Disorders of Calcium and Phosphorus Metabolism

Key Points

Neonatal hypocalcemia may be asymptomatic or present with signs of increased neuromuscular excitability, including focal or generalized seizures.
Neonatal hypocalcemia is classified by the timing of onset, with early and late hypocalcemia having different causes and approaches to evaluation.
Neonatal hypercalcemia may be asymptomatic if there are only mild elevations in calcium level or may lead to severe symptoms such as failure to thrive, polyuria, lethargy, and seizures.
The causes of hypercalcemia can differ but are due to the dysregulation of calcium regulatory systems.
Metabolic bone disease of prematurity is caused by deficiencies in dietary phosphate and calcium, early withdrawal of placental estradiol and progesterone, lack of mobility, and therapy with medications that can increase urinary calcium excretion and contribute to serum mineral imbalance and osteopenia.
Osteopenia in preterm infants usually appears between 6 and 12 weeks of age, and fractures may be seen. The incidence and severity increase with decreasing gestational age and birthweight and are more common in preterm infants having a complicated medical course and delayed nutrition.

Homeostatic Control of Calcium and Magnesium

Calcium plays two important physiologic roles. Calcium salts in bone provide structural integrity. Calcium ions present in the cytosol and extracellular fluid (ECF) are essential for the maintenance and control of many biological processes, including cell-cell communication, cell aggregation and division, coagulation, neuromuscular excitability, membrane integrity, and permeability, enzyme activity, and secretion. This functional diversity is made possible by the maintenance of a large electrochemical gradient between the ECF ionized calcium (Ca ²⁺ ) concentration, which is in the 1-mmol/L range, and the resting intracellular (cytosolic) Ca ²⁺ concentration, which is about 0.1 μmol/L.

Significant alterations in serum calcium concentration frequently occur in the neonatal period. It is important to evaluate these potential derangements in light of normal dynamic changes that occur during the perinatal transition. After the first 2 to 3 days, normal total serum calcium concentrations vary only slightly with age and a range between 8.8 and 10.6 mg/dL (2.2 to 2.6 mmol/L), with an ionized serum calcium concentration of 4 to 5.6 mg/dL (1 to 1.4 mmol/L). The metric measurement unit conversion factors are 0.2595 and 0.2495, respectively, as used everywhere other than the United States.

Approximately 55% to 60% of the total plasma calcium is diffusible (or ultrafilterable), the remainder being protein bound. Most diffusible calcium is ionized, but about 5% of total circulating calcium is complexed to plasma anions, such as phosphates, citrate, and bicarbonate. Ca ²⁺ is the only biologically available fraction of ECF calcium. It is subject to precise metabolic control based on the integrated regulation of calcium fluxes with respect to the intestine, kidneys, and bone. The precise regulation of circulating Ca ²⁺ is controlled by calcium itself, through a calcium receptor and several hormones, the most important of which are parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH) ₂ D).

Hypoalbuminemia leads to a decline in total serum calcium, but proportionate increases in the ionized fraction usually maintain serum Ca ²⁺ concentration within the normal range. Acute alkalosis (e.g., hyperventilation or bicarbonate infusion) or rapid administration of citrate-buffered blood (e.g., during exchange transfusion, initiation of extracorporeal membrane oxygenation [ECMO], cardioplegia, or organ transplant) may acutely lower serum Ca ²⁺ concentration by increasing albumin binding or citrate chelation. These conditions can produce transient clinical manifestations of hypocalcemia but do not lower the total serum calcium concentration. In general, for routine clinical purposes, measurement of total serum calcium concentration often suffices, and the correction formula in the setting of hypoalbuminemia for total serum calcium concentration measured as mg/dL is:

\begin{matrix} Corrected Ca Level \\ = [0 .8 \times (Normal Albumin Level - Patient' s Albumin Level)] \\ + Serum Ca Level \end{matrix}

$\begin{matrix} Corrected Ca Level \\ = [0 .8 \times (Normal Albumin Level - Patient' s Albumin Level)] \\ + Serum Ca Level \end{matrix}$

Large amounts of calcium exchange occur in the kidney, bone, and intestine. Although the intestine has considerable calcium absorptive capacity, renal tubular calcium reabsorption usually exceeds intestinal absorption by at least 40-fold. Most of the tubular Ca ²⁺ load is reabsorbed in the proximal tubule and thick ascending limb of the loop of Henle via paracellular, passive flux (coupled with sodium reabsorption) driven by the existing electrochemical gradient. A transcellular pathway in the distal nephron tightly regulates the rest of urinary Ca ²⁺ reabsorption. Calcitropic hormones regulate the distal Ca ²⁺ -selective, Na ⁺ -independent channels. More than 98% of total body calcium is deposited in the skeleton as hydroxyapatite (Ca ₅ [OH][PO ₄ ] ₃ ); the ECF and soft tissues contain the remainder. A small fraction of skeletal calcium freely exchanges with the ECF and serves as an important buffer of circulating calcium. Consequently, decreased skeletal calcium is a hallmark of most metabolic bone diseases (MBDs).

