transported to the fetus in early pregnancy — not TSH," he told Medscape Medical News.

"It is the case that not enough attention has been paid to free T4 as [compared with] TSH, but I believe this is changing as a result of this and other studies."

Dr Alexander agreed: "It is becoming increasingly logical that free hormone measurements [of thyroxine and triiodothyronine], and not only levels of maternal TSH, should be accurately assessed in all patients, especially as part of future clinical trials."

Perhaps the most notable aspect of this study is "the anatomical MRI data obtained from more than 600 children, showing a reduction in total gray matter and cortical volume when maternal free thyroxine concentration was less than the tenth percentile or more than the 90th percentile," he added.

"Never before has such extensive imaging data been available to assess the effects of maternal thyroid dysfunction on fetal brain development."

Dr Lazarus concurred that the inclusion of MRI findings is important but pointed out the study has the limitation of not being randomized.

"This is the first large study to show these findings, so it should be replicated by others. It is not a randomized trial, which is considered the best evidence for health recommendations."

Fetal Programming: Role of Maternal Thyroid Function Debated

The issue of the influence of maternal thyroid function on offspring development was also a focus of much discussion and debate throughout the meeting, including a talk describing the emerging concept of "fetal programming," supported by various recent additional studies linking thyroid levels in pregnancy with fetal outcomes.

"The hypothesis of fetal programming by maternal thyroid disease is biologically plausible for disorders linked to alterations during fetal brain development," said speaker Stine Linding Andersen, MD, PhD, of the departments of endocrinology and clinical biochemistry at Aalborg University Hospital, Denmark.

Dr Andersen described wide-ranging studies linking maternal thyroid conditions, including hyper- and hypothyroidism, iodine deficiency, and high and low function to neurodevelopmental conditions in offspring, including seizure disorders, autism-spectrum disorders, attention-deficit/hyperactivity disorders, and psychiatric disorders.

"It can be speculated that if maternal thyroid dysfunction in pregnancy can disrupt fetal brain development in terms of structural and functional changes, this may predispose the development of disease in the offspring," she said.

With several attendees expressing skepticism on some of the findings, noting the numerous potential confounders that could explain the associations, Dr Andersen agreed that much more work needs to be done.

"While clinical studies support the hypothesis of fetal programming by maternal thyroid disease, all are observational in design," she said.

"Further studies are needed to expand the hypothesis, including those with actual measurement of maternal thyroid function during pregnancy and long-term follow-up on the children, followed by intervention studies."

The study received funding from the Netherlands Organization for Health Research and Development (ZonMw) and the European Community's Seventh Framework Program. Dr Korevaar and coauthors, Dr Lazarus, and Dr Andersen had no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online October 20, 2015. Abstract, Editorial

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