Treatment and prognosis of congenital hypothyroidism

INTRODUCTION — Congenital hypothyroidism is one of the most common treatable causes of intellectual disability. Screening programs have been established in most developed countries to detect and treat this disorder, which affects approximately 1 in 2000 to 1 in 4000 newborns [1,2].

The treatment and neurocognitive outcome of congenital hypothyroidism will be reviewed here. The clinical features and detection of congenital hypothyroidism are reviewed separately. (See "Clinical features and detection of congenital hypothyroidism" and "Thyroid physiology and screening in preterm infants".)

Effects of maternal thyroid disease, iodine deficiency, or iodine excess on the offspring are discussed separately. (See "Overview of thyroid disease and pregnancy" and "Iodine deficiency disorders", section on 'Consequences of iodine deficiency' and "Clinical features and detection of congenital hypothyroidism", section on 'Transient congenital hypothyroidism'.)

TREATMENT

Rationale — Delays in diagnosis and treatment of congenital hypothyroidism will result in impaired neurocognitive outcome, as measured by intelligence quotient (IQ). Even after diagnosis, IQ and neurologic development may suffer if the infant has suboptimal management during the first two to three years of life, a time when thyroid hormone is critical for normal brain development. Thus, appropriate initial therapy and follow-up are essential to ensure optimal dosing of thyroid hormone, with monitoring and dose adjustments and support for the family to encourage close adherence to treatment [3]. (See 'Neurodevelopment and functional outcomes' below.)

Levothyroxine — Oral levothyroxine is the treatment of choice. Although triiodothyronine (T3) is the biologically active thyroid hormone, the majority of brain T3 is derived from local deiodination of thyroxine (T4); thus, in most cases, it is not necessary to use T3.

Both the timing and dose of thyroid hormone replacement are important [4,5]:

Timing and dose — To correct hypothyroxinemia as rapidly as possible, treatment should be initiated for any infant with a clearly positive screening test as soon as confirmatory blood samples have been drawn, pending results. In cases in which screening tests are borderline (eg, thyroid-stimulating hormone [TSH] <40 mIU/L in serum units or 20 mIU/L in whole blood units), a treatment decision can be postponed until after results of the confirmatory tests return [5]. (See "Clinical features and detection of congenital hypothyroidism", section on 'Newborn screening'.)

●Term infants – We suggest a starting levothyroxine dose of 10 to 15 mcg/kg/day for term infants, consistent with recommendations from the American Academy of Pediatrics (AAP), the United States Pediatric Endocrine Society (PES), the European Society for Paediatric Endocrinology (ESPE), and the American Thyroid Association (ATA) [5-7]. This usually amounts to giving 37.5 or 50 mcg/day since these doses can be readily prepared from the available levothyroxine tablets (25 or 50 mcg). Liquid levothyroxine formulations are another treatment option [5]. (See 'Administration' below.)

A preponderance of studies suggests that dosing in this range achieves optimal neurocognitive outcome, with normal growth and school progression despite some cases with free T4 (fT4) values somewhat above the reference range [8,9]. (See 'Neurodevelopment and functional outcomes' below.)

●Preterm infants – In preterm and other low birth weight infants, we also recommend using a levothyroxine dose of 10 to 15 mcg/kg/day, though in milder cases, often characterized by delayed TSH elevation, a starting dose of 8 to 12 mcg/kg/day is sufficient to normalize thyroid function. (See "Thyroid physiology and screening in preterm infants".)

●Severe hypothyroidism – For infants with severe hypothyroidism (eg, those with a pretreatment serum total T4 <5 mcg/dL [<65 nmol/L]) or a fT4 <0.4 ng/dL (<5 pmol/L), we suggest selecting a dose in the upper one-half of the recommended range (ie, 12.5 to 15 mcg/kg/day). Studies show that higher dosing in these more severe cases will rapidly normalize serum fT4 levels and is both safe [10] and results in a better outcome, as assessed by psychometric testing [11,12]. (See 'Neurodevelopment and functional outcomes' below.)

●Mild hypothyroidism – In mild cases of congenital hypothyroidism (confirmatory serum TSH 5 to 20 mU/L, with a borderline low or normal fT4), we suggest starting at a levothyroxine dose of 8 to 10 mcg/kg/day.

