Hypothyroidism in pregnancy and postpartum

Are you sure the pregnant or post-partum patient has hypothyroidism?

Symptoms of hypothyroidism may include fatigue, difficulty concentrating, cold intolerance, hoarseness, dry skin, constipation, and weight gain. It is important to note that not all hypothyroid women are symptomatic. In addition, there is some overlap between hypothyroid symptoms and symptoms of a normal pregnancy.

Signs of hypothyroidism include dry skin, delayed relaxation of deep tendon reflexes, bradycardia, hoarseness, and non-pitting edema. Goiter may be present.

Key laboratory findings include an increased serum thyroid stimulating hormone (TSH) value. In overtly hypothyroid patients the serum free thyroxine (T4) level will be decreased, while in subclinically hypothyroid women the free T4 is within the trimester-specific reference range.

What else could the patient have?

Hashimoto’s thyroiditis is the most common cause of hypothyroidism in iodine sufficient areas of the world such as the United States. Hashimoto’s thyroiditis is a chronic autoimmune condition characterized by the presence of high serum thyroid antibody concentrations and goiter (thyroid enlargement). Typically, patients with Hashimoto’s thyroiditis experience a gradual loss of thyroid function, progressing from subclinical to overt hypothyroidism. Once overt hypothyroidism occurs it is usually permanent.

Postpartum thyroiditis is an autoimmune disorder which causes thyroid inflammation within the first few months after delivery. It occurs in up to 10% of US women. It is far more common in women with elevated thyroperoxidase (TPO) antibodies in the first trimester of pregnancy or immediately postpartum. It is also more common in women with other autoimmune disorders, such as type I diabetes and in women with a family history of autoimmune thyroid disease.

Thyroiditis may cause transient thyrotoxicosis due to leakage of pre-formed thyroid hormone from the damaged thyroid gland into the blood. As the thyroid gland becomes depleted of pre-formed thyroid hormone, there is progression to hypothyroidism before the thyroid gland heals and euthyroidism is restored. Overall, only one third of patients with postpartum thyroiditis will experience the classic triphasic thyroid hormone pattern. Thyrotoxicosis typically begins 1-6 months post-partum, and lasts for 1-2 months. A hypothyroid phase may follow, starting 4-8 months post-partum and lasting 4-6 months. While 80% of women will recover normal thyroid function within a year, in one long-term follow-up study 50% became permanently hypothyroid within 7 years. There is a 70% chance of recurrence with subsequent pregnancies in women with a previous episode of postpartum thyroiditis.

Other, less common, causes of hypothyroidism in pregnancy and the postpartum period include drug-induced hypothyroidismfrom medications such as amiodarone or lithium; hypothyroidism resulting from partial or total surgical resection of the thyroid; hypothyroidism resulting from the treatment of hyperthyroidism with radioactive iodine; and, rarely, hypothyroidism resulting from pituitary hypofunction.

Key laboratory and imaging tests

TSH

A serum TSH level is the best and most cost-effective initial test for diagnosing hypothyroidism. The serum TSH will be elevated in hypothyroid pregnant women. It is important to note that the normal serum TSH range in the first trimester is lower than in non-pregnant populations. Where trimester-specific laboratory reference ranges are not available, current guidelines recommend that the upper limit for TSH should be considered 2.5 mIU/L in the first trimester and 3.0 mIU/L in the second and third trimesters. However, recent large population studies suggest that an upper TSH limit of up to 4.0 mIU/L may be more appropriate.

Free thyroxine (T4)

Free T4 values will be decreased in overtly hypothyroid women and normal in women with subclinical hypothyroidism. As is the case for serum TSH, there are physiologic alterations in serum thyroid hormone levels throughout pregnancy so that trimester-specific reference ranges should optimally be employed. In addition, clinicians should be aware that most commercial free T4 assays function poorly in pregnancy.

Other tests that may prove helpful diagnostically

Free triiodothyronine (T3): Free T3 assays are unreliable in pregnancy and should not be used in pregnant women.

Thyroperoxidase (TPO) antibodies: TPO antibodies may be measured as a marker for thyroid autoimmunity. TPO antibodies are detectable in most patients with Hashimoto’s thyroiditis. About 50% of women with detectable TPO antibodies in the first trimester of pregnancy will go on to develop postpartum thyroiditis.

