KEY POINTS
- 1.
Thyroid hormone signaling is required for both normal fetal and pediatric development.
- 2.
The identification of genes critical for thyroid gland development and migration and thyroid hormone metabolism, transport, and receptor function has revealed that derangement of local thyroid hormone signaling can impact development, even in the absence of primary thyroid disease.
- 3.
The goal of thyroid hormone replacement in neonates is to optimize normal growth and development.
- 4.
For many neonates, levothyroxine (LT4) replacement is anticipated to be lifelong; however, there is potential to discontinue LT4 in patients with transient congenital hypothyroidism.
- 5.
In neonates with hyperthyroidism, there is a risk of acute morbidity and mortality as well as some evidence to suggest the potential for long-term adverse neurocognitive outcomes.
- 6.
Further clinical research is needed to better understand the long-term consequences of fetal and neonatal hypothyroxinemia, as well as thyrotoxicosis, to better understand the potential benefits and risks of treatment.
Introduction
The incidence of congenital hypothyroidism (CH) is reported to be between 1 in 2000 and 1 in 4000 births, with the higher incidence associated with lowering of the thyroid-stimulating hormone (TSH) diagnostic level for diagnosis. The most common inheritable cause of primary CH is failure of normal thyroid gland development (dysgenesis) or failure of a eutopic thyroid gland (a gland located in its usual position, anterior to the second to fourth tracheal rings) to produce thyroid hormone normally (dyshormonogenesis). Thyroid dysgenesis accounts for approximately 85% of permanent CH, and thyroid ectopy is the most common cause of dysgenesis, with the ectopic thyroid tissue located anywhere along the path of migration, from the foramen cecum in the base of the tongue to the thyroid bed. The identified transcription factors critical for thyroid gland formation include NKX2-1 , FOXE1 , and PAX8 ; for thyroid folliculogenesis, NKX2-1 and PAX8 ; and for migration, FOXE1 and CDCA8 /Borealin. , Several of these transcription factors are also involved in nonthyroid related organogenesis. As an example, expression of NKX2-1 is critical in the development and function of interneurons in the central nervous system, surfactant producing cells in the lungs, and expression of thyroid peroxidase and thyroglobulin. Mutations in NKX2-1 are associated with brain-lung-thyroid syndrome, characterized by hereditary chorea, respiratory distress syndrome, and congenital hypothyroidism secondary to thyroid dysgenesis. Tables 26.1 and 26.2 review the genetic alterations and phenotypes for thyroid gland dysgenesis ( Table 26.1a ) and dyshormonogenesis ( Table 26.1b ).
| Gene (OMIM) | Name | Thyroid Phenotype | Additional Features |
|---|---|---|---|
| NKX2-1 (600635) | NK2 homeobox 1 or thyroid transcription factor 1 | Thyroid hypoplasia, hemiagenesis, or athyreosis | Brain-lung-thyroid syndrome; benign hereditary chorea, infant respiratory distress syndrome (surfactant deficiency) |
| PAX8 (167415) | Paired box 8 | Thyroid hypoplasia, ectopy, or athyreosis | Urogenital tract abnormalities |
| FOXE1 (602617) | Forkhead box protein E1 or thyroid transcription factor 2 | Thyroid hypoplasia or athyreosis | Bamforth-Lazarus syndrome; cleft palate, choanal atresia, bifid epiglottis, and spiky hair |
| TSHR (603372) | Thyroid stimulating hormone receptor | Thyroid hypoplasia | None |
| HHEX (604420) | Hematopoietically expressed homeobox | Thyroid hypoplasia and ectopy | None |
| Gene (OMIM) | Name | Mode of Inheritance | Phenotype |
|---|---|---|---|
| TSHR (603372) | Thyroid stimulating hormone receptor | AD | TSH resistance with elevated TSH and T4 in the normal range |
| SLC5A5 (601843) | NIS: sodium-iodide symporter | AR | Absent or low iodide uptake on scintigraphy with elevated serum Tg; variable hypothyroidism and goiter |
| SLC26A4 (605646) | Pendrin: anion transporter | AR | High level of uptake on scintigraphy with positive perchlorate discharge test and elevated serum Tg; sensorineural hearing loss with enlarged vestibular aqueduct hypothyroidism and goiter |
| DUOX1/DUOX2 (606758/606759) | Dual oxidase 1 and 2 | AR or AD | High level of uptake on scintigraphy with positive perchlorate discharge test and elevated serum Tg; transient or permanent hypothyroidism and goiter |
| DUOXA2 (612772) | Dual oxidase associated protein | AR | High level of uptake on scintigraphy with positive perchlorate discharge test and elevated serum Tg; transient or permanent hypothyroidism and goiter |