Administration — Levothyroxine tablets have been used successfully to treat infants with congenital hypothyroidism for decades. The tablet strengths most commonly used in infants are 25, 37.5, and 50 mcg. The tablet should be crushed and mixed with a small amount of breast milk, formula (except soy-based formula), or water and fed to the infant. A medication syringe can be used to administer the medication; it should not be added to a bottle of breast milk or formula.

Commercial liquid formulations of levothyroxine are approved by the US Food and Drug Administration for children of any age. They are available as multidose ampules or dose selected by syringe volume, administered orally. However, there is limited experience with the use of liquid preparations to treat infants with congenital hypothyroidism and dosing may not be equivalent to dosing with tablets [9,13,14]. Levothyroxine suspensions ("compounded") prepared by individual pharmacists may result in unreliable dosing and are not recommended [5].

With either preparation, dosing should be adjusted based on serum fT4 and TSH levels.

The absorption of levothyroxine is somewhat reduced by administration with food and formula. However, requiring that the medication be given separately from meals may be difficult for the family and reduce compliance [15]. Thus, instead of requiring that it be administered on an empty stomach, we ask the family to be consistent in how they administer the medication, in both time of day and with or without food [5]. The levothyroxine dose then can be adjusted based on serum fT4 (or T4) and TSH levels. (See 'Laboratory monitoring and dose adjustment' below.)

Avoid coadministration of levothyroxine with any of the following, which may reduce drug absorption:

●Soy formula. If soy formula cannot be avoided, levothyroxine should be administered midway between feedings [16-18].

●Supplements with iron or calcium [19].

●Antacids (aluminum hydroxide) or infant "colic" drops (simethicone) [20].

Although the US Food and Drug Administration considers all forms of levothyroxine to be bioequivalent, a prospective randomized crossover study concluded that generic and brand-name levothyroxine are not bioequivalent for children with severe congenital hypothyroidism [21], while another retrospective study found no differences [22]. Consequently, if an infant is switched from tablet to liquid formulation, from brand to generic, from one brand to another brand, or from one manufacturer of generic to another manufacturer of generic levothyroxine, we recommend checking serum TSH and fT4 after six weeks to determine if a dosing adjustment is required. (See 'Laboratory monitoring and dose adjustment' below.)

Treatment goals — The overall goals of treatment are to assure normal growth and neurodevelopmental outcome. This is achieved by restoring the serum fT4 (or T4) and TSH concentrations to the normal range as rapidly as possible, followed by dose adjustment to ensure continued clinical and biochemical euthyroidism.

●FT4 or T4 – Target is serum fT4 or T4 concentration in the upper one-half of the reference range for age [5]:

•For serum fT4, the target varies with the assay method used in the testing laboratory. For example, if the reference range for a specific fT4 assay method is 0.8 to 2.3 ng/dL (10.3 to 30.0 pmol/L), the aim of treatment would be to keep the serum fT4 between 1.4 and 2.3 ng/dL (18 to 30 pmol/L).

•For serum T4, the target is 10 to 16 mcg/dL (130 to 206 nmol/L).

●TSH – Target is serum TSH in the reference range (ie, 0.5 to 5.0 mU/L) and, optimally, the lower end of this range (ie, 0.5 to 2.0 mU/L). For infants with congenital central hypothyroidism, serum free T4 should be used to guide treatment because measurement of serum TSH is not helpful.

These fT4 and TSH target ranges are based primarily on expert opinion and rationale because clinical trial evidence to support them is lacking.

The serum fT4 (or T4) concentration typically reaches the target range within one to two weeks after initiating levothyroxine therapy. Serum TSH may take two to four weeks to reach the target range, depending on the degree of elevation prior to treatment. However, despite what appears to be a normal levothyroxine dose, some infants with congenital hypothyroidism will manifest persistent mild serum TSH elevations (5 to 20 mU/L) despite serum fT4 (or T4) values in the target range [23]. This appears to be the result of transient mild thyroid hormone resistance, due to resetting of the pituitary-thyroid feedback threshold because of intrauterine hypothyroidism. In a study of 42 patients with congenital hypothyroidism, this thyroid hormone resistance was more common in infants (less than one year of age) than in older children (43 versus 10 percent, respectively) [24]. These data suggest that the thyroid hormone resistance improves with age but can persist. In such cases, if the levothyroxine dose is increased to lower serum TSH into the normal range, the infants may manifest clinical features of overtreatment. Thus, in these cases, we recommend using serum fT4 (or T4) as the primary test to adjust levothyroxine dosing.

