Thyroid Function in the Premature Newborn

In the preterm infant, the hypothalamic-pituitary-thyroid axis demonstrates decreased hypothalamic thyrotrophin-releasing hormone (TRH) production and secretion, a less robust response of the thyroid gland to TSH, reduced thyroid organification of iodine, and a reduction in the peripheral conversion of thyroxine (T4) to triiodothyronine (T3). Concentrations of T4 and free T4 are therefore lower in the cord serum of preterm compared with term infants, and these concentrations correlate with gestational age and birth weight. Thyroid-binding globulin (TBG) concentrations are low also; TSH and T3 concentrations are normal to low.

After birth both, the normal neonatal surge of TSH and the rise in T4, free T4, and T3 concentrations are attenuated in the preterm infant. In infants born at 30 to 37 weeks gestation, T4 and free T4 concentrations have been shown to increase after birth, peak between 12 and 72 hours, and then decline in a pattern similar to that of term infants. In these infants, T4 and free T4 concentrations remain lower than those of term infants and then increase over 4 to 8 weeks to concentrations comparable with those of term infants. Their TSH surge is similar to term infants in magnitude and timing (peak of approximately 70 μU/mL at 30 to 90 minutes). In contrast, in the most premature or VLBW infants (less than 30 to 31 weeks gestation or less than 1500 g) T4 and free T4 concentrations decline progressively in the first 1 to 2 weeks after birth, after which there is progressive recovery. Their TSH peak is significantly lower (approximately 8 μU/L) than that of full-term infants. Transient hypothyroxinemia is therefore the most prevalent thyroid disorder of premature and LBW infants.

Transient Hypothyroxinemia of Prematurity

Transient hypothyroxinemia is characterized by temporary low concentrations of T4 and free T4 with normal or low concentrations of TSH. It has been shown to occur with a frequency of 24% to 50% of premature and LBW/VLBW infants. There has been no consensus regarding the concentrations considered to be low, partly because it is unclear as to what constitutes normal thyroxine concentrations in preterm infants. Both absolute cut-off values and standard deviations below the mean have been used to define transient hypothyroxinemia.

The etiology of transient hypothyroxinemia is multifactorial and includes the loss of the maternal T4 transfer, a less responsive hypothalamic-pituitary-thyroid axis, low TBG concentrations, nonthyroidal illness, medications such as glucocorticoids and dopamine, which reduce pituitary secretion of TSH, and iodine deficiency and iodine exposure by means of antiseptics, drugs, and contrast media.

Almost all reports document an association between hypothyroxinemia in preterm infants and adverse outcome. Low thyroid hormone concentrations have been shown to be associated with increases in perinatal mortality and morbidities including intraventricular central nervous system hemorrhage and periventricular echolucencies, prolonged oxygen supplementation, and mechanical ventilation. In those infants who survive, an increased risk of neurodevelopmental complications, lower IQ, and cerebral palsy have been reported.

It is unclear, however, whether low thyroid hormone concentrations are causative of these acute and long-term complications or simply a reflection of severe illness in premature infants. Consequently, numerous studies have been done with thyroid supplementation in preterm infants to determine whether treatment results in improvement in clinical outcome. Most of these studies showed that thyroxine supplementation did not improve complications, mortality, or neurodevelopmental outcomes.