| TPO (606765) | Thyroid peroxidase | AR | High level of uptake on scintigraphy with positive perchlorate discharge test and elevated serum Tg; severe hypothyroidism and goiter |
| Tg (188450) | Thyroglobulin | AR | Positive uptake on thyroid scintigraphy and low to undetectable serum Tg; variable hypothyroidism and goiter |
| IYD/DEHAL1 (612025) | Iodotyrosine dehalogenase | AR | Positive uptake on thyroid scintigraphy and elevated serum Tg; variable hypothyroidism and goiter |
| GNAS (139320) | Alpha subunit of the stimulatory guanine nucleotide-binding G-protein | Imprinted gene | Hypothyroidism with partial TSH resistance |
Congenital central hypothyroidism is rare, with an incidence between 1 in 16,000 and 1 in 20,000. Because transcription factors regulate expression of multiple pituitary cell types, multiple pituitary hormone deficiencies are present in about 75% of infants with congenital central hypothyroidism ( Table 26.1c ).
| Level of Defect | Gene(s) Involved (Primary Mode[s] of Inheritance) | Phenotype |
|---|---|---|
| Congenital Central Hypothyroidism | ||
| Isolated central hypothyroidism a | TRHR (AR); TSHB (AR) IGSF1 (X-linked) | Central hypothyroidism (low T4, normal or low TSH) |
| Thyroid Hormone Cell Membrane Transport Defect | ||
| Allan-Herndon-Dudley syndrome | SLC16A2 (X-linked) | Abnormal serum thyroid tests (high T3, low T4, low rT3, normal or high TSH); low body mass index, central hypotonia, spastic quadriplegia, mental retardation, speech delay |
| Thyroid Hormone Metabolism Defect | ||
| SBP2 defect | SECISBP2 (AR) | Abnormal serum thyroid tests (high T4 and rT3, low T3, normal or high TSH); growth retardation, delayed bone maturation, developmental delay |
| Thyroid Hormone Action Defect | ||
| RTHα | THRA (AD) | Abnormal serum thyroid tests (low T4 to T3 ratio); impaired cognition, short lower limbs, delayed bone/dental development, macrocephaly, constipation |
| RTHβ | THRB (AD) | Abnormal serum thyroid tests (high T4, nonsuppressed TSH); goiter, attention deficit hyperactivity disorder, tachycardia |
a Central hypothyroidism may also develop as a component of combined pituitary deficiency from HESX1 , LHX3 , LHX4 , SOX3 , PROP-1 , or POU1FI mutations. AD, Autosomal dominant; AR, autosomal recessive; rT3, reverse T3; TSH, thyroid stimulating hormone.
Lastly, several extrinsic factors can cause hypothyroidism in neonates. Iodine deficiency remains the most common cause of neonatal hypothyroidism worldwide. Preterm infants are at increased risk of iodine-related thyroid dysfunction; iodine deficiency–associated hypothyroidism can occur due to low iodine content of preterm infant formulas and parenteral nutrition. Iodine excess can also cause hypothyroidism secondary to iodine-induced decreased synthesis of thyroid peroxidase, leading to decreased organification of iodine and production of thyroid hormone (called the Wolff-Chaikoff effect). The most common sources of excess iodine are exposure to topical iodine-based antiseptics, exposure to high content iodine medications such as amiodarone, radiographic contrast agents, , or high maternal dietary intake of iodine that is passed through breast milk. Other extrinsic causes include transplacental passage of antithyroid medications used to treat hyperthyroidism (methimazole, carbimazole, or propylthiouracil), transfer of maternal immunoglobulin G antibodies that block activation of the TSH receptor, and many additional medications that can alter thyroid hormone levels (see Table 26.2 ). ,
| Level of Alteration | Medications |
|---|---|
| Decreased TSH secretion | Glucocorticoids Dopamine Octreotide |
| Decreased T3 and T4 secretion | Iodide Amiodarone Lithium |
| Decreased T4 absorption | Aluminum hydroxide Omeprazole (proton pump inhibitors) Ferrous sulfate |
| Displacement of T3 and T4 from binding proteins | Furosemide Heparin |
| Increased hepatic metabolism | Phenobarbital Phenytoin Carbamazepine |
Neonatal thyrotoxicosis (hyperthyroidism) is less common than congenital hypothyroidism; however, it can lead to significant morbidity and mortality if not promptly recognized and adequately treated. The majority of cases are transient, secondary to transplacental passage of maternal thyroid-stimulating immunoglobulin (maternal Graves disease, [GD]); however, neonatal hyperthyroidism can also occur secondary to activating mutations in the TSH receptor or activating mutations in the alpha subunit of stimulatory G proteins (GNAS) in McCune-Albright syndrome.
