Congenital hypothyroidism (CH) is the commonest preventable cause of mental retardation. Worldwide the commonest cause of CH is iodine deficiency. In regions where iodine deficiency is severe, CH is endemic (endemic cretinism), whereas in regions where iodine deficiency is mild or absent, CH is usually sporadic.</sec><sec id="sec002"><title>Epidemiology

JNNFI

Journal of Neonatology

0973-21870973-2179

National Neonatology Forum

jn-19-2-008

REVIEW ARTICLE

Thyroid Screening in Neonates

Arya

Archana D.

Consultant Pediatric & Adolescent Endocrinologist

Centre for Child Health Sir Ganga Ram Hospital New Delhi - 110 060 adayal35@hotmail.com

42005

192149154

Congenital hypothyroidism (CH) is the commonest preventable cause of mental retardation. Worldwide the commonest cause of CH is iodine deficiency. In regions where iodine deficiency is severe, CH is endemic (endemic cretinism), whereas in regions where iodine deficiency is mild or absent, CH is usually sporadic.</sec><sec id="sec002"><title>Epidemiology

The worldwide incidence of CH is 1:3500-4000 live births (1-3) and it is twice as common in girls. A higher incidence (1:2000) has been reported in Asians and Hispanics. The incidence of CH in India is not known. A study conducted in Mumbai suggested an incidence of 1:2800 live births (4). This may be the tip of the iceberg and further screening would reveal the extent of this problem in our country.

Types of Congenital Hypothyroidism

CH may be Peripheral (primary hypothyroidism) due to a primary disorder of the thyroid gland or Central, due to a defect at the level of the pituitary (secondary hypothyroidism) or hypothalamus (tertiary hypothyroidism). Compensated hypothyroidism refers to the condition in which levels of T4 and T3 are normal and TSH is elevated. CH may be permanent or transient in nature. Permanent CH has the most deleterious effect on the intellectual outcome of the infant. An analysis of 7 studies involving 675 children with CH and 570 controls demonstrated that the developmental outcome depended on the initial degree of severity of CH. A significant drop in IQ was observed in children with severe CH compared with the controls (5).

Etiology of Congenital Hypothyroidism (Table –1) 80-90% cases of Primary CH are due to developmental defects of the thyroid gland (thyroid dysgenesis) (1-3). This includes absence of the thyroid gland (athyreosis) or arrested migration of the thyroid gland in the sublingual area (ectopic thyroid) and functional defects in one of the steps involved in the biosynthesis of thyroid hormone (thyroid dyshormonogenesis), which occurs in 10-20% cases. Table 1

Etiologies of CH

Etiology	Prevalence

Thyroid dysgenesis	1:4000
Thyroid dyshormonogenesis	1:30,000
Hypothalamic-Pituitary hypothyroidism	1:100,000
Transient hypothyroidism	1:40,000

Genetic Basis of Congenital Hypothyroidism

Recent studies have re-evaluated the role of genetic factors involved in thyroid dysgenesis and suggest autosomal dominant inheritance with incomplete penetrance (6).

In humans, single gene defects are responsible for some cases of familial thyroid dysgenesis but most cases are sporadic or due to unknown mechanisms (7). Thyroid dysgenesis may occur due to mutations of thyroid specific transcription factors TTF-2 and PAX-8. Thyroid dyshormonogenesis follows an autosomal recessive mode of inheritance.Central hypothyroidism may be caused by mutations that inactivate the gene coding for subunit of TSH or TRH receptor or PIT-1 (PROP gene).

Importance of Screening

It has been observed that most babies with CH appear normal at birth and show minimal evidence of thyroid deficiency (8). Clinical diagnosis is made in only 10% children in the first month of life and 30% in the first 3 months. Hence there is a high risk of delayed diagnosis based on clinical examination alone.

Early diagnosis and therapy improves the intellectual outcome and growth of the baby. Prior to routine screening for CH, the mean IQ of children with CH was 76 (9). Specific cognitive defects were found even in those children who had normal IQ’s. Study of the developmental outcome after routine newborn screening was implemented, revealed absence of intellectual impairment due to early initiation of treatment (10).

Studies have shown that if therapy for CH is started before 3 months of age, the mean intelligence quotient (IQ) is 89. If it is delayed, the IQ drops to 70 between 3-6 months of age and is as low as 54 after 6 months of postnatal life (11).

Thus it is very important to screen every newborn for CH within a few days of birth.

Most developed countries have their own newborn screening program for early detection of congenital hypothyroidism and these programs have been found to be cost effective (12).

Screening Strategies for Congenital Hypothyroidism

There are 2 primary approaches to neonatal screening for hypothyroidism.

Primary measurement of T₄ followed by determination of TSH if the T₄ value is low. This approach is being used in North America for screening.

Primary measurement of TSH followed with T₄ measurement if TSH levels are high. This method is followed in most parts of Europe and Japan. Both approaches have their advantages and disadvantages.

Advantages and PitfallsPrimary T4 Screening

Screening programs with primary T₄ measurement will detect

Primary, secondary or tertiary hypothyroidism (1: 50,000-1:100,000 live births)

Babies with low T₄ but delayed rise in TSH (7.5% infants)

TBG deficiency and

Hyperthyroxinemia, They may miss out on infants with

Normal T₄ and raised TSH (compensated hypothyroidism).

Primary TSH Screening

A primary TSH screening program will detect • Frank and compensated hypothyroidism It will miss out on those with:

Hypothalamic-pituitary hypothyroidism (5%, 1:50,000-150,000)

Primary hypothyroidism with delayed TSH response

Congenital TBG deficiency (1:5000-1:12,000) and

Hyperthyroxinemia.

Both programs will miss the rare infant whose initial screen is normal, but who later develops hypothyroidism (late onset CH –1:30,000). It would be ideal to screen all newborns by both T₄ and TSH measurements, but this may not be financially feasible. Screening for elevated TSH concentration is the most reliable indicator of primary hypothyroidism and is being practiced in most countries.

Changes in Thyroid Hormones at Birth

The pediatrician must be familiar with the physiological changes in thyroid hormone secretion that occur at birth. During the first hours after birth, there is an abrupt increase in pituitary TSH secretion, perhaps as a result of cooling and stress reaching levels of 60-80mU/ml within 30 minutes after delivery. This rise in TSH stimulates a two to six-fold increase in secretion of T4 and T3 from the thyroid gland, by 24 hours of life. The T₄ levels are in the 15-19mg/dl range and T₃ levels in the 300ng/dl range. This TSH surge is short lived, and declines slowly over the next 72-96 hours, to < 8mU/L by 5-7 days. This decline is due to feedback inhibition by the elevated serum T₄ at the hypothalamic or pituitary level (or both). In preterm infants the amplitude of rise in TSH and T₄ is blunted compared to term newborns but the time of peak and fall remain the same.

Interpretation of Results

Correct interpretation of the test results is very important and every screening program should have their own norms.

All infants with abnormal screening are recalled and subjected to testing of serum sample for T4 and TSH. The threshold value for a high TSH after 24 hours is 20-25 mIU/ml and after the first week of life, is more than 8-10mIU/ml, for most screening programs. Since laboratory errors are frequent, all doubtful results should be confirmed by re-testing. Standards for the Indian population are not available, but with ongoing screening programs we would soon have our own guidelines for screening. In USA where T₄ is measured for screening newborns, babies with T₄ values below the 10th percentile are called for re-testing. In most programs the ratio of false positive to confirmed CH is 2.5-5:1. The ratio will depend on the threshold value established for a significant TSH elevation by the individual program. The recall rate is 17-35 times higher in newborns weighing < 1500gms.

