Congenital Hypothyroidism

In most infants with CH, the disorder is permanent and results from abnormal development of the thyroid gland or a defect in HT synthesis.1 Less commonly, CH may be the result of hypothalamic or pituitary control. abnormal thyroid function.

In some infants with CH, thyroid dysfunction is transient.2–6 Transient CH may be caused by the transplacental passage of maternal antithyroid medications (carbimazole, methimazole, or propylthiouracil) or thyroid-stimulating hormone receptor blocking antibodies (TRBAb). thyroid (TSH), iodine deficiency or excess, or certain genetic forms of dyshormonogenesis.

Neonatal screening (NC) for HC (and other disorders) is performed at 24 to 72 hours of life. Additionally, CH can also be detected in a second neonatal test performed at 2 to 4 weeks of age.7 Clinical and laboratory follow-up of children with CH is essential for appropriate management.7–9

Iodine is a critical component in the production of TH, and its deficiency also remains one of the most common preventable causes of intellectual disability worldwide. Although North America is generally an iodine-sufficient region, recent data indicate that more than half of pregnant women in the United States may have mild iodine deficiency.10,11 A prenatal vitamin containing 150 mcg of iodine daily It should be taken by all women before and during pregnancy and breastfeeding.12,13

CN for HC followed by prompt initiation of levothyroxine (L-T4) treatment can prevent severe intellectual disability, psychomotor dysfunction, and growth impairment2,7–9,14–16 and has been adopted in many countries throughout the world.2,7–9,17,18

The incidence of HC varies from 1 in 2000 to 1 in 4000 newborns in countries in which CN data are available.18 This incidence is significantly higher than that reported in the first years of CN (~1 in 4000), mainly due to changes in screening strategies that have led to increased detection of milder cases of HC.18–21

Some CN programs report results in units of whole blood, and other programs report results in serum. Based on the assumption that the average hematocrit of the newborn is ~55%, the results expressed in serum units are 2.2 times higher than those expressed in whole blood units; For example, a TSH detection of 15 mIU/L in whole blood is approximately equivalent to a TSH detection of 33 mIU/L in serum.22

Clinicians should identify whether NC results in their region are expressed in units of whole blood or serum. Most NC programs in the United States and some in Canada express their results in serum units, but many in Canada and the rest of the world express results as whole blood units. Throughout this report, results are expressed in serum units.

I. Neonatal screening

A. NC for HC should be performed on all infants in conjunction with state or provincial public health laboratories.7–9

1. Obtain a drop of dried blood for CN by heel prick on approved filter paper card samples.

2. For the normal newborn, obtain the CN sample after 24 hours of life (preferably between 48 to 72 hours) and before hospital discharge or one week of life, whichever comes first.

3. If the newborn is discharged before 24 hours of age, obtain the CN sample before hospital discharge. CN before 24 hours of age has a higher risk of false positive results. Perform the initial NC before a blood transfusion, if required before 48 hours of life.

4. Any of the 3 CN strategies can be used to detect HC: Primary measurement of TSH with reflex thyroxine (T4); Primary measurement of T4 with reflex TSH; or combined measurement of T4 and TSH.

B.  If a newborn is referred to another hospital, the transferring hospital must indicate whether the CN sample has been obtained. If the sample has not been obtained, the receiving hospital must collect a sample for CN after referral.

C.  If any HC CN results are abnormal, serum TSH and free thyroxine (T4-L) should be measured.

D.  If the first NC is normal, perform a second NC at 2 to 4 weeks of age in newborns who:

• are seriously ill (admitted to the NICU);

• are premature (< 32 weeks of gestation);

• have very low birth weight (< 1500g);

• received a transfusion before obtaining the CN sample;

• have a monozygous twin (or a twin of the same sex, if zygosity is not known) or come from multiple births; either

• have trisomy 21

Repeat CN testing is recommended instead of measuring serum TSH and T4-L due to the much lower cost of CN.

E.  If a second CN performed before the corrected gestational age of 36 weeks is normal, it is recommended to repeat the CN test 4 weeks later (at 6-8 weeks of age) or at 36 weeks corrected gestational age, which happens first.23

F.  When CN is performed after 1 week of age, age-specific reference ranges should be used to interpret the results. CN programs should provide age-specific reference ranges for interpretation.

