Thyroid Hormones in the Neonate An Overview of Physiology and Clinical Correlation Chris Schmaltz, MSN, RNC-NIC, CCRN, NNP-BC

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1 KSENIA ZUKOWSKY, RN, PHD, CRNP Section Editor Thyroid Hormones in the Neonate An Overview of Physiology and Clinical Correlation Chris Schmaltz, MSN, RNC-NIC, CCRN, NNP-BC 2.3 HOURS Continuing Education ABSTRACT This article reviews the pathological actions of the thyroid hormones in the neonate. A review of the thyroid gland, thyroid hormones, fetal thyroid development, and healthy neonatal thyroid actions is explored as a basis to comprehend common thyroid diseases. KEY WORDS ORDS: neonatal endocrinology, neonatal thyroid diseases, thyroid function of the neonate NEONATAL ENDOCRINOLOGY The endocrine system consists of an array of organs and glands responsible for maintaining homeostasis, ensuring optimal cellular function and ontogenesis (growth). An intact and properly functioning nervous system is required to detect changes in the cellular milieu and external environment to produce an appropriate response by the endocrine system. This symbiotic relationship between the nervous system and the endocrine system is known as the neuroendocrine system. 1 The neuroendocrine system maintains a constant dialogue with the body through feedback systems, which stimulate the production and release of various chemicals called hormones. Hormones can be classified into 2 major categories, hydrophilic (water loving) and hydrophobic (water repealing). 1 Hydrophilic hormones are composed of large protein molecules, able to bind to target receptor cells to produce a response. Once the target receptor site has been stimulated, the cell is able to change its metabolic function, via either opening or closing membrane channels, or alter genetic expression by stimulating the cells nucleus. 1 Hydrophobic hormones are also known as steroid hormones. 1 These hormones are able to diffuse freely Author Affiliation: Pediatrix Medical Group, Austin, Texas. The author have disclosed that he has no financial relationships related to this article. Correspondence: Chris Schmaltz, MSN, RNC-NIC, CCRN, NNP-BC, Pediatrix Medical Group, 5053 Fort Clark Dr, Austin, TX (NNPUPENN@gmail.com). Copyright 2012 by the National Association of Neonatal Nurses DOI: /ANC.0b013e into all cells in the body. Steroids only elicit a response from cells that have internal receptors of the hormone. Once internal receptors have been stimulated, cellular genetic expression is altered. Successful hormone stimulation is dependent on proper chemical makeup of the hormone, proper hormone release, and proper end organ cellular receptors. Endocrine disorders arise when hormones fail to elicit or halt a proper end organ response. Endocrine disorders are broadly divided into 2 categories: hormone excess (hyperactive states) and hormones deficiencies (hypoactive states). As already discussed, hormone production and release are controlled by various feedback loops. The thyroid gland is controlled by a specific type of feedback loop known as a negative feedback loop (Figure). Negative feedback refers to any regulation where the reaction (ie, output of the thyroid gland) is controlled and blunted inversely to the stimulus (ie, input from the nervous system). The thyroid gland is regulated by a negative feedback system between the pituitary gland and hypothalamus. 1 The elegant feedback system ensuring equilibrium of thyroid hormones (THs) is defined as the hypothalamic-pituitary-t hyroid axis. Once the hypothalamus is stimulated, it responds by secreting thyrotropin-releasing hormone (TRH). The TRH serves as a catalyst for the pituitary to produce thyroid-stimulating hormone (TSH) in the anterior pitui tary. Once the pituitary has released TSH, the thyroid is then stimulated to release THs. Elevated levels of THs serve as the off-switch for the feedback loop; hence, the hypothalamus downregulates TRH. 1 When evaluating the endocrine system, the astute clinician must take a stepwise approach to determine where the feedback system has failed to maintain balance. Advances in Neonatal Care Vol. 12, No. 4 pp Copyright National Association of of Neonatal Nurses. Unauthorized reproduction of of this this article article is prohibited. is

