Understanding the Thyroid and Pregnancy

FERTILITY nurses first Understanding the Thyroid and Pregnancy Tamara Tobias, ARNP Human chorionic gonadotropin (hcg) and estrogen are two hormones that play an important role during pregnancy. They can, however cause increased thyroid hormone levels in the blood, making thyroid function tests during pregnancy difficult to interpret. The information below gives an overview of thyroid function and then shows the relationship between thyroid function and pregnancy. Physiology The function of the thyroid gland is to synthesize the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Thyroid cells are the only cells in the body that can absorb the element iodine, which can be found in many foods. These cells combine iodine and the amino acid, tyrosine, to produce T3 and T4. The T3 and T4 hormones are then released into the bloodstream and are transported throughout the body where they play an important role in controlling metabolism. 1,2 The thyroid gland is controlled by the pituitary gland. When levels of T3 and T4 drop too low, the hypothalamus produces thyrotropin releasing hormone (TRH), which stimulates the pituitary gland to produce thyroid stimulating hormone (TSH). The TSH in turn stimulates the thyroid gland to produce more thyroid hormones (Figure). 1,2 Under the influence of TSH, the thyroid will manufacture and secrete T3 and T4, thereby raising their blood levels. The hypothalamus senses this change and responds by decreasing its TRH production (Figure). 1,2 Figure. Thyroid Physiology Hypothalamus TRH (thyroid-releasing hormone) Pituitary TSH Thyroid T 3 and T 4 to target cells throughout body issue 33 SP12872_FertilityNurses_0310_k.indd 1 4/8/10 10:53:31 AM

Thyroid Hormones Thyroid hormones are present in the circulation but are mainly bound to proteins. Approximately 75 percent to 80 percent are bound to thyroxine-binding globulin (TBG) (inactive), and about 20 percent are bound to albumin (less active). Because only a small fraction of thyroid hormones is unbound and biologically active, measuring free thyroid hormones is generally the most useful in determining thyroid function. 1 The TBG protein is generally increased by estrogens, and rises especially during pregnancy. Growing levels of estrogen leads to an increase in thyroid hormone binding. Less free hormones lead to the stimulation of TSH and further production of thyroid hormones. A normally functioning thyroid is able to adapt to these changes, and the level of free thyroid hormone is not altered. Thyroxine (T4) Thyroxine is a hormone referred to as T4 because it contains four iodine atoms. The normal thyroid gland produces about 80 percent of T4 and is its primary secretory product. To exert its effects, T4 is converted to T3 by the removal of an iodine atom. Predominantly bound by proteins, T4 is prevented from entering tissues. Free T4, however is able to enter tissues and exert its effects. This ability makes free T4 the most effective way to determine thyroid function. 1 Triiodothyronine (T3) Although the thyroid gland directly secretes about 20 percent of T3, this hormone is responsible for most of the thyroid action in the body. As previously stated, 80 percent of T3 comes from the conversion of T4. In addition, T3 is approximately four times more potent than T4. 1 Although measuring T3 may help diagnose hyperthyroidism, testing for T3 is rarely used to determine hypothyroidism. Thyroid Stimulating Hormone (TSH) Measuring TSH is the most effective way to initially test thyroid function. Although TSH is regulated by T4, this process happens only after T4 is converted to T3 in the pituitary cells. The measurement of T4 and TSH provide the most accurate assessment of thyroid function. 1,3 Thyroid Antibodies There are two common thyroid antibodies that damage the thyroid gland. These are 1) antithyroid peroxidase (anti- TPO) and 2) antithyroglobulin (anti-tg). Measuring these antibodies helps to diagnose the most common cause of hypothyroidism. 4 Common Disorders of the Thyroid Hypothyroidism Hypothyroidism occurs when the thyroid fails to produce adequate amounts of thyroid hormone. This condition is often present for a number of years before it is recognized and treated. 2 A typical person with an underactive thyroid will have elevated TSH levels with low, free T4. The most common cause of hypothyroidism is thyroiditis, which includes a group of individual disorders that cause thyroidal inflammation resulting in different clinical presentations. Hashimoto s disease is the most common autoimmune thyroid disorder. It increases with age and occurs more frequently in women or persons with a family history of thyroid disease. Hashimoto s disease typically targets women and is characterized by high thyroid antibody titers along with increased TSH and low, free T4. 1,2 Synthetic T4 is the most effective treatment for Hashimoto s disease. Levothyroxine is a drug that can be prescribed with a wide range of doses. It is used to treat low thyroid activity and to treat or suppress different types of goiters. It is recommended to take levothyroxine on an empty stomach approximately 30 minutes before or two hours after meals. It is important to space this drug at least four hours apart from other medications, including iron (e.g., prenatal vitamins) and antacids which can impair absorption. 1,2 2 SP12872_FertilityNurses_0310_k.indd 2 4/8/10 10:53:31 AM