Prolonged overtreatment (>3 months) should be avoided because it can lead to complications. Persistently high serum fT4 or T4 concentrations for age (especially if the fT4 is above 2.4 ng/dL [30.5 pmol/L] or T4 is above 16 mcg/dL [206 nmol/L]), combined with suppressed TSH concentrations (<0.5 mU/L), may adversely affect the tempo of brain development [25]; have adverse effects on cognitive development [26], temperament [27] or attention span [28]; and cause premature craniosynostosis.

Laboratory monitoring and dose adjustment

Primary hypothyroidism

●Monitoring schedule – For infants with congenital primary hypothyroidism, we monitor serum fT4 (or T4) and TSH at the following intervals, to ensure optimal levothyroxine dosing:

•Initially – Test two weeks after the initiation of levothyroxine treatment and every 2 weeks until serum TSH level is normalized.

•First year of life – Test every one to two months and monthly for those with moderate to severe hypothyroidism. Infants in this age group typically need frequent dose adjustments due to their rapid growth [29], and those with moderate to severe hypothyroidism are particularly likely to require dose adjustments [30].

•Between one and three years of age – Test every one to three months.

•Thereafter – Test every 6 to 12 months until growth is complete.

•Additional monitoring – Test four to six weeks after any change in dose or after changing brands of levothyroxine (eg, changing from one generic to a different generic brand) (see 'Administration' above). Also test at more frequent intervals when compliance is questioned or abnormal results are obtained.

This monitoring schedule is similar to that recommended by the society guidelines noted above (AAP, PES, ESPE, and ATA), except that we monitor a bit more frequently for infants with more severe hypothyroidism and those between one and three years of age [5,7]. In addition to this laboratory monitoring, a clinical evaluation should be performed every few months during the first three years of life.

●Dose adjustment – The levothyroxine dose should be adjusted as needed to target the serum fT4 or T4 concentration in the upper one-half of the reference range for age and the TSH in the reference range (and, optimally, the lower one-half of this range). (See 'Treatment goals' above.)

For some infants, the thyroid function test results may be difficult to interpret because of disparate fT4 and TSH results. Two patterns and possible explanations are outlined in the table (table 1).

A careful history and physical examination, along with review of previous thyroid function test results to examine the relationship between dosing and fT4 and TSH levels, often will provide clues to help decide whether to continue the same or increase the levothyroxine dose. If unsure, we recommend monitoring thyroid function tests at more frequent intervals. As noted above, the preponderance of evidence suggests that children will achieve an optimal neurocognitive outcome with close monitoring, including cases with some fT4 values above the reference range [8].

Central hypothyroidism — For infants with congenital central hypothyroidism, the schedule for monitoring is similar to that for primary hypothyroidism, but serum fT4 should be used to guide treatment as measurement of serum TSH is not helpful. (See 'Treatment goals' above.)

LONG-TERM MANAGEMENT — In the first few decades following initiation of newborn screening, approximately 90 percent of cases had permanent congenital hypothyroidism requiring lifelong treatment. Beginning around the year 2000, the incidence of congenital hypothyroidism increased from 1:4000 to 1:2000; this increase was due to detection of milder cases of hypothyroidism, including cases in preterm or low birth weight infants with delayed thyroid-stimulating hormone (TSH) elevation, in which the hypothyroidism is often transient. With the detection of these milder cases, follow-up studies showed that approximately 70 percent were permanent, while 30 percent had a transient form of hypothyroidism [31].

Patients with congenital hypothyroidism should be treated with levothyroxine for the first few years of life unless a transient form of hypothyroidism has been definitively established. Even in transient cases, we recommend levothyroxine treatment until it is determined that thyroid function has returned to normal.

Assessment of permanent versus transient hypothyroidism — The cause of hypothyroidism (if known) is often sufficient to determine whether it is permanent or transient. An approach to distinguishing between these categories is outlined in the algorithm (algorithm 1).

