Endocrinology and Metabolism

Published on 28/05/2015 by admin

Filed under Neonatal - Perinatal Medicine

Last modified 28/05/2015

Print this page

This article have been viewed 1760 times

Endocrinology and Metabolism

Marisa Censani, MD, Mary Pat Gallagher, MD, Wendy K. Chung, MD, PhD and Sharon E. Oberfield, MD

Hypocalcemia

1. What perinatal factors are associated with hypocalcemia in the immediate newborn period?

Maternal diabetes

Maternal hyperparathyroidism

Transient congenital hypoparathyroidism

Congenital absence or hypoplasia of the parathyroid glands (sporadic or as part of DiGeorge syndrome)

2. How are calcium levels expected to change in premature infants during the first few days of life?

In newborn infants there is a physiologic decline in serum total and ionized calcium during the first 48 hours of life. This decline is exaggerated in preterm infants compared with term infants, with a direct correlation between serum calcium and gestational age ( Fig. 8-1). Because no symptoms are specific for early hypocalcemia in preterm infants, the diagnosis is made by demonstrating a serum calcium level below 7 mg/dL (1.75 mmol/L).

Figure 8-1 Serum calcium in relation to gestational age at 24 hours of age. (From Tsang RC, Light IJ, Sutherland JM, et al. Possible pathogenetic factors in neonatal hypocalcemia of prematurity. J Pediatr 1973;82:423–9.)

3. Is treatment of hypocalcemia necessary in premature infants?

Calcium therapy may block the normal physiologic adaptation to hypocalcemia, which includes increasing serum levels of parathyroid hormone (PTH) and 1,25(OH)₂ vitamin D in the first few days of life.

Further arguments against the need for the treatment of incidentally noted hypocalcemia in the preterm infant are the following:

Hypocalcemia of prematurity is usually asymptomatic.

It resolves spontaneously.

Long-term follow-up studies have shown no benefit with treatment.

Total serum calcium level is a poor predictor of ionized serum calcium in premature infants.

Intravenous (IV) calcium is associated with complications such as cardiac arrhythmias and ulcerations as a result of soft-tissue infiltration of the infusate. ^∗^†

4. When is treatment of hypocalcemia recommended in premature infants?

In the absence of additional data, it is conventional to treat all serum calcium levels below 6 mg/dL, even in asymptomatic neonates. The addition of 200 mg/kg/day of 10% calcium gluconate to standard IV solutions provides 20 mg/kg/day of elemental calcium. If symptoms are present (especially cardiac arrhythmia or seizures), a bolus of 100 mg/kg of 10% calcium gluconate (10 mg/kg elemental calcium) may be given intravenously over 10 minutes with careful cardiac monitoring. One should be cautious using a peripheral IV means to administer calcium because calcium can be very irritating to tissues.

KEY POINTS: HYPOCALCEMIA

1. Neonatal hypocalcemia is associated with prematurity, asphyxia, maternal diabetes, transient hypoparathyroidism, permanent congenital hypothyroidism, and (rarely) maternal hyperparathyroidism.

2. The most common reason for hypocalcemia in the newborn period is prematurity.

3. Breast milk rickets is seen in premature infants because of the relatively low mineral (e.g., calcium and phosphorus) content of breast milk.

4. Serum calcium levels are frequently elevated in patients with Williams syndrome.

5. Normal magnesium levels are needed for optimal functioning of the parathyroid glands.

5. How can the calcium requirements for premature infants be met by oral feedings?

Recent studies in premature infants using stable isotopes of calcium showed a true calcium absorption rate of 50% to 90%. Thus to meet an accretion rate of 100 mg/kg/day with an absorption rate of 75% and an assumed retention rate of 75% (which may be on the high side), oral intake of calcium for growing premature infants should be about 200 mg/kg/day. This large intake in infants with very low birth weight can be achieved only with special formulas for low-birth-weight infants or mineral fortifiers for breast milk–fed preterm infants. ^∗

6. How can the calcium requirements for premature infants be met by hyperalimentation solutions?

This problem is much more difficult to address, although intestinal absorption is not a factor. In the early weeks of life with fluid intakes of 150 mg/kg/day, it is difficult to exceed an IV calcium intake of 60 mg/kg/day in the smallest premature infants (weight <1000 g) with standard total parenteral nutrition (TPN) solutions. When the concentration of calcium exceeds 60 mg/dL (3 mEq/dL) in TPN solutions, precipitation with phosphate may occur, depending on variables such as temperature, pH, amino acid content, and even the method by which the nutrients are added to the solution.

