Excess thyroid hormone harmful to fetus

August 10, 2004

Researchers from the University of Chicago have showed, for the first time, that an excess of thyroid hormone during pregnancy has a direct toxic effect on the fetus, tripling the risk of miscarriage and reducing the average birth weight of infants who survive.

The problems caused by a lack of sufficient thyroid hormone during pregnancy are well known and approximately two percent of all pregnant women now take supplements to prevent a shortage. A recent article in the New England Journal of Medicine proposed that all women being treated prior to conception for low thyroid hormone -- a common occurrence -- "increase the dose by 29 percent" as soon as they learn they are pregnant.

The University of Chicago study, however, published in the 11 August 2004 issue of JAMA, shows that increasing the dose without careful testing is hazardous. Overcompensating for a mother's shortage of thyroid hormone, the authors note, can be equally harmful.

"Although the risks of insufficient thyroid hormone during pregnancy are established," said study author Samuel Refetoff, M.D., professor of medicine and pediatrics and the committees on genetics and molecular medicine at the University of Chicago, "we have not, until now, been able to determine the consequences of an excess. We now see that having too much is just as bad as having too little. This tells us that hormonal replacement must be assessed and fine-tuned so as not to exceed the normal requirements."

Physicians have not been able to study the effect on the fetus of excess thyroid hormone, which regulates metabolism, because it was impossible to separate the effects on the fetus from the effects on the mother.

This innovative study, however, provides a perfect example of how "errors of nature can help us understand normal hormone action," said Refetoff.

Nearly 40 years ago, he found such an error. In 1967, Refetoff described a clinical syndrome involving resistance to thyroid hormone. In persons with a mutation of the thyroid hormone receptor gene the hormone was less effective. People with the mutation produce more thyroid hormone than normal but they do not experience the anxiety, weight loss or elevated heart rate usually caused by such excess.

The genetic defect is transmitted as a dominant trait, which means that affected mothers or affected fathers transfer the mutation to half of their progeny. Thus, the high thyroid hormone levels of affected mothers, which are normal for them because of reduced hormone sensitivity, will be excessive only to the unaffected fetuses they carry. In contrast, unaffected mothers, bearing fetuses of affected fathers, will provide a normal environment to an unaffected fetus but less than optimal thyroid hormone levels to a fetus harboring the mutation.

Scientists now know of more than 200 families with this syndrome. One of the best studied is an extended family in the Azores, a cluster of small islands about 900 miles west of Portugal. In this family, the mutation has been traced back four generations to a single founder couple in the late 19th century.

In this paper, Refetoff, working with Azorean endocrinologist João Anselmo, looked at pregnancy outcomes of 36 married couples from this extended family. Their sample included 18 couples in which either the mother or father was resistant to thyroid hormone and 18 unaffected couples.

They found that mothers with the mutation, who required higher levels of thyroid hormone to maintain a normal life, had a much higher rate of miscarriage, 23.7 percent, about three times the rate for couples in which only the father had the mutation (6.7%) or neither parent had the mutation (8.8%).

Although one would expect roughly half of the children born to affected mothers to have the mutation, two-thirds (20 out of 31) shared this mutation and only one-third of the infants born to affected mothers did not. This suggests that the high rate of miscarriage primarily involved unaffected fetuses. The mutation appears to have protected affected fetuses from the effects of excess maternal thyroid hormone.

Unaffected mothers, with no increased rate of miscarriages, gave birth, as expected, to equal numbers of affected and unaffected infants.

The mean birth weight of the unaffected infants born to affected mothers was 20 percent below average. Three of these infants had birth weights below the World Health Organization's criteria for low birth weight. "This suggests," the authors note, that high maternal thyroid hormone levels, could "induce a catabolic state during fetal life, similar to what happens in children and adults with uncontrolled hyperthyroidism."

Unaffected infants born to affected mothers also had extremely low levels of thyroid stimulating hormone (TSH), a definite sign of thyroid hormone excess. After birth, TSH levels slowly rose, reaching normal values after 4 weeks.

"Taken together," the authors conclude, "these findings represent the first evidence in humans that T[hyroid] H[ormone] excess can, by itself, impair embryogenesis of growing fetuses through transplacental passage of maternal TH.... Given the established importance of providing TH replacement to even mildly hypothyroid pregnant women, it is important to recognize that over-replacement appears to be equally detrimental."
The National Institutes of Health funded this study. Additional authors include Dingcai Cao, Theodore Karrison and Roy Weiss of the University of Chicago.

University of Chicago Medical Center

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