New propylthiouracil warnings change face of hyperthyroid treatment in pregnancy

Untreated hyperthyroidism in pregnancy places the mother and child at an elevated risk for a number of adverse outcomes, including preeclampsia and congestive heart failure. Because radioactive iodine is not a viable option during pregnancy, and surgery is risky, health care professionals are limited to propylthiouracil and methimazole.

Recent warnings from the FDA, however, have addressed serious adverse reactions to propylthiouracil, including severe liver injury and acute liver failure — some fatal — leading the agency to recommend reserving use for patients who cannot tolerate other available treatments.

“It has been known since the 1940s that PTU can cause severe, potentially life-threatening hepatotoxicity. While this risk is not necessarily new to endocrinologists, there has recently been a push to recognize it as a potential problem,” David S. Cooper, MD, professor of medicine and international health at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, told Endocrine Today.

Physicians are faced with an additional challenge in treating pregnant women with hyperthyroidism because of risks for birth defects observed with the commonly used drug methimazole. Experts, professional guidelines and the FDA currently recommend PTU as the treatment of choice before and during the first trimester of pregnancy.

A study published in the Journal of Clinical Endocrinology & Metabolism in June revealed that methimazole is now the most commonly prescribed antithyroid treatment. Prescriptions for methimazole increased ninefold between 1991 and 2008, from 158,000 to 1.36 million per year, and the number of prescriptions has surpassed PTU as the most frequently prescribed antithyroid drug. In the study, women of childbearing age were the only demographic for which methimazole prescriptions decreased.

Endocrine Today interviewed leading experts about their experiences with antithyroid drugs in pregnancy and their preferred treatment regimen.

Risks of therapy

Of the 4 million pregnancies in the United States each year, 4,000 women are treated with antithyroid drugs and, until recently, most were prescribed PTU. Although in-depth data on hyperthyroid pregnancies are generally unavailable, it is estimated that four pregnant women per year will develop severe hepatic issues linked to PTU use, according to information provided by the FDA.

In June 2009, the FDA released a black box warning highlighting hepatic dangers associated with PTU treatment, including serious liver injury, liver failure and death in adults and children. The warning was based on 32 cases of serious liver injury — 10 in children — which resulted in 13 deaths and 11 liver transplants.

According to the FDA alert, methimazole was also linked to serious liver injury but to a lesser extent: five adult cases resulting in three deaths.

The FDA updated its warning in April 2010 and recommended reserving use of PTU for those who cannot tolerate other treatments. The agency also required that a medication guide be distributed to each patient who fills a prescription for PTU.

“PTU had always been the preferred treatment in pregnancy over methimazole in the United States because it was thought from early studies that it did not cross the placenta to the same extent as methimazole. In the last 10 years or so, that has been disproven,” Cooper said. Recent studies, such as one published by Mortimer and colleagues in JCEM in 2007, have shown that PTU and methimazole “have similar placental transfer kinetics.”

“The original rationale for PTU no longer exists. However, PTU is still preferred, but not because of the reason initially thought; rather, it is now because of rare reports of birth defects associated with methimazole,” said Cooper, who is also director of the Johns Hopkins Thyroid Clinic.

Although the primary dangers of PTU treatment involve hepatic injury to the mother, the dangers of methimazole are concentrated on the developing fetus. The risks of methimazole include embryopathies such as aplasia cutis congenita, choanal atresia, esophageal atresia and tracheoesophageal fistula.

According to the most recent FDA warning, congenital malformations were reported approximately three times more often with prenatal exposure to methimazole vs. PTU: 29 cases vs. nine cases. In addition, a distinct and consistent pattern of congenital malformations was observed with methimazole use.

“Developmental abnormalities such as cutis aplasia can occur with methimazole use early in the first trimester,” Stephanie L. Lee, MD, PhD, associate professor of medicine at Boston University School of Medicine and Endocrine Today Editorial Board member, said in an interview. “However, putting it in perspective, these abnormalities almost never occur.”

Susan J. Mandel

According to Susan J. Mandel, MD, professor of medicine and associate chief and director of the division of endocrinology, diabetes and metabolism at University of Pennsylvania School of Medicine, it is not clear what the association is between methimazole and embryopathy. Physicians lack substantial data from large-scale studies.

