Newborn Screening

Newborn screening (NS) for congenital hypothyroidism (CH) is one of the major achievements of preventive medicine [1, 2]. Although since 1972 the problem of CH has been resolved in developed countries by the implementation of NS for CH, the problem exists for developing countries that still have no NS programs for CH [2, 3]. Since diagnosis based on clinical findings is delayed in most instances because of few symptoms and signs, hypothyroidism in the newborn period is almost always overlooked and delayed diagnosis leads to the most severe outcome of CH, mental retardation. In a study from Denmark, it was emphasized that only 10% of the affected infants were diagnosed within the first month of life, 35% within 3 months. 70% were diagnosed within the first year, while in the remainder the diagnosis was delayed to the 3rd and 4th years of life [4]. In a retrospective analysis of 1,000 cases of CH from Turkey, the mean age at diagnosis was 49 months and only 3.1% of cases were diagnosed within the first month, whereas 55.4% were diagnosed after 2 years of age [5].

The first CH screening was performed by Dussault and Laberge [6, 7], in Quebec, Canada in 1972. They detected 7 hypothyroid infants among 47,000 newborns during 3 years. The high frequency of false-positives delayed the diagnosis and increased the cost and they arranged the cutoffs used for recall. The babies recalled underwent thyroid hormones and TSH blood studies. In the meantime, radioactively labeled antibodies for determining T4 in dried blood spots began regionally in the USA and Europe. They went parallel with screening programs of PKU. In the initial report by Dussault et al. [8], the method was recommended as a confirmatory test knowing that it would miss cases with hypothlamic-pituitary hypothyroidism which they reported to be 10% of the cases. In 1976, it was reported in the Lancet that cord blood TSH measurements were shown to have greater sensitivity and specificity to cord blood T4 and blood spot T4 (collected on 3- to 4-day-old newborns) and false-positives were high in T4 method with high costs [9]. Walfish [9], suggested routine T4 screening supplemented by TSH estimation be used in mass screening.

Blood spot T4 or TSH or both could be used in NS for CH. The latter, which is more sensitive, is not cost effective so the first two are used in different programs around the world. North America usually prefers primary T4 testing supplemented with TSH and Europe prefers primary TSH in the detection of CH [10-14]. TSH screening was shown to be more specific in the diagnosis of CH, T4 screening was more sensitive in detecting newborns especially with rare hypothalamic-pituitary hypothyroidism but less specific with a high frequency of false-positives mainly in low-birth-weight and premature babies. Thyroxine-binding globulin (TBG)-deficient babies who are euthyroid could be detected by T4 screening who are not targets for NS.

1982, a Neonatal Thyroid Screening Conference held in Tokyo recommended NS programs oriented to detect infants with elevated serum concentrations of TSH [15]. They suggested that this could be accomplished by measuring TSH in filter paper blood spot or by measuring T4 supplemented by TSH on the same blood spot of infants who have T4 values in the lower 3rd to 10th percentile.

Methods

The aim is to detect all cases with the disease, as early as possible, with an acceptable cost-benefit ratio and to avoid false-positive results. Today more sensitive and automated methods (chemiluminescence, fluoroimmunoassay, etc.) for determining both T4 and TSH in dried blood spots have been introduced [16-21]. They have increased sensitivity and specificity. Besides the development of more accurate test programs, some children may still be missed in any screening program. The reasons could be failure of sample collection, unsatisfactory samples, misinterpretation of samples and unsatisfactory recalls.

The ideal time to obtain the blood spot is 3-5 days after birth to minimize the false-positive high TSH due to the physiological neonatal TSH surge that elevates TSH levels and causes dynamic T4 and T3 changes in the first 1 or 2 days after birth. Early discharge of mothers postpartum has increased the ratio of false-positive TSH elevations. The difficulty in screening for CH using cord blood samples is in the handling and transport of the samples, making it an impractical method for mass screening [22].

Whichever method is used, babies whose initial TSH is >50 |xU/l are most likely to have permanent CH, whereas a TSH between 20 and 49 |xU/l is frequently a false-positive or represents transient hypothyroidism. Transient CH is particularly common in premature infants in borderline iodine deficient areas.

In the primary TSH method, when 15 |xU/l (immunofluorometric method) or 20 |xU/l (radioimmunological method) is used as cutoff, the recall rate is quite low to be 0.05%. Iodine deficiency could increase false-positives and increase recall rate. The sensitivity of TSH method for CH is suggested to be 97.5% and specificity 99% [23, 24].

Neonatal screening with the primary TSH method detects: (a) overt and compensated primary hypothyroidism.

Neonatal screening with the primary TSH method misses:

(a) secondary-tertiary hypothyroidism;

(b) TBG deficiency;

(c) premature babies with very LBW with a delayed TSH surge.

