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17 September 2010

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.
 
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.
 
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. That has been proven wrong over the last 10 years. 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. 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. However, these abnormalities are quite rare. It is not clear what the association is between methimazole and embryopathy due to lack of substantial data from large-scale studies. What is known is that  based on several studies that looked at large cohorts of people,  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. 
 
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 theAmerican 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. Based on the cases and a critical literature review, they proposed that the mother’s disease might be the causal factor, and not the methimazole treatment.
 
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.”  There should not be any methimazole-related birth defects after the first trimester.
 
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 control is lost, it should be regained as soon as quickly as possible.
 
Goals of therapy
 
Ultimately, the risks for hyperthyroidism in pregnancy outweigh the risks for rare hepatic injury and embryopathy associated with these antithyroid drugs.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. It is preferred for the patient to be mildly clinically hyperthyroid. Subclinical hyperthyroidism does not have any adverse effect of pregnancy or delivery or the baby, but it reduces the amount of drugs given to patients. Not overtreating a woman during pregnancy is integral.
 
Pre-pregnancy planning
 
A further consideration regarding hyperthyroid pregnant women is that of prevention. The first question to ask a hyperthyroid patient 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. 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. 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. However, after giving birth, some women may become hyperthyroid again, and some women will develop postpartum thyroiditis despite being fine during their pregnancy.
 
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.Surgery is also sparingly used. 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.
 
Summary recommendation
 
Based on the currently available information, 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. However, this recommendation is based on incomplete data and more studies in this area are needed.
 
Edited by Hanifullah Khan from an article by Matthew Brannon published in Endocrine Today on 1 September 2010.


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