Hyperthyroidism Rebound in Pregnancy Boosts Adverse Outcomes

Discontinuing antithyroid drugs during early pregnancy is linked to a possible rebound of hyperthyroidism and a high risk of adverse pregnancy outcomes, new research shows.

"Our study provides preliminary evidence that the risk of rebound increases in women with subnormal thyroid stimulating hormone (TSH) and/or positive thyrotropin receptor antibody (TRAb) who stop antithyroid drugs in early pregnancy," first author Xin Hou told Medscape Medical News.

"When discussing the pros and cons of antithyroid drug withdrawal early in pregnancy [clinicians] should consider the level of TSH and TRAb in early pregnancy," said Hou, of the Department of Endocrinology and Metabolism, Institute of Endocrinology, The First Affiliated Hospital of China Medical University, in Shenyang.

Suvi Turunen, MD, of the University of Oulu, Finland, who has also conducted research on the issue, said the study adds important insights.

"I find this study very interesting," Turunen told Medscape Medical News. "It is well known that medical treatment of hyperthyroidism outweighs the potential harms of antithyroid treatment."

The new findings add to the evidence, she added. "I think that withdrawal of antithyroid drugs should be carefully considered, especially with autoantibody-positive patients," Turunen said.

Hyperthyroidism a Risk in Pregnancy — With or Without Treatment

The potential risks of hyperthyroidism in pregnancy are well-established and can range from preeclampsia to premature birth or miscarriage.

However, antithyroid drugs, including methimazole and propylthiouracil, carry their own risks. In crossing the placental barrier, the drugs can increase the risk of birth defects, particularly during 6 to 10 weeks of gestation, yet their discontinuation is linked to as much as a 50% to 60% risk of relapse, the authors explain.

Due to the risks, the American Thyroid Association recommends that "women with a stable euthyroid state on 5-10 mg methimazole per day achieved within a few months, and a falling TRAb level, are likely candidates to withdraw from antithyroid drug therapy in early pregnancy," the authors note.

However, as the recommendations for women who are already pregnant are largely based on evidence from nonpregnant patients, Hou and colleagues sought to evaluate withdrawal among women who were pregnant.

For the study, published in July in Thyroid, they enrolled 63 women who were pregnant and part of an outpatient service of the Department of Endocrinology and Metabolism, First Affiliated Hospital of China Medical University, between September 2014 and March 2017, who had well-controlled hyperthyroidism in early pregnancy and discontinued the drugs.

The women were an average age of 27 years, and 28 were multigravida. Twenty-two had a history of miscarriage.

A follow-up of the patients until the end of their pregnancy showed that overall, 20 (31.7%) had a rebound of hyperthyroidism during their pregnancy after withdrawing from the drugs.

Key factors associated with the highest risk of a rebound after discontinuation included having subnormal TSH levels (TSH < 0.35 mIU/L; odds ratio [OR], 5.12; P = .03) or having positive TRAb (TRAb > 1.75 IU/L; OR, 3.79; P = .02) at the time of medication withdrawal, compared with those with either normal TSH levels or negative TRAb.

The combination of both subnormal TSH and positive TRAb at the time of antithyroid medication withdrawal further boosted the risk of hyperthyroidism rebound (83.3%, 5 of 6) compared with those who had both normal TSH and negative TRAb (13%, 3 of 23; OR, 33.33; P = .003).

Adverse Pregnancy Outcomes Increased

Importantly, among the 20 patients who had a rebound, 11 (55%) had adverse pregnancy outcomes, including miscarriage, premature birth, induced labor, gestational hypertension, and gestational diabetes, compared with only four (9.3%) of the 43 who had no rebound (OR, 11.92; P = .0002).

Neonatal abnormalities were also higher among those experiencing a rebound (20% vs 4.7%), however, the authors note that "larger prospective studies are required to conclude whether antithyroid drug withdrawal affects fetal outcome."

In the rebound group, the mean duration of antithyroid medication use was 24.7 months versus 35.1 months in the non-rebound group, however, the difference was not statistically significant (P = .07). And 40% of the rebound group had a history of miscarriage versus 32.6% in the non-rebound group, but was also not significantly different (P = .56).

The authors note that half of those in the rebound group developed hyperthyroidism more than 4 weeks after their withdrawal from antithyroid medications, "which seemed to have circumvented the most sensitive period of teratogenesis between 6 and 10 weeks of pregnancy."

Hou added that restarting antithyroid medication did not increase the risk of adverse outcomes for offspring.

"A low dose of antithyroid medications may be a good choice for women with subnormal TSH and/or positive TRAb in early pregnancy," Hou concluded.

"Because of the small size of our study, a larger prospective study is needed to overcome the potential selection bias and to verify the conclusions."

Findings Consistent With Finnish Study

In her own recent study, which included 2144 women in Finland who experienced hyperthyroidism during pregnancy, Turunen and colleagues found that having hyperthyroidism, with or without antithyroid drug treatment, was associated with an increased odds of pregnancy and/or prenatal complications compared with those without thyroid disease.

"In our study, we observed an increased risk of adverse pregnancy outcomes also in mothers with previous diagnosis and/or treatment of hyperthyroidism, not only with overt hyperthyroidism treated with antithyroid drugs," she told Medscape Medical News.

"I think that especially those patients with positive antibodies [TRAbs] are at risk even if they are euthyroid," she noted. "Withdrawal of antithyroid drugs in these patients is a risk."

"Probably continuing antithyroid treatment with low dose is a better option," she said.

Agreeing with Turunen, Kristen Kobaly, MD, an associate professor of clinical medicine in the Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, said that the study underscores the concerns with antithyroid treatment discontinuation in pregnancy.

"It is not surprising that uncontrolled hyperthyroidism would lead to adverse pregnancy outcomes, but it reinforces that patients stopping antithyroid drugs need to be selected carefully and monitored closely," she told Medscape Medical News.

"There are rare but real risks of fetal malformations with thionamides, so in appropriately selected patients who should be followed closely, discontinuing therapy is a reasonable strategy that these data further support," Kobaly said.

"Close follow-up both biochemically and with any clinical hyperthyroid symptoms is essential so that we can intervene early in patients that relapse."

The authors, Turunen, and Kobaly have reported no relevant financial relationships.

Thyroid. Published online July 18, 2022. Full text

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