Permanent hypothyroidism — Permanent hypothyroidism is certain in patients with:

●Thyroid dysgenesis or a confirmed defect in thyroid hormone biosynthesis or secretion (dyshormonogenesis) – Thyroid dysgenesis is likely if ultrasonography shows absent thyroid tissue or an ectopic gland or if a scan shows an ectopic gland. If an initial radionuclide scan shows absence of thyroid tissue, this should be confirmed by ultrasonography because a scan can appear to show aplasia in infants with TSH receptor-blocking antibodies, a transient form of hypothyroidism. These tests are considered optional at initial diagnosis because in most cases, the results are not required for management decisions. Some clinicians elect to perform these studies after age three years in cases where permanent hypothyroidism has not been established. In a report of 33 children with congenital hypothyroidism who underwent reevaluation at age three years, 27 percent had an absent or ectopic thyroid, 36 percent had dyshormonogenesis, and 36 percent had transient hypothyroidism [32]. (See "Clinical features and detection of congenital hypothyroidism", section on 'Etiology'.)

●Central hypothyroidism – Most infants with confirmed central hypothyroidism have permanent hypothyroidism, in particular, those with other documented pituitary hormone deficiencies, those with demonstrated congenital midline defects (eg, optic nerve hypoplasia/septo-optic dysplasia), or those confirmed to be caused by a genetic etiology (eg, IGSF1 gene mutation) [33]. (See "Clinical features and detection of congenital hypothyroidism", section on 'Central hypothyroidism'.)

By contrast, hypothyroidism may not be permanent in children with isolated TSH deficiency without a known congenital anatomic defect; isolated TSH deficiency occurs in approximately 20 percent of cases of congenital central hypothyroidism. In these cases, we recommend reevaluation after age three years determine whether the hypothyroidism is permanent. (See 'Trial off of treatment' below.)

If the cause of congenital hypothyroidism is unknown, the patterns of thyroid function tests can provide supportive evidence. Permanent hypothyroidism is likely if the patient has ever had a rise in the serum TSH concentration to above 10 mU/L after the first year of life in the setting of insufficient levothyroxine replacement.

Transient hypothyroidism — Transient hypothyroidism has several causes, and the predicted duration depends on the cause:

●Maternal autoimmune thyroid disease – Maternal autoimmune thyroid disease (including Graves disease, current or past) is often associated with transplacental transfer of maternal TSH receptor-blocking antibodies. The blocking antibody levels typically fall and disappear between six weeks to six months of age. Thyroid hormone treatment may be discontinued at this point, although it is also reasonable to treat until age two to three years of age before discontinuing treatment and confirming normal thyroid function.

●Excessive iodine exposure to the fetus or newborn – The majority of cases of hypothyroidism caused by iodine excess will recover normal thyroid function within a few weeks of discontinuing the iodine; such cases require monitoring of TSH and free thyroxine (fT4) to confirm recovery to euthyroidism but generally do not need treatment.

●Iodine deficiency – Cases of iodine deficiency are quickly corrected by adequate iodine ingestion.

●Hepatic hemangioma – Large hepatic hemangiomas can cause "consumptive hypothyroidism," which requires levothyroxine treatment until the hemangioma resolves, typically by one year of age [34]. (See "Infantile hemangiomas: Management".)

●Pattern of "delayed TSH elevation" in preterm infants – Some preterm infants have delayed serum TSH elevation, characterized by low serum T4 values on initial newborn screens and delayed elevation in screening TSH values (eg, TSH rising to >20 mU/L [serum] or >10 mU/L [whole blood] at 15 to 30 days of age). For infants with this pattern, we recommend levothyroxine treatment, with a trial off after two to three years of age [35,36]. (See 'Management of patients with transient hypothyroidism' below and "Thyroid physiology and screening in preterm infants", section on 'Transient versus permanent hypothyroidism'.)

These causes are discussed in more detail separately. (See "Clinical features and detection of congenital hypothyroidism", section on 'Transient congenital hypothyroidism'.)

If the cause of congenital hypothyroidism is unknown, transient hypothyroidism is likely if initial imaging by ultrasound showed a normally located (eutopic), normal-sized thyroid gland [37,38] and if the infant has never had an abnormal TSH elevation while on levothyroxine treatment, never required an increase in dose, or requires a relatively low dose to maintain euthyroidism (eg, <2.5 mcg/kg/day) [32,39,40].

Trial off of treatment — If permanent hypothyroidism has not been established by one of the above findings and the child is three years or older, the possibility of transient hypothyroidism can be evaluated by a trial of discontinuing levothyroxine therapy for 30 days (algorithm 1) [5,7]:

●If a low serum fT4 (or T4) and high TSH concentration are found, permanent hypothyroidism is confirmed and treatment should be restarted. The clinician may consider further evaluation to determine the cause of the hypothyroidism (eg, thyroid imaging and/or genetic testing in families with affected siblings), if not already done. (See "Clinical features and detection of congenital hypothyroidism", section on 'Etiology' and "Clinical features and detection of congenital hypothyroidism", section on 'Thyroid imaging'.)

