Contents
Contributors
Search

The diagnosis of primary hypothyroidism in infants appears to be associated with a higher incidence of congenital anomalies.147 A recent population-based study of greater than 1300 infants found that the prevalence of major anomalies was 8.4% in infants with congenital hypothyroidism, compared with 1-2% in the general population.148 Cardiac anomalies were the most common associated congenital anomalies, although anomalies of the nervous system and eyes were noted as well. The mechanisms underlying these associations remain to be elucidated.

If left untreated, neonatal and early childhood hypothyroidism results in profound mental and developmental retardation. It is important to note that both the severity of thyroid hormone deficiency and the time of onset during development determine the degree and potential reversibility of the ensuing brain damage. As would be expected, the earlier hypothyroidism occurs during fetal development, the more severely affected the neonate. Onset of hypothyroidism after the age of 2 years appears to exert little if any irreversible effects on mental development.

Intrauterine hypothyroidism is detected by the presence of elevated TSH concentrations and low serum T₄ concentrations.149 Clinically, neonates with hypothyroidism, even those with thyroid agenesis, are usually normal with regard to appearance, size, weight, behavior, and immediate postnatal development. Of note, however, bone maturation is delayed at birth in approximately 60% of affected infants. Because of the absence of pathognomonic features at birth, fewer than 5% of patients are diagnosed in the neonatal period on the basis of clinical presentation alone.

Prompt identification and treatment of newborn infants with congenital hypothyroidism is vital to ensure their appropriate neuropsychological development. Identification through screening programs, with immediate institution of replacement therapy, leads to a normal IQ at 5 to 7 years of age.150,151,152,153 Aggressive early treatment with thyroid hormone may be beneficial (e.g., 8 to 10 mg T₄/kg body weight).

ETIOLOGY

The causes of congenital fetal and neonatal thyroid dysfunction are varied, ranging from thyroid dysgenesis to thyroid hormone resistance. The various causes of congenital hypothyroidism are outlined in Table 4. The most common cause of congenital fetal/neonatal thyroid dysfunction is primary hypothyroidism, estimated to occur in approximately 1 in 4000 births.154 Thyroid dysgenesis may be due to thyroid aplasia, hypoplasia, or ectopy. Of children with thyroid dysgenesis, approximately 40% have ectopic thyroid tissue, 40% have thyroid aplasia, and 20% have thyroid hypoplasia. 155Rare disorders of thyroid function include dyshormonogenesis, hereditary TSH deficiency, TSH receptor mutations, and thyroid hormone resistance. Recently, the presence of thyroid-growth-blocking antibodies has been reported in mothers who give birth to hypothyroid infants.156,157,158,159,160 However, seasonal variation in the incidence of congenital hypothyroidism suggests the possibility that environmental factors may play a role. It is important to consider potential fetal exposure to antithyroid drugs or other agents when evaluating neonatal hypothyroidism.

A reduction in maternal serum T₄ as a result of maternal iodine deficiency during early pregnancy compromises the development of the fetal nervous system and can lead to profound neurologic impairment (neurologic cretinism).161,162 Iodine deficiency in later pregnancy or infancy resulting in fetal or neonatal hypothyroidism exerts effects on somatic development (myxedematous cretinism). Neonatal thyroid screening programs have been instituted to ensure prompt detection and treatment of neonatal thyroid dysfunction.

Thyroid Dysgenesis

The cause of thyroid dysgenesis is unknown. The term "athyreotic cretinism" has been used, although it is important to note that some thyroid tissue is usually present.163 A variety of mechanisms are probably involved, including importantly single-gene mutations. Families have been identified with a mutation in the Pit-1 gene, a pituitary transcription factor that activates expression of TSH and growth hormone genes. Hypopituitarism results, associated with in utero TSH deficiency.164It has been postulated that autoimmune antibody thyrocytotoxic factors may be transferred across the placenta, resulting in destruction of the fetal thyroid. However, anti-TPO and anti-TG antibodies present in many women freely cross the placenta and appear to do no harm..165 Transplacental transfer of a thyrosuppressive factor has been observed in one family.166

Inborn Errors of Thyroid Function

Defects in thyroid hormone synthesis occur in approximately 1 child in 30,000. Usually these defects in thyroid hormone biosynthesis are inherited as autosomal recessive traits. Biochemical defects have been identified that correspond to each step in hormone biosynthesis, including defects in organification, iodide transport, thyroglobulin and deiodinase activity. These children may not have significant thyroid enlargement at birth, as maternal-fetal transfer of thyroid hormone can suppliy the fetus with sufficient concentrations of thyroid hormone to suppress goiter formation. Progressive, defective thyroid hormone synthesis ultimately results in goitrous cretinism, if left untreated.167 A family history of goitrous cretinism should alert the physician to this possibility in the neonate.

Drug-Induced Hypothyroidism

Numerous compounds have been identified that possess anti-thyroid activity, including thinoamides, amiodarone, lithium and potassium iodide. Maternal exposure to these compounds results in fetal exposure, and may adversely affect fetal thyroid function. The effects are usually transient. Neonatal thyroid screening program data suggests that transient hypothyroidism may occur in 1 in 10,000 births.

Children who have been exposed to PTU in utero may be born with a small goiter and transient hypothyroidism.168,169,170 Based on screening data, 1 infant in 100 exposed to PTU in utero may develop transient hypothyroidism. The hypothyroidism resolves postpartum, as exposure of the neonate to the antithyroid medication is eliminated.