7. What is the pathophysiology of “breast milk rickets” in premature infants?

Clinical rickets develops in preterm infants with very low birth weight who are fed human milk not fortified with minerals and vitamins. Typically, the disease presents after 8 weeks of life with severe hypophosphatemia, “relative hypercalcemia,” and hypercalciuria. The x-ray findings mimic those of rickets resulting from vitamin D deficiency. The biochemical findings are the result of low mineral intake. Because human milk is low in both calcium and phosphorus, the very low phosphorus intake (about 50% of calcium intake) severely limits deposition of calcium in bone.

Caution: Because treatment with phosphorus alone can result in severe hypocalcemia, supplements of both minerals are imperative.

8. What is the differential diagnosis of the etiology of a hypocalcemic seizure in a 14-day-old term infant?

Seizures secondary to hypocalcemia are very unlikely in a previously healthy term infant at 2 weeks of age. The differential diagnosis includes late infantile tetany associated with high phosphate load (e.g., feedings with cow milk), acid–base disturbances caused by diarrhea treated with alkali therapy, and congenital hypomagnesemia (rare).

9. What is the appropriate therapy for a hypocalcemic seizure in a 14-day-old term infant?

Treatment of hypocalcemic seizures is the same for both premature and term infants. In general, 10% calcium gluconate containing 9.4 mg/mL of elemental calcium is the drug of choice. The usual dose of 2 mL/kg body weight (18 mg/kg of elemental calcium). Infusion should occur slowly over the course of 10 minutes with heart rate monitoring. Make sure the line is patent before infusing calcium.

Hypercalcemia

10. How many fractions of calcium are found in the serum? Which can be measured in the clinical laboratory?

There are three fractions of calcium in serum: ionized calcium (50%), calcium bound to serum proteins (40%), and calcium complexed to serum anions (10%). Ionized calcium and total calcium can be measured in most hospital laboratories.

11. What are the normal serum calcium values in term infants?

Normal values (in milligrams per deciliter, expressed as mean± standard deviation and range) depend on chronologic age and laboratory variation (to a lesser degree):

Cord: 10.2 +/− 0.6 (9.3–11.7)

2 hours: 9.7 +/− 0.6 (8.8–11.3)

24 hours: 9 +/−0.6 (7.8–10) ^∗

12. What are the normal serum values in preterm infants?

Normal values (in milligrams per deciliter, expressed as mean ± standard deviation and range) depend on gestational age:

23–27 weeks: 10.0 +/−1.0 (8.1–11.9)

28–31 weeks: 10.2 +/−1.2 (8–12.5)

32–34 weeks: 10.5 +/−1 (8.6–12.4)

35–36 weeks:10.4 +/−1.1 (8.3–12.5)

>36 weeks: 10.9 +/−0.5 (9.8–11.9) ^∗

13. List the manifestations of hypercalcemia in neonates.

Failure to thrive

14. What values “define” hypercalcemia in newborn infants?

Total serum calcium above 10.8 mg/dL or ionized serum calcium above 5.4 mg/dL.

15. What are some of the causes of hypercalcemia in neonates?

Iatrogenic hypercalcemia

Subcutaneous fat necrosis

Idiopathic infantile hypercalcemia

Williams syndrome

Hyperparathyroidism (primary and secondary)

PTH-related peptide tumor

Hyperprostaglandin E syndrome

Hypophosphatasia

Familial hypercalciuric hypercalcemia

Blue diaper syndrome

Vitamin A intoxication

Chronic thiazide toxicity

Excessive maternal intake of vitamin D

16. How is acute hypercalcemia managed in newborn infants?

Promote diuresis by administering IV fluids (normal saline).

Administer furosemide, and monitor serum electrolytes carefully only after adequate hydration is given.

Hydrocortisone (1 mg/kg every 6 hours) is of value only in chronic situations to reduce intestinal absorption of calcium.

In severe cases dialysis may be required to lower calcium levels while the patient is awaiting definitive treatment of the underlying cause. ^∗

17. A 3-day-old infant born small for gestational age at term has a total serum calcium level of 13.2 mg/dL. She was delivered by emergency cesarean section and was diagnosed with supravalvular aortic stenosis. What is the likely diagnosis?

Williams syndrome is the likely diagnosis in an infant with hypercalcemia and supravalvular stenosis who was born small for gestational age. It results from a deletion of the elastin gene on 7q11.23. Affected infants are often described as having “elfin” faces. ^∗

18. A term infant is incidentally noted to have a calcium level of 12.2 mg/dL at 4 days of age. Family history reveals that the father has also been evaluated for elevated calcium levels. What would you expect to find on measurement of the infant’s urinary calcium level? What is the most likely diagnosis? What is the appropriate therapy?

The most likely diagnosis is an autosomal dominant mutation of the calcium-sensing receptor, or “hypocalciuric hypercalcemia.” The infant’s urinary calcium level will be inappropriately low for the serum calcium. In the heterozygous state this is generally thought to be a benign condition, and treatment is not indicated. Rare cases of homozygous mutations result in severe neonatal hyperparathyroidism, which is a life-threatening disorder. ^∗

19. Why is the diaper blue in blue diaper syndrome?

A defect in the intestinal transport of tryptophan causes excretion of blue, water-insoluble tryptophan metabolites. The reason that these children have high calcium levels is not well understood.

Hypomagnesemia and Hypermagnesemia

20. How are millimoles (mmol) of magnesium converted to milliequivalents (mEq) and milligrams (mg)?

21. What two types of magnesium reactions are important in human physiology?

Intracellular and extracellular types of magnesium reactions are important.

22. What is the role of magnesium in intracellular reactions?

Magnesium is the second most abundant intracellular cation after potassium and helps to regulate cellular metabolism. As part of the magnesium-adenosine triphosphate complex, it is essential for all biosynthetic processes, including glycolysis, formation of cyclic adenosine monophosphate, and transmission of the genetic code. In addition, any reaction that uses or produces energy requires magnesium.

23. What are the extracellular reactions that involve magnesium?

Only 1% of magnesium is contained in extracellular fluid. However, extracellular concentrations are critical for maintenance of electric potentials of nerve and muscle membranes and for the transmission of impulses across the neuromuscular junction. Magnesium and calcium may act synergistically or antagonistically in many of these processes.

24. What causes magnesium depletion in neonates?

Maternal diabetes

Maternal magnesium deficiency

Renal losses of magnesium in acidotic states

Use of nutrient solutions containing insufficient amounts of magnesium

Renal tubular defects

Intestinal wasting of magnesium (rare X-linked condition)

Gastrointestinal losses (through emesis, nasogastric suctioning, and diarrhea)

Prematurity, which increases the risk for magnesium deficiency

Intrauterine growth retardation ^∗

25. What are the signs and symptoms of magnesium deficiency in neonates?

Most infants are asymptomatic. On rare occasions the following signs and symptoms may be seen:

Color: pallor, cyanosis, or duskiness

Affect: out of touch with surroundings, apathetic, irritable when disturbed, restless

Eyes: staring with infrequent blinking, oculogyric crises

Heart: tachycardia (bradycardia during apneic episodes)

Respiration: brief apnea, sometimes followed by tachypnea

Neuromuscular system: motor weakness, transient spasticity, abnormal reflexes; if hypocalcemia develops (discussed later), the infant may show signs associated with calcium deficiency, including seizures

26. What are the effects of hypomagnesemia on calcium homeostasis?

Hypomagnesemia usually increases the secretion of PTH, thereby increasing calcium levels. In chronic magnesium-deficient states, however, secretion of PTH is reduced. In such circumstances hypomagnesemia may induce hypocalcemia. ^∗

27. What causes hypermagnesemia in neonates?

Maternal treatment with magnesium (for preeclampsia or tocolysis)

Excessive magnesium administration to neonate (e.g., TPN, antacids, treatment of pulmonary hypertension)

28. How should hypomagnesemia be treated parenterally?

Hypomagnesemia usually is treated intravenously or intramuscularly with a 50% solution of magnesium sulfate.

One milliliter of a 50% solution contains 4 mEq of elemental magnesium. The usual dose is 0.1 to 0.25 mL/kg/day.

Serum magnesium levels should be monitored every 12 hours.

29. What are the signs of hypermagnesemia in neonates?

Unresponsiveness

Respiratory insufficiency

Apnea (especially when aminoglycoside antibiotics are used concurrently)

Delayed passage of meconium

In extreme cases cardiorespiratory function ceases, and death ensues.

30. How is hypermagnesemia treated?

Stop the administration of magnesium.

Make sure the infant is well hydrated.

Consider diuretic therapy.

In severe cases exchange transfusion (with acid-citrate-dextrose solution) is effective.

The effects of calcium salts are equivocal.

Thyroid Disorders

31. What is the incidence of congenital hypothyroidism?

Congenital hypothyroidism occurs in 1 in 4000 liveborn infants.

32. What are the embryonic stages of development of the fetal hypothalamic–pituitary–thyroid axis?

Thyroid tissue is first identified at the base of the tongue 16 to 17 days after conception.

By 7 weeks’ gestation the gland has migrated to its final position in the anterior neck and has developed its characteristic bilobed structure.

By 10 weeks’ gestation the fetal thyroid gland is trapping iodine and synthesizing thyroxine (T₄).

By 10 weeks’ gestation, the fetal hypothalamus is synthesizing thyrotropin-releasing hormone (TRH). Most fetal TRH, however, is made in extrahypothalamic tissues (e.g., placenta, pancreas). Hypothalamic TRH production does not mature fully until the perinatal period.

By 10 to 12 weeks’ gestation, the fetal pituitary gland is synthesizing thyroid-stimulating hormone (TSH). ^∗

33. When does the fetal hypothalamic–pituitary–thyroid axis begin to function?

The hypothalamic–pituitary–thyroid axis is in place by the end of the first trimester. The thyroid and pituitary glands reach mature secretory capacity by 30 to 35 weeks of gestation. The feedback interrelationship among the units is fully established when hypothalamic TRH maturation is completed by 1 to 2 months after birth. ^∗

34. Describe the pattern of secretion of T₄ during gestation.

The amount of T₄ secreted by the fetal thyroid gland increases slowly until midgestation (20 to 24 weeks) when, stimulated by increasing amounts of TSH from the fetal pituitary, T₄ levels begin to increase more rapidly, reaching a normal adult level by approximately 30 weeks’ gestation. Thereafter T₄ increases slowly to high normal levels at term gestation. ^∗

35. Describe the pattern of TSH secretion during gestation.

The amount of circulating TSH begins to increase in midgestation (20 weeks) and reaches a peak level of approximately 15 μU/mL by 30 weeks’ gestation. The TSH level then declines gradually to about 10 μU/mL at term.

36. Do maternal TSH and maternal iodine cross the placenta?

Maternal TSH does not cross the placenta, but maternal iodine crosses the placenta freely and is essential for the synthesis of thyroid hormones by the fetus.

37. Do maternal T₃ and T₄ levels have any effect on the fetus?

The placenta is a barrier to the passages of thyroid hormones and contains enzymes that break down maternal T₄ and T₃ into inactive metabolites. Only a small percentage of circulating maternal T₄ and very little (if any) T₃ reaches the fetus. However, the amount of maternal T₄ that does cross the placenta is significant. During the first 10 to 12 weeks of gestation, all of the circulating T₄ in the fetus is from maternal sources; thus early brain development depends on maternal hormone. Even after the fetus synthesizes its own T₄ in the second and third trimesters, maternal T₄ is essential for normal neurologic development, including neuronal proliferation and maturation, dendritic arborization, and synapse formation. It accounts for approximately 30% of fetal T₄ levels at term. ^∗^†

38. What happens to TSH levels at parturition?

Within 15 to 20 minutes after birth, the fetal pituitary releases a surge of TSH, probably in response to cooling. TSH reaches a peak of about 80 μU/mL in approximately 30 minutes, decreases rapidly over the first 24 hours of life, and then drops more gradually to levels comparable to normal adult levels by the end of the first 1 to 2 weeks of life.

39. How does the TSH surge affect T₄ levels?

Serum T₄ levels increase rapidly, reaching a peak level of about 17 μg/dL at 24 hours. T₄ then gradually decreases to levels at the upper limit of normal adult values over the first 4 to 5 weeks of life. Free T₄ levels follow the same pattern, reaching a peak of 3.5 ng/dL at 24 to 36 hours.

40. How do levels of thyroid hormone differ in premature and term infants?

The levels of TRH, TSH, T4, free T₄, and T₃ are lower in premature infants than in term infants, and the postnatal surges of TSH and T₄, although qualitatively similar, are blunted. These differences are related directly to gestational age: the lower the gestational age, the lower the levels and responses of thyroid-related hormones ( Table 8-1).

TABLE 8-1

SERUM THYROXINE (µg/dL) AT DIFFERENT GESTATIONAL AGES ^∗

^∗Mean (standard deviation).

Adapted from Cuestas RA. Thyroid function in healthy premature infants. J Pediatr 1978;92:963–7.

41. What is hypothyroxinemia of prematurity?

The term refers to infants with low birth weight (30 to 35 weeks’ gestation) or very low birth weight (<30 weeks’ gestation), who have an even more attenuated rise in T₄, after which T₄ levels drop below cord levels in the first week of life. Then they rise gradually over 3 to 6 weeks to approach levels of term infants ( Table 8-2).

TABLE 8-2

THYROID FUNCTION IN PRETERM AND TERM INFANTS ^∗

T₄, Thyroxine; T₃, triiodothyronine; TSH, thyroid-stimulating hormone; free T₄, free thyroxine.

^∗Mean (standard deviation).

http://www.uptodate.com/contents/image?imageKey=PEDS%2F72215&topicKey=PEDS%2F5840&rank=4~150&source=see_link&search=thyroid+function&utdPopup=true

Adapted from Williams FL, Simpson J, Delahunty C, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab 2004;89:5314.

42. Should hypothyroxinemia of prematurity be treated?

The premature infant with low T₄ and persistently elevated TSH has either transient or permanent hypothyroidism and should be treated with T₄ until the nature of the condition becomes clear. However, whether premature infants with low T₄ and normal TSH levels should be treated remains controversial. ^∗^†

43. Does breastfeeding provide needed T₄ to premature infants with an immature hypothalamic–pituitary–thyroid axis?

This question has not yet been answered. There are some case reports in the literature suggesting that breastfeeding delays the onset of hypothyroidism, but others argue against that finding.

44. Why do we screen for congenital hypothyroidism?

Signs and symptoms of hypothyroidism are subtle at birth, and the characteristic appearance of cretinism may not be apparent for 3 to 4 months. The brain requires thyroid hormone for normal development until approximately 2 to 3 years of age, and deficiency of thyroid hormone during this period causes irreversible brain damage to an extent related directly to the length of time of the hypothyroidism. Thus it is of vital importance to identify a hypothyroid infant as quickly as possible, even before clinical signs appear.

45. When and how is thyroid screening done?

A heel-stick blood sample is taken at discharge or 3 days of life, whichever is earlier. In most parts of the United States, T₄ is measured first, then TSH is measured in samples with the lowest 10% to 29% of T₄ results. ^∗^†

46. What are the causes of congenital hypothyroidism and the incidence of each type?

TABLE 8-3

CAUSES OF CONGENITAL HYPOTHYROIDISM AND INCIDENCE OF EACH

From Fisher FA. Disorders of the thyroid in the newborn and infant. In: Sperling MA, editor. Pediatric endocrinology. Philadelphia: Saunders; 1996. p. 57.

47. How does maternal Graves disease affect the fetus and neonate?

The thyroid-stimulating immunoglobulins (TSIs) cross the placenta and may cause fetal thyrotoxicosis, resulting in goiter, tachycardia, rapid skeletal maturation, premature birth, and congestive heart failure. Long-term neurologic deficits may result because excessive T₄ reduces neuronal proliferation.

Only approximately 1 in 70 neonates born to thyrotoxic mothers exhibit clinical thyrotoxicosis. Such infants may show a phase of transient hypothyroidism caused by antithyroid drugs (half-life, 2 to 3 days), then thyrotoxicosis resulting from maternal TSIs. Transient congenital hypothyroidism can result from transplacental transfer of maternal thyrotopin-blocking antibodies. ^∗

Buy Membership for Neonatal and Perinatal Medicine Category to continue reading. Learn more here

Related

Fetal _ Neonatal Secrets 3e