G.  The CN program must communicate abnormal results directly to the primary care professional (PAP) in a timely manner to facilitate appropriate follow-up. The CN program should communicate results promptly to both the birthplace/hospital (where they should be entered into the electronic medical record, if possible) and the PAP (if known), along with an interpretation of the test results. and recommendations on follow-up, if appropriate.24 PAPs are responsible for reviewing the CN test results of infants in their care, as they would any test results of their patients.

H.  If a PAP receives CN results for a patient they do not care for or cannot locate, they must notify the CN program immediately. It is suggested that CN programs work to create a system in which CN results are automatically entered into the patient’s electronic medical record and are available to both maternity and PAP. Electronic health records could provide some support for clinical decision making in accordance with the guidance in this document.

II. Management of abnormal CN

A.  When the PAP receives an abnormal CN result for HC, a confirmatory measurement of TSH and T4-L in a serum sample should be obtained as soon as possible (ideally within 24 hours).

B.  Consultation with pediatric endocrinology is indicated, if possible, to assist in diagnosis and management.

C.  Immediate follow-up actions are based on the CN TSH level:

1. If the TSH of the CN is > 40 mIU/L, treatment with L-T4 should be started after obtaining the confirmatory serum sample, without waiting for the results.

2. If the TSH of the CN is ≤ 40 mIU/L, wait for the results of the confirmatory serum sample (preferably with a turnaround time of 24 hours), and postpone the start of treatment with L-T4.

D.  The infant should be evaluated by a physician (PAP or pediatric endocrinologist) without delay, optimally within 24 hours or the next office day after the NC results are received. The doctor must:

1. Obtain a complete history including maternal prenatal thyroid status, maternal medication, and family history.

2. Perform a complete physical examination.

3. Assess the risk of TRBAb-mediated hypothyroidism and consider measuring TRBAb in the infant and/or mother if there is a history of maternal autoimmune thyroid pathology or a previous infant affected by maternal TRBAb. If TRBAbs are present, no specific additional treatment is required beyond management of hypothyroidism, and a transient course can be anticipated.

4. Consider obtaining images to establish the etiology of CH but only if the results influence clinical management.

E.  Subsequent actions are based on the results of the confirmatory serum sample:

• If serum TSH is elevated and serum T4-L is low, start (or continue) treatment with L-T4.

• If serum TSH is >20 mIU/L and serum T4-L is normal, initiate (or continue) treatment with L-T4.

• If serum TSH is elevated but is ≤ 20 mIU/L and serum T4-L is normal, treatment with L-T4 can be initiated, or serum TSH and T4-L can be monitored every 1 to 2 weeks without treatment. If L-T4 is low, or if TSH >10 mIU/L persists beyond 4 weeks of age, treatment with L-T4 is recommended.

• In infants with elevation of serum TSH to >5 mIU/L but ≤10 mIU/L that persists beyond 4 weeks of age, there is insufficient evidence to recommend treatment versus observation. In these cases, consultation with a pediatric endocrinologist is recommended (if not already done) to formulate a patient-specific management plan.

• If serum TSH is normal or low and serum T4-L is low, evaluate for possible central hypothyroidism with further testing as clinically indicated. Confirmatory serum tests should be obtained, including measurement of TSH and FT4-L. Measurement of the thyroxine-binding globulin concentration when T4 is low but T4-L is normal may help distinguish central hypothyroidism from thyroxine-binding globulin deficiency.25 Infants with central CH should be evaluated, in consult with a pediatric endocrinologist, for other hypothalamic-pituitary dysfunctions. This point should be considered before starting treatment with L-T4, because such treatment can reduce cortisol levels.

III. Images

A.  Thyroid imaging is optional in the evaluation of infants with CH and may be performed if the results will influence clinical management. The decision to perform imaging may be assisted by consultation with a pediatric endocrinologist.

B  Attempts at imaging should never delay treatment of HC.

• Ultrasound or thyroid scintigraphy images can help establish the etiology of CH.26 However, in many cases, imaging does not alter the clinical management of the patient before the age of 3 years. An accurate scan can only be performed when TSH is elevated; It can be done before starting treatment with L-T4 or within the first 2 to 3 days after starting it. Scintigraphy can also be performed after 3 years of age during a trial treatment with L-T4.

IV. Genetic testing

A.  For children with isolated primary CH, genetic testing is an option when genetic diagnosis can modify clinical management.

B.  For central HC or HC associated with clinical features of a recognizable syndrome or underlying genetic condition, consultation with a geneticist is recommended. The decision to pursue genetic testing may be assisted by consultation with a pediatric endocrinologist or geneticist.