●If the serum fT4 (or T4) and TSH values remain normal, the hypothyroidism was probably transient. In this case, the child can be observed off of levothyroxine. (See 'Management of patients with transient hypothyroidism' below.)

●If the results of thyroid function tests are inconclusive, careful follow-up and subsequent retesting are indicated.

Management of patients with transient hypothyroidism — If transient hypothyroidism is likely and thyroid function tests are normal after a 30-day trial off of levothyroxine, the child can be observed off of treatment. The child should be examined periodically. Laboratory assessment of thyroid status should be performed if the child develops any clinical features suspicious for hypothyroidism, such as slowing of growth.

Patients with permanent hypothyroidism — Patients in whom congenital hypothyroidism proves to be permanent will require thyroid hormone replacement throughout life. These patients are managed by titrating the levothyroxine dose based on periodic measurements of serum TSH and fT4 (or T4), as for an adolescent or adult with acquired hypothyroidism. (See "Acquired hypothyroidism in childhood and adolescence", section on 'Levothyroxine dose'.)

Because the overall goal of thyroid hormone treatment is to assure optimal neurocognitive development (including hearing) and normal growth and pubertal development, it is particularly important to monitor each of these clinical features together with routine thyroid function tests. (See 'Prognosis' below.)

PROGNOSIS — Several programs, primarily in North America, Europe, and Australia, have reported long-term follow-up of infants detected through newborn screening. In general, these infants grow and develop normally. The psychometric outcome is much improved over the prescreening era, but some infants with severe hypothyroidism or those who are inadequately treated in the first two or three years of life have intelligence quotients (IQs) below those of normal children.

Neurodevelopment and functional outcomes

●Primary hypothyroidism – The long-term neurodevelopmental and functional outcome of individuals with congenital hypothyroidism is generally good for infants who are treated early (beginning at two to six weeks of life) and optimally through the first three years of life; their global IQs are similar to those of normal infants [41-44]. As an example, a long-term observational study of 76 patients with congenital hypothyroidism reported that IQ scores were no different from those of sibling controls [8].

However, other reports describe variable neurocognitive outcomes, with IQ deficits of up to 20 points for some groups of individuals with congenital hypothyroidism [42,45]. The variable neurocognitive outcomes seem to be correlated with the following factors:

•Inadequate treatment including noncompliance – Suboptimal levothyroxine dosing during infancy and the first few years of life adversely affects neurocognitive outcomes. In one study, infants who were inadequately treated in the first three years of life (estimated levothyroxine dose <5 mcg/kg/day) had worse cognitive outcomes compared with the larger, adequately treated group (mean IQ score 87 versus 105) [46].

Noncompliance can also affect cognitive performance in older children and adolescents, but, in these age groups, the deficit may be reversible. This was shown in a study of 14-year-old adolescents with congenital hypothyroidism who had thyroid function testing without forewarning at home visits [47]. The results showed that 44 percent of these patients were poorly controlled (serum thyroid-stimulating hormone [TSH] concentration >15 mU/L), and the majority had low serum thyroxine (T4) concentrations (<6.6 mcg/dL [86 nmol/L]). Cognitive tests were normal and similar to those with better controlled hypothyroidism but still improved one year later after compliance was stressed and serum thyroid hormone concentrations normalized, with an increase in mean IQ score from 106 to 112.

•Severity of disease – Some screening programs report that more severely affected infants, as judged by a lower serum T4 concentration or immature skeletal maturation at diagnosis, have lower IQ scores later in life [48]. As an example, the Quebec screening network found that infants with severe hypothyroidism (as indicated by initial serum T4 values below 2 mcg/dL [26 nmol/L] and a bone surface area less than 0.05 cm²) had a mean IQ score of 89 at 12 years of age, compared with 104 in less severely affected infants [49]. In a literature review of 30 studies comparing psychometric outcome in infants with more severe versus moderate or mild congenital hypothyroidism, nine studies reported no difference in IQ, while 21 studies reported a 5.5 to 23 point decrease in IQ in the more severely affected infants [45].

More severe disease also appears to be associated with hearing loss. (See 'Other neurologic sequelae' below.)