Hyperthyroidism Hyperthyroidism occurs when there is an overabundance of thyroid hormone being produced. A typical person with an overactive thyroid will have decreased TSH levels and high, free T4. 1,2 The most common cause of hyperthyroidism is Graves disease, an autoimmune disorder. The antibodies in this case stimulate the thyroid gland. Graves disease is characterized by an enlarged thyroid that produces an overabundance of thyroid hormone. This overproduction occurs more often in women between their 30s and 40s and tends to run in families. 1,2,4 The treatment for hyperthyroidism may include the use of anti-thyroid drugs such as methimazole or propylthiouracil (PTU)/6-N-propylthiouracil (PROP). These medications provide prompt relief but cannot be used as permanent treatment. Beta blockers, such as propranolol may be used to treat symptoms including tremors or palpations. Radioactive iodine is the most widely recommended, permanent treatment. Women should avoid pregnancy for six to 12 months post-treatment, and men should consider sperm banking prior to treatment with radioactive iodine. 2,3 Thyroid Dysfunction in Pregnancy Thyroid function is especially important during the first 12-14 weeks of pregnancy when fetal brain development is dependent on maternal thyroid hormone (Table). Table. Thyroid Dysfunction in Pregnancy 3,5 Hypothyroidism Maternal increased risks Preeclampsia Pre-term delivery Placental abruption Postpartum hemorrhage Spontaneous abortion (SAB) Neonatal increased risks Low birth weight Perinatal death/stillbirth Children born with: Adverse effects in cognition, intellect and motor development Impairment in neuropsychological development indices, IQ scores and school learning abilities Hyperthyroidism Heart failure Low birth weight Neonatal thyroid dysfunction Perinatal death/stillbirth Placental abruption Preeclampsia Pre-term delivery SAB Thyroid storm Thyroid function test results change during pregnancy due to the hcg and estrogen hormones. Being a glycoprotein hormone, hcg is produced during pregnancy by the developing embryo soon after conception and later by the syncytiotrophoblast. This hormone acts as a weak thyroid stimulator, causing a drop in TSH in the first trimester. After this happens, TSH returns to normal throughout 3 SP12872_FertilityNurses_0310_k.indd 3 4/8/10 10:53:31 AM