2 218 Schmaltz FIGURE. Negative feedback and the thyroid. Abbreviations: THs, thyroid hormones; TRH, thyrotropinreleasing hormone; TSH, thyroid-stimulating hormone. THE THYROID AND THS Thyroid Gland The thyroid consists of 2 lobes that are connected by an isthmus. This butterfly-shaped organ is located in the anterior portion of the neck, on the trachea, and below the larynx. The thyroid is nourished from a blood supply from the superior and inferior thyroid arteries, which come off the carotid artery. The thyroid is made of epithelium containing follicles (hollow spheres) supported by soft connective tissue. The follicles are lined with a special type of cell, unique to the thyroid, known as thyrocyte cells. Thyrocyte cells are the only cells in the body able to secrete a specific glycoprotein known as thyroglobulin (Tg). A glycoprotein is a molecule made of both a carbohydrate and a protein. In the case of Tg, the protein foundation consists of a tyrosine base. Recognition of the tyrosine base is important to understanding THs formation. THs Formation Once Tg is produced by the thyrocytes, it is then stored in the follicles to serve as a precursor to the THs. Once stored, Tg awaits to be bathed in iodine extracted from the arterial blood supply in a process known as the organification of the Tg. Once engaged in an iodine bath, the tyrosine portion of Tg forms a covalent bond to iodine. The bond created between tyrosine and iodine functions as the building blocks of THs-diiodotyrosine (DIT) and monoiodotyrosine (MIT). When tyrosine first reacts with iodine, MIT is formed, and further oxidization is required to produce DIT. These building blo cks of DIT and MIT are bonded together to form either thyroxine (T4) or triiodothyronine (T3). T4 is created when 2 DIT molecules join in a loose bond, and T3 composed of one MIT molecule and one DIT molecule are paired together in a bond. 1 THs Delivery and Cellular Uptake Once the thyroid has been stimulated by TSH, both T4 and T3 enter into circulation. Upon first release into the blood, 99% of T4 and T3 bind to a transport protein. 1 There are 3 proteins that serve as binding agents to THs: thyroxine-binding globulins (TBG), albumin, and thyroxine-binding prealbumin all of which are produced by the liver. 1 A small amount of free TH remains unattached to a binding agent and becomes the biological active hormone ready for immediate usage, not burdened with the task of being cleaved from a transport protein. THs that are bound to the transport proteins are eventually released to exert a response toward the target cell. T4 is released at a slower rate than T3, because of a stronger molecular bond between thyroxine and its carrier protein. After diffusing across the cell membrane, THs will then be stored for a period of days or weeks before finally binding to the TH receptors found in the cell s nucleus. 1 Once inside the cell, the majority of thyroxine is turned to triiodothyronine with an enzymatic reaction called monodeiodination. 1 Monodeiodination converts T4 into T3 by removing the extra iodine bond. This reaction is fueled by the enzyme deiodinase, which is selenium dependent. 1 Once T3 attaches to the TH receptors, it activates gene transcription to upregulate activity of the mitochondria, which increases cellular energy production. 1 Basic thyroid effects on body mechanisms are outlined in Table 1. THYROID DEVELOPMENT AND THS, DURING FETAL LIFE AND AFTER BIRTH Fetal Thyroid Development Neonatal thyroid formation is etched out of the foregut at the base of the tongue, approximately 3 weeks gestation. During the next few weeks, the primitive thyroid gland continues its migration until reaching its final resting place posterior to the larynx and hyoid bone at 7 weeks gestation. 2 The primitive thyroid remains mostly nonfunctional until the second trimester. 3-5 While the primitive thyroid gland is forming, the placenta is responsible for maintaining TH equilibrium in the fetus. 4 Maternal-derived THs are partially permeable to the placenta and enter fetal circulation. These quantitatively low levels of THs are critical for the survival of the fetus. Proper neurological development is dependent upon monodeiodination of maternal THs. In fact, thyroid receptors are concentrated in the cerebral cortex to ensure proper neurological development. 3-5 Maternal hypothyroxinemia is present during early gestation, while the fetus is dependent on the maternal THs results in fetal hypothyroidism. 4,5