Experience with primary TSH screening has yielded an incidence of 1 per 33,000 false negative findings. In USA 2 cases are missed out for every 1 million infants screened. Most of these are due to laboratory errors (13).

Method of Screening

Newborn CH screening tests are usually carried out with a dried blood spot sample on a filter paper, obtained from the heel by skin puncture. The sample can be tested by immunoradiometric (IRMA) assays or immunoflourimetric assay (IFA). Some screening programs may use cord blood for screening. Measurement of TSH in cord blood has been found to be effective in a number of screening programs although TSH levels in cord blood are affected by perinatal factors (14).

Ideal Time of Screening

The preferred time for blood sampling is 3-5 days after birth. However since most mothers are discharged from the hospital within 3 days of delivery, early screening increases the prevalence of false positive results due to the physiological neonatal TSH surge. Some programs have a higher threshold value for infants discharged on day one.

Rescreening

Since some babies develop hypothyroidism after the initial screen, several screening programs routinely retest at 2-6 weeks of age, all infants with a normal initial screen. Another 10% of all affected infants are detected by the second screening only (15). The prevalence of CH resulting from second screening is 1:30,000.

The American Academy of Pediatrics recommends that thyroid functions should be repeated during infancy (16), when there is a

clinical suspicion of hypothyroidism

history of thyroid disease during pregnancy

family history of thyroid dyshormonogenesis

infants with Down syndrome (high prevalence of late onset CH, with or without aberration on the initial thyroid function tests) (17).

Evaluation of Abnormal Screening Results

Abnormal screening results may fall into the following categories:

Low T₄ and elevated TSH

Low T₄ and normal TSH

Normal T₄ and elevated TSH

Low T4 and Elevated TSH

Elevated TSH with low levels of T₄ and T₃ are suggestive of primary congenital hypothyroidism which may be permanent or transient.

Permanent primary CH (PPCH) This is due to a permanent defect in the thyroid gland due to thyroid dysgenesis or thyroid dyshormonogenesis, which may present at a later age.

Transient CH In transient CH, T₄ levels are low and TSH is elevated, but they normalize spontaneously. These individuals are often started on thyroxine replacement, only to be found to have normal thyroid functions later in life. This picture could be due to transplacental passage of thyroid antibodies, maternal iodine deficiency, excess exposure to iodine by the mother during pregnancy (iodine crosses the placenta and suppresses the fetal thyroid gland) or infant during the postnatal period, antithyroid drugs and dietary goitrogens.

Low T4 and normal TSH

Congenital TBG deficiency If Total T₄ has been measured, then TBG deficiency, which is an Xlinked condition must be ruled out by measuring TBG or Free T₄ levels. TBG levels are low and FT₄ is normal in these babies. They are clinically euthyroid and do not need to be treated.

Transient hypothyroxinemia of the newborn This is more common in low birth weight infants with or without prematurity, especially if they are sick, but may occur in normal newborns occasionally. Mercado et al (18) reported symptoms of CH in 8 preterm infants which resolved with thyroxine replacement for a short period, whereas another double blind study showed no benefit of thyroxine replacement on the growth and development of preterm infants with low T₄ levels (19). Transient hypothyroxinemia does not cause significant ill effects on the development of the newborn, hence routine supplementation may not be required, although they need to be followed up closely.

Central (secondary-tertiary or hypopituitary hypothalamic hypothyroidism) This results in deleterious effects on development if untreated. More often central hypothyroidism is associated with deficiency of other pituitary hormones. Patients with hypoglycemia, prolonged jaundice, micropenis, hypogonadism, diabetes insipidus, and other midline deformities must be investigated for hypopituitarism.

Normal T4 and elevated TSH

Such patients are clinically asymptomatic as long as their T₄ levels remain normal.

TSH levels may remain elevated for a prolonged period of time, may normalize spontaneously later, or may decompensate to develop full blown hypothyroidism. 27 infants with serum TSH of 16+13mu/ml and a normal level of T₄, were evaluated. Of these infants 17 had dyshormonogenesis and 5 had an ectopic gland. (20). It has been demonstrated that infants with a TSH >7mu/ml have a decreased metabolic rate which normalizes with thyroid replacement therapy (21). TSH response to thyrotropin releasing hormone (TRH) can be assessed in these infants (22). It is impossible to predict the course of these patients and they need to be evaluated thoroughly by an experienced pediatric endocrinologist to determine the need for treatment, since a hypometabolic state may exist in these infants and neurodevelopmental outcome is not known. Treatment may be stopped in some of these infants for re-evaluation after 3 years of age.

Diagnostic Evaluation

A detailed history must be obtained for signs and symptoms of hypothyroidism, a history of CH in other family members or autoimmune thyroid disease in the mother. General physical examination should be done. These babies are often large for gestational age. Icterus, patent posterior fontanelle, large anterior fontanelle and widened cranial sutures are frequently found even in neonates. Umbilical hernia may be present. If hypothyroidism has been prolonged, the child may have coarse facies, dry skin, large tongue, hypotonia, hoarse cry and delayed milestones. The baby’s neck should be hyper-extended to look for a goiter. If dyshormonogenesis is suspected, a perchlorate discharge test should be performed and hearing must be tested if Pendred syndrome (thyroid dyshormonogenesis with 8th nerve sensorineural deafness) is suspected. Look for other associated abnormalities such as cleft palate, split hair syndrome and cardiac abnormalities since a five fold increase in the prevalence of minor defects in septation of embryonic heart has been reported in children with thyroid dysgenesis. It is important to make a precise diagnosis of permanent CH and also to identify the risk for future siblings, as in dyshormonogenesis. Hence wherever possible, a thyroid radionuclide scan should be obtained. The isotope of choice is 99mTc (sodium pertechnetate) which has low radioactivity. The scan should be performed just before starting treatment or within the first few days before the TSH normalizes, but it should never be a reason for delaying treatment. If scan is not possible during the initial phase of treatment, it can be done after 3 years of age, after stopping therapy for 8 weeks, since the brain development is complete by that time and there is no risk to the child. Inability to visualize the thyroid gland on nuclear scan may suggest athyreosis, although sometimes transplacental thyroid antibodies from the mother may prevent visualization of the gland. Undetectable thyroglobulin levels confirm a diagnosis of athyreosis. Anti thyroglobulin and microsomal antibodies should be checked in the mother and the infant. AP X-Ray of the knee should be done to look for distal femoral epiphyses. It has diagnostic importance and also reflects the severity and duration of the disease in utero (8). A bone age x-ray should be obtained before treatment and at one year of age.

Treatment

As soon as the diagnosis of CH is confirmed, treatment with L-thyroxine should be initiated immediately at a dose of 10-15µg/kg/day to normalize the T₄ level as soon as possible (16). It is well documented that early initiation of therapy and higher doses of thyroxine are essential for an optimal developmental outcome (23).

Thyroxine is available only as a tablet. It is given as a single dose preferably ½ hour before the morning feed. It is available as 25, 50 and 100µg tablets in India. Brand names are Thyronorm, Eltroxin and Thyrox.

Monitoring

Treatment should be monitored by periodic thyroid functions. Assess thyroid functions within a week to ensure normalization of T₄ levels and then after 14 days to look for normalization of TSH. The serum T₄ should be maintained in the upper half of the normal range. The American Thyroid Association recommends that thyroid functions should be checked every 1-2 months in the first year of life and then every 2-3 months from 1-3 years of age (16). The dose of thyroxine should be titrated based on the results of the thyroid functions. The use of T₃ is not recommended because most brain T₃ is obtained by intracellular conversion from T₄. If a baby is already being treated and a diagnostic error or transient hypothyroidism is suspected, therapy can be discontinued at 3 years of age to re-evaluate the child.

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