Thyroglobulin antibodies: Anti-thyroglobulin antibodies are detectable in about 60% of patients with Hashimoto’s thyroiditis.

Thyroid stimulating IgG (TSI): Serum TSI levels are frequently elevated in Graves’ disease and usually normal in postpartum thyroiditis.

The 24-hour radioactive iodine uptake may be used to definitively distinguish the thyrotoxic phase of postpartum thyroiditis from postpartum Graves’ disease, as uptake will be low (<5%) in thyroiditis rather than elevated as in Graves’ disease. The radioactive iodine uptake is not useful for determining the etiology of hypothyroidism. Radioactive iodine scans are contraindicated during pregnancy. The use of 131I is contraindicated during pregnancy and lactation. If required, 123I can be employed in breastfeeding women if breast milk is pumped and discarded for several days before breastfeeding is resumed.

Management and treatment of the disease

Treatment with levothyroxine should be initiated for all pregnant women with serum TSH ≥10 mIU/L because overt hypothyroidism in pregnancy has been associated with adverse maternal and fetal outcomes including prematurity, miscarriage and fetal death.

Subclinical hypothyroidism has been associated with adverse obstetric outcomes such as miscarriage, hypertension, preeclampsia, gestational diabetes, low birth weight, preterm delivery, and perinatal/neonatal death in some, but not all, studies. Mild maternal hypofunction (either an elevated serum TSH or a low free T4) has also been associated with decreased intellectual function in children, although to date two randomized clinical trials have failed to demonstrate that treatment of pregnant women with mild thyroid hypofunction improves neurodevelopmental outcomes.

There is a single prospective trial demonstrating improved obstetric outcomes with levothyroxine treatment of TPO antibody positive subclinically hypothyroid women. Observational studies have consistently demonstrated that obstetric risk is apparent at lower TSH levels (>2.5 mIU/L) in women known to be TPO antibody positive, whereas adverse effects are typically observed in women who are TPO antibody negative only when TSH is greater than 4-5 mIU/L. Therefore, it is recommended that levothyroxine should be used to treat TPO antibody positive women with serum TSH values >2.5 mIU/L. Levothyroxine may be used to treat TPO antibody negative pregnant women with serum TSH >2.5 mIU/L but <10.0 mIU/L, although there is currently limited evidence for benefit. Isolated maternal hypothyroxinemia in the setting of a normal serum TSH should not be treated in pregnancy.

The goal of levothyroxine therapy in pregnancy is the normalization of trimester-specific serum TSH values: to <2.5 mIU/L. Serum TSH levels should be monitored in hypothyroid women at least every 4 weeks until 16 weeks gestation, and then at least once between weeks 26 and 32 of gestation.

Most women treated for hypothyroidism prior to pregnancy will require a 25-50% levothyroxine dose increase starting early in pregnancy in order to remain euthyroid. One strategy to accomplish this is to recommend that women take two additional levothyroxine tablets per week starting as soon as pregnancy is confirmed. In most cases, the pre-pregnancy levothyroxine dose can be resumed immediately after delivery, although it is important to ensure that the serum TSH has normalized on the post-pregnancy dose at 6-8 weeks postpartum.

Women in the hypothyroid phase of postpartum thyroiditis may not require levothyroxine treatment since hypothyroidism is most frequently mild and self-limited. If hypothyroidism is prolonged, the patient is symptomatic, or the patient is attempting to become pregnant L-T4 should be employed. When L-T4 is started, it should be weaned after 6-12 months in order to determine whether thyroid function has normalized.

Many pregnant women take prenatal multivitamins containing iron or calcium, or take iron tablets for anemia. Women should be advised to separate their levothyroxine dose by at least four hours from any calcium- or iron-containing preparations in order to avoid decreased levothyroxine absorption.

What’s the Evidence?/References

Stagnaro-Green, A, Abalovich, M, Alexander, E, Azizi, F, Mestman, J. “American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum 2011 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum”. Thyroid. vol. 21. 2011. pp. 1081(These are the most recent clinical guidelines regarding the treatment of hypothyroidism in pregnancy and the postpartum period. Note that a revised guideline will be published in 2016.)