Pathophysiology
Hypothyroidism
Normal embryonic development requires the coordinated action of thyroid hormones. In mammals, these iodothyronine hormones (T3 and T4) are derived from both maternal and fetal sources and regulate the proliferation, differentiation, and apoptosis of developing tissues in a temporally and anatomically precise manner. During most of gestation, extracellular concentrations of active thyroid hormones in the fetus are low (compared with maternal serum) and the local action of thyroid hormones is regulated by the dynamic expression of cellular thyroid hormone transporters, metabolizing enzymes, and nuclear receptors.
During the first trimester, maternal T4 production increases by approximately 20% under stimulation of placental human chorionic gonadotropin. Maternal T4 then crosses the placenta to augment fetal organogenesis and development after conversion to T3 by type 2 deiodination within fetal tissues. During the second trimester, concentrations of thyroid hormone in fetal serum rise, and in the early third trimester (25 weeks), the fetal pituitary response to thyroid-releasing hormone (TRH) develops, as well as maturation of the negative feedback control of pituitary TSH from T3 and T4. After delivery the infant begins transitioning to an adult pattern of thyroid hormone metabolism over the ensuing 2 to 4 weeks. This transition may be altered by the gestational age at the time of delivery, illness, exogenous medications administered to the mother or infant, abnormal development of the hypothalamic-pituitary-thyroid axis, or disorders of thyroid hormone production and/or metabolism.
Thyroid hormone deficiency has a negative impact on fetal development. In humans, this is most significantly illustrated by the permanent neurocognitive injury associated with combined maternal and fetal thyroid deficiency due to either profound, untreated maternal autoimmune hypothyroidism (Hashimoto thyroiditis) or severe maternal iodine deficiency. , In other settings, where at least one thyroid axis is intact, thyroid hormones from either maternal or fetal secretion can function as a protective homeostatic mechanism for the fetus. As an example, in complete fetal athyreosis, maternal thyroid hormone alone is sufficient to support normal fetal development as is illustrated by the normal growth and intellectual outcome of athyreotic children who receive adequate levothyroxine treatment from birth. , The effective transplacental transfer of maternal thyroid hormone in this setting has been directly documented in humans by the demonstration of T4 and T3 in the serum of infants with complete organification defects or athyreosis prior to treatment.
In contrast to the protection afforded by maternal thyroid hormones, fetal compensation for the converse pathophysiology of maternal hypothyroidism appears to be incomplete. In pregnant women who have associated maternal hypothyroxinemia, offspring have decreased intellectual outcome even in the presence of normal fetal thyroid gland development and function. , The risk is greatest in the first trimester when the fetal thyroid is developing and does not have secretory capacity. This is the rationale for current recommendations to monitor thyroid status frequently upon the diagnosis of pregnancy in women with preexisting hypothyroidism. However, even in the unfortunate occurrence of untreated, overt maternal hypothyroidism discovered late in pregnancy (second or third trimester), aggressive thyroid hormone replacement therapy to achieve a maternal TSH <3 μU/mL may result in infants without significant cognitive delay.