Maternal iodide ingestion during pregnancy is an important cause of neonatal hypothyroidism and goiter. It is important to note that fetal goiter may develop with maternal ingestion of as little as 12 mg of iodide daily.171 Studies of neonatal response to therapy with iodides document sensitivity to relatively low doses of iodide therapy. Indeed, a recent case report of oral iodide therapy for neonatal hyperthyroidism secondary to maternal Graves' Disease demonstrated rapid normalization of neonatal thyroid indices using doses of 8mg of KI three times a day (total 24mg/day)172 One could extrapolate from this that administration of iodides to euthyroid fetuses/neonates might induce hypothyroidism. Radiopaque dyes used for radiology procedures, including amniography, contain large amounts of iodides, and may result in transient neonatal hypothyroidism.173

The antiarryhthmic drug amiodarone contains 75 mg of iodine in each 200-mg capsule. There have been case reports of women who have received the amiodarone throughout gestation. The majority of the resulting offspring have been euthyroid without goiter, but there are exceptions.174,175,176,177,178,179 The hypothyroidism is usually transient, but mental retardation has occurred. Maternal iodide ingestion may result in significant enlargement of the fetal thyroid, and the goiters may be large and obstructive.180 Large goiters may be detected in utero by ultrasonography. The presence of a large goiter makes maintenance of an adequate airway difficult. With extremely large goiters, surgery may be necessary. Treatment with intra-amniotic injection of thyroid hormone may also be of benefit in reducing the size of the goiter and restoring euthyroid status.181

Diagnosis

To ensure adequate treatment of neonatal hypothyroidism, and abrogation of the deleterious effects of the hypothyroid state, it is crucial that the diagnosis of hypothyroidism be made during the first weeks of life. Unfortunately, clinical features of hypothyroidism are uncommon at this point, and the diagnosis is rarely suspected on the basis of clinical presentation alone. Clinical features of neonatal hypothyroidism are variable and include: prolonged gestation with macrosomia, feeding and respiratory difficulties, protracted icterus, abdominal distention with vomiting, and constipation. In addition, delayed bone age, hypothermia, cyanosis, umbilical hernia, dry skin, and a large posterior fontanel,have been observed.182,183,184

Laboratory evaluation revealing a low serum T₄ (<6 mg/dl), associated with an elevated TSH (>80 mU/dl), is diagnostic of hypothyroidism. Neonatal screening may detect infants with borderline T₄ or borderline TSH. Radiographs for bone age estimation may be helpful, as hypothyroidism is associated with low osteoblastic activity. This is reflected in bone radiographs as delayed skeletal maturation. Specifically, a lack of ossification of the distal femoral epiphysis of the proximal tibial epiphysis suggests a history of in utero thyroid hormone deficiency.185

Epiphyseal dysgenesis has also been described, commonly affecting the proximal femoral epiphysis. Of note, any center of endochondral ossification may be affected.186 The ossification center originates as multiple small centers scattered throughout the epiphysis. These centers eventually coalesce to form a single center with an irregular shape and a stippled appearance.

Full assessment of neonates with borderline thyroid function should include a thyroid scan. Infants who have residual thyroid tissue, no signs or symptoms of hypothyroidism, normal serum T₃ concentration and normal bone age have an excellent prognosis for normal development. In contrast, infants lacking visible thyroid tissue, with low serum T₄ and T₃ concentrations, and with detectable signs of bone age retardation, have a more guarded prognosis for entirely normal development, even with early treatment.

It is important to distinguish cretinism from other syndromes, with which it may share common features. Both cretinism and Down syndrome are characterized by short stature and mental retardation. However, the child with Down syndrome is more active and has specific stigmata. Cretinism may also be confused with the Beckwith-Wiedemann syndrome, which includes umbilical hernia and macroglossia.187

MANAGEMENT OF CONGENITAL HYPOTHYROIDISM

The efficacy of thyroid hormone replacement therapy depends on the promptness of its institution. Numerous studies have documented minimization of mental retardation and neuropsychological delay with early neonatal treatment.188,189 There appears to be benefit to instituting therapy in utero, if the diagnosis of fetal hypothyroidism has been made.

In Utero Therapy

Because of the mounting evidence to suggest that in utero hypothyroidism is associated with irreversible central nervous system damage and developmental delay190 there has been interest in intrauterine treatment of fetal hypothyroidism. Although the intrauterine diagnosis of hypothyroidism is difficult,191,192 evaluation of cord blood via cordocentesis can help clarify the clinical situation. In addition, fetal ultrasonography is useful in identifying the presence of fetal goiter.

It has been estimated that third trimester fetal thyroxine requirements are in the range of 6mg/kg/day.193 Therapeutic interventions have been designed to take advantage of the fact that the fetus effectively absorbs T₄ from amniotic fluid. Numerous case reports document intra-amniotic injection of thyroxine for treatment of fetal hypothryroidism194,195,196 One early study utilized such therapy in a pregnant woman who had inadvertently received 150 mCi of ¹³¹I during weeks 10 to 11 of pregnancy.197 Because of the potential risks of fetal hypothyroidism, an amniocentesis was performed weekly from week 33 until delivery, with an injection of 500 mg of T₄ each week. The concentration of T₄ in the cord serum was in the hypothyroid range, and the TSH concentration was low. At birth, however, the infant was not hypothyroid.

A recent study of antenatal diagnosis and treatment of fetal goitrous hypothyroidism successfully employed intra-amniotic injections of thyroxine at a dose of 10 mg/kg/day every 7 days. Investigators documented improvement in the fetal goiter with intra-amniotic T₄ therapy.198 Current recommendations cite intra-amniotic administration of 250-500 ?g of L-thyroxine at 7-10 day intervals for the managment of fetal hypothyroidism.