3 Thyroid Hormones in the Neonate 219 TABLE 1. Effects of Thyroid Hormone on the Body Body System Metabolism Cardiovascular Respiratory Gastrointestinal Muscular Nervous system Endocrine Effect of Thyroid Hormones Increases cellular metabolism Stimulates effective carbohydrate utilization Increased cardiac output secondary to increased metabolic rate Respiration rate and depth increase secondary to an increased rate of metabolism tissue oxygen consumption increased Increases production and secretion of digestive enzymes and gastric motility Muscular development and strength Regulates sleep-wake cycles, normal cerebration Increases the release of other hormones and increases the tissues need for hormones to match the new metabolic rate Prior to midgestation, the fetal thyroid gland develops the capability to store and utilize iodine as the primitive hypothalamic region of the brain is synthesizing a TRH. 4 Endogenous fetal derived THs are shallow until 20 weeks gestation and then proportionally increase in size with gestation. 4,5 As fetal production of THs increases, the placenta begins to restrict permeability of maternal THs. 5 Normal THs Following Delivery After delivery, the neonate undergoes a cascade of changes to allow proper transition to extrauterine life. The dramatic fall in temperature that a neonate experiences at delivery serves as a catalyst for outpouring of TRH and TSH. 5,6 The dramatic rise of TSH is predictably followed by a rise of THs. In the term population, the postdelivery spike in THs ebbs by 6 weeks of life. 4 The preterm neonate also experiences a rise in THs, although quantitatively mitigated when compared with their term cohort. 6 Preterm neonates TH levels will rise over a span of 8 weeks to analogous values to the term population. 3 Curiously, very low-birth-weight neonates do not experience the same thyroid trajectory. 6 In fact, T4 and free T4 levels decline steadily following delivery until 2 weeks of age when they experience a TH nadir in the presence of muted TSH levels. 6 It is important to note that although THs levels remain elevated during the first weeks of life, TSH levels exponentially fall within the second hour of life, and within 2 days, the neonate experiences TSH levels that resemble the uterine environment, reflecting the intact negative feedback system. 4,6 ALTERED THYROID STATES Congenital Hypothyroidism Congenital hypothyroidism (CH) refers to an umbrella diagnosis describing endocrine disorders resulting in suboptimal TH levels. Failure to identify the neonate who has hypothyroidism can result in the development of mental retardation; however, screening and early treatment can alter the life course of the neonate who experiences hypothyroidism. 4-8 The underlining cause of CH can be subdivided into 3 major categories: endogenous (from within), transient (self-limiting and self-resolving), and euthyroid (sick thyroid or disorders of TH carrier proteins). Knowledge of thyroid function is necessary to appropriately diagnose and treat thyroid disorders. Signs of hypothyroidism vary in clinical presentations, depending upon the origin and severity of the dysfunction. The most common signs are outlined in Table 2. Endogenous CH Endogenous manifestations of hypothyroidism include thyroid dysgenesis (lack of thyroid gland tissue), thyroid dyshormonogenesis (improper formation of THs), and a central defect (problems stimulating the thyroid). Thyroid dysgenesis is the most common cause of CH. 4 In its most severe case, the neonate will present with a total absence of any thyroid tissue. Less-severe thyroid dysgenesis occurs when ectopic that is, displaced thyroid tissue is able to produce THs to the neonate. Thyroid dyshormonogenesis describes the neonate who has a structurally normal thyroid but experiences hypothyroidism secondary to a failure of proper synthesis/ metabolism of TH. The inability to produce normal THs can be attributed to a resistance to TSH, iodine transport defects, organification defect, Tg abnormality, or deiodinase deficiency. 4,5 Because the thyroid does not act independently yet relies on signaling from the pituitary and hypothalamus, a disorder of either gland will dispose the neonate to central or hypothalamic-pituitary hypothyroidism. 4-6 Neonates born with endogenous CH will require synthetic thyroid supplementation throughout their lifetime, monitored by an endocrinologist. 4-6 Advances in Neonatal Care Vol. 12, No. 4