•Early versus delayed treatment – In a literature review, infants who started "early" (12 to 30 days of age) had IQ scores 15.7 points higher than infants who started "later" (>30 days of age) [45]. Most studies with long-term follow-up (eg, outcomes in early adulthood) involve patients who were born during the 1980s or before [50-52]. These adults were born in the first years of their respective screening programs and were started on treatment at a later age and with lower doses of levothyroxine than are currently recommended. As most infants are now started at an earlier age and treated with higher levothyroxine doses, future results may be better.

•High versus low starting dose of levothyroxine – Most evidence for an association between starting doses of levothyroxine and neurocognitive outcomes is based on long-term observational studies [8,53,54]. A preponderance of evidence suggests that children treated with the recommended starting dose of 10 to 15 mcg/kg/day have a better IQ outcome than children started on lower doses. As an example, a longitudinal study found that patients with severe hypothyroidism had compromised neurocognitive outcomes in young adulthood only if treatment was started with levothyroxine doses <10 mcg/kg [8]. In another long-term study, subjects with congenital hypothyroidism had lower total, verbal, and performance IQ scores compared with sibling controls (total IQ 102.4 versus 111.4) as well as deficits in arithmetic skills, memory, attention, and behavior [53,54]. Higher initial levothyroxine dose and higher mean serum T4 levels at diagnosis were associated with higher verbal IQ scores and arithmetic skills.

Only one small randomized study has examined this issue. Subjects who were started on a levothyroxine dose of 50 mcg/day as infants had full-scale IQ scores that were 11 points higher in childhood compared with those who started on 37.5 mcg/day [4]. Similarly, infants who achieved normal thyroid function within two weeks after therapy was started had better cognitive, attention, and achievement scores compared with those who took longer than two weeks to normalize their thyroid function [4]. This is likely because there is an inverse correlation between the starting levothyroxine dose and the time to achieve the goal serum T4 concentration [55].

●Central hypothyroidism – In a study of cognitive and motor outcomes in children with congenital central hypothyroidism detected by the neonatal screening program in the Netherlands, the Dutch reported that, at an average age of 11 years, full-scale IQ in children with isolated TSH deficiency was 98.2 versus 98.6 in sibling controls; in children with multiple pituitary hormone deficiencies, full-scale IQ was 90.7 [56].

Hearing — Sensorineural hearing loss was reported in up to 20 percent of children with congenital hypothyroidism in cohorts that were diagnosed before the initiation of newborn screening programs [57]. Studies after the initiation of newborn screening programs show that approximately 10 percent of individuals with congenital hypothyroidism report that they have some hearing impairment as young adults (approximately three times the rate in the general population) [52]. Hearing loss was seen more frequently in patients with athyreosis and a gland in situ (suggesting a link to dyshormonogenesis, such as Pendred syndrome) but not in patients with an ectopic gland. The hearing loss was sensorineural and associated with disease severity at the time of diagnosis of congenital hypothyroidism (as measured by bone maturation delay at the time of the neonatal diagnosis); a hearing aid was required in 17 percent of affected patients [58].

We recommend routine hearing tests for infants with congenital hypothyroidism; screening for hearing loss at birth is now part of many newborn screening programs, including a majority of American states. Repeated screening for hearing loss is also important and especially if learning differences are detected. (See "Screening the newborn for hearing loss" and "Hearing loss in children: Screening and evaluation".)

Other neurologic sequelae — A small proportion of infants with congenital hypothyroidism, including those with normal IQ scores, can have other neurologic problems, such as gross and fine motor incoordination, ataxia, increased or decreased muscle tone, short attention span, speech defects, and strabismus [59]. Infants with syndromic forms of congenital hypothyroidism may have additional neurologic defects that are not directly related to the hypothyroidism itself.

Growth — Long-term follow-up of children with congenital hypothyroidism detected by newborn screening shows that treated children have normal growth patterns [60] and normal adult height [61]. Moreover, a study comparing high versus low initial doses of levothyroxine showed no evidence of somatic overgrowth in infants treated with the higher dose up to 18 months of age [62].

Morbidity and mortality — Some reports have suggested possible metabolic abnormalities in children with treated hypothyroidism. A study from Switzerland reported an increased risk for overweight at age five years [63]. Another study investigating cardiac function in young adults with congenital hypothyroidism reported left ventricular diastolic dysfunction, impaired exercise capacity, and increased intima-media thickness [64]. The significance of these findings is unknown; they need to be confirmed by other investigators.