“We do know, based on several studies that looked at large cohorts of people, that children exposed in utero to methimazole were at a greater risk for embryopathy compared with the general population. However, just how frequently it occurs remains unknown,” Cooper said, adding that the reason why more research has not been conducted is because it is an extremely rare situation.

It has been postulated that perhaps the embryopathy risk is not necessarily due to methimazole but rather the hyperthyroidism itself, according to a study cited by Mandel that was published in the American Journal of Genetics in 2008. Barbero and colleagues conducted the multicenter, case-control study to compare the frequency of maternal hyperthyroidism treated with methimazole during pregnancy in children with choanal atresia. According to the results, prenatal exposure to methimazole was identified in 10 of 61 cases (16.4%) compared with two of 183 (1.1%) in a control group (OR=17.75; 95% CI, 3.49-121.40). The researchers concluded that prenatal exposure to maternal hyperthyroidism treated with methimazole appears to be associated with choanal atresia. They noted: “In addition, based on our cases and a critical literature review, we propose that the mother’s disease might be the causal factor, and not the methimazole treatment.”

“As of yet, PTU has not been implicated in causing these conditions,” Endocrine Today Editorial Board member Jerome M. Hershman, MD, said.

Combination treatment

To avoid overt hyperthyroidism and adverse effects to the mother and baby, many experts and the FDA suggest a patchwork solution: treatment with PTU during the first trimester and, after organogenesis, a switch to methimazole.

Guidelines from the American Thyroid Association and The Endocrine Society recommend: “Because available evidence suggests that methimazole may be associated with congenital anomalies, PTU should be used as a first-line drug, if available, especially during first-trimester organogenesis. Methimazole may be prescribed if PTU is not available or if a patient cannot tolerate or has an adverse response to PTU.”

Experts interviewed by Endocrine Today recommended a range from 11 to 17 weeks.

While, some physicians may prefer to use methimazole throughout pregnancy, Hershman said he believes that PTU is a better first option.

“Up to 16 weeks of pregnancy, it is better to use PTU. At 16 weeks, the organs have been developed and the mother can be safely converted to methimazole,” said Hershman, who is associate chief in the endocrinology and diabetes division at West Los Angeles VA Medical Center and distinguished professor of medicine at The David Geffen School of Medicine at UCLA.

Scott A. Rivkees

In a joint editorial published in JCEM in 2009, Cooper and Scott A. Rivkees, MD, associate chair of pediatrics and chief of the Yale Pediatric Thyroid Center and Yale Child Health Research Center, said the risks of PTU for expectant mothers can be reduced by limiting use to the first trimester and then switching. There should not be any methimazole-related birth defects after the first trimester, Cooper added.

However, “Worldwide, far more women are treated with methimazole, so some clinicians may opt for methimazole in the first trimester because the association between methimazole and embryopathy may not be as clear-cut as previously thought,” Mandel said. “Whenever the FDA does something, people usually shift patterns of behavior, and certainly in our practice, we have started to do that.”

But, the transition from PTU to methimazole presents a unique set of problems.

“One worry is that after managing the patient’s hyperthyroidism with PTU, control may be lost during the switch to methimazole. If you do lose control, you want to be able to regain it as quickly as possible,” Mandel said. “Many obstetricians have never had to write a prescription for methimazole, so there may be some resistance. Endocrinologists treat non-pregnant and pregnant women, and in the past, the majority has used methimazole as a first-line therapy in non-pregnant patients and PTU in pregnant patients and are experienced in the dosing of both drugs.”

Goals of therapy

Ultimately, the risks for hyperthyroidism in pregnancy outweigh the risks for rare hepatic injury and embryopathy associated with these antithyroid drugs, experts said. Management with antithyroid drugs should be approached not with the goal of attaining mid-range thyroid hormone levels, but those at the upper limits of normal.

“When we give antithyroid drugs during pregnancy, we do not do so in order to completely normalize thyroid function. We actually prefer the patient to be mildly clinically hyperthyroid,” Lee said. “That is in part because we know that subclinical hyperthyroidism does not have any adverse effect of pregnancy or delivery or the baby, but it reduces the amount of drugs that we give to patients.”