A Cochrane review published in 2000 summarized four randomized or quasi-randomized controlled trials. ² Chowdrey and colleagues found no significant difference between preterm infants at 25 to 28 weeks gestation who received thyroxine treatment compared with placebo in terms of weight gain, linear growth, and head circumference at 10 months of age or psychomotor development at 12 and 24 months and found no difference in mortality. Vanhole and colleagues, in a double-blind placebo controlled study in infants between 25 and 30 weeks gestation, found no effect on respiratory complications, intraventricular hemorrhage, growth, retinopathy of prematurity, and mortality between those receiving thyroxine treatment compared with placebo. Amato and colleagues, in a study of infants less than 32 weeks gestation requiring more than 40% supplemental oxygen, found no significant difference in mortality and long-term respiratory complications between those receiving thyroxine and those who did not receive treatment. A double-blind, placebo-controlled study by Van Wassenaer and colleagues of thyroxine supplementation in infants of 25 to 29 weeks gestation demonstrated no significant difference in respiratory disease, intraventricular hemorrhage, periventricular hemorrhage, or mortality. It also showed no significant difference in neurodevelopmental outcomes at 6, 12, and 24 months of age. Additional analysis by gestational age revealed a significant difference in the Bayley mental development index at 24 months in the thyroxine-treated infants of 25 to 26 weeks gestation at birth compared with placebo. A significantly lower mental development index, however, was shown in those infants treated with thyroxine compared with placebo in infants born at 27 to 29 weeks gestation. This raised the concern that thyroxine supplementation may be detrimental to preterm infants older than 26 weeks gestation. In a Cochrane review of studies up to 2001, a meta-analysis of five studies found no significant difference in mortality in infants given thyroid hormone supplementation compared with controls. Another meta-analysis of two studies showed no significant difference in the incidence of cerebral palsy or the Bayley Mental Psychomotor Development indices.

There is insufficient evidence to determine whether thyroxine supplementation in preterm infants who have transient hypothyroxinemia results in reductions in morbidity, mortality, or neurodevelopmental impairments.

Nonthyroidal Illness (Sick Euthyroid Syndrome)

Preterm infants have an increased susceptibility to morbidities, including birth trauma, hypoxemia, acidosis, infection, hypoglycemia, and hypocalcemia. These conditions, in addition to overall relative malnutrition, inhibit peripheral conversion of T4 to T3. Hence, a low concentration of T3, which is characteristic of preterm infants, is aggravated. Serum T3 concentrations may remain low for 1 to 2 months after birth. In addition to low T3 concentrations, these infants tend to have a variable but usually elevated reverse T3 concentration, normal or low total T4 concentration, and a free T4 concentration that is usually in the normal range for healthy preterm infants of matched weight and gestational age. Their TSH concentrations are low. Treatment of these thyroid abnormalities caused by nonthyroidal illness is not beneficial and therefore not recommended.

Primary Hypothyroidism

Primary hypothyroidism, characterized by low T4 and elevated TSH concentrations, occurs more commonly in preterm, VLBW, and ill infants than in term infants, and it is often transient. Etiologies of primary hypothyroidism in this population of infants include iodine deficiency, increased susceptibility to the thyroid-suppressive effects of iodine in topical antiseptics, and recovery from sick euthyroid syndrome. Some infants have a delayed rise in the TSH concentration that is not detected until days to weeks after birth following initial newborn screens with normal TSH concentrations. In addition to the etiologies already mentioned, other causes of this late rise of TSH include developmental delay in the maturation of the hypothalamic-pituitary-thyroid axis and exposure to medications frequently used in premature and ill newborns that can suppress initial TSH concentrations (eg, dopamine and glucocorticoids). Studies of newborn screening databases have shown that this delayed rise of TSH occurs more frequently in VLBW infants. In a retrospective study of infants in the NICU at the authors’ institution, the authors determined the frequency of late rise of TSH to be 1.4% Most of these infants were premature, and many had evidence of significant iodine exposure. In more than half of these infants, the elevation in TSH concentration persisted, continued to rise, or was severe enough to require treatment with thyroxine replacement.

Primary hypothyroidism, especially when detected as a delayed rise of TSH, is likely transient; in these infants, the long-term effects are not known but may include adverse developmental outcomes. Therefore, many investigators recommend retesting of VLBW infants and those in the NICU between 2 and 6 weeks of age to detect and treat this form of hypothyroidism in a timely manner.

Early Neonatal Hypocalcemia

Early hypocalcemia results from an exaggeration of the normal decline of serum calcium concentrations during the first 24 to 48 hours of life. After birth, as the infant is withdrawn from the maternal supply of calcium through the placenta, the serum calcium concentration falls. Parathormone (PTH) secretion is stimulated; however, the parathyroid gland’s response is slow, resulting in a physiologic nadir in serum calcium concentrations within the first 48 hours of life. In some newborns, total and ionized calcium concentrations decline more rapidly and to lower nadir values. This occurs most frequently in premature, small for gestational age, LBW, and asphyxiated infants, and in infants born to mothers with gestational or permanent diabetes mellitus. In a study by Tsang and Oh, 30% of LBW infants developed hypocalcemia at a mean age of 29 hours. The hypocalcemic infants were more ill and premature and had lower birth weights and lower calcium intake. Roberton and colleagues, in a study of ill LBW infants, showed that 39% developed hypocalcemia within 96 hours of life. In addition to low birth weight, other factors associated with early hypocalcemia were low calcium intake and longer exposure to high inspired oxygen concentrations, reflecting the severity of their illnesses.

In premature infants, early hypocalcemia has been attributed to an attenuated physiologic postnatal rise in PTH secretion, a relative resistance of the renal tubules to PTH, and prolonged elevation of calcitonin concentrations. In LBW infants hypocalcemia also may be caused by the rapid skeletal accretion of calcium and relative resistance of the intestinal tract and bone to calcitriol. Asphyxiated and perinatally stressed newborns often have a reduced calcium intake, an increased phosphate load caused by cellular injury, and elevated calcitonin resulting in hypocalcemia.

The frequency of hypocalcemia in infants of mothers who have diabetes is approximately 50%. The etiology is multifactorial and hypothesized to be caused by significant maternal urinary excretion of calcium and magnesium, resulting in reduced placental transfer of calcium and magnesium, decreased neonatal secretion of PTH, elevated neonatal calcitonin, and deficient intake and impaired absorption of calcium by the infant.

Common treatments in the NICU have been associated with early hypocalcemia. Aminoglycoside antibiotics increase urinary excretion of calcium and magnesium. Compounds that complex with and sequester calcium, such as phosphates, citrate, and fatty acids, can lower ionized calcium concentrations. Ionized calcium also can be reduced in infants given bicarbonate, which increases calcium binding to albumin.

Late Neonatal Hypocalcemia

Hypocalcemia also can occur in infants in the NICU after 3 days of age. One of the most frequent causes is excessive intake of phosphate, usually through the diet. Other etiologies include chronic renal insufficiency caused by renal hypoplasia or obstructive nephropathies, hypomagnesemia, and vitamin D deficiency associated with maternal vitamin D insufficiency.

Hypoparathyroidism in infancy usually is caused by delayed maturation of parathyroid gland function. It also may be caused by parathyroid gland dysembryogenesis, however. The most common forms of dysgenesis are the DiGeorge and velocardiofacial syndromes, in which there is maldevelopment of the third and fourth branchial pouches. These syndromes usually are associated with microdeletions of chromosome 22q11.2. The clinical phenotype and severity of infants who have this chromosomal anomaly are variable. They often have characteristic facial and aortocardiac anomalies. Infants who have classic DiGeorge syndrome have the triad of hypocalcemia caused by parathyroid gland hypoplasia, defective T-lymphocyte function and impaired cell-mediated immunity caused by impaired thymic differentiation, and conotruncal defects of the heart or aortic arch. Syndromes associated with 22q11.2 deletions have been grouped as the CATCH-22 syndromes (cardiac anomalies, abnormal facies, thymic hypoplasia or aplasia, cleft palate, and hypocalcemia with deletion at 22q). Some infants who have deletions of 22q11.2 may have neonatal hypoparathyroidism as the only manifestation. Hypoparathyroidism may be permanent but is often transient, with resolution during infancy and possible recurrence during times of stress or severe illness.

Evaluation and Management of Neonatal Hypocalcemia

In infants who have persistent or recurrent hypocalcemia, the following should be obtained before initiating treatment: serum total and ionized calcium, magnesium, phosphate, creatinine, calcidiol, calcitriol, intact PTH, and spot urinary calcium and creatinine concentrations. Decreased PTH concentrations are common in early hypocalcemia, but persistently low concentrations suggest impaired PTH secretion. Elevated PTH concentrations occur in infants who have PTH resistance, renal insufficiency, or vitamin D deficiency. Low calcidiol concentrations usually occur in vitamin D deficiency associated with maternal vitamin D insufficiency. Low calcitriol concentrations can be caused by severe renal insufficiency, hypoparathyroidism, or 1 alpha hydroxylase deficiency. Elevated calcitriol implies vitamin D resistance. Serum total and ionized calcium, phosphate, and intact PTH should be measured in mothers of infants who have unexplained hypocalcemia. In infants who have suspected DiGeorge syndrome, evaluation should include a complete blood cell count and T (CD4) lymphocyte counts. A chest radiogram may be useful to look for a thymic shadow. The diagnosis is confirmed by a microdeletion of chromosome 22q11.2 by fluorescent in situ hybridization (FISH).

Treatment of newborns who have acute or symptomatic hypocalcemia is accomplished best by the intravenous infusion of calcium salts; 10% calcium gluconate (9.3 mg/mL of elemental calcium) is used most commonly. In asymptomatic newborns, treatment generally is indicated when the total serum calcium concentration is less than 6 mg/dL in the preterm infant and less than 7 mg/dL in the term infant. Calcium supplementation can be given either by the intravenous or oral route, depending on the clinical status of the infant. Effective oral therapy involves adding calcium glubionate or calcium carbonate to a low phosphate formula such as Similac PM 60/40 (calcium to phosphate ratio of 1.6:1) to establish an overall ratio of calcium to phosphate intake of 4:1. Additional therapy depends on the cause of hypocalcemia. Infants who have hypoparathyroidism require calcitriol in addition to calcium supplementation to restore and maintain eucalcemia. Infants who have vitamin D deficiency will benefit from vitamin D supplementation. If magnesium concentrations are low, treatment with intravenous or intramuscular magnesium sulfate is essential for correction of the hypocalcemia.

Early Neonatal Hypocalcemia

Early hypocalcemia results from an exaggeration of the normal decline of serum calcium concentrations during the first 24 to 48 hours of life. After birth, as the infant is withdrawn from the maternal supply of calcium through the placenta, the serum calcium concentration falls. Parathormone (PTH) secretion is stimulated; however, the parathyroid gland’s response is slow, resulting in a physiologic nadir in serum calcium concentrations within the first 48 hours of life. In some newborns, total and ionized calcium concentrations decline more rapidly and to lower nadir values. This occurs most frequently in premature, small for gestational age, LBW, and asphyxiated infants, and in infants born to mothers with gestational or permanent diabetes mellitus. In a study by Tsang and Oh, 30% of LBW infants developed hypocalcemia at a mean age of 29 hours. The hypocalcemic infants were more ill and premature and had lower birth weights and lower calcium intake. Roberton and colleagues, in a study of ill LBW infants, showed that 39% developed hypocalcemia within 96 hours of life. In addition to low birth weight, other factors associated with early hypocalcemia were low calcium intake and longer exposure to high inspired oxygen concentrations, reflecting the severity of their illnesses.

In premature infants, early hypocalcemia has been attributed to an attenuated physiologic postnatal rise in PTH secretion, a relative resistance of the renal tubules to PTH, and prolonged elevation of calcitonin concentrations. In LBW infants hypocalcemia also may be caused by the rapid skeletal accretion of calcium and relative resistance of the intestinal tract and bone to calcitriol. Asphyxiated and perinatally stressed newborns often have a reduced calcium intake, an increased phosphate load caused by cellular injury, and elevated calcitonin resulting in hypocalcemia.

The frequency of hypocalcemia in infants of mothers who have diabetes is approximately 50%. The etiology is multifactorial and hypothesized to be caused by significant maternal urinary excretion of calcium and magnesium, resulting in reduced placental transfer of calcium and magnesium, decreased neonatal secretion of PTH, elevated neonatal calcitonin, and deficient intake and impaired absorption of calcium by the infant.

Common treatments in the NICU have been associated with early hypocalcemia. Aminoglycoside antibiotics increase urinary excretion of calcium and magnesium. Compounds that complex with and sequester calcium, such as phosphates, citrate, and fatty acids, can lower ionized calcium concentrations. Ionized calcium also can be reduced in infants given bicarbonate, which increases calcium binding to albumin.