the duration of pregnancy. If TSH is above 2.3 miu/l in early pregnancy, it may be indicative of subclinical hypothyroidism, which can be defined as an elevated TSH with normal, free T4. Because there are no universal reference ranges for thyroid function tests in pregnancy, TSH may be in the nonpregnant, normal range. However, the normal drop in TSH with pregnancy needs to be taken into consideration. 3,6 Women who are already on T4 treatment prior to pregnancy usually need to increase their replacement dose by 30 percent to 50 percent during pregnancy. They also need to recheck their TSH every four weeks until it is normalized, and then every six to eight weeks after that. The goal for these women is to maintain a TSH level of at least 2.3 miu/l in the first trimester. 3,6,7 Infertility as a Risk Factor Infertility is considered to be a risk factor for thyroid dysfunction. Checking TSH levels with a second hcg pregnancy test may be beneficial for detecting early thyroid dysfunction. A TSH level greater than 2.5-3 miu/l during early pregnancy may indicate subclinical hypothyroidism and treatment may be warranted. This is because pregnancy unmasks an incipient, hypothyroid state that would eventually become clinically evident. Thyroid antibody testing may also be useful in determining if the woman is at risk for developing hypothyroidism in the future. 3,8 Because the fetus relies on maternal thyroid hormone and iodine is necessary for the production of thyroid hormones, it is important that pregnant women have adequate iodine in their prenatal vitamin. Iodine is recommended at 150 mcg - 250 mcg in the form of potassium iodide. This dose is especially important for women who use sea salt (noniodized) or follow vegan, low-sodium or dairy-free diets, as these diets are iodine-deficient. 2,3 Screening Infertile Patients for Thyroid Dysfunction Abnormal thyroid function can alter levels of sex hormonebinding globulin (SHBG), prolactin and gonadotropinreleasing hormone (GnRH), which can all lead to menstrual dysfunction. One of the beneficial effects of T4 treatment for hypothyroidism is the restoration of regular menstrual cyclicity. The presence of thyroid antibodies is also associated with increased risk of miscarriage. Many studies propose the upper limit of normal TSH for fertility patients as 2.5 miu/l, but further research is needed. Increased estrogen from ovarian stimulation or pregnancy may place too high a strain on the thyroid gland in women who already have thyroid autoimmunity. Negro R, et al. demonstrated a decrease in spontaneous miscarriages and premature deliveries in euthyroid, anti-tpo positive, pregnant women treated with thyroxine. 6,9 Women with positive thyroid antibodies but normal TSH levels may benefit from treatment to stop or slow the progression to hypothyroidism, but further research is needed. 3 Studies report an increase in prevalence of autoimmune thyroid disease in infertile women. Screening infertility patients could help detect and prevent an evolution to overt thyroid dysfunction after ovarian stimulation in women with autoimmune disease. Treatment with T4 is recommended when subclinical hypothyroidism is present in women with infertility, irregular menses or after ovarian stimulation. 3,8 Summary In conclusion, TSH and free T4 are useful, initial laboratory markers for determining thyroid function. Common disorders among women of reproductive age include hypothyroidism as well as hyperthyroidism. The presence of thyroid antibodies is associated with a risk of miscarriage. Screening for thyroid dysfunction and autoimmunity should be considered as part of the general work up in women facing infertility issues. 4 SP12872_FertilityNurses_0310_k.indd 4 4/8/10 10:53:31 AM

References About the author: Tamara Tobias, ARNP received her nursing degree from the College of St. Benedict in St. Joseph, Minnesota, nurse practitioner training at Harbor-UCLA Medical Center, Torrance, California, and Master of Science degree in nursing from California State University, Long Beach, California. She is currently a certified women s health care nurse practitioner with Seattle Reproductive Medicine in Seattle, Washington. Ms. Tobias was a founding member of the Reproductive Nursing Association of San Diego and Southern Orange County, California, as well as the Seattle Tacoma Area Reproductive Society. She is an active member of the American Society for Reproductive Medicine (ASRM). She has also served as a speaker at ASRM conferences, as well as at various other nursing meetings. 1. Speroff L, Glass R, Kase N. Clinical Gynecologic Endocrinology and Infertility. 6th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; 1999:809-828. 2. The American Thyroid Association Web site. http://www.thyroid.org/patients/index.html. Accessed January 27, 2010. 3. Abalovich M, Amino N, Barbour L, et al. Clinical practice guideline, management of thyroid dysfunction during pregnancy and postpartum: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2007;92(8 Suppl):S1-S47. 4. Singer P, Cooper D, Levy E, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA. 1995;273(10):808-812. 5. Loh J, Wartofsky L, Jonklaas J, Burman K. The Magnitude of increased levothyroxine requirements in hypothyroid pregnant women depends upon the etiology of the hypothyroidism. Thyroid. 2009;19(3):269-275. 6. Negro R, Gormoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: Effects on obstetrical complications. J Clin Endocrinol Metab. 2006;91(7):2587-2591. 7. 8. AACE Thyroid Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8(6):457-469. Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction. Clin Endocrinol. 2007;66(3):309-321. 5 SP12872_FertilityNurses_0310_k.indd 5 4/8/10 10:53:32 AM