Magnesium homeostasis is largely mediated through the kidneys. Approximately 80% of total plasma magnesium is filtered through the glomerulus and is reabsorbed mainly in cortical segments of the thick ascending limb of the loop of Henle. Once the maximal tubular reabsorption is exceeded, filtered magnesium is excreted into the urine. Hormones regulate magnesium reabsorption by changing the transepithelial voltage and paracellular permeability of tubular cells. Magnesium is required to maintain normal PTH secretory responses.

Homeostatic Control of Phosphorus

Blood inorganic phosphate concentration varies with age. It is highest during infancy and gradually declines to adulthood. Approximately 10% of plasma inorganic phosphate is noncovalently bound to protein, whereas 90% circulates as ions or as complexes with sodium, calcium, or magnesium. About 80% to 85% of total body phosphorus contributes to mechanical support as part of the hydroxyapatite lattice of bone. The remainder is distributed in the ECF, largely as inorganic ions or complexes, and in soft tissues as phosphate esters. Intracellular phosphate esters and phosphorylated intermediates regulate cell metabolism and gene expression (via phosphorylase, kinase, and phosphatase activities) and generate and transfer cellular energy (i.e., via adenosine triphosphate). Cytosolic and ECF phosphorus levels (approximately 0.1 and 0.2 mmol/L, equivalent to 0.31 and 0.62 mg/dL, respectively) are less stringently regulated than are levels of Ca ²⁺ and magnesium (Mg ²⁺ ).

Dietary phosphate is generally absorbed in proportion to its content in food. Although phosphorus and calcium can be absorbed along the entire length of the small intestine, most phosphate absorption occurs in the jejunum and ileum. In contrast, most calcium absorption occurs in the duodenum. The renal proximal tubule is the principal regulatory site for phosphorus homeostasis. Renal regulation is accomplished primarily by variation of the threshold for phosphate reabsorption (the tubular maximum for inorganic phosphate [TmP]/glomerular filtration rate [GFR]). Hormones (PTH, PTH-related protein [PTHrP], growth hormone) and dietary phosphate reset this theoretical threshold by regulating apical tubular Na ⁺ -TmP cotransporters. Essentially, TmP/GFR is the “setpoint” that defines the fasting serum phosphorus concentration. At lower serum phosphorus levels, most filtered phosphorus is reabsorbed; at higher levels, most filtered phosphorus is excreted. To assess TmP/GFR, a fasting urine specimen is obtained to measure phosphorus and creatinine, along with the simultaneous determination of serum phosphorus and creatinine. A nomogram has been constructed so that TmP/GFR can easily be derived from these values.

The higher serum phosphate levels in infants (e.g., 4.5 to 9.3 mg/dL) compared with those in adults (3.0 to 4.5 mg/dL) reflect infants' greater tubular phosphate resorption. This adaptation permits avid tubular phosphate conservation despite high ambient serum phosphate levels. For this reason, neonatal disorders of chronic hypophosphatemia and/or phosphorus depletion usually result from an inadequate dietary supply (as in preterm infants) or intrinsic (e.g., familial hypophosphatemic rickets) or extrinsic (e.g., hyperparathyroidism) alterations in TmP/GFR. Similarly, chronic hyperphosphatemia usually implies either intrinsic (e.g., renal insufficiency) or extrinsic (e.g., hypoparathyroidism) abnormalities in TmP/GFR.

Parathyroid-Renal Hormonal Axis

In mammals, calcium and phosphate homeostasis is controlled by a parathyroid-renal hormonal axis involving PTH and 1,25(OH) ₂ D. The influence of these two hormones on bone deposition, mobilization of minerals, and regulation of intestinal and renal absorption is depicted in Fig. 83.1 . Deficiency or excess of either hormone causes hypocalcemia or hypercalcemia, respectively.

Fig. 83.1, Hormonal Regulation of Calcium and Phosphate by Parathyroid Hormone (PTH) and 1,25-Dihydroxyvitamin D (1,25[OH] 2 D).