C.  Infants with trisomy 21 who do not have CH are at risk of developing primary hypothyroidism during the first year of life. Therefore, in babies with trisomy 21:

• A second NC should be performed at 2 to 4 weeks of age.

D.  Serum TSH should be measured at 6 and 12 months of age.

V. Treatment (Table 1)

A.  HC should be treated with enteral L-T4 at an initial dose of 10 to 15 mcg/kg/day administered once daily.8–10,27

B.  Treatment should be initiated as soon as possible after confirmation of diagnosis (optimally at 2 weeks of age if identified at first NC).

C.  Downward dose adjustment may be necessary after laboratory evaluation at 2 weeks of age to avoid overtreatment.28

D.  Enteral administration of L-T4 tablets is the treatment of choice. L-T4 tablets can be crushed and suspended in 2 to 5 ml (1 teaspoon) of human milk, soy-free formula, or water. A commercial oral solution of L-T4 was approved by the US Food and Drug Administration (FDA) for use in children; however, limited experience with its use has shown that dosing may differ slightly from tablets.29,30 Pharmacy-prepared L-T4 suspensions may result in unreliable dosing.31,32

E.  L-T4 can be administered at any time of day in infants and young children (morning or afternoon, with or without food), as long as the timing and manner of administration are consistent. Coadministration with soy, fiber, iron, or calcium may affect L-T4 absorption. Breastfeeding can continue without interruption.33 If enteral administration is not possible, L-T4 can be administered intravenously at 75% of the enteral dose.34

F.  The endocrinologist and/or PAP should provide parents with critical education regarding (1) the etiology of HC, (2) the benefit of early diagnosis and treatment to prevent intellectual disability, (3) the appropriate method for administering L-T4, (4) substances that may interfere with L-T4 absorption (e.g., soy, iron, calcium, and/or fiber), and (5) the importance of adherence to the plan treatment, including follow-up care. Providing written instructions to caregivers can enable adherence and prevent administration errors.

G.  The goal of L-T4 treatment is to support normal growth and neurocognitive development. Achieving an optimal outcome depends on early initiation of appropriate L-T4 treatment (optimally at 2 weeks of age when detected in the first NC), particularly in severe cases of CH.27,35 Rapid normalization of serum levels of T4-L and TSH (optimally within 2 to 4 weeks of starting treatment) leads to better neurocognitive outcomes.36–40 Delay in starting treatment and longer time to normalization of thyroid function are associated with better outcomes. poorest.41,42

After initial normalization, serum TSH should be maintained in the age-specific reference range; Serum T4-L levels should be maintained in the upper half of the age-specific reference range unless achieving a serum T4-L level in that range results in a TSH level less than the reference range.

Ideally, the same L-T4 formulation should be kept constant until 3 years of age to achieve consistent euthyroidism and minimize the need for further laboratory monitoring. If feasible, the use of a commercial pharmaceutical formulation of L-T4 may be superior in children with severe CH.43 If generic L-T4 is prescribed, it is preferable to use L-T4 from a consistent manufacturer.

Treatment with liothyronine is generally not indicated. The use of liothyronine in patients with

severe persistent thyroid hormone resistance (elevated TSH despite elevated T4-L), in whom adequate control cannot be established with L-T4 alone has not been shown to improve outcomes and should be considered only in consultation with an endocrinologist pediatric.44,45

SAW. Monitoring (Table 1)

A.  During the first 3 years of life, a clinical evaluation (as specified below), including evaluation of growth and development progress, should be performed regularly.

B.  Due to the increased risk of hearing impairments in people with HC, formal hearing evaluation should be considered whenever there is clinical concern for a hearing deficit or abnormal language development.14,46

C.  TSH and FT4-L should be measured10,47,48:

1. One to 2 weeks after the start of L-T4 treatment and every 2 weeks until the serum TSH level is normal;

2. Every 1 to 2 months during the first 6 months of life (monthly in infants with severe CH, that is, initial serum TSH >100 mIU/L or T4-L < 0.4 ng/dl);

3. Every 2 to 3 months during the second 6 months of life; and

4. Every 3 to 4 months between one year and 3 years of age.

Ideally, blood samples for laboratory testing should be obtained at least 4 hours after L-T4 administration to avoid spurious elevation of T4-L level.

VIII. Long-term monitoring

A.  After 3 years of age, TSH measurement is recommended:

1. Every 6 to 12 months until growth is complete;

2. Four to six weeks after any change in L-T4 dosage or formulation; and

3. At more frequent intervals in children with severe CH, problems with adherence to the L-T4 treatment plan, or TSH levels outside age-specific reference ranges.