4 220 Schmaltz TABLE 2. Signs of Hypothyroidism Clinical Manifestation Large, open posterior fontanelle ( 1 cm) Hypothermia Abdominal distention Poor feeding Prolonged hyperbilirubinemia Umbilical hernia Midline facial defects (cleft lip and palate) Hypoglycemia Microphallus Goiter Abbreviation: TH, thyroid hormone. Physiological Origin Skeletal immaturity Diminished metabolic state Hypomotility Diminished metabolic state, lethargy Altered bilirubin metabolism Lack of proper muscular development secondary to a lack of thyroid hormone in utero Abnormal or absent fetal thyroid gland development Abnormal hypothalamus/pituitary development Reflective of a central hypothyroid problem, inadequate hormone release, including TH Reflective of a central hypothyroid problem, inadequate hormone release, including TH Enlarged thyroid gland secondary to dyshormonogenesis Transient Hypothyroidism Transient hypothyroidism describes the neonate who is experiencing low levels of circulating THs, usually because of 1 of 3 common etiologies maternal antithyroid medications, maternal antibodies, or excessive neonatal iodine expose. 4,6,9 If the mother has a history of thyroid disorders, it is prudent to identify pharmacological agents ingested during the pregnancy that can cross the placenta. In particular, propylthiouracil (a thyroid-suppressing pharmacological agent) is able to enter fetal circulation, thus inhibiting neonatal thyroid function. The second cause of transient hypothyroidism is an accumulation of maternal antibodies. 4,9 These neonates present with a maternal history of euthyroid or autoimmune thyroid disease. 9 Neonates and their mothers are able to be screened by measuring the TSH receptor autoantibodies in maternal and cord blood. If the neonate is exposed to suppressive antibodies, the fetus experiences a block in TSH, hence preventing the stimulation of the thyroid. The third cause of transient hypothyroidism, which is rare, is excessive iodine exposure. 4,9 Neonates diagnosed with transient hypothyroidism are generally not treated unless they continue to demonstrate altered TH levels past the second week of life, at which time thyroid supplementation under the guidance of an endocrinologist is recommended. 4,9 Transient Hypothyroxinemia of Prematurity Preterm neonates experience suboptimal thyroid health during their hospitalizations. This is theorized to be a result of an immature hypothalamic-pituitary axis. Neonates with transient hypothyroxinemia will have low levels of T4 and low to normal levels of TSH. However, these levels rise in response to TRH, suggesting normal yet still immature function of the hypothalamic-pituitary axis. 6 Treatment for preterm neonates experiencing transient hypothyroxinemia is controversial. While traditional treatment of preterm hypothyroxinemia has been observation, there is a current attempt to identify evidence-based protocols for treatment. Currently, it is known that low levels of circulating T4 are associated with poor neurological outcomes, yet supplemental THs in neonates older than 27 weeks have proven to be detrimental to cognitive function. 3,6 Data suggest that thyroxine treatment is beneficial to neonates born 25 to 26 weeks. 3 These data were obtained from van Wassenaner and Kok, 3 who conducted a double-blind, placebo-controlled study of thyroxine administration in neonates born prior to 30 weeks gestation. While acute NICU problems were not altered between groups, Bayley Mental and Psychomotor Developmental tests were higher at 24 months of age in neonates delivered at 25 to 26 weeks who received treatment. 3 The beneficial effects were not seen in neonates who received treatment and where born at 27 to 30 weeks gestation. 3 Current thyroxine substitution should be limited to clinical trials. Euthyroid Euthyroid, or sick euthyroid, refers to low thyroid levels, despite normal thyroid function, that have appeared during chronic and acute illness. 10 There is currently no recommended treatment for a neonate diagnosed with euthyroid. 10 Neonates can also present in a relative hypothyroid state, despite having a healthy thyroid, if the carrier proteins (eg, TBG) are abnormal. 4 Identification of altered TH carrier proteins is necessary to prevent a misdiagnosis of altered thyroid activity. 4,5,10

5 Thyroid Hormones in the Neonate 221 Identification of Hypothyroidism in the Term Neonate Mental retardation secondary to CH is preventable and easy to screen for. The American Academy of Pediatrics 7 first published recommendations for CH screening in With the recommendations of the American Academy of Pediatrics, 7 more than 5 million neonates are annually screened, and nearly 1400 patients with CH are identified. Coordinated discharge planning is crucial to ensure that all neonates are screened before leaving the hospital. The American Academy of Pediatrics currently recommends neonates to be screened between days 2 and 4 of life. Neonates who are screened prior to 48 hours of life often lead to false-positive TSH elevations. 8 Traditionally, there are 2 strategies to identify CH. The first measures TSH levels and supplements questionable results with a backup T4 level. 7,8 Other screening programs utilize T4 levels and supplement questionable results with a backup TSH result. Both screening tools have been called into question secondary concerns of CH cases that can be/have been missed. 8 Programs that rely on primary TSH levels run the risk of reporting false negatives when the neonate has a TBG deficiency, central hypothyroidism. 8 Screening programs that utilize abnormal T4 levels will fail to identify the neonate with abnormal TSH levels. 8 The American Academy of Pediatrics has issued a gold standard in neonatal CH screening where both T4 and TSH are measured at the same time, thus eliminating any false-negative results. 8 Neonatal nurses who obtain and report out laboratory specimens should be aware of their state s CH screening technique and recognize the limitations for the test. Hyperthyroidism in the Neonate Hyperthyroidism in the neonate is rare. Clinical manifestations of hyperthyroidism can present in the fetus and up to the first 2 months of postnatal life. 4 The 2 major causes of neonatal hyperthyroidism are maternal thyrotoxicosis (Graves disease or Hashimoto thyroiditis), or a genetic mutation of the thyroid-stimulating hormone receptor (TSHR). 6 Alterations in the genomic sequence of the TSHR gene illustrate a failed negative feedback system: the pitui tary is not sensitive to circulating thyroid levels, resulting in permanent thyroid stimulation due to continued signaling from the pituitary. Signs and symptoms of hyperthyroidism are outlined in Table 3. It has been reported that only 0.01% of all neonates born to mothers with thyrotoxicosis will ever be affected because of the partial barrier protection of the placenta. 6,11 However, because of the serious sequela of a hyperactive thyroid, neonatal screening should occur if there is a maternal history of either active or inactive Graves disease or Hashimoto thyroiditis due to accumulation of thyroid-stimulation TABLE 3. Signs of Hyperthyroidism Clinical Manifestation Physiological Origin Craniosynostosis/frontal Advanced skeletal maturation bossing Exophthalmos Improper fat storage Tachycardia, arrhythmias, Excessive myocardial stimulation congestive heart failure from THs and increased metabolic state Vomiting, diarrhea GI hyperactivity secondary to THs stimulation Hyperthermia Heightened metabolic state Tremors, hyperactivity THs stimulation of muscular tissues, and CNS sleep-wake cycles Abbreviations: CNS, central nervous system; GI, gastrointestinal; THs, thyroid hormones. antibodies (TSA) received by the fetus. Screening should even be performed when the maternal history reveals a thyroidectomy due to continued maternal production/fetal acquisition of TSA. Screening in the perinatal period includes measuring maternal TSA levels, monitoring for fetal tachycardia, and fetal growth. 11 Maternal thyroid antibodies consist of both TSH receptor-stimulating antibodies and TSH receptorblocking antibodies. 12 The concentration of stimulating/blocking antibodies will determine the effect to the neonate and the timing of clinical symptoms. If the fetus has been exposed to a greater number of stimulating antibodies, the neonate will have hyperthyroidism. 