De Groot, L, Abalovich, M, Alexander, EK, Amino, N, Barbour, L. “Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline”. J Clin Endocrinol Metab. vol. 97. 2012. pp. 2543-65. (These are the most recent clinical guidelines from the Endocrine Society regarding the treatment of hypothyroidism in pregnancy and the postpartum period.)

Haddow, JE, Palomaki, GE, Allan, WC, Williams, JR, Knight, GJ. “Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child”. N Engl J Med. vol. 341. 1999. pp. 549-55. (This observational study demonstrates the potential adverse effects of maternal subclinical hypothyroidism on fetal neurodevelopment.)

Henrichs, J, Bongers-Schokking, JJ, Schenk, JJ, Ghassabian, A, Schmidt, HG. “Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the Generation R Study”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 4227-34 . (This observational study demonstrates the potential adverse effects of maternal isolated hypothyroxinemia on fetal neurodevelopment.)

Negro, R, Schwartz, A, Gismondi, R, Tinelli, A, Mangieri, T. “Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 1699-707. (This prospective trial randomized first-trimester pregnant women to a case-finding vs. universal thyroid screening strategy. Women who were TPO antibody positive with TSH >2.5 mIU/L were treated with levothyroxine. While the universal screening approach did not result in an overall decrease in adverse outcomes, treatment of thyroid dysfunction identified by screening the low-risk group was associated with a lower risk of a composite adverse obstetric outcome.)

Casey, BM, Dashe, JS, Wells, CE, McIntire, DD, Byrd, W. “Subclinical hypothyroidism and pregnancy outcomes”. Obstet Gynecol. vol. 105. 2005. pp. 239-45. (This large observational cohort study demonstrates potential adverse obstetric effects of subclinical hypothyroidism in pregnancy.)

Yassa, L, Marqusee, E, Fawcett, R. “Alexander EK 2010 Thyroid hormone early adjustment in pregnancy (the THERAPY) trial”. J Clin Endocrinol Metab. vol. 95. pp. 3234-41. (This prospective trial demonstrated that a two-tablet increase in levothyroxine initiated at confirmation of pregnancy significantly reduces the risk of maternal hypothyroidism during the first trimester, and that monitoring TSH every 4 weeks through midgestation is the optimal monitoring strategy in levothyroxine-treated pregnant women.)

Best Pract Res Clin Endocrinol Metab. vol. 18. pp. 303-16. (This is a review article describing the diagnosis and treatment of postpartum thyroiditis.)

Lee, RH, Spencer, CA, Mestman, JH, Miller, EA, Petrovic, I. “Free T4 immunoassays are flawed during pregnancy”. Am J Obstet Gynecol. vol. 200. 2009. pp. 260.e1-6. (This study evaluated the performance of free T4 assays in pregnancy.)

Lazarus, JH, Bestwick, JP, Channon, S, Paradice, R, Maina, A. “Antenatal thyroid screening and childhood cognitive function”. N Engl J Med.. vol. 366. 2012. pp. 493-501. (This is a clinical trial in which testing for and treating low maternal thyroid function was not associated with improved neurocognitive outcomes in children at age 3.)

Brian, Casey. “Effect of treatment of maternal subclinical hypothyroidism or hypothyroxinemia on IQ in offspring”. (This is the abstract from a large rcent multicenter randomized clinic trial in which testing for and treating either subclinical hypothyroidism or maternal hypothyroxinemia was not associated with improved neurocognitive outcomes in children at age 5.)

Liu, H, Shan, Z, Li, C, Mao, J, Xie, X, Wang, W, Fan, C, Wang, H, Zhang, H, Han, C, Wang, X, Liu, X, Fan, Y, Bao, S, Teng, W. “Maternal subclinical hypothyroidism, thyroid autoimmunity, and the risk of miscarriage: a prospective cohort study”. Thyroid. vol. 24. 2014. pp. 1642-9. (This is a prospective cohort study which demonstrated increased risk for miscarriage in women with TPO antibodies and a serum TSH >2.5 mIU/L and in TPO antibody negative women with TSH > 5.0 mIU/L.)

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