“The goal of treatment for Graves’ disease during pregnancy is to aim for a subclinical hyperthyroid state,” Rivkees told Endocrine Today.

“Not overtreating a woman during pregnancy is integral,” Rivkees said.

Pre-pregnancy planning

A further consideration regarding hyperthyroid pregnant women is that of prevention.

Mandel recommended discussing pregnancy up front and early with hyperthyroid patients.

“The first question to ask is: When do you plan on conceiving?

“The best approach for a woman with Graves’ disease may be to avoid the entire question of methimazole and PTU during pregnancy, and render her hypothyroid before she conceives,” Mandel said.

If antithyroid drugs are necessary during pregnancy, a positive trend is that the condition generally improves with treatment.

“Autoimmune diseases such as Graves’ disease do tend to improve during pregnancy, so it is often possible to stop the treatment late in pregnancy,” Hershman said. But each patient is different, and the doses will need to be adjusted and monitored.

Other times, the physician will be able to wean the woman off of treatment late in the second trimester, Rivkees said.

“However, after giving birth, some women may become hyperthyroid again, and some women will develop postpartum thyroiditis despite being fine during their pregnancy,” he said.

Further treatment factors

Although antithyroid drugs are ideally limited during pregnancy, other treatments are avoided altogether. Surgery and radioactive iodine — common treatments for general hyperthyroidism — are usually not feasible options during pregnancy.

“Radioactive iodine will cross the placenta, placing the fetus at an elevated risk for hypothyroidism, which is why it is never used during pregnancy,” Hershman said.

Surgery is also sparingly used. Cooper said this option is something of a “last resort to be turned to only if the patient is allergic or non-adherent to both methimazole and PTU, or if hyperthyroidism is uncontrolled.” If necessary, it is safest in the second trimester, he said.

Changes in treatment preferences

Changes in treating hyperthyroidism in pregnancy are not globally novel.

“This is a big paradigm shift in the United States, but not in Europe or Asia because carbimazole or methimazole are typically used there. In the United States, we have been stuck on using PTU for so long that many physicians are hesitant to make an adjustment. Now we are having to change our thoughts about using it,” Lee said. “I believe this reluctance will decrease over time as methimazole treatment becomes more commonplace during pregnancy here.”

According to the JCEM study by Cooper and colleagues, methimazole surpassed PTU in 1996 as the most frequently prescribed antithyroid drug (see chart). It is now prescribed about 1.36 million times per year. The annual number of PTU prescriptions also increased by 19% during the study period (2002 to 2008), but only from 348,000 to 415,000 per year. Before 1996, PTU held two-thirds of the market share, according to the researchers. Results also showed that men were more likely to take methimazole compared with women (82% vs. 74%; P<.001), despite data that indicated 72% of total methimazole prescriptions were for women.

The only subgroup in which methimazole use did not increase was women of child-bearing age, 18 to 44 years. The researchers said this may reflect society and FDA recommendations about not using methimazole until the second trimester of pregnancy.

“Because the proportion of women using PTU in this age group also decreased, it is possible that more women of childbearing age are choosing radioiodine therapy before pregnancy,” the researchers wrote.

Future considerations

Experts Endocrine Today interviewed said further research is required to better understand the adverse effects of antithyroid drugs in pregnant hyperthyroid women. Investigations are currently under way, though, as the recent PTU warnings have provided the topic increased attention.

“We are currently studying this issue and will be releasing data to define the true incidence of Graves’ disease during pregnancy, the risks to the liver caused by antithyroid medications during pregnancy and a more complete look at the true risks to the fetus caused by PTU vs. methimazole,” Rivkees said.

The American Thyroid Association and American Association of Clinical Endocrinologists are also working on updated clinical practice guidelines that will address the issue of treating hyperthyroidism during pregnancy.

Still, much work remains, Rivkees said.

“Based on the information we have now, the best course of action to minimize the risk for mother and fetus is PTU treatment during the first trimester — strongly advising the patient on signs of liver injury and with careful monitoring — and then switch to methimazole following organogenesis,” Rivkees said. “However, this recommendation is based on incomplete data and more studies in this area are needed.” – by Matthew Brannon

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