Untreated congenital hypothyroidism (CH) leads to intellectual disabilities. Prompt diagnosis by newborn screening (NBS) leading to early and adequate treatment results in grossly normal neurocognitive outcomes in adulthood. However, NBS for hypothyroidism is not yet established in all countries globally. Seventy percent of neonates worldwide do not undergo NBS.
The initial treatment of CH is levothyroxine, 10 to 15 mcg/kg daily. The goals of treatment are to maintain consistent euthyroidism with normal thyroid-stimulating hormone and free thyroxine in the upper half of the age-specific reference range during the first 3 years of life. Controversy remains regarding detection of thyroid dysfunction and optimal management of special populations, including preterm or low-birth weight infants and infants with transient or mild CH, trisomy 21, or central hypothyroidism.
Newborn screening alone is not sufficient to prevent adverse outcomes from CH in a pediatric population. In addition to NBS, the management of CH requires timely confirmation of the diagnosis, accurate interpretation of thyroid function testing, effective treatment, and consistent follow-up. Physicians need to consider hypothyroidism in the face of clinical symptoms, even if NBS thyroid test results are normal. When clinical symptoms and signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, and/or hypothermia), measurement of serum thyroid-stimulating hormone and free thyroxine is indicated, regardless of NBS results.
Background and Statement of the Problem
Congenital hypothyroidism (CH) is one of the most common preventable causes of intellectual disability worldwide. CH is an inborn condition in which thyroid hormone (TH) levels are insufficient for the normal development and function of body tissues. In the majority of affected infants, the disorder is permanent and results from abnormal thyroid gland development or a defect in TH synthesis. In rare cases, CH may result from abnormal pituitary or hypothalamic control of thyroid function. In some infants with CH, thyroid dysfunction is transient and normalizes at a later time.1–4 Clinical and laboratory follow-up of children with CH is essential for appropriate management.5–7
Newborn screening (NBS) for CH followed by prompt initiation of levothyroxine (L-T4) therapy can prevent severe intellectual disability, psychomotor dysfunction, and impaired growth.1,5–10 NBS has been adopted in many countries throughout the world.1,5–7,11,12 However, there continue to be inconsistent diagnostic definitions for CH and a need for further research regarding preventable risk factors for the development of permanent and transient CH. In addition, the influence of severity at diagnosis, timing of treatment initiation, and L-T4 dose on long-term outcomes remains a matter of debate. Although the majority of treated patients achieve normal cognitive outcomes, the influence of L-T4 therapy on neurologic development is less certain, and some studies show persistent deficits in treated patients compared with euthyroid healthy controls.13,14
Much has been learned about the pathophysiology, genetics, diagnosis, and management of CH in recent years. Lowering of screening TSH cutoffs has resulted in detection of milder, sometimes transient forms of hypothyroidism. If a permanent form of CH has not been established, L-T4 treatment is maintained until 3 years of age, after which thyroid function is reevaluated following a 4- to 6-week discontinuation of L-T4.5–7
New data, particularly on long-term neurodevelopmental outcomes, provide opportunities to refine diagnostic criteria and optimize monitoring and treatment protocols. A review of past practices and future directions, as well as updated evidence for the management of CH, are provided.15
Most cases of CH are caused by dysfunction of the thyroid gland (primary hypothyroidism). The most common causes are a defect in thyroid gland development (thyroid dysgenesis) and an intrinsic defect in TH synthesis (dyshormonogenesis). Less commonly, neonatal thyroid function may be transiently impaired by extrinsic factors, such as maternal antithyroid medications, TSH receptor-blocking antibodies (TRBAb) acquired through transplacental passage, or maternal or infant iodine deficiency or excess. Rarely, CH is caused by hypothalamic or pituitary defects that lead to inadequate secretion and/or bioactivity of TSH (central hypothyroidism).16
The normal development of many fetal tissues, especially the nervous system, is critically dependent on TH. The fetal thyroid begins to form around 3 weeks of gestation and begins to synthesize TH at around 10 to 12 weeks of gestation. Hypothalamic and pituitary control of the thyroid is asserted around midgestation and develops through the third trimester, reaching maturity around term gestation. Before the onset of TH synthesis, the fetus is completely dependent on maternal thyroxine (T4), which crosses the placenta in limited amounts throughout gestation.17,18 In infants who are unable to synthesize T4, cord blood T4 concentrations are one third to one half of normal because of transfer of maternal T4.19 Maternal T4, along with increased conversion of T4 to the more bioactive triiodothyronine (T3),20 is partially protective against the adverse developmental consequences of fetal hypothyroidism. For this reason, normal or near-normal neurocognitive outcome is attainable even in infants with severe CH, as long as maternal thyroid function is normal and adequate postnatal L-T4 treatment is initiated early. In contrast, when combined maternal and fetal hypothyroidism are present—as may occur with severe iodine deficiency or untreated maternal hypothyroidism—significant neurodevelopmental impairment can occur despite adequate postnatal L-T4 therapy. This highlights the importance of timely prenatal care that includes careful detection and management of maternal thyroid disease before and during pregnancy. This report focuses exclusively on the problem of CH; identification and treatment of maternal hypothyroidism have been addressed in recent reviews and consensus guidelines.21
Iodine is a critical component of TH production, and hypothyroidism caused by iodine deficiency remains 1 of the most common preventable causes of intellectual disability worldwide. However, adequate iodine supplementation before and during pregnancy will normalize thyroid function in the iodine-deficient mother and newborn infant.22 Universal salt iodization is recommended by the World Health Organization and the United Nations Children’s Fund23 and has been implemented in more than 100 countries.24 Nevertheless, iodine deficiency in pregnant women remains common in many areas of the world.21 Although North America is an iodine-sufficient region overall, recent data indicate that more than half of pregnant women in the United States may have mild iodine deficiency.25 Intake of a prenatal vitamin containing 150 mcg of iodine daily by all women before and during pregnancy and lactation will promote iodine sufficiency in mother and newborn infant.21,26
NBS for CH was introduced in the 1970s and is now practiced across North America, Europe, Australia, and parts of Asia, South America, and Africa.12 The incidence of CH ranges from approximately 1 in 2000 to 1 in 4000 newborn infants in countries from which NBS data are available.12 This incidence is significantly higher than that reported in the early years of NBS (around 1 in 4000), primarily because of changes in screening strategies that have led to increased detection of milder cases of CH.27–29 Genetic factors may also be influential as data suggest that CH is more common in certain populations.30 There is a 1.5 to 2-fold greater incidence in females than in males of thyroid ectopia (but not of agenesis or dyshormonogenesis), and there is an increased risk for CH in infants with trisomy 21.
