An unruly thyroid during pregnancy puts both mother and child at great risk for complications. Fortunately, this complex field of medicine has made significant advances in the past 5 years. The recent benchmarks motivated The Endocrine Society to release updated guidelines (August 2012), which give physicians the latest recommendations for everything from screening to antithyroid drugs.
A team of experts, led by Dr. Leslie De Groot of the University of Chicago Medical Center, rewrote the 2007 version after extended discussion and debate, ultimately producing Management of Th yroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline.
The report is organized around eight different conditions, including management of hypothyroidism, management of hyperthyroidism, gestational hyperemesis and hyperthyroidism, autoimmune thyroid disease and miscarriage, thyroid nodules and cancer, iodine nutrition, postpartum thyroiditis, and screening for thyroid dysfunction during pregnancy. The strength of each recommendation made in the guideline received a rating of A, B, C, D, or I for “insufficient,” along with visual indicators for quality of evidence.
Rethinking Diagnoses
The diagnosis of hypothyroidism is one of the first changes in the new report. De Groot describes the well-known effects of maternal hypothyroidism on unborn children as, “a common cause of mental deficiency around the world due to iodide deficiency.” Hypothyroid women are already predisposed to infertility, abortion, postpartum hemorrhage, and a number of other negative symptoms. But, it is not yet proven that detecting hypothyroidism in non-iodide deficient parts of the world and treating it will prevent damage to fetal mental development. The committee thus cautioned physicians in their interpretation of free T4 levels during pregnancy, noting that laboratories should establish trimester-specific ranges of norms and conduct alternative measurements.
“We recommend maintaining pregnant women with a total thyroxin at 1.5 times that of normal levels,” De Groot remarks. The free thyroxine index, also known as adjusted T4, is recommended as a reliable assay by the report. If the mother is found to be positive for thyroid peroxidase antibodies, T4 replacement is suggested and dosage should be reevaluated every four to six weeks of pregnancy, because an increase up to 30 percent may be necessary. Most women will have to return to higher levels of T4 replacement after the baby is delivered.
Hyperthyroidism requires entirely different action. For diagnosis, physicians can determine whether subnormal serum TSH concentration is a symptom of gestational thyrotoxicosis or Graves’ disease by looking for a typical goiter and TSH receptor antibodies. If physicians discover Graves’ disease or thyroid nodules, antithyroid (ATD) drug therapy should begin as quickly as possible, ideally before pregnancy.
The committee recommends propylthiouracil (PTU) as the first defense against hyperthyroidism, but only during the first trimester. Methimazole (MMI) can be prescribed for the remainder of gestation, but the slim risk of congenital abnormalities during the first dozen weeks of pregnancy makes it a slightly lesser option for the beginning. Unfortunately, PTU has been tied to very rare incidences of severe liver toxicity, which is why the new guidelines suggest switching to MMI after 3 months.
“The problem is that the FDA has recommended that doctors avoid using propylthiouracil during pregnancy, or anytime, because of the low, but possible, risk of liver damage. And the other problem is that methimazole is known to have the rare but recognized possibility of causing abnormalities in the fetus during the first trimester, so we recommend that doctors put their patients on PTU and switch to MMI,” De Groot explains.
That said, practitioners should use their professional judgment when deciding a course of treatment. If a patient cannot tolerate one of the drugs, the other drug will likely yield satisfactory results throughout pregnancy without hurting fetus or mother. “The high probability is that either drug would work out without any trouble,” De Groot says. Patients that convert from PTU to MMI should have thyroid function checked after two weeks and in two-to-four-week intervals thereafter. Liver function may be monitored in those on PTU every three to four weeks and patients should be told to keep a careful eye out for any new symptoms.
Fetal Interventions
Controlling the effects of hyperthyroidism in the fetus is trickier than in the mother. De Groot hopes that testing mechanisms for the thyroid condition of an unborn child will soon improve.
“Maternal hypothyroidism in pregnancy is not rare and assessing the status of the fetus is a problem,” he explains. The medication and antibodies both cross the placenta and affect the fetal thyroid, but how much can be difficult to determine. “There is a serious risk for fetal problems, and the methods of detection are not good.”
Right now, physicians rely on ultrasounds and the mother’s free T4 to screen for fetal thyroid dysfunction. Diagnosis can be challenging, and testing umbilical cord blood instead poses danger to the child that is only worth the risk under certain conditions.
In some cases, Graves’ disease may be a motivating factor for the riskier but more direct cord blood test. Unborn infants with a family history of Graves’ should be checked by ultrasound to ensure that their thyroid is functioning properly by the 22nd week of gestation. “The change is that we made more explicit the timing and indications for measuring the antibodies,” De Groot explains. If antibodies exceed 2-3 times the normal level, the fetus should be screened for thyroid dysfunction, such as a fetal goiter or heart failure, both of which may happen if the unborn child becomes hypothyroid.
Treatment Risk Assessment
The guidelines committee also commented on whether it is appropriate to give thyroxine to mothers with antibodies, due to the relationship with miscarriage. A recent study in Finland found that the children of women who were positive for antibodies in the first trimester were more likely to give birth preterm and the children had a mean intelligence score of 10 points lower than control children at 25-30 months of age. One school of thought is to treat such mothers with antithyroid pills, but the guidelines reject this notion based on a lack of evidence. More research is needed to prove that the benefits outweigh the risks because, as always, overtreatment can be just as detrimental as undertreatment.
This philosophy also comes into play when thyroid nodules are found in a pregnant woman. Although the use of fine needle aspiration (FNA) has become more general in the new recommendations, surgery on even malignant tumors should be delayed until the second trimester. Any nodule over one centimeter in size may undergo FNA, but in women with a history of thyroid dysfunction, FNA may be applied to nodules as small as five millimeters. Radiation should be entirely avoided during pregnancy and until at least four weeks after breastfeeding has ended.
Among other notable updates in the new guidelines, the experts now encourage all women of childbearing age to consume 150ug of iodine per day to maintain normal thyroid activity. Even before conception, women intending to become pregnant should increase to 250ug and continue supplementation throughout gestation and breastfeeding. “Women taking vitamins should verify that they contain that much iodine,” says De Groot. Those living in countries with known iodine deficiency must take special care to ensure adequate intake.
Value of Early Testing
The largest point of controversy among the committee centered on testing for thyroid issues during the early weeks of pregnancy. “Our committee did not agree on that, and we had long and complicated debates,” De Groot explains. The symptoms of dysfunction can be confused with normal discomforts of pregnancy, which can lead to problems if left untreated. De Groot believes that the serum TSH of all women should be tested within the first nine weeks of pregnancy to make sure the thyroid is working normally, but roughly half of the committee differed, so they decided to make a set of recommendations for practitioners of each philosophy. A recent editorial from the Journal of Clinical Endocrinology & Metabolism, titled “When Thyroidologists Agree to Disagree,” describes the deliberation that occurred during the creation of the guidelines.
The pro-testing group encourages testing of all pregnant women by the ninth week, while the other group believes testing is only necessary in at-risk women, such as those with a history of thyroid malfunction. For practitioners against universal screening, aggressive case finding can help ensure that patients with thyroid issues do not go untreated. De Groot hopes that the next committee will reach an agreement on whether or not testing should be mandatory.
De Groot has further ambitions for thyroid management in pregnancy and postpartum that he anticipates the upcoming generation of researchers will accomplish. “I hope that we’ll have a more uniformly available and well-validated assay of free thyroid hormones in pregnant women. That would be universally valuable.”
He also sees the questions about thyroid drugs being answered, such as the potential issues with PTU and MMI. Though treatments are yet to be perfected, the immense advances made between the 2007 and 2012 guidelines provide a brighter future for women with thyroid dysfunction and their children.
—Mapes is a freelance writer in Washington, D.C., and regular contributor to Endocrine News.
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