4 The reverse is also true; fetuses exposed to higher concentrations of blocking antibodies will experience a hypothyroidism secondary to a depression of TSH. 4 Fetal acquisition of both antibodies is responsible for the development of late-onset neonatal Graves disease. Neonates who present 4 to 6 weeks after birth in a thyrotoxicosis state will have received both TSH receptor blocking and stimulating antibodies in utero. 4 However, the blocking antibodies will inhibit the effects of the stimulating antibodies. Classic symptoms of neonatal Graves disease will be absent until the level of TSH blocking antibodies has decreased. Postnatal thyrotoxicosis treatment is tailored according to the origin of the disease. Neonates who develop neonatal Graves disease secondary to maternal antibodies require supportive treatment and monitoring until the maternal TSA becomes biologically irrelevant. Pharmacological agents are administered to alter and blunt the effects of TH on the neonate. Iodine, such as Lugol s solution, is administered to prohibit the release of THs, often in combination with propylthiouracil to prevent the conversion of T4 to Advances in Neonatal Care Vol. 12, No. 4

6 222 Schmaltz T Therapeutic responses should be observed within 24 hours of treatment to determine adequate dosage. If there is no measurable response, then a dose increase in the pharmacological agent is warranted. 4-6 Treatment should continue until thyroid-stimulating immunoglobulines are no longer detectable. 4 Neonates who experience hyperthyroidism secondary to genetic causes will require a thyroidectomy with radioiodine ablation of remaining thyroid tissue if pharmacological agents fail to produce a stable metabolic state. 13 The prognosis for the neonate who experienced a h yperactive thyroid varies, and the neonate requires collaborative management to ensure optimal recovery. Long-term follow-up is needed to monitor growth and assess the normal progression of developmental milestones. References 1. Guyton A, Hall J. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006;76: Sandler T. Langman s Medical Embryology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; van Wassenaner AG, Ko k JH. Hypothyroxinemia and thyroid function after preterm birth. Semin Neonatal. 2004;9:3. 4. Polk D, Fisher D. Disorders of the thyroid gland. In: Taeusch H, Ballard R, Gleason C, eds. Avery s Diseases of the Newborn. 8th ed. Philadelphia, PA: Elsevier Saunders; 2005: Stokowski L. Endocrine system. In: Kenner C, Wright Lott J, eds. Comprehensive Neonatal Care: An Interdisciplinary Approach. 4th ed. Philadelphia, PA: Elsevier Sanders; 2007: American Academy of Pediatrics, Section on Endocrinology and Committee of Genetics; American Thyroid Association, Committee on Public Health. Newborn screening for congenital hypothyroidism: recommended guidelines. Pediatrics. 1993;91: American Academy of Pediatrics, Susan R. Rose, and the Section on Endocrinology and Committee on Genetics, American Thyroid Association, Rosalind S. Brown, and the Public Health Committee and Lawson Wilkins Pediatric Endocrine Society. Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics. 2006;117; Kratzsch J, Pulzer F. Thyroid gland development and defects. Best Pract Res Clin Endocrinol Metabol. 2008;22(57): Dalahunty C, Falconer S, Hume R, et al; and the Scottish Preterm Thyroid Group. Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcome at 5½ years: millennium cohort study. J Clin Endocrinol Metabol. 2010;10: Williams F, Hume R. The measurement, definition, aetiolo gy and clinical consequences of neonatal transient hypothyroxinaemia. Ann Clin Biochem. 2011;48: Lee M, Moshang T. In: MacDonald M, Mullett M, Seshia M, eds. Avery s Neonatology Pathophysiology & Management in the Newborn. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: Montoro M. Thyroid and other endocrine disorders during pregnancy. In: Decherney A, Nathan L, Goodwin T, Laufer N, eds. Current Diagnosis & Treatment Obstetrics & Gynecology. 10th ed. New York, NY: McGraw-Hill Medical Publishing Division; 2007: Zimmerman D. Fetal and neonatal hyperthyroidism. Thyroid. 1999;9(7): For more than 59 additional continuing education articles related to neonatal, go to NursingCenter.com/CE.