The hypothalamic-pituitary-thyroid axis is finely tuned to maintain a stable concentration of free T4 (FT4) in each individual. In primary hypothyroidism, the serum TSH concentration increases in response to decreased thyroidal production of TH. Because TSH secretion is sensitive to small changes in serum FT4 levels, in primary hypothyroidism the serum TSH increases before FT4 concentrations decrease below normal. In central hypothyroidism, serum FT4 is reduced, although often still remaining in the low normal range, but the pituitary is unable to respond appropriately, and serum levels of TSH usually remain inappropriately normal or low. These principles form the basis of NBS strategies for diagnosing CH.
Newborn Screening for CH
Newborn Screening Programs
Detection of CH in newborn infants is accomplished by screening a population of newborn infants within a defined geographic area (eg, a state, province, or region). Population screening is performed cost-effectively by state or provincial public health laboratories working closely with birthing hospitals or other birthing centers within their geographic area. NBS programs that employ a multidisciplinary team are best able to conduct comprehensive care of detected cases. NBS programs undertake communication with the infant’s primary care provider (PCP), along with ongoing education of pediatric providers and birthing hospitals or centers.
A dried blood spot (DBS) for NBS is obtained by heel stick on an approved filter paper card using appropriate collection methods. After drying, filter paper specimens are transmitted to the NBS laboratory for testing. Failure to follow NBS program instructions for collection may result in an unsatisfactory specimen that will not undergo testing.
The preferred age for collection of the NBS specimen to screen for CH is 48 to 72 hours of age. This timing reflects the normal surge in TSH concentration (to 60–80 mIU/L) that occurs within hours after birth in term newborn infants and resolves over the next 5 days.31 Specimens collected in the first 24 to 48 hours of life may lead to false-positive TSH elevations when using any screening test approach.32,33 However, obtaining a specimen for NBS at the preferred time may be challenging given the trend toward early postnatal discharge of infants: up to 90% of healthy term newborn infants in the United States and Europe may be discharged from the birthing hospital before 48 hours of age.34 For such patients, obtaining a sample before discharge is preferable to potentially missing a diagnosis of CH. Similarly, collection of a specimen for NBS before blood transfusion, even if before 48 hours of life, is important to avoid missing a diagnosis of CH. However, collection of the NBS specimen before 48 hours of age, and particularly before 24 hours of age, necessitates the use of age-specific TSH reference ranges or repeat screening, particularly to avoid false-positive results. False-negative NBS results may occur when screening an acutely ill newborn infant or after transfusion or from errors in the processing of specimens or reporting of results.
Some hospitals have adopted the practice of screening all infants at the time of admission to the NICU, with the goal of collecting samples before possible transfusion of blood products. This practice results in most samples being obtained too early (often before 24 hours of life), which may increase the risk of false-positive results. Therefore, it is preferable to screen infants admitted to the NICU at 48 to 72 hours of age, but before any actual transfusion of blood products, if required earlier.
The responsibility for collecting the NBS specimen rests with the hospital or birthing center where the infant is born or with the midwife or other supervising personnel in the case of home delivery. When a newborn infant is transferred to another hospital, communication between the transferring and receiving hospital is important to prevent missing collection of the NBS specimen.
NBS thyroid test cutoffs (TSH or T4) may vary from state to state, reflecting their own population’s experience with achieving desired separation of true from false-positive test results. If NBS is performed after 30 days of life, interpretation of results uses age-specific reference ranges.
NBS Test Strategies
The chief priority of NBS programs is the detection of infants with moderate or severe primary hypothyroidism, which results in intellectual disability if not detected. Secondary priorities include the detection of infants with mild primary hypothyroidism, primary hypothyroidism of delayed onset (“delayed TSH elevation”), or central hypothyroidism.
Three test strategies are used to screen for CH: (a) primary TSH – reflex T4 measurement; (b) primary T4 – reflex TSH measurement; and (c) combined T4 and TSH measurement. All 3 test strategies detect moderate to severe primary CH with similar accuracy. Comparison of cases detected by these different methods within the same population shows that a few infants missed by one strategy will be detected by another strategy,35 and most differences in case detection between strategies likely result from differences in test cut-offs and in the timing and number of specimens.36 The majority of NBS programs in the United States, Canada, and worldwide employ a primary TSH test strategy.12
Although all NBS programs measure TSH and T4 from whole blood specimens obtained by heel stick, some programs report results in whole blood units, whereas other programs report results in serum units. Based on the assumption that the average newborn hematocrit is ≈55%, results expressed in serum units are approximately 2.2-fold those expressed in whole blood units; for example, a screening TSH of 15 mIU/L in whole blood is roughly equivalent to a TSH of 33 mIU/L serum.37 Clinicians can identify whether NBS results in their region are expressed in whole blood or in serum units. Most NBS programs in the United States and some in Canada express results in serum units, and many in Canada and the rest of the world express results in whole blood units. Throughout this report, results are expressed in serum units, unless otherwise noted.