At birth, the neonate rapidly shifts to postnatal thyroid physiology. Thyroid secretion is acutely stimulated, with a rapid peak in TSH (as high as 60–80 μU/mL) approximately 30 to 60 minutes after delivery, followed by elevations in T4 and a decrease in reverse T3 levels (the neonatal surge). The TSH surge is transient, decreasing to around 20 μU/mL at 24 hours, with a continued, gradual decline over the first week. Subsequent to the TSH surge, there is an increase in T4 levels, which peak about 3 days after delivery. , For the majority of healthy, term infants, the serum concentration of TSH approximates adult levels within 2 weeks. Serum T3 levels increase more slowly than T4 up to approximately 3 months of age, when both T3 and T4 begin to decrease toward adult levels.
The above transition from fetal to neonatal thyroid physiology is altered in prematurely born infants. Neonates born before 28 weeks’ gestation often exhibit a blunted TSH and T4 surge, followed by a period of prolonged hypothyroxinemia (total T4) with inappropriately normal or low serum TSH concentrations. A major contributor of the fall in T4 is loss of transplacental maternal T4 and iodine secondary to early parturition. Due to immaturity of the hypothalamic-pituitary-thyroid (HPT) axis, serum TSH does not increase in response to the low T3 and T4 and may remain “inappropriately” low for 2 to 3 months until the HPT axis begins to mature.
This pattern of altered HPT tone is called transient hypothyroxinemia of prematurity and the etiology is multifactorial, reflecting persistence of the fetal thyroid hormone metabolic state (low T3 and T4 with elevated reverse T3 [rT3]), reduced maternal transfer of iodine and T4, and a lack of response of the neonatal HPT axis feedback loop to low T3 and T4 levels, which begins to mature at approximately 30 weeks adjusted gestational age. Nonthyroidal illness syndrome, the suppression of thyroid function that occurs in patients of all ages during critical illness, is often confounded by administration of drugs or agents known to suppress TSH release (dopamine, glucocorticoids) and/or production and secretion of T3 and T4, including iodine-containing antiseptics, amiodarone, and iodine-containing radiologic contrast agents. The overlap between the severity of illness and common therapies used in the ICU setting complicates the interpretation of the thyroid axis laboratory values and may prolong the period of HPT axis maturation. , In nonthyroidal illness syndrome, T3 and the reverse T3 (rT3) levels correlate with severity of illness and mortality, respectively, T3 negatively and rT3 positively.
The severity of the transient hypothyroxinemia correlates with increased morbidity and decreased survival. Although some studies have shown an association between the severity of this hypothyroxinemia and later intellectual outcome, none have demonstrated a consistent benefit of levothyroxine treatment. Consequently, controversy exists regarding the appropriateness of treatment, and more research is needed to address this.
While the HPT axis matures, preterm infants display a delayed elevation in TSH (dTSH). The increase in TSH may be modest (between 5 and 15 μU/mL) or more significant (>25 μU/mL), and it typically occurs between 2 weeks and 6 months of age, with a mean of 30 days. T4 levels are also low and decrease to a nadir 2 to 3 weeks after delivery, with lower levels correlating with the degree of prematurity and birth weight. , , Although the majority of infants who develop dTSH have a normal thyroid on imaging and ultimately recover normal thyroid function, up to 25% have permanent hypothyroidism. , Fig. 26.1 reviews an algorithm for screening infants with potential congenital hypothyroidism.
Hyperthyroidism
Neonates of mothers with GD are at increased risk for neonatal GD, but hypothyroidism can also occur. There are two types of TSH-receptor (TSHR) antibodies (TRAbs): TSHR-stimulating immunoglobulins, which cause overproduction of thyroid hormone (hyperthyroidism), and TSH-receptor inhibitory (blocking) immunoglobulins, which can cause hypothyroidism. Fetal thyroid hormone synthesis begins at approximately 10 to 12 weeks’ gestation, and the fetal TSH receptor starts responding to stimulation, including stimulation by thyroid-stimulating immunoglobulins, during the second trimester. TRAbs, which belong to the immunoglobulin G class, freely cross the placenta, similar to iodine, thyroxine (T4), and antithyroid drugs (ATDs) the mother may be taking for the treatment of GD. The balance of stimulatory and inhibitory TRAbs, as well as ATD dose, influence the thyroid status in the fetus and neonate, and the fluctuation of maternal antithyroid antibody titers may result in different risks to the fetus or neonate. In cases of transient neonatal GD, maternal TRAbs typically clear from the infant’s circulation by 4 to 6 months of age, with resultant resolution of hyperthyroidism.