In primary T4 screening, performed in some states of the USA, cutoff to the 10th percentile resulted in 1.5% missed cases, whereas cutoff to the 5th percentile T4 values resulted in 3.5% cases. Only 0.2% of cases were missing using the 20th percentile as a cutoff, but off course with increased cost in terms of repeat testing [25]. Optimal screening requires initial T4 determination to be followed by TSH determinations on low T4 samples.

Neonatal screening with the primary T4 method detects:

(a) overt primary hypothyroidism;

(b) secondary-tertiary hypothyroidism (1 in 50,000-100,000 live births);

(c) hypothyroxinemia in a sick and preterm newborn;

(d) TBG deficiency;

(e) hyperthyroxinemia.

Neonatal screening with the primary T4 method misses:

(a) compensatory hypothyroidism with subnormal T4 and elevated TSH levels;

(b) transient hyperthyrotropinemia where iodine deficiency is present. Reliability of the laboratories is as crucial as the reliability of detection methods (with emphasis on sensitivity, specificity and positive predictive value). According to the recommendations of the working group of NS of ESPE (European Society for Pediatric Endocrinology), screening should be conducted in centralized laboratories covering 100,000 newborns per year [26]. These laboratories should participate in international control programs. In North America it is estimated that 6-12% of the neonates with CH are missed due to biological factors and screening errors [27, 28].

Neonatal Screening Results Hypothyroxinemia (Low T4 and Normal TSH)

It occurs most commonly in premature infants, in whom it is found in 50% of babies of less than 30 weeks' gestation [26]. Screening programs that employ primary TSH analysis will miss these infants because of normal TSH levels. Often the free T4 is less affected than the total T4. The reasons for the hypothy-roxinemia of prematurity are complex. In addition to hypothalamo-pituitary immaturity, low TBG levels and decreased conversion of T4 to T3 exists in prematures. Numerous studies have shown that there is a correlation between the degree of lowering of T4 and negative outcomes; both mortality and developmental problems. Systematic supplementation of all low-birth-weight babies is not recommended at this time [23, 29, 30].

Other causes of low T4 in the face of normal TSH are euthyroid sick syndrome, TBG deficiency, laboratory errors and central hypothyroidism [3]. Immature liver function, undernutrition and illness are the reasons for low T4 and normal TSH levels in euthyroid sick syndrome. Euthyroid sick syndrome may be seen in the sick term newborns as well [23]. TBG deficiency is an X-linked condition discovered only by screening programs using the primary T4 approach. It does not require treatment since the plasma levels of free thyroid hormone levels are normal and subjects are euthyroid. Its incidence is estimated to be 1 in 2,800 [31]. TBG deficiency should be estimated especially in male infants with low T4 and normal TSH and could be confirmed by measuring TBG levels in the serum. Loss of protein from nephrotic syndrome may also lead to low total T4. Errors in measurement may be caused by errors in sample gathering, impregnation with water due to improper sample handling or less amounts of blood spots or extremes hematocrit values which adversely affect the measurements.

In a term neonate with a low free T4 but normal TSH level, true central hypothyroidism, which is quite rare, should be ruled out. Mutations in the gene coding for the beta subunit of TSH or the TRH receptor could be the causes [32, 33]. Central hypothyroidism could coincide with other anterior pituitary hormone deficiencies: hypoglycemia, microphallus, prolonged jaundice and/or cryptorchidism [34-36].

Isolated Hyperthyrotropinemia (Normal T4 and Elevated TSH)

Elevated TSH, despite a normal or low normal T4 indicates inadequate hormone production. It is most common in premature babies. Although some babies have compensated hypothyroidism, the etiology is not clear in the others. In early discharged babies (in the first day or two), because of the cold-induced TSH surge, TSH values are found to be elevated. It could be a transient finding due to goitrogens, iodine deficiency or medications. Genetic defects of hormone biosynthesis and also dysgenesis especially ectopia could be the causes. TSH rises with normal T4 levels could persist for years [37].

Table 1. Causes of transient hypothyroidism

Maternal antithyroid medication Exposure of topical iodine Maternal iodine deficiency or excess Maternal TSH receptor blocking antibodies Medications (dopamine, steroid) Prematurity (<30 weeks)

Table 2. Causes of childhood hypothyroidism

(a) Congenital hypothyroidism

(b) Acquired hypothyroidism

- Autoimmunity (Hashimoto thyroiditis)

- Drug-induced hypothyroidism Antithyroid

Anti-TBC

Iodine compounds

Lithium, cobalt, sulfonamides

- Thyroidectomy

- Endemic goiter Iodine deficiency Environmental goitrogens

- Irradiation of thyroid Therapeutic radioiodine

External irradiation of nonthyroid tumors

- Infiltrative disorders Amyloidosis Histiocytosis Cystinosis

Low T4 and Elevated TSH

The most common cause is primary CH. There might be transient cases as shown in table 1.

Although transient hypothyroidism may occur frequently, all the suspected infants should be treated as CH for the first 3 years of life by taking into account the risks of mental retardation. A re-evaluation after 3 years is needed in such patients [1, 38-40].

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