Parathyroid Hormones

PTH mobilizes calcium and phosphorus from bone, stimulates calcium reabsorption in kidneys, inhibits phosphorus reabsorption by reducing TmP/GFR, and stimulates the renal synthesis of 1,25(OH) ₂ D, which participates with PTH in calcium reabsorption in kidneys, increases the efficiency of intestinal absorption of calcium and phosphorus, and mobilizes calcium from bones. Therefore PTH secretion causes the serum calcium concentration to rise and the serum phosphorus concentration to be maintained or decline.

PTH is a 9500-Da, single-chain polypeptide. It is synthesized by the four parathyroid glands embedded within the thyroid gland poles, which are derived from the embryonic third and fourth pharyngeal pouches. The messenger ribonucleic acid (mRNA) for PTH (preproPTH) encodes the 84 amino acids of the mature peptide, an amino-terminal (N-terminal) “pre” sequence of 25 amino acids, and a basic “pro” hexapeptide, which is clipped intracellularly. After secretion, the intact PTH molecule, PTH (1 to 84), is further metabolized and rapidly cleared from the circulation, with a half-life of less than 4 minutes. The N-terminal region of the PTH molecule, PTH (1 to 34), binds the PTH receptor and shows full biological activity, whereas the carboxyl terminal (C terminal) has specific, albeit poorly understood, activities in osteoclasts and osteoclastic precursors.

Secretion of PTH fragments by the parathyroid glands and prolonged clearance of the C-terminal PTH metabolites add considerable immunoheterogeneity to circulating PTH. The numerous inconsistencies found in reports on PTH pathophysiology until the late 1980s are due to the use of earlier generation “C-terminal” and “midmolecule” PTH assays. In contrast, current two-site “intact PTH” assays are sufficiently sensitive and specific to detect physiologic levels of biologically active PTH (1 to 84) and to distinguish hypoparathyroid from euparathyroid states. The normal circulating levels of intact PTH range from approximately 10 to 60 picogram (pg)/mL; the maximally stimulated (hypocalcemic) and maximally suppressed (hypercalcemic) levels for normal parathyroid function are about 100 to 150 pg/mL and 2 to 5 pg/mL, respectively.

Parathyroid cells are exquisitely responsive to changes in ambient Ca ²⁺ concentration. PTH secretion may be described as an inverse sigmoid hysteretic relationship between serum PTH and Ca ²⁺ with a parathyroid cell setpoint (the Ca ²⁺ concentration at which PTH secretion is half maximal) of 1.2 to 1.25 mmol/L. The parathyroid “calcistat” detects perturbations of blood Ca ²⁺ concentration as small as 0.025 to 0.05 mmol/L and promptly adjusts PTH secretion. The molecular mechanism that enables specific cells (e.g., parathyroid cells, thyroidal C cells, renal tubular cells, osteoblasts) to sense these minute changes in ECF Ca ²⁺ concentration involves a member of the family C of G protein–coupled receptors, Ca ²⁺ -sensing receptor (CaSR). ECF Ca ²⁺ (and, at lower affinity, Mg ²⁺ ) binds the CaSR, activates several intracellular effector pathways, and ultimately leads to oppositely directed changes in PTH secretion, and altered renal cation handling CaSR activation inhibits renal cellular Ca ²⁺ absorption induced by PTH, as well as passive paracellular Ca ²⁺ transport. As described later, loss-of-function (or inactivating) mutations in the CaSR gene are responsible for neonatal hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH). In contrast, gain-of-function CaSR mutations result in autosomal dominant neonatal hypocalcemia.

PTHrP is a second member of the PTH family, first identified as the cause of humoral hypercalcemia of malignancy. The amino acid sequences of PTHrP and PTH are homologous at the N terminal, and 8 of the first 13 amino acids are identical. Beyond this region, the sequences have little in common. PTHrP is a multifunctional molecule, like neuropeptides such as proopiomelanocortin (the precursor of corticotropin, endorphins, and melanocyte-simulating hormones). The three PTHrP isoforms (139, 141, and 173 amino acids) give rise to several secreted peptide fragments. PTHrP is widely expressed, especially in fetal tissues, and has important local functions in morphogenesis and differentiation. The normal circulating levels of PTHrP are considerably lower than the levels of PTH, and it is doubtful that PTHrP has a major role in calcium homeostasis. Two important exceptions are in the fetus and the lactating woman, for whom PTHrP appears to be an important calcitropic hormone.

