Hypothyroid Pregnant Women Benefit From Increasing Thyroid Replacement CME

<script></script> News Author: Laurie Barclay, MD
CME Author: Charles Vega, MD, FAAFP

July 14, 2004 — Hypothyroid pregnant women benefit from increasing thyroid replacement, according to the results of a prospective trial published in the July 15 issue of the New England Journal of Medicine.

“Hypothyroidism during pregnancy has been associated with impaired cognitive development and increased fetal mortality,” write Erik K. Alexander, MD, from the Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues. “During pregnancy, maternal thyroid hormone requirements increase. Although it is known that women with hypothyroidism should increase their levothyroxine dose during pregnancy, biochemical hypothyroidism occurs in many.”

The authors observed 19 women with hypothyroidism before and throughout their pregnancies and measured thyroid function, human chorionic gonadotropin, and estradiol before conception, twice monthly during the first trimester, and monthly thereafter. Throughout pregnancy, the dose of levothyroxine was increased as needed to maintain the thyrotropin concentration at preconception values.

Of 20 pregnancies, there were 17 full-term births. During 17 pregnancies, the levothyroxine dose had to be increased, with median onset of increase at eight weeks of gestation. The mean levothyroxine requirement increased by 47% during the first half of pregnancy and reached a plateau by week 16, with the increased dose required during the remainder of pregnancy.

“Levothyroxine requirements increase as early as the fifth week of gestation,” the authors write. “Given the importance of maternal euthyroidism for normal fetal cognitive development, we propose that women with hypothyroidism increase their levothyroxine dose by approximately 30% as soon as pregnancy is confirmed. Thereafter, serum thyrotropin levels should be monitored and the levothyroxine dose adjusted accordingly.”

The National Institutes of Health and the Endocrine Fellows Foundation supported this study. One of the authors reports having served as a consultant for Genzyme and Laboratory Inisiba.

In an accompanying editorial, Anthony Toft, MD, from the Royal Infirmary in Edinburgh, Scotland, suggests that it would be more practical to increase the levothyroxine dose by 25 to 50 μg daily as soon as pregnancy is confirmed. Thyroid function testing should be done within the following four to six weeks, and after the 20th week of gestation, one additional test is probably sufficient.

“Although the debate continues about the wisdom of screening women of childbearing age by measuring serum thyroxine, thyrotropin, or both in order to detect unrecognized thyroid failure in advance of pregnancy, the evidence is beginning to stack up in favor of doing so,” Dr. Toft writes. “If screening is not to be performed universally, it would be reasonable to test those under the age of 35 years who already have one or more of the organ-specific autoimmune diseases, such as type 1 diabetes mellitus, or who have a strong family history of thyroid disease.”

N Engl J Med. 2004;351:241-249, 292-294

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Describe the physiology of hypothyroidism in pregnancy.
• Recommend thyroid screening and treatment regimens for women with hypothyroidism who become pregnant.

Clinical Context

Hypothyroidism is a common condition during pregnancy that can produce devastating consequences for both the mother and child. The authors of the current study, along with an editorial by Toft accompanying the research, do an excellent job of reviewing our current knowledge of changes in thyroid physiology in pregnancy. Early in pregnancy in euthyroid women, human chorionic gonadotropin provides a weak stimulation to the thyroid gland, increasing free thyroxine levels and reducing thyrotropin concentration. However, a combination of factors, the most salient of which is the estrogen-driven increase in thyroid-hormone binding globulin, causes a later reduction in free thyroxine.

Women with primary hypothyroidism lack the compensatory mechanism to maintain adequate levels of free thyroxine during pregnancy, and, therefore, it is recommended to follow thyroid hormone levels at least every eight weeks during pregnancy in these women. Dosage of levothyroxine should be increased according to these levels and the stage of pregnancy, bearing in mind that the steepest increase in dosage is usually necessary in the first half of the pregnancy.

The authors of the current study performed a prospective study of pregnant women with hypothyroidism to better understand the timing of changes in thyroid physiology during pregnancy.

Study Highlights

• Women with hypothyroidism who desired pregnancy were recruited from one medical center to join the study.
• Subjects were followed up with tests for thyroid function, estradiol levels, and human chorionic gonadotropin levels after their first missed menstrual cycle, every two weeks during their first trimester, and monthly, thereafter, until completion of the pregnancy. Thyroid function was rechecked 6 weeks following delivery.
• The target thyrotropin levels were less than 5 µU/mL in women without a history of thyroid cancer and less than 0.5 µU/mL in women with a history of cancer.
• If the thyrotropin level was found to be elevated at the initial test, all women had their dose of levothyroxine increased by 25 µg. At subsequent tests of noncancer patients, levothyroxine was increased by 12.5 µg if the thyrotropin levels were between 5 to 10 µU/mL and 25 µg if the thyrotropin level was more than 10 µU/mL. Participants with a history of thyroid cancer underwent a similar protocol to maintain their goal thyrotropin level.
• The main study outcome was a better definition of the natural history of hypothyroidism in this cohort of closely observed pregnant women.
• 19 women entered the study, and most subjects had hypothyroidism either due to Hashimoto’s disease or treatment for Graves’ disease. 6 women had a history of thyroid cancer.
• There were 20 pregnancies in the cohort, 3 of which were facilitated by assisted reproductive techniques. 17 pregnancies produced full-term deliveries.
• Thyrotropin levels rose quickly early in pregnancy, from a mean prepregnancy level of 1.0 to 4.2 µU/mL at 10 weeks’ gestation. This was particularly evident for women who used assisted reproductive techniques, 2 of whom needed an increase in levothyroxine at 4 weeks of gestation. Higher estradiol concentrations early in pregnancy in these women could explain this difference.
• The authors accomplished their goal of maintaining stable thyrotropin values throughout the study by increasing the dose of levothyroxine. Overall, 85% of women required an increase in levothyroxine during the first 10 weeks of gestation, with a mean 29% increase in the dosage for the whole cohort during this period. By 20 weeks of gestation, the mean dose of levothyroxine had increased by 48%.
• Most increases in levothyroxine dosage occurred between weeks 6 to16 of gestation. This correlated with the most rapid decrease in thyroid hormone-binding ratio as levels of thyroxine-binding globulin increased.
• Following 20 weeks of gestation, both the thyroid-hormone binding ratio as well as the mean dosage of levothyroxine were stable in the study cohort.
• The rates of dosage increases for levothyroxine were similar in participants regardless of the etiology of hypothyroidism.
• Within 2 weeks of delivery, women resumed taking their prepregnancy dose of levothyroxine. In the 14 women who had postpartum care at 6 to 8 weeks after delivery, all had normal thyrotropin levels.

Pearls for Practice

• Women with hypothyroidism frequently require higher dosages of thyroid replacement therapy during pregnancy.
• Given that the increased need for levothyroxine treatment occurs early in pregnancy, women with hypothyroidism should present promptly for thyroid function testing. The authors of the current study suggest patients take two extra doses of levothyroxine per week following a positive pregnancy test result until they can arrange to have thyroid testing performed.

http://www.medscape.com/viewarticle/483441

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