As mentioned in the introduction, neonatal hyperthyroidism can also occur secondary to activating mutations in the TSH receptor or activating mutations in the alpha subunit of stimulatory G proteins (GNAS) in McCune-Albright syndrome. This form of hyperthyroidism is permanent. Long-term antithyroid medical therapy is indicated until the child is old enough to safely complete definitive therapy to convert to hypothyroidism. Thyroidectomy is the treatment of choice, with some patients requiring radioactive iodine even after thyroidectomy if residual tissue is associated with persistent or recurrent hyperthyroidism.
Clinical Features
Fetuses of euthyroid women are protected from the effects of hypothyroidism by placental transfer of maternal thyroid hormone and because they commonly have some functioning thyroid tissue. Prenatal treatment of CH may be considered in rare cases of dyshormonogenesis that present with a large fetal goiter, which can cause polyhydramnios and airway compromise that may obstruct breathing after birth. The pattern and timing of dyshormonogenesis-associated goiter may vary based on the genetic etiology. Mutations in TG , TPO , and DUOXA2 have been reported as etiologies of fetal goiter.
Infants with severe congenital hypothyroidism may present with hypothermia, bradycardia, poor feeding, hypotonia, large fontanelles, myxedema, macroglossia, and umbilical hernia. This presentation is most common when both fetal and maternal hypothyroidism are present, as in iodine deficiency or untreated maternal hypothyroidism. However, many neonates manifest few or no symptoms even with significant hypothyroidism, making clinical diagnosis difficult in this age group. Implementation of universal newborn screening has nearly eradicated severe intellectual impairment due to CH in areas where screening is practiced, but CH remains a leading cause of preventable intellectual impairment in areas without newborn screening programs.
Signs of hyperthyroidism can be detected in the fetus, and if present, are highly predictive of neonatal hyperthyroidism. Particularly in cases where maternal GD is poorly controlled, features concerning for fetal hyperthyroidism include fetal tachycardia (heart rate >160 beats/min), thyroid enlargement (goiter; fetal neck circumference >95%), intrauterine growth retardation, polyhydramnios or oligohydramnios, advanced bone age, craniosynostosis with microcephaly, and hydrops. , Polyhydramnios is typically associated with a goiter with resultant esophageal and/or tracheal obstruction. Fetal bone age is assessed at the distal femur as the distal femoral epiphysis becomes detectable at about 32 weeks’ gestation. An advanced bone age is present if the femoral epiphysis is present prior to the 31st gestational week. For fetuses with severe thyrotoxicosis, there is an increased risk for premature delivery, and at the extreme, fetal death may occur.
After delivery, a newborn may present with tachycardia, irritability with tremors, poor feeding, sweating, and difficulty sleeping secondary to thyrotoxicosis. Newborns may also have an emaciated appearance, proptosis with stare, and a goiter. Premature closure of cranial sutures (craniosynostosis) may be noted in severely affected infants. Other signs of neonatal hyperthyroidism, which may be confused with infection/sepsis, include thrombocytopenia, hepatosplenomegaly, and jaundice. Fulminant liver failure and pulmonary hypertension secondary to neonatal hyperthyroidism may also be features of thyrotoxicosis.
Evaluation
Screening protocols vary but generally begin with measurement of TSH and/or T4 in a dried blood spot collected from the infant within a few days after delivery. The initial sample generally should be obtained at least 24 hours after delivery to avoid false-positive results due to the physiologic TSH surge. , Prompt diagnosis and treatment of CH is critical to optimize developmental outcome, so any abnormal newborn screen result should prompt immediate confirmation of TSH and free T4 concentrations in a serum sample. If a repeat newborn screen is obtained after the first few days of life, whether to confirm an abnormal result or as standard practice in all or selected newborns, gestational age– and postnatal age–specific reference ranges must be used to avoid misinterpreting an elevated TSH as normal in the context of the higher TSH reference range that is applicable only to the first few days after birth.