The actions of PTH on its two major target organs, kidney, and bone, are mediated through the type 1 PTH/PTHrP receptor (PTHR1), a G protein–coupled receptor belonging to a receptor subfamily that includes receptors for calcitonin, secretin, and corticotropin-releasing hormone. This versatile receptor mediates the actions of its two physiologic ligands in multiple tissues and signals through several second-messenger pathways. The best-characterized effector of PTH action is cyclic adenosine monophosphate (cAMP).

Vitamin D

A main biological function of 1,25(OH) ₂ D is to increase intestinal absorption of calcium and phosphorus. During low calcium intake, increased PTH levels stimulate the renal conversion of 25-hydroxyvitamin D (25[OH]D) to 1,25(OH) ₂ D, which in turn stimulates osteoclast differentiation and bone resorption. Most of the identified biological actions of 1,25(OH) ₂ D are mediated via binding to vitamin D receptor (VDR), a member of the intracellular receptor superfamily. VDR interacts with specific response elements in promoters of vitamin D–responsive genes.

Vitamin D is a secosteroid synthesized in the skin or absorbed from the diet. Exposure to sunlight (290 to 320 nm) cleaves the B ring of 7-dehydrocholesterol, or provitamin D, the immediate precursor of cholesterol, to form a sterol, previtamin D. Previtamin D in the skin undergoes isomerization to the biologically inert vitamin D. Vitamin D enters the circulation bound to vitamin D–binding protein and is transported to the liver, where a mitochondrial cytochrome P450 vitamin D 25-hydroxylase produces 25(OH)D. 25(OH)D (provitamin D) is the major circulating vitamin D metabolite. Because the activity of hepatic 25-hydroxylase is not tightly regulated, the measurement of serum 25(OH)D is a useful assessment of vitamin D stores. In renal proximal tubule cells, mitochondrial 25(OH)D 1α-hydroxylase metabolizes 25(OH)D to the biologically active hormone, 1,25(OH) ₂ D. The normal circulating level of 25(OH)D is approximately 10 to 50 ng/mL. The normal circulating concentration of 1,25(OH) ₂ D ranges from 30 to 75 pg/mL, or about 1/1000 that of 25(OH)D.

Serum 25(OH)D levels are increased by sunlight exposure and by vitamin D ingestion and are decreased in vitamin D deficiency and in hepatobiliary disorders. Circulating 1,25(OH) ₂ D levels are increased by hyperparathyroidism and phosphate depletion and are reduced in hypoparathyroidism. 1,25(OH) ₂ D is biologically inactivated through a series of reactions beginning with 24-hydroxylation. 1,25(OH) ₂ D induces the 24-hydroxylase in vitamin D target cells. Hypocalcemia, by increasing PTH levels, suppresses this enzyme. 24-Hydroxylase metabolizes 25(OH)D as well as 1,25(OH) ₂ D. In vitamin D–sufficient states, the kidney preferentially 24-hydroxylates the prohormone, 25(OH)D, to 24,25-dihydroxyvitamin D (24,25[OH] ₂ D). In contrast, when vitamin D action is required, 25(OH)D 1α-hydroxylase is preferentially activated for 1,25(OH) ₂ D synthesis.

The parathyroid-renal (PTH–1,25[OH] ₂ D) axis, reminiscent of the hypothalamic-pituitary-adrenal axis, is the principal means for systemic response to a sustained or major hypocalcemic challenge. In this long-loop feedback system, 1,25(OH) ₂ D-mediated calcium absorption provides the ultimate feedback on PTH secretion. PTH secreted in response to hypocalcemia is the principal regulator of renal production of 1,25(OH) ₂ D, which, in turn, feeds back to suppress PTH gene expression (see Fig. 83.1 ). Hypocalcemia directly stimulates PTH mRNA transcription. PTH regulates minute-to-minute perturbations of ECF Ca ²⁺ concentration. Maximal adjustments of intestinal calcium absorption via the PTH-1,25(OH) ₂ D axis require 1 to 2 days to become fully operative, so 1,25(OH) ₂ D effects come into play only when hypocalcemic stress persists.

Calcitonin

Calcitonin, a peptide hormone synthesized by thyroid parafollicular C cells (also known as clear cells ), has an antihypercalcemic effect (i.e., opposite that of PTH). Human calcitonin is a 32-amino-acid chain with a 1,7-disulfide bridge and a C-terminal prolinamide. Alternative splicing of several transcripts from the calcitonin gene produces several polypeptide products, some of which have uncertain calcitropic importance. The primary stimulus for calcitonin secretion is a rise in circulating calcium concentration. