The collection of samples is scheduled so that coverage of 100% of newborns is ensured, along with treatment of 100% of the detected cases.

Screening for early detection of primary congenital hypothyroidism is performed by measurement of the levels of TSH at 48h post birth to avoid the initial physiological elevation of this hormone after birth.

A capillary blood sample is obtained from the newborn by heel puncture and collected on standard filter paper; this procedure needs to be performed by specially trained health care staff to optimise yield.8

The serum levels of TSH are measured by immunofluorescence assay (DELFIA®, Laboratorios Perkinelmer). The cut-off point above which CHT is suspected has been established at 7–10IU/mL. When the TSH value exceeds the established threshold, the total thyroxine level (tT4) is measured as well.

At present, all centres that screen for CHT in Spain measure the levels of TSH, while the levels of both TSH and tT4 are only measured simultaneously in the initial test in a few autonomous communities (Basque Country, Navarre and Cantabria).

Central hypothyroidism (secondary or tertiary) is not detected by screening programmes that only measure TSH.10,11

In case of a positive screen result, the facility that did the screening urgently contacts the patient for referral to the corresponding CFUC, where testing will be performed for confirmation of hypothyroidism and to establish the aetiology of the abnormal thyroid function, without delaying initiation of treatment.12–17

The aetiology of congenital hypothyroidism is multifactorial. In 95% of cases the patient has primary hypothyroidism (abnormalities in the thyroid gland), while central hypothyroidism is less frequent.

Congenital and neonatal hypothyroidism are present from birth. Depending on the aetiology, the hypothyroidism may be permanent and require lifelong treatment, or it may be transient and resolve spontaneously when the underlying cause disappears (e.g. excessive concentration of iodine or the presence of maternal antithyroid antibodies). Notwithstanding, every patient requires treatment to normalise thyroid function during the period of brain development, and treatment is inefficient if it starts later (existence of a “window of opportunity”).4

The most frequent cause of primary CHT is thyroid dysgenesis (85%–90%), in most cases thyroid ectopia (60%–65%), followed by thyroid agenesis or athyreosis (35%–40%). Different forms of thyroid dyshormonogenesis (Table 3) account for 10% of cases. Specific mutations in the transcription termination factor 2 gene (TTF2) and genes encoding other thyroid transcription factors have been identified in some patients with thyroid dysgenesis.

In some cases, the aetiology of hypothyroidism cannot be determined. Numerous genes may be involved in the multifactorial aetiology of primary congenital hypothyroidism.17–24

This is a key step in the diagnosis and treatment of CHT. The purpose is to help parents understand the benefits of early diagnosis in the prevention of brain damage, teach them how to correctly administer medication, and promote adherence to treatment and to follow-up care for the duration of CHT (months, years, or life). The initial results should be conveyed by experienced staff, ensuring that parents fully understand the information.

Fig. 1 presents the protocol for management following a positive result of neonatal screening.

Figure 1.

Algorithm of the protocol for early detection of congenital hypothyroidism.

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A detailed personal and family history is taken in every case, with particular emphasis on potential consumption of pharmacological agents or iodine-containing substances, family history of thyroid disease (especially in the mother) and of symptoms of underactive thyroid.

The patient also undergoes a clinical evaluation to identify the signs and symptoms of hypothyroidism (Table 4).

If CHT is detected in a newborn through screening and later confirmed by the thyroid function study conducted in the CFUC, differential diagnoses need not be considered and treatment must not be delayed under any circumstances to attempt to determine the exact aetiology of hypothyroidism. In many cases, the definitive diagnosis is established in the re-evaluation performed at 3 years of chronological age, while in other cases, especially those of transient CHT, the aetiology may not ever be established.

Paediatricians have to evaluate newborns from countries where screening is not performed to verify normal thyroid function.

There are special situations where performance of repeat TSH measurements at 2 and 4 weeks of life is recommended due to the potential for delayed elevation of TSH or the need to measure both T4 and TSH (Table 5).25–28

In congenital and neonatal hypothyroidism, the degree of brain damage is directly associated with the time elapsed between onset of hypothyroidism and initiation of treatment. Thus, treatment should be initiated as soon as possible, preferably before age 15 days. Treatment should start the day the diagnosis is made, and its initiation should not be delayed pending performance of additional diagnostic tests.

The first-line drug is synthetic levothyroxine via the oral route, administered 30min before a feeding once every 24h at a dose of 10–15μg/kg/day.29–33

Generic formulations of levothyroxine do not exhibit the same bioavailability.34 Liquid compounded formulations of levothyroxine are not stable. The absorption of levothyroxine is hindered by ingestion of foods or products containing soy, iron, calcium, aluminium hydroxide, omeprazole, fibre, sucralfate or bile acid sequestrants.

Once treatment with levothyroxine starts, the patient must undergo frequent clinical and laboratory follow-up evaluations to optimise treatment. We recommend a second visit 2 days after diagnosis to confirm acceptance of the diagnosis and prescribed treatment, a third evaluation at 15 days with measurement of TSH and fT4 levels, then monthly visits in the first 6 months of life, followed by visits every 2 months until age 1 year, and visits every 3–4 months until the patient is re-evaluated at age 3 years.

Each follow-up visit should include a full physical examination and measurement of fT4 and TSH levels. The aim of treatment is to quickly normalise fT4 and TSH levels. Free thyroxine levels must remain in the upper range of normal to avoid subclinical hypo- and hyperthyroidism.35 The levels of TSH and fT4 must be measured 4 weeks after any dosage change.