Primary TSH – Reflex T4 Screening
NBS programs using this strategy start with measurement of TSH in the DBS specimen. When screening TSH is elevated above the defined cutoff, total T4 is measured in the same DBS specimen. Depending on the NBS program algorithm, an elevated TSH and/or low T4 may lead to recall for a confirmatory serum sample or to collection of a second DBS specimen for repeat testing. Because many DBS specimens are obtained before 48 hours of age or after the first week of life, some NBS programs have developed age-specific TSH cutoffs.38,39
The primary TSH screening strategy is more likely to detect mild cases of CH than the primary T4 strategy. Infants with delayed TSH elevation will (by definition) have normal TSH on initial testing and so will not be detected by a primary TSH screening programs unless a second DBS specimen is collected either from all infants or specifically from infants at risk for delayed TSH elevation (see section below on Preterm or Low Birth Weight Infants and other special populations). Primary TSH screening programs will not detect babies with central CH, in which TSH concentrations are not elevated and low TSH values are not reported.
The recall rate (percentage of infants recalled for testing because of abnormal NBS results) generally is lower in primary TSH programs compared with programs employing a primary T4 strategy, but this varies depending on the TSH cut-off. For example, the NBS program in Newcastle, United Kingdom reported a recall rate of 0.08% using a cutoff of 10 mIU/L whole blood, but the recall rate increased to 0.23% when the cutoff was lowered to 6 mIU/L whole blood.40
Primary T4 – Reflex TSH Screening
This strategy begins with measurement of total T4 in the DBS specimen. (FT4 is not measured by most screening programs for technical reasons.) If the total T4 concentration falls below the defined cutoff, TSH is then measured in the same DBS specimen. A low T4 and/or elevated TSH may lead to recall for a confirmatory serum sample or to collection of a second DBS specimen for repeat testing. Compared with the primary TSH strategy, the primary T4 strategy is less sensitive for detecting mild cases of primary hypothyroidism in which TSH concentrations are elevated but T4 concentrations remain low normal. However, the primary T4 strategy is more likely to detect cases with delayed TSH elevation (if the program performs repeat screening in cases with initial low T4 and normal TSH), because the infants at highest risk for delayed TSH elevation are also likely to have low total T4 concentrations on initial screen (eg, preterm, low birth weight [LBW], or acutely ill newborn infants).
Primary T4 screening programs have the potential to detect newborn infants with central CH.41,42 Such cases are best detected by programs that collect 2 screening specimens either on all infants or on infants with low T4 and normal TSH on the first specimen. However, some cases of central hypothyroidism are not detected by this strategy, either because they have a T4 concentration in the lowest third of the normal range, or because the NBS program does not recall for repeat testing infants with a low T4 and a nonelevated TSH. These cases of congenital central hypothyroidism will usually present later in infancy with additional pituitary hormone deficiencies.42
The recall rate is approximately 0.3% in programs that follow-up only cases with low T4 and elevated TSH,41 similar to the primary TSH screening programs using a lower cutoff. In programs that collect 2 routine specimens or that follow-up on infants with low T4 on both the first and second specimen regardless of the TSH level, the recall rate is higher.43
Combined T4 and TSH Screening
Some state NBS programs in the United States and elsewhere measure both total T4 and TSH to screen for CH.43,44 Criteria for recall vary by program, but a combination of low T4 and elevated TSH generally leads to a request for a confirmatory serum sample. Other combinations of screening results may lead to a request for either a serum sample or a second DBS specimen. Combined T4 and TSH screening will detect primary hypothyroidism, including mild hypothyroidism, and has the potential to detect many cases of congenital central hypothyroidism.45,46 The combined screening will also detect infants with delayed TSH elevation if a second specimen is requested, either in all infants or in those at high risk for this disorder. As of 2015, 12 states in the United States mandated or suggested that a second NBS specimen be obtained at 2 weeks of age. The recall rate in combined T4 and TSH screening programs is higher than primary TSH or primary T4 programs.
NBS in Special Populations
Preterm or Low Birth Weight Infants
Infants born preterm (<37 weeks’ gestation) and/or with low birth weight (<2500 g) have lower serum T4 levels after birth than do term infants. The decrease in serum T4 is proportional to the degree of prematurity.47 In addition, preterm infants have a reduced TSH surge after birth compared with term infants.48 Multiple factors affect thyroid function in preterm infants: early loss of maternal T4, decreased production of thyroxine-binding globulin (TBG) resulting in lower total T4 levels, limited thyroid gland reserve, and immaturity of the hypothalamic-pituitary-thyroid axis. Preterm infants are also at increased risk of iodine deficiency because of greater weight-based iodine requirements and parenteral nutrition and preterm infant formulas commonly used in NICUs may provide inadequate iodine nutrition.49 In addition, preterm or LBW infants often have comorbidities that can result in the nonthyroidal illness syndrome, which has a typical pattern of low T4 with normal to low TSH concentrations. As a result, preterm or LBW infants are often detected with low T4 and normal TSH (termed hypothyroxinemia) by NBS programs that use a primary T4-reflex TSH strategy. Although this pattern of results is also compatible with central hypothyroidism, preterm or LBW infants are less likely than infants with central hypothyroidism to have low levels of serum FT4, particularly if measured by a dialysis method.50 Hypothyroxinemia appears to be transient in most preterm babies, and over time DBS T4 levels increase to those present in term infants.51
Although TSH concentrations are often normal or low in preterm or LBW infants, as they recover from hypothyroxinemia serum, TSH levels may rise transiently above normal (6–15 mIU/L).52 In some infants, this increase in TSH is significantly greater (>100 mIU/L). This pattern of “delayed TSH rise” is more common in preterm or LBW infants than in term or normal birth weight infants. Reports from the New England and Wisconsin NBS programs indicate that delayed TSH elevation occurred in 1 in 54 to 95 very low birth weight (VLBW [<1500 g]) infants, 1 in 737 preterm infants (<32 weeks) with birth weight >1500 g, and 1 in 30 329 infants of normal birth weight (>2500 g).53,54 In these reports, delayed TSH elevation was first detected at 22 to 46 days; TSH elevation peaked around 58 days of life (range 11 to 101 days) in the New England study. In the Wisconsin study, a delayed TSH rise that peaked above 100 mIU/L was detected in infants at a mean of 3 weeks of age, and milder TSH elevations were detected in infants later (mean, 59 days). Most infants with delayed TSH rise whose confirmatory serum TSH was above 20 mIU/L had low serum FT4 concentrations, whereas FT4 was normal in infants whose confirmatory serum TSH was below 20 mIU/L3.54