A national population-based study from France reported a slightly higher all-cause mortality (standardized mortality ratio [SMR] = 1.24) in patients with congenital hypothyroidism diagnosed in the first decade of newborn screening [65]. SMR was highest for diseases of the central nervous system (SMR 5.22) and congenital malformations (SMR 3.15). In addition, the risk of developing an associated chronic disease was twice as high as the reference population. Thus, the increased mortality may be related to comorbidities associated with hypothyroidism, including congenital neurologic abnormalities or other malformations, and possibly mental illness.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypothyroidism" and "Society guideline links: Pediatric thyroid disorders".)

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●Basics topic (see "Patient education: Congenital hypothyroidism (The Basics)")

SUMMARY AND RECOMMENDATIONS

●When to initiate treatment – Prompt identification and treatment of infants with congenital hypothyroidism is essential to assure normal growth and neurodevelopmental outcome. For infants with a clearly positive screening test, treatment should be initiated as soon as confirmatory serum samples for thyroid-stimulating hormone (TSH) and free thyroxine (fT4) measurements have been drawn, rather than waiting until the diagnosis is confirmed. In cases in which screening tests are borderline, a treatment decision can be deferred until after results of the confirmatory serum tests become available. (See 'Treatment' above.)

●Starting dose – All infants with suspected congenital hypothyroidism should be treated with levothyroxine by mouth. We suggest starting at a dose of 10 to 15 mcg/kg/day (Grade 2B). (See 'Timing and dose' above.)

•For neonates with more severe hypothyroidism, we use initial doses at the upper end of this range (ie, levothyroxine 12.5 to 15 mcg/kg/day). Rapid correction of thyroid dysfunction is particularly important in infants with severe hypothyroidism to prevent neurodevelopmental deficits. Severe hypothyroidism is suggested by markedly abnormal pretreatment thyroid test results, eg, serum total T4 <5 mcg/dL (<65 nmol/L) or fT4 <0.4 ng/dL (<5 pmol/L). (See 'Neurodevelopment and functional outcomes' above.)

•In mild cases of congenital hypothyroidism (confirmatory serum TSH 5 to 20 mU/L, with a borderline low or normal fT4), we suggest starting at a levothyroxine dose of 8 to 10 mcg/kg/day.

●Monitoring and dose adjustment – For infants and young children with primary hypothyroidism, the aim of treatment is to keep the serum fT4 (or T4) concentration in the upper one-half of the pediatric reference range and serum TSH in the reference range for age. Monitoring is important to avoid prolonged under- or overtreatment. Target values during the first three years of life are (see 'Treatment goals' above):

•Serum fT4 – Target varies with the assay method; for example, if the reference range is 0.8 to 2.3 ng/dL, aim for 1.4 to 2.3 ng/dL (18 to 30 pmol/L)

•Serum T4 – 10 to 16 mcg/dL (130 to 206 nmol/L)

•Serum TSH – 0.5 to 5.0 mU/L (and, optimally, 0.5 to 2.0 mU/L)

●Interpretation of disparate results – Some children with primary hypothyroidism have disparate results for TSH and fT4, requiring further considerations. Two patterns and possible explanations are outlined in the table (table 1).

●Congenital central hypothyroidism – For children with central hypothyroidism, serum fT4 should be used to guide treatment, because measurement of serum TSH is not helpful. (See 'Treatment goals' above.)

●Assessment of permanent versus transient hypothyroidism – Up to 30 percent of children with congenital hypothyroidism have a transient form and will regain normal endogenous thyroid function during early life. Therefore, in those cases where permanent congenital hypothyroidism has not been established, thyroid function should be reevaluated around three years of age to determine whether the hypothyroidism is permanent or transient (algorithm 1). In most cases, this is done by discontinuing therapy for 30 days and then measuring serum TSH and fT4. (See 'Assessment of permanent versus transient hypothyroidism' above.)

●Prognosis – For infants with congenital hypothyroidism who are treated early (beginning between two and six weeks of life) and appropriately treated throughout the first three years of life, the prognosis for neurocognitive and physical development is good. The prognosis worsens for infants who are detected later in life, have more severe hypothyroidism, and/or receive inadequate doses of levothyroxine. (See 'Neurodevelopment and functional outcomes' above.)