In preterm infants, the timing of thyroid hormone testing should be adjusted to surveil over the time required for HPT axis maturation and acute illness. In an effort to avoid missing appropriate treatment, serial thyroid hormone monitoring should be implemented. A standardized monitoring schedule should be considered, with two examples including testing at (1) 48 hours, 2 weeks, 6 weeks, 10 weeks, or until the infant is >1500 g, or (2) 72 to 120 hours, 1 week, 2 weeks, 4 weeks, and at term-corrected gestational age (see Fig. 26.1 ). There is no consensus on criteria for initiation of thyroid hormone replacement therapy, but treatment should be considered if the TSH is >10 μU/mL with a low T4. Levothyroxine (LT4) replacement should also be considered if the TSH is persistently between 5 and 10 μU/mL or if the TSH is >5 μU/mL with an upward trend on serially repeated thyroid function testing.
Determining the etiology of CH via radiologic imaging rarely alters initial management but may provide insight into prognosis. Ultrasound or thyroid scintigraphy (using 99 mTc or 123 I) can be used to assess the presence or absence of a normally located thyroid gland. Although hypothyroidism due to dysgenesis is usually permanent, about 35% of patients with a eutopic thyroid gland have transient disease and will not require lifelong therapy. ,
Neonates considered to be at high risk for development of thyrotoxicosis include (1) infants born to mothers with GD, especially if the maternal TRAb level is greater than twice the upper limit of normal; (2) infants in whom intrauterine surveillance revealed fetal signs of hyperthyroidism; and (3) infants with a known family history of genetic causes of congenital hyperthyroidism including activating mutations in the TSH receptor. If possible, TRAbs should be measured in cord blood of infants at high risk for neonatal hyperthyroidism, because there is a strong correlation between maternal and neonatal TRAb levels. Cord blood TSH and free thyroxine (fT4) are less helpful in predicting the onset of neonatal hyperthyroidism. Maternal ATDs are usually metabolized and excreted by 5 days of life. Unless symptoms of hyperthyroidism develop earlier, thyroid function studies (TSH and fT4) should be sent between 3 and 5 days of life, when biochemical hyperthyroidism typically develops in neonates with hyperthyroidism secondary to maternal GD. Onset of signs and symptoms of thyrotoxicosis may be delayed for several days, either from the effect of maternal ATDs or due to a coexistent effect of blocking antibodies. Thyroid function studies should therefore be sent again at 10 to 14 days of life, as studies have shown that most cases of neonatal GD present within the first 2 weeks of life. However, there have been case reports of overt thyrotoxicosis secondary to neonatal GD occurring as late as 45 days of life. After 2 weeks of age, infants with no clinical or biochemical hyperthyroidism should continue close monthly follow-up with their primary care providers. Algorithms summarizing the evaluation and management of neonatal hyperthyroidism are available. ,
Management
Hypothyroidism
In newborns whose screening whole blood TSH is ≥40 mIU/L, LT4 should be initiated as soon as the confirmatory serum sample is obtained, without awaiting the results. In infants with screening TSH <40 mIU/L, LT4 should be initiated if the confirmatory serum TSH is >20 mIU/L or between 6 and 20 mIU/L with a low free T4 concentration (see Fig. 26.1 ). The management of infants with mild TSH elevation (serum TSH 6–20 mIU/L) and normal free T4 levels is controversial. Although such patients are frequently identified by more stringent newborn screening thresholds, the neurodevelopmental risks posed by untreated mild disease remain uncertain. Although there is a lack of consensus, if the TSH remains in the 6 to 20 mIU/L, beyond 21 days in a healthy, term neonate, LT4 replacement may be initiated with reevaluation for the need of continued therapy at 2 to 3 years of life.
The initial dose of LT4 for CH is 10 to 15 micrograms (μg)/kg daily. For the majority of term infants, the typical starting dose is 37.5 mcg/day of LT4. For infants with marked elevation in TSH, >100 mIU/L, 50 mcg/day may be considered as a starting dose , with close follow-up and dose reduction to avoid overtreatment that may be associated with altered neurodevelopmental outcome. , Serum thyroid function testing is monitored every 1 to 2 weeks until normal, and then every 1 to 2 months during the first year of life and every 2 to 4 months during the 2nd and 3rd year of life with LT4. The target parameter for LT4 treatment is normalization of TSH within the first weeks of initiation of therapy. , LT4 dose is adjusted to maintain the serum TSH in the midnormal range and the serum free T4 in the mid- to upper half of the normal range. A subgroup of infants with CH displays variable degrees of thyroid hormone resistance with persistently elevated TSH levels despite high-normal or frankly elevated free T4 concentrations. For these patients, the addition of LT3 to LT4 therapy can facilitate normalization of the TSH, but whether this improves outcomes is unknown. To initiate combined therapy, the LT4 dose is typically decreased by 10% to 20% with addition of liothyronine (LT3) between 0.3 and 0.66 μg/kg/day, with the minimal reliable dose of 2.5 μg/day (1/2 tab) based on the smallest available tablet size (5 μg).
In patients with suspected transient CH, based on the presence of a normal-appearing, eutopic thyroid gland on ultrasound and an initial borderline elevated TSH between 6 and 20 mIU/L, an LT4 dose of <1.7 μg/kg/day at 1 year of life or <1.45 μg/kg/day, without a need for an increase in LT4 dose despite normal growth and development, is associated with a high likelihood of normal thyroid function after discontinuation of LT4 supplementation. , , LT4 doses >4.9 μg/kg/day or >4.7 μg/kg/day at 12 months or 24 months, respectively, are associated with an increased likelihood for permanent hypothyroidism. A trial off of LT4 is typically delayed until the child is 2 to 3 years of age, when the risk of potential hypothyroidism-related neurocognitive development is lower.
In central hypothyroidism, the TSH is low or inappropriately normal despite low T4 levels, secondary to abnormalities in the hypothalamus (thyrotropin-releasing hormone, TRH) or pituitary gland (TSH). The goal of treatment in central hypothyroidism, in which, by definition, serum TSH does not reflect systemic thyroid status, is to maintain the serum free T4 level in the upper half of the reference range. However, before initiation of thyroid hormone replacement therapy in patients with suspected central hypothyroidism, assessment of the other anterior pituitary hormone axes must be completed to avoid inducing adrenal insufficiency secondary to thyroid hormone–associated increased clearance of cortisol.
LT4 tablets should be crushed, suspended in a small volume of water, breast milk, or non–soy-based infant formula, and administered via a syringe or teaspoon (not in a bottle). LT4 should not be administered with multivitamins containing calcium or iron. Limited data suggest that brand-name LT4 may be superior to generic in children with severe congenital hypothyroidism but not in those with equally severe acquired hypothyroidism. , Compounded LT4 solutions do not provide reliable dosing and should not be used. Tirosint-SOL is a stable liquid form of levothyroxine that is available in Europe and the United States with reported unaltered absorption when administered with milk (and other breakfast beverages, in adults). With the potential of improved absorption, optimal dosing of liquid LT4 preparations in neonates may differ compared with tablet formulations. , In patients that cannot tolerate LT4 by mouth or by nasogastric or gastrostomy tube, intravenous levothyroxine may be administered with a dose reduction of 25% based on a 70% to 80% absorption rate of oral levothyroxine in healthy subjects (thyroid hormone is absorbed in the jejunum and ileum).
Prenatal treatment of CH may be considered in rare cases of dyshormonogenesis that present with a large fetal goiter, which can cause polyhydramnios as well as airway compromise that may obstruct breathing after birth. Intraamniotic injection of LT4 may help decrease fetal goiter size to prevent these complications. Although there is no consensus on intraamniotic LT4 dose or schedule, several reports have employed 150 to 500 μg/dose (or 10 μg/kg estimated fetal weight) every 2 weeks, with adjusted frequency based on fetal goiter response. , , Intrauterine demise and need for intubation at birth are potential complications in such cases.
Hyperthyroidism
In cases of suspected neonatal GD with biochemical hyperthyroidism, antithyroid drugs, (methimazole (MMI), and others) should be started at a dose of 0.2 to 0.5 mg/kg/day. Propranolol should be added at a dose of 2 mg/kg/day for signs of sympathetic hyperactivity including tachycardia and hypertension. Propylthiouracil (PTU) is not recommended in neonates and throughout childhood due to the increased risk for hepatotoxicity. In severe cases with hemodynamic compromise, Lugol’s solution or potassium iodide may be given. Glucocorticoids may also be beneficial in the short term ( Fig. 26.2 ). Because neonatal hyperthyroidism is more often transient and resolves with clearance of maternal TRAbs from the circulation, thyroid function tests should be monitored every 1 to 2 weeks after initiation of treatment to ensure appropriate MMI dose titration.