With recognition of the relatively high frequency of delayed TSH elevation, many NBS programs have elected to undertake repeat NBS in infants born preterm (<32 weeks’ gestation) or with VLBW (<1500 g).55,56 For routine rescreening of these infants, repeat NBS testing is preferred to measurement of serum TSH and FT4 because of the much lower cost of NBS. Gestational age-specific reference ranges for NBS TSH are available according to gestational age at birth (22 to 27 weeks versus 28 to 31 weeks).57
Acute Illness or Admission to a NICU
Newborn infants with acute illness, particularly illness requiring admission to a NICU, are likely to experience a nonthyroidal illness. Most newborn infants admitted to a NICU are born preterm and/or are LBW, and many are treated with drugs that can impact thyroid function, such as glucocorticoids or dopamine, which decrease TSH secretion.52,58,59 The combination of acute illness, preterm birth, and treatment with these medications results in low T4 levels without TSH elevation that may be detected by primary T4-reflex TSH NBS programs.60 These infants have a higher risk for delayed TSH elevation (see section on Preterm or Low Birth Weight Infants, above). Term newborn infants of normal birth weight who are admitted to a NICU may have a risk of delayed TSH elevation as high as that of VLBW newborn infants.61
Multiple Births, Same-Sex Twins, In Vitro Fertilization
The incidence of CH appears to be increased in pregnancies with multiple births (1:876 in twin births and 1:575 in higher-order multiple births in 1 study).61 Another study showed the incidence of CH in same-sex twins to be 1 in 593, compared with 1 in 3060 in different-sex twins.62 Most twin pairs (>95%) are discordant for CH.61,63 However, in monozygotic twins who share placental circulation, blood from a euthyroid fetal twin with normal TH levels may cross to a fetal twin with CH, temporarily correcting the hypothyroidism and preventing its detection by initial NBS at 24 to 72 hours of life. Thus, all monozygotic twins, or same-sex twins for whom zygosity is unknown, should undergo repeat NBS around 2 weeks of age.
Elevated TSH that would be detected by collection of a second NBS has been reported at 2 to 4 weeks of age in up to 10% of neonates following in vitro fertilization.64 However, in all cases TSH elevation was mild (<10 mIU/L) and FT4 was normal. The clinical significance of these findings remains uncertain, and evidence is insufficient to recommend repeat NBS in infants conceived by in vitro fertilization.
Infants with trisomy 21 have a high incidence of CH that ranges from 1% to 12% in various reports.65–69 For reasons that are not understood, newborn infants with trisomy 21 tend to have lower T4 concentrations and higher TSH concentrations than do infants without trisomy 21.69,70 Trisomy 21 is associated with other comorbidities (such as congenital heart disease) that may further increase the risk of abnormal NBS results because of acute illness or excess iodine exposure.
Infants with trisomy 21 who do not have CH are still at significant risk of developing primary hypothyroidism during the first year of life (approximately 7% in 1 prospective study).66 Therefore, in these infants, a second NBS should be performed at 2 to 4 weeks of life and serum TSH should be measured at 6 and 12 months of life. Hypothyroidism may develop before 6 months in some infants with trisomy 21,69 so a high level of clinical suspicion remains important, but there is insufficient evidence to suggest additional routine TSH screening.
Communication of NBS Test Results to the Primary Care Physician
Direct communication between the NBS program and PCP is important for timely receipt of abnormal results and appropriate follow-up care.43,71 Consultation with a pediatric endocrinologist will facilitate diagnostic evaluation and management. Management of abnormal NBS results is as described in the clinical report.15
Confirmatory Serum Testing After Abnormal NBS
In any child whose NBS results suggest CH, the next steps are to perform a physical examination (for goiter, lingual thyroid gland, and/or physical signs of hypothyroidism) and to measure serum concentrations of TSH and FT4 (or total T4), optimally with use of a laboratory that has a 24-hour turn around. Measurement of other thyroid hormones (such as T3, free T3, or reverse T3) is rarely of clinical value in the evaluation of possible CH.
For confirmation of abnormal NBS results, measurement of FT4 is preferred over measurement of total T4. However, the decision to measure FT4 or total T4 is based on cost, time to obtain results, and clinical factors. For example, preterm or LBW infants with normal thyroid function may have alterations in protein binding that result in low total T4 concentrations despite normal FT4. Therefore, if TSH is normal, low serum total T4 concentrations may be evaluated by measuring FT4. If concern for a binding abnormality exists, measuring FT4 by a dialysis method (which physically separates free T4 from bound T4 before measurement) performed in a reference laboratory may be more reliable than the standard analog method.
Interpretation and Management of Confirmatory Serum Testing Results
Elevated TSH and Low FT4
Elevated TSH with low FT4 on the confirmatory serum testing indicates overt primary hypothyroidism.
Elevated TSH and Normal FT4
This pattern of confirmatory serum results is termed hyperthyrotropinemia or subclinical hypothyroidism and represents a mild primary thyroid abnormality. There is controversy regarding the need for L-T4 therapy in this setting, because there are few and conflicting studies regarding the effect of mild CH on cognitive development. One study found that children with TSH elevation on NBS that remained persistent and untreated at 6 years of age had an increased risk of developmental delay compared with control children.72 Another study of nearly 500 000 Australian children demonstrated an association of mild TSH elevation on NBS with poorer academic performance and an increased risk of special educational needs.73 In contrast, studies of nearly 300 Belgian children showed no association of their NBS TSH with adverse cognitive, psychomotor, or behavioral outcomes at 4 to 6 years of age.74–76 Similarly, a study in New Zealand showed that children with mild or moderately elevated TSH on NBS (8–14 mIU/L blood or 17–31 mIU/L serum) who received no treatment or follow-up had similar neurocognitive outcomes to sibling controls at 10 years of age.77 There are currently no studies demonstrating a beneficial effect of L-T4 therapy on outcomes in patients with mild CH. In particular, heterozygous inactivating mutations of the TSH receptor gene may cause mild hyperthyrotropinemia that does not progress over time and may not benefit from L-T4 treatment.78,79 No evidence exists to define the precise TSH thresholds associated with potential adverse outcomes in mild CH.