The treatment of children identified through screening programmes for early detection of CHT must be maintained without interruption through age 3 years to ensure normal thyroid function until brain growth is complete, whether the hypothyroidism is transient or permanent. At age 3 years, patients without a definitive diagnosis may undergo re-evaluation (Fig. 2).

Figure 2.

Algorithm for re-evaluation and definitive diagnosis of congenital hypothyroidism.

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Children with an initial diagnosis of thyroid agenesis or ectopic thyroid, which are both permanent, do not require re-evaluation. The diagnosis ought to be re-evaluated in children with CHT and a normally positioned thyroid at the time of initial diagnosis, and in children with CHT of unknown aetiology.36,37 Re-evaluation should also be contemplated in patients in whom the diagnosis was not confirmed (by scintigraphy) at the time treatment was initiated. There are 2 possible approaches to the diagnostic re-evaluation, which should always be performed after the patient reaches age 3 years.

To determine whether the hypothyroidism is permanent or transient, it is sufficient to half the current dose of levothyroxine and measure the levels of TSH and fT4 one month after: if the TSH level is 10mIU/L or higher, the hypothyroidism is considered permanent and the patient will resume treatment with levothyroxine at the dose that achieved normal thyroid function. In patients with a very high initial level of TSH and an eutopic thyroid gland, discontinuing levothyroxine for just 2 weeks should be enough to produce elevation of TSH.

If the aim is to make a definitive diagnosis, treatment with levothyroxine should be suspended for 1 month, followed by measurement of levels of fT4, TSH, thyroglobulin and antithyroid antibodies (antithyroglobulin or anti-thyroid peroxidase). If it was not performed before initiation of treatment, thyroid scintigraphy with technetium 99 can be used to diagnose an ectopic thyroid or possibly thyroid agenesis, which would be confirmed with a thyroid ultrasound scan. In patients with permanent CHT with eutopic thyroid gland, thyroid scintigraphy with sodium iodide I 131 allows performance of a perchlorate discharge test for assessment of dyshormonogenesis. Molecular genetic testing is very useful in the diagnosis of CHT.

The following findings are suggestive of permanent CHT in patients with an eutopic thyroid gland: history of goitre or primary congenital hypothyroidism with eutopic thyroid gland in first-degree relative, thyroid hypoplasia at the time of initial diagnosis, need for high doses of levothyroxine (>2μg/kg/day) during the follow-up, thyroid hyperplasia at the time of re-evaluation.

Table 3 summarises the aetiological classification of CHT based on the results of the diagnostic re-evaluation. If a permanent aetiology is confirmed, the family needs to be informed of the need to maintain treatment with levothyroxine for life with the required dose adjustments. In case of transient hypothyroidism, treatment is discontinued.

Early detection of CHT through neonatal screening prevents the intellectual disability formerly observed in these children when the diagnosis was clinical and delayed. Patients with CHT that receive early and adequate treatment have normal intellectual quotients.17,18,36,38,39

In some cases, mild brain impairment occurs despite early initiation of treatment, resulting in behavioural problems, and impairment in language comprehension, fine motor skills and visual-perceptual motor skills, usually with little impact on the ability to carry out a normal life. These abnormalities have been associated with the age at initiation of treatment (greater than 15–21 days), the dose of levothyroxine (usually lower than recommended), the initial severity of hypothyroidism and fT4 levels below or above the recommended range during the follow-up. Excessive levels of fT4 in the early months of life may be associated to inattention in subsequent years.35

Discontinuation of treatment before age 3 years without medical supervision or subsequent follow-up can have dire effects on neurologic development.

Follow-up in these patients is important not only to achieve healthy maturation, but also optimal growth and development. In countries where there are no CFUCs for patients with CHT, the reported proportion of patients that discontinue treatment prematurely ranges between 25% and 30%.37,40

Children with CHT should be followed up in a CFUC through puberty and until reaching their final height.16,17 Thereon, follow-up visits should be scheduled every 6–12 months, or more frequently in case of poor adherence. The purpose of followup is to monitor thyroid function to prevent subclinical hypo- or hyperthyroidism and the associated cardiovascular problems, excess weight and bone mineralisation defects in adulthood.

Only 70% of adults with CHT adhere to treatment correctly. This is particularly alarming in the case of women who are or wish to become pregnant, whose thyroid hormone requirements are greater. Optimal treatment of maternal hypothyroidism is essential to achieve a normal pregnancy with healthy neurocognitive development in the child. Monitoring of treatment is recommended throughout childhood and adulthood. Educational strategies need to be developed and implemented to improve adherence to treatment, especially during the transition to adult care.

Even if the results of screening are normal, if there is clinical suspicion of hypothyroidism the paediatrician should request urgent measurement of serum fT4 and TSH levels, as the elevation of TSH may occur later in some patients. Other infrequent causes, such as consumptive hypothyroidism in the postnatal period secondary to overexpression of type 3 deiodinase in patients with large haemangiomas, will not be detected in screening tests due to normal levels of TSH and T4 in the early stages.27

The screening protocol that measures TSH alone cannot identify cases of central CHT.10,11 The incidence of central CHT, whether isolated or associated with hypopituitarism, is higher (1 per 16,000 to 20,000 live births) than previously reported (1 per 100,000), so expanded screening with simultaneous measurement of TSH and tT4 levels is recommended. For now, we advocate for measurement of T4 levels in the newborn screening sample, as this would prevent delayed diagnosis in these patients, in many of whom symptoms may be either absent or nonspecific.

Abnormalities in TSH-α and TSH-β may manifest with a late elevation of TSH. Changes in the monocarboxylate transporter 8 (MCT8) gene should be suspected in patients with neurologic manifestations in the first year of life and initially manifest with normal thyroid function.16,17