9. Negro R, Mangieri T, Coppola L, et al. Levothyroxine treatment in thyroid peroxidase antibody positive women undergoing assisted reproduction technologies: a prospective study. Hum Reprod. 2005;20(6):1529-1533. Resources Beckmann C, Ling F, Barzansky B, et al. Obstetrics and Gynecology. 2nd Ed.;1995:95-96. Bussen S, Steck T, Dietl J. Increased prevalence of thyroid antibodies in euthryoid women with a history of recurrent in-vitro fertilization failure. Hum Reprod. 2000;15(3):545-548. Geva E, Vardinon N, Lessing JB, et al. Organspecific autoantibodies are possible markers for reproductive failure: A Prospective Study in an In Vitro Fertilization-Embryo Transfer Program. Hum Reprod. 1996;11(8):1627-1631. Kim CH, Chae HD, Kang BM, Chang YS. Influence of antithyroid antibodies in euthryoid women on in vitro fertilization-embryo transfer outcome. Am J Reprod Immunol. 1998;40(1):2-8. Poppe K, Glinoer D, Tournaye H, et al. Assisted reproduction and thyroid autoimmunity: An unfortunate combination? J Clin Endocrinol Metab. 2003;88(9):4149-4152. Poppe K, Velkeniers B, and Glinoer D. The role of thyroid autoimmunity in fertility and pregnancy. Nat Clin Pract Endocrinol Metab. 2008;4(7):394-405. Poppe, K, Glinoer D, Tournay H, Schiettecatte J, Haentjens P, Velkeniers B. Thyroid function after assisted reproductive technology in women free of thyroid disease. Fertil Steril. 2005;83(6):1753-1757. Singh A, Dntas ZN, Stone SC, Asch RH. Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies. Fertil Steril. 1995;63(2):277-281. Vaidya B, Anthony S, Bilous M, et al. Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding. J Clin Endocrinol Metab. 2007;92(1):203 207. Kutteh WH, Schoolcraft WB, Scott Jr RT. Antithyroid antibodies do not affect pregnancy outcome in women undergoing assisted reproduction. Hum Reprod. 1999;14(11):2886-2890. Ladenson P, Singer P, Ain K, et al. American Thyroid Association Guidelines for Detection of Thyroid Dysfunction. Arch Intern Med. 2000;160(11):1573-1575. Muller AF, Verhoeff A, Mantel MJ, Berghout A. Thyroid autoimmunity and abortion: A prospective study in women undergoing in vitro fertilization. Fertil Steril. 1999;71(1):30-34. Panesar N, Li C, Rogers M. Reference intervals for thyroid hormones in pregnant chinese women. Ann of Clin Biochem. 2001;38(Pt 4):329-332. 6 SP12872_FertilityNurses_0310_k.indd 6 4/8/10 10:53:32 AM

Walgreens is proud to be part of the following upcoming fertility events for 2010: Pacific Coast Reproductive Society (PCRS) April 14-18, 2010 Renaissance Esmeralda Resort Indian Wells, CA www.pcrsonline.org Michigan Reproductive Nurses Association April 17, 2010 Eagle Crest, Marriott Ypsilanti, MI 7.5 REI CEU $70.00 kristine.klinger09@comcast.net The Midwest Reproductive Symposium and MRS Nurse Practicum June 3-5, 2010 The Drake Hotel Chicago, IL www.mwrs.org Walgreens is pleased to be the official provider for nurse accreditation at this year s event. UCLA-Santa Barbara Meeting July 11-14, 2010 Four Seasons Biltmore Santa Barbara, CA www.cme.ucla.edu/courses American Society for Reproductive Medicine Annual Meeting October 23-27, 2010 Colorado Convention Center Denver, CO www.asrm.org 7 SP12872_FertilityNurses_0310_k.indd 7 4/8/10 10:53:32 AM

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