Despite the lack of clear evidence regarding outcomes of hyperthyrotropinemia and whether L-T4 treatment is of clinical benefit, there is physiologic reason to believe that an elevated TSH concentration indicates that the hypothalamic-pituitary axis is sensing less TH than required by the body’s endogenous set-point. Therefore, on the basis of expert opinion, if the confirmatory serum TSH is >20 mIU/L, L-T4 treatment should be initiated even if FT4 is normal. If the confirmatory serum TSH is elevated but ≤20 mIU/L, treatment may be initiated, or alternatively serum TSH and FT4 may be followed closely every 1 to 2 weeks without treatment. However, repeated TSH elevation above 10 mIU/L has been associated with adverse outcomes in children with CH.80 Therefore, expert opinion suggests that persistent TSH elevation >10 mIU/L is an indication to initiate L-T4 treatment. Consultation with a pediatric endocrinologist can facilitate a patient-specific management plan.
The management of infants with persistent serum TSH elevations between 5 and 10 mIU/L after 4 weeks of age is even more controversial. The upper limit of normal TSH in infants age 1 to 3 months is around 4.1 to 4.8 mIU/L.81–84 TSH elevation above 5 mIU/L beyond 1 to 3 months of life is generally abnormal but does not demonstrate that L-T4 treatment is necessary or beneficial. Thus, in infants with serum TSH elevation between 5 and 10 mIU/L that persists beyond 4 weeks of age, there is insufficient evidence to support treatment versus observation. Consultation with a pediatric endocrinologist can facilitate a patient-specific management plan.
Normal TSH and Low T4
This pattern of thyroid function tests is observed in patients with central hypothyroidism, prematurity, LBW, acute illness, or TBG deficiency.41,42,85 Central hypothyroidism may be suspected in the presence of midline defects, visual abnormalities (blindness or nystagmus), or findings consistent with other pituitary hormone deficits (such as hypoglycemia, conjugated hyperbilirubinemia, microphallus, and/or cryptorchidism). The presence of multiple pituitary hormone deficiencies suggests a defect in hypothalamic or pituitary development.86,87
The incidence of central CH is between 1 in 16 000 and 1 in 25 000.41,42,85,88 Although the chief objective of NBS programs is detection of primary hypothyroidism, some primary T4 test programs can detect infants with central hypothyroidism. However, some neonates with central CH commonly have T4 levels within the lowest third of the normal range, so CH will not be diagnosed until later in life.40–43 Detection of central CH is facilitated in NBS programs that collect a second specimen from all infants with T4 below a specified cutoff.41 Primary TSH testing programs will not detect central hypothyroidism. To assist in distinguishing central hypothyroidism from TBG deficiency, a TBG concentration can be obtained, although this distinction can be challenging.85
The concept that central hypothyroidism is usually mild appears unfounded: a study from the Netherlands found that mean pretreatment serum FT4 levels in central CH were similar to those of patients with moderately severe primary CH.45 Therefore, L-T4 treatment of central CH is indicated. In addition to permitting early treatment of infants with central CH, detection of neonates with this disorder by NBS facilitates identification of associated pituitary hormone deficiencies (some of which may be life-threatening) and congenital anomalies, such as optic nerve hypoplasia and brain malformations.
Imaging with thyroid ultrasonography or scintigraphy, performed in an experienced center, may assist in establishing the etiology of CH.87 Controversy exists regarding the utility of routine thyroid imaging for patients with CH. Imaging may inform prognosis if it identifies an ectopic or a dysgenic thyroid gland suggesting a permanent form of CH, or if it guides counseling on the likelihood of disease recurrence in a future child of the same parents (see “Genetic Testing”). However, in most cases imaging does not alter clinical management of the patient before age 3 years.
Thyroid ultrasonography can identify the presence and location of thyroid tissue without radiation exposure89–92 and can be performed at any time after the diagnosis of CH. Ultrasonography has lower sensitivity than scintigraphy for detecting ectopic thyroid tissue,93 the most common cause of CH, although its sensitivity is improved by the use of color Doppler.92,94 The absence of a normally located thyroid gland on ultrasonography confirms a permanent form of CH, whether or not an ectopic gland is detected. A eutopic thyroid gland in combination with a low serum thyroglobulin concentration (in the setting of elevated TSH) is consistent with a thyroglobulin synthesis defect or a defect in TSH receptor signaling (including maternal TRBAb or a mutation in thyroid-stimulating hormone receptor (TSHR) or guanine nucleotide-binding protein [G-protein] subunit α [GNAS].95 An enlarged, eutopic thyroid, particularly in combination with elevated serum thyroglobulin, indicates a defect in TH synthesis.95
Thyroid scintigraphy allows localization of functional thyroid tissue based on its uptake of either 123I or 99mTc. 123I may provide more accurate uptake and images but may not be available in all imaging centers. 99mTc is less expensive and is widely available. 131I is not used in infants because of the higher exposure to ionizing radiation. A TSH concentration less than 30 mIU/L or performing scintigraphy more than 20 days after initiating therapy may result in falsely low uptake.96
If scintigraphy demonstrates an ectopic thyroid, a permanent form of CH has been established. The absence of eutopic thyroid iodine uptake is most often associated with thyroid aplasia or hypoplasia (or, less frequently, exposure to excess iodine). However, iodine uptake may be absent from a eutopic thyroid gland because of a genetic iodine-transport defect (SLC5A5) or a defect in TSHR signaling (including maternal TRBAb or a mutation in TSHR or GNAS). In the case of TRBAb, this may lead to an erroneous, permanent diagnosis of thyroid agenesis in a patient with transient CH. A defect in iodine transport may be suspected when normal 123I uptake in the salivary glands is absent.97
Iodine uptake in an enlarged, eutopic gland is consistent with a defect in TH synthesis. Measurement of serum thyroglobulin will distinguish a thyroglobulin synthesis defect from other genetic causes of dyshormonogenesis or exposure to an exogenous goitrogen other than iodine, such as antithyroid drugs.98
Infants with normal thyroid imaging at birth may have a transient form of hypothyroidism. In these patients, reevaluation off TH therapy after 3 years of age to assess for persistent hypothyroidism may be useful (see “Assessment of Permanence of Hypothyroidism”).
CH has a complex etiology and is sporadic in most cases. However, CH can be associated with one of several known monogenic causes or broader syndromes.99 Monogenic causes of CH may be categorized generally as causing thyroid dysgenesis or dyshormonogenesis. Thyroid dysgenesis is usually sporadic, but in rare cases may be related to mutations in specific genes (Table 1).100,101 Many of these genes encode transcription factors that are important during embryogenesis in multiple tissues, and therefore mutations in these genes frequently cause other abnormalities in addition to CH.101
Thyroid dyshormonogenesis is usually caused by defects in genes involved in thyroid hormone synthesis, such as TSH receptor signal transduction or iodide transport or organification (Table 2).101 Recent studies show some phenotypic overlap between genes classically associated with thyroid dysgenesis and dyshormonogenesis; indeed, a significant proportion of CH cases may be caused by interactions among mutations in 2 or more CH-related genes.102–104
Dual oxidase 2 (DUOX2) is an enzyme that generates the hydrogen peroxide required for TH synthesis. Genetic defects in DUOX2 cause CH with a eutopic thyroid gland.105 CH caused by DUOX2 mutations can be transient or permanent, but there is little correlation between the resolution or persistence of hypothyroidism and the number of DUOX2 mutations present (monoallelic or biallelic) or their severity.105
Abnormalities in the development or function of the hypothalamus or pituitary can result in central CH.86,87 Genetic causes of central CH include mutations in a variety of transcription factors involved in pituitary and hypothalamic development, including HESX1, LHX3, LHX4, SOX3, OTX2, PROP1, or POU1F1.84,85 These genetic defects also cause associated abnormalities specific to the causative gene. Additional pituitary hormone deficits are present in most cases of central CH (about 75%). Isolated central CH is rare, and the most common genetic cause are mutations in IGSF1, which cause an X-linked syndrome of central CH and macro-orchidism. Rare genetic causes of isolated central CH include mutations in the thyrotropin-releasing hormone receptor, the β subunit of TSH (TSHB), TBL1X, or IRS4.86,87
Syndromes associated with CH can be monogenic or can be part of other conditions or syndromes. In addition to trisomy 21, CH may be associated with CHARGE syndrome and Williams syndrome. Even in the absence of an evident syndrome, infants with CH are at increased risk of congenital anomalies, which are present in 10% of infants with CH compared with 3% of the general population. The most common are cardiovascular anomalies, such as pulmonary stenosis, atrial septal defect, and ventricular septal defect, but dysmorphic features, neural tube defects, hip dysplasia, and renal or other urinary tract anomalies are also documented.106–110
Recent advances in genetic testing allow for the assessment of many genes simultaneously, at lower cost and with faster turnaround time than in the past. Genetic information may be perceived as valuable by families, but genetic testing can present challenges of cost and interpretation of indeterminate results, and in many cases a genetic diagnosis may not alter clinical management. For children with isolated primary CH, genetic testing should be considered when a genetic diagnosis would alter clinical management. For cases that have a recognizable syndrome, central CH, or clinical features that suggest a genetic condition, referral to a geneticist is recommended. In such cases, genetic findings may enable counseling of families about recurrence risks or may identify other family members at risk. In all cases, the choice of whether to pursue genetic testing is made in consultation with the patient’s family.
CH is treated with enteral L-T4 at a starting dose of 10 to 15 mcg/kg per day, administered once daily. L-T4 tablets are the treatment of choice. Use of a brand name L-T4 formulation to provide a consistent formulation may be superior for children with severe CH.111 However, generic tablets suffice for most children. A commercial oral solution of L-T4 is approved by the US Food and Drug Administration for use in children of any age; however, limited experience with its use showed that dosing may not be equivalent to dosing with tablet formulations.112,113 L-T4 suspensions prepared by compounding pharmacies may result in unreliable dosing.114,115 Breastfeeding does not interfere with L-T4 administration.116 If enteral administration is not possible, L-T4 can be administered intravenously at 75% of the enteral dose.117
The goal of L-T4 treatment is to support normal growth and neurocognitive development. Achieving optimal outcome depends on early initiation of adequate L-T4 treatment (generally by 2 weeks of life when detected with the first NBS), particularly in severe cases of CH.21,118 Therefore, the goal of initial L-T4 therapy is to normalize serum FT4 and TSH concentrations as quickly as possible. The prognosis is poorer for infants who are detected later in life, receive inadequate doses of L-T4, or have more severe hypothyroidism.118–120 Rapid normalization of serum TH levels leads to improved neurocognitive outcomes.121–125 Normalization of serum TSH may lag after the initiation of treatment, particularly in severely affected infants. Although age-specific TSH reference ranges vary by laboratory, recent studies indicate that the upper limit of normal TSH in infants 1 to 3 months of age is 4.1 to 4.8 mIU/L80–84 ; therefore, TSH values above 5 mIU/L generally are abnormal if observed after 3 months of age. Whether overtreatment (defined by elevated serum FT4) is harmful remains unclear and evidence is conflicting.120,126–128 The typical L-T4 starting dose (10–15 mcg/kg per day) frequently results in elevated FT4 levels, so dose reduction is often needed 2 weeks after starting L-T4 treatment.129
Some infants with CH have persistent serum TSH elevation despite FT4 levels at or above the upper limit of the reference range. This central resistance to TH may be caused by alteration of pituitary-thyroid feedback caused by intrauterine hypothyroidism.130–132 Resistance to TH is more common in infants younger than 1 year and typically resolves over time but may persist in up to 10% of children with CH.132 In patients with CH and resistance to TH, there is insufficient outcome-based evidence to determine whether to prioritize normalizing TSH or normalizing FT4 with L-T4 treatment. The addition of liothyronine (L-T3) to L-T4 monotherapy (only in consultation with a pediatric endocrinologist) may normalize both TSH and FT4 in patients with resistance to thyroid hormone, but there is no evidence that this improves patient outcomes.133
The required dose of L-T4 may be stable or may change with time. L-T4 dose requirements can be affected by chronic illness, organ dysfunction, medications, or changes in weight, dietary soy intake, L-T4 absorption, or serum estrogen concentrations.