B.  After 3 years of age, TSH monitoring is sufficient. T4-L may be measured if medication adherence or suboptimal control is a concern.

C.  After the first 3 years of life, clinical evaluation and assessment of growth and development should be performed every 6 to 12 months.

D.  Pediatric endocrinologists should establish follow-up protocols for children with CH in their practice to optimize management and prevent loss to follow-up. Currently, many patients diagnosed with CH are lost to follow-up.49–52 Because inadequate treatment of CH can have negative developmental consequences, the endocrinologist can establish protocols to help prevent children with CH from being lost to follow-up. monitoring. Some examples may include monitoring consultations/shift scheduling and prescription loading. The PAP also has an important role in ensuring that affected children maintain L-T therapy4.53

VIII. Evaluation of the permanence of hypothyroidism

A.  HC is confirmed to be permanent in cases of thyroid dysgenesis or if serum TSH increases >10 mIU/L after the first year of life.

B.  Patients with permanent CH should remain on L-T4 treatment for life.

C.  If the diagnosis of permanent CH has not been confirmed, a free L-T4 test at 3 years of age should be strongly considered, particularly if the patient is adequately treated with a low dose of L-T4 (<2 mcg/ kg/day). The L-T4 free test can be performed as follows:

1. Discontinue L-T4 for 4 weeks, and then measure serum TSH and T4-L levels.54

2. If TSH and T4-L levels remain within the reference range for age, it is confirmed that CH is transient.

3. If TSH is >10 mIU/L and/or T4-L is low, permanent CH is confirmed and treatment with L-T4 is reinstated.

4. If TSH is mildly elevated (greater than the age-specific reference range, but ≤10 mIU/L) and T4-L is normal, repeat serum TSH and T4-L levels in another 4 to 8 weeks to determine if there is (1) normal thyroid function (indicating transient CH), (2) permanent CH (TSH >10 mIU/L or low T4-L), or (3) persistent hyperthyrotropinemia (TSH persistently elevated but ≤ 10 mIU/L, with normal T4-L). There is not enough evidence to determine whether treating persistent hyperthyrotropinemia is of clinical benefit, but many doctors choose to treat it out of an abundance of caution.

5. It is critical that patients are not lost to follow-up while L-T4 therapy is being evaluated.

CN has substantially improved neurodevelopmental outcomes in patients with HC, and severe intellectual impairment typically does not occur in patients who are diagnosed and treated early and appropriately.

Appropriate treatment of HC with L-T4 (early initiation of L-T4 at 10 to 15 mcg/kg/day, with normalization of thyroid function within 2 weeks) results in normal neurocognitive function in adulthood.27 However , detailed studies reveal neuropsychological deficits in some children with HC, including problems in visuospatial processing and deficits in memory and sensorimotor function.

If a child with CH is treated adequately but developmental progress and/or growth is abnormal, evaluation for intercurrent illness, hearing deficit,46 or other potential hormonal deficiency is warranted.

Despite the obvious success of CN, clinicians should consider hypothyroidism when there are clinical symptoms suggesting this diagnosis, despite previous normal CN thyroid test results.

Abnormal neurodevelopment may result from hypothyroidism in infants with normal NC results when it manifests or is acquired after NC, or when screening errors occur.

Hypothyroidism may be present in infants in whom NC was not performed (e.g., home births) or if the results were not communicated to the baby’s PAP.55 Therefore, when clinical symptoms or signs of hypothyroidism are present ( such as large posterior fontanel, macroglossia, umbilical hernia, prolonged jaundice, constipation, lethargy and/or hypothermia), measurement of TSH and T4-L in serum should be indicated, regardless of the results of the CN.

Table 1. Treatment and follow-up of congenital hypothyroidism.

Congenital hypothyroidism is a generally permanent condition in which thyroid hormone levels are insufficient for the normal development and functioning of body tissues, being one of the most common preventable causes of intellectual disability worldwide.

Neonatal screening for CH and other disorders, performed at 24 to 72 hours of life, is an extremely useful tool for early detection; However, the diagnosis of hypothyroidism should be considered when there are suggestive clinical symptoms, despite having previous normal screening results.

Early treatment and clinical and laboratory follow-up of children with CH are essential for adequate management and to avoid associated short- and long-term complications, mainly those related to growth and neurodevelopment.