Late Neonatal Hypocalcemia

Hypocalcemia also can occur in infants in the NICU after 3 days of age. One of the most frequent causes is excessive intake of phosphate, usually through the diet. Other etiologies include chronic renal insufficiency caused by renal hypoplasia or obstructive nephropathies, hypomagnesemia, and vitamin D deficiency associated with maternal vitamin D insufficiency.

Hypoparathyroidism in infancy usually is caused by delayed maturation of parathyroid gland function. It also may be caused by parathyroid gland dysembryogenesis, however. The most common forms of dysgenesis are the DiGeorge and velocardiofacial syndromes, in which there is maldevelopment of the third and fourth branchial pouches. These syndromes usually are associated with microdeletions of chromosome 22q11.2. The clinical phenotype and severity of infants who have this chromosomal anomaly are variable. They often have characteristic facial and aortocardiac anomalies. Infants who have classic DiGeorge syndrome have the triad of hypocalcemia caused by parathyroid gland hypoplasia, defective T-lymphocyte function and impaired cell-mediated immunity caused by impaired thymic differentiation, and conotruncal defects of the heart or aortic arch. Syndromes associated with 22q11.2 deletions have been grouped as the CATCH-22 syndromes (cardiac anomalies, abnormal facies, thymic hypoplasia or aplasia, cleft palate, and hypocalcemia with deletion at 22q). Some infants who have deletions of 22q11.2 may have neonatal hypoparathyroidism as the only manifestation. Hypoparathyroidism may be permanent but is often transient, with resolution during infancy and possible recurrence during times of stress or severe illness.

Evaluation and Management of Neonatal Hypocalcemia

In infants who have persistent or recurrent hypocalcemia, the following should be obtained before initiating treatment: serum total and ionized calcium, magnesium, phosphate, creatinine, calcidiol, calcitriol, intact PTH, and spot urinary calcium and creatinine concentrations. Decreased PTH concentrations are common in early hypocalcemia, but persistently low concentrations suggest impaired PTH secretion. Elevated PTH concentrations occur in infants who have PTH resistance, renal insufficiency, or vitamin D deficiency. Low calcidiol concentrations usually occur in vitamin D deficiency associated with maternal vitamin D insufficiency. Low calcitriol concentrations can be caused by severe renal insufficiency, hypoparathyroidism, or 1 alpha hydroxylase deficiency. Elevated calcitriol implies vitamin D resistance. Serum total and ionized calcium, phosphate, and intact PTH should be measured in mothers of infants who have unexplained hypocalcemia. In infants who have suspected DiGeorge syndrome, evaluation should include a complete blood cell count and T (CD4) lymphocyte counts. A chest radiogram may be useful to look for a thymic shadow. The diagnosis is confirmed by a microdeletion of chromosome 22q11.2 by fluorescent in situ hybridization (FISH).

Treatment of newborns who have acute or symptomatic hypocalcemia is accomplished best by the intravenous infusion of calcium salts; 10% calcium gluconate (9.3 mg/mL of elemental calcium) is used most commonly. In asymptomatic newborns, treatment generally is indicated when the total serum calcium concentration is less than 6 mg/dL in the preterm infant and less than 7 mg/dL in the term infant. Calcium supplementation can be given either by the intravenous or oral route, depending on the clinical status of the infant. Effective oral therapy involves adding calcium glubionate or calcium carbonate to a low phosphate formula such as Similac PM 60/40 (calcium to phosphate ratio of 1.6:1) to establish an overall ratio of calcium to phosphate intake of 4:1. Additional therapy depends on the cause of hypocalcemia. Infants who have hypoparathyroidism require calcitriol in addition to calcium supplementation to restore and maintain eucalcemia. Infants who have vitamin D deficiency will benefit from vitamin D supplementation. If magnesium concentrations are low, treatment with intravenous or intramuscular magnesium sulfate is essential for correction of the hypocalcemia.