The endocrinologist and PCP provide critical parental education as detailed in the accompanying clinical report.15,71 Educational resources can be obtained from the American Thyroid Association (www.thyroid.org/congenital- hypothyroidism/), the Pediatric Endocrine Society (https://pedsendo.org/patient-resource/congenital-hypothyroidism/), the Endocrine Society (education.endocrine.org/content/congenital-hypothyroidism-pim-diagnosis-and-management), the National Institutes of Health (ghr.nlm.nih.gov/condition/congenital-hypothyroidism), the Magic Foundation (www.magicfoundation.org/Misc/ViewContent.aspx?ContentID=856ac9d3-dec2-4f96-81be- b36e257afb88), and others.
Close laboratory monitoring is necessary during L-T4 treatment to maintain serum TSH and FT4 in the target range and to avoid under- or overtreatment.16 Because FT4 measurements vary among assays, age- and assay-specific reference ranges are necessary when interpreting FT4 values133–136 (www.aap.org/en-us/Documents/periodicity_schedule.pdf). Because of relatively rapid growth and increased metabolic clearance of thyroid hormone, studies support measuring serum TSH and free T4 every 1 to 2 months in the first 6 months of life, every 2 to 3 months in the second 6 months of life, and then every 3 to 4 months between 1 and 3 years of age for children with CH.15 In addition to the role of the pediatric endocrinologist, the PCP has an important role in promoting adherence to L-T4 therapy by children with CH.71
Particular attention to behavioral and cognitive development is necessary, because children with CH may be at higher risk for neurocognitive and socioemotional dysfunction compared with their unaffected peers, despite adequate treatment of CH.137,138 Hearing deficits are reported in approximately 10% of children with congenital hypothyroidism.139
Inadequate treatment of CH may have negative consequences for development. Nevertheless, a significant proportion of children diagnosed with CH do not continue L-T4 replacement therapy until 3 years of age, and up to half of patients with a diagnosis of CH may be lost to follow-up.140–142 Institution of clinical follow-up protocols may help prevent children with CH from being lost to follow-up and potentially experiencing adverse outcomes.
ASsessment of Permanence of Hypothyroidism
The increasing incidence of CH largely is attributable to increased detection of mild or transient CH, often with a eutopic gland.27–29,143–149 Overall, when patients with a eutopic gland are trialed off L-T4 therapy, approximately 40% prove to have permanent CH (low FT4 and high TSH), 25% have persistent hyperthyrotropinemia (normal FT4 and high TSH), and 35% have had transient CH (prior abnormality but now normal FT4 and normal TSH).147–155
CH is confirmed to be permanent in cases of thyroid dysgenesis or if the serum TSH increases above 10 mIU/L after the first year of life (on treatment). In patients with a eutopic thyroid, TSH concentration at diagnosis is not necessarily predictive of permanent versus transient disease, and permanent hypothyroidism cannot be assumed solely on the basis of a very elevated TSH level at diagnosis.147 Additional features that suggest transient hypothyroidism include a low L-T4 requirement (particularly below 2 mcg/kg per day) to maintain euthyroidism after 1 year of age, lack of need for increasing L-T4 doses over time, and absence of abnormal TSH levels during treatment.147,156–158
Unless a diagnosis of permanent CH has been confirmed (by imaging or TSH elevation while on treatment), a trial off L-T4 therapy performed at 3 years of age can assess whether lifelong L-T4 treatment is necessary.5–7,15 It is critical that patients not be lost to follow-up while trialing off L-T4 therapy.
Specific Causes of Transient Congenital Hypothyroidism
Maternal Graves Disease
Antithyroid drugs (carbimazole, methimazole, or propylthiouracil) used during pregnancy cross the placenta and can cause transient CH until they are cleared from the infant’s circulation (about 7–10 days). Mothers with autoimmune thyroid disease may have circulating immunoglobulin G antibodies that block activation of the TSH receptor (TRBAb). Transplacental passage of these antibodies is a rare cause of transient CH, accounting for approximately 2% of CH detected by NBS.159 A maternal history of autoimmune thyroid disease (including Graves disease) or of a previously affected child (or concurrently affected twin) may raise suspicion for TRBAb. However, the absence of such a history does not reliably exclude this diagnosis.160 CH resolves once TRBAb are cleared from the serum of affected infants, usually by 3 to 6 months of age.161
Maternal hyperthyroidism that is not adequately controlled during pregnancy can lead to neonatal central hypothyroidism after birth, probably resulting from suppression of the fetal hypothalamic-pituitary-thyroid axis by excess maternal TH that crossed the placenta.162 Such central hypothyroidism is usually transient but can persist in rare cases.163 TH treatment may be required for 6 to 24 months or until reevaluation after 3 years of therapy.163
Iodine is required for TH synthesis, and iodine deficiency is an important cause of CH worldwide, but iodine supplementation will restore normal TH production.
Excessive iodine intake causes reduced synthesis of TH (the Wolff-Chaikoff effect), which can cause hypothyroidism in infants. Because the fetal thyroid gland is highly sensitive to this effect, preterm infants are at particular risk of iodine-induced hypothyroidism. Excessive iodine exposure may occur prenatally from maternal use of amiodarone164 or postnatally from iodine-containing antiseptics,165,166 radiologic contrast agents,167,168 or excessive maternal iodine intake.169,170 Infants with iodine deficiency or excess that occurs after birth may have normal NBS results in the first few days after birth, but CH may be detected on a second test performed at 10 to 14 days of age.171
Growth and adult height are generally normal in children with CH in whom L-T4 therapy is maintained with TSH and FT4 in target range.172,173 NBS has substantially improved neurodevelopmental outcomes from CH, and severe intellectual impairment does not occur in patients who are diagnosed and treated early and adequately. Adequate initial L-T4 treatment of CH (early initiation of L-T4, 10–15 mcg/kg per day, with normalization of thyroid function within 2 weeks) results in grossly normal neurocognitive function in adulthood.118 However, detailed studies report neuropsychological deficits in some children with CH compared with controls, including impaired visuospatial processing and deficits in memory and sensorimotor function. Mild to moderate deficits may be identified by early childhood and may persist into adolescence and adulthood.13,174,175 If a child is adequately treated for CH but growth or developmental progress is abnormal, evaluation for potential intercurrent illness, hearing deficit, or other hormone deficiency is warranted.
Some studies have found an association between the severity of CH (defined by pretreatment serum T4 level, delayed skeletal maturation at diagnosis, or the presence of thyroid agenesis) and worse developmental outcome, despite early L-T4 treatment.14,126,176–180 However, other studies demonstrate that early initiation of doses of L-T4>10 mcg/kg per day may abrogate the effect of initial CH severity on developmental outcome, with severely affected patients achieving similar outcomes to more mildly affected children.118,181,182 Negative influences on cognitive, psychomotor, and behavioral development have been demonstrated with delayed or inadequate treatment; adverse outcomes attributable to overtreatment have been observed in some studies, but evidence is conflicting, and this association remains unclear.121,122,126
In contrast to the overall favorable outcome in infants with CH who are treated early, the neurodevelopmental prognosis is less certain in those in whom CH is not detected and, as a result, begin treatment late. Although physical recovery is good and stature is normal when L-T4 replacement therapy is begun within the first 2 months of life,173 infants with severe CH and intrauterine hypothyroidism (as indicated by retarded skeletal maturation at birth) may have a low-to-normal intelligence.182 Similarly, although more than 80% of infants given L-T4 replacement therapy before 3 months of age have an intelligence greater than 85, 77% of these infants show signs of cognitive impairment in arithmetic ability, speech, or fine motor coordination later in life.
Despite the evident success of NBS, physicians need to consider hypothyroidism in the face of clinical symptoms, even if newborn screening thyroid test results were normal. Failure of normal neurodevelopment can result from hypothyroidism in infants who initially had normal NBS results but in whom hypothyroidism manifests or is acquired after NBS or with errors in NBS tests. Hypothyroidism can occur in infants in whom NBS is not performed (eg, some home deliveries) or for whom results are not properly communicated to the infant’s PCP.183 Therefore, when clinical symptoms or signs of hypothyroidism are present (such as large posterior fontanelle, large tongue, umbilical hernia, prolonged jaundice, constipation, lethargy, or hypothermia), measurement of serum TSH and FT4 is indicated, regardless of NBS results.
This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication.
Technical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, clinical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent.
The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.
All technical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.
Susan R. Rose, MD, FAAP
Ari J. Wassner, MD, American Thyroid Association Representative
Kupper A. Wintergerst, MD, FAAP
Nana-Hawa Yayah Jones, MD
Robert J. Hopkin, MD, FAAP
Janet Chuang, MD
Jessica R. Smith, MD, Pediatric Endocrine Society Representative
Katherine Abell, MD
Stephen H. La Franchi, MD, FAAP
Section on Endocrinology Executive Committee, 2020–2021
Kupper A. Wintergerst, MD, FAAP
Kathleen E. Bethin, MD, FAAP
Brittany Bruggeman, MD, FAAP (Fellowship Trainee)
Jill L. Brodsky, MD, FAAP
David H. Jelley, MD, FAAP
Bess A. Marshall, MD, FAAP
Lucy D. Mastrandrea, MD, PhD, FAAP
Jane L. Lynch, MD, FAAP (Immediate Past Chairperson)
Laura Laskosz, MPH
Council on Genetics Executive Committee, 2020–2021
Leah W. Burke, MD, MA, FAAP
Timothy A. Geleske, MD, FAAP
Ingrid A. Holm, MD, FAAP
Wendy J. Introne, MD, FAAP
Kelly Jones, MD, FAAP
Michael J. Lyons, MD, FAAP
Danielle C. Monteil, MD, FAAP
Amanda B. Pritchard, MD, FAAP
Pamela Lyn Smith Trapane, MD, FAAP
Samantha A. Vergano, MD, FAAP
Kathryn Weaver, MD, FAAP
Aimee A. Alexander, MS, CGC – Centers for Disease Control and Prevention
Christopher Cunniff, MD, FAP – American College of Medical Genetics
Mary E. Null, MD – Section on Pediatric Trainees
Melissa A. Parisi, MD, PhD, FAAP – National Institute of Child Health & Human Development
Steven J Ralson, MD – American College of Obstetricians & Gynecologists
Joan Scott, MS, CGC – Health Resources and Services Administration
Drs Rose, Wassner, Wintergerst, Yayah-Jones, Hopkin, Chuang, Smith, Abell, and LaFranchi were equally responsible for conceptualizing, writing, and revising the manuscript and considering input from all reviewers and the board of directors; and all authors approve of the final publication.
COMPANION PAPER: A companion to this article can be found at http://www.pediatrics.org/cgi/doi/10.1542/peds.2022-060419.
This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this publication. Technical reports from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and external reviewers. However, technical reports from the American Academy of Pediatrics may not reflect the views of the liaisons or the organizations or government agencies that they represent. The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. All technical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.
FUNDING: No external funding.
FINANCIAL/CONFLICT OF INTEREST DISCLOSURES: Dr LaFranchi reported a financial relationship with UpToDate as an author on the topic of congenital hypothyroidism.
guanine nucleotide-binding protein (G-protein) subunit α
low birth weight
primary care provider
thyrotropin receptor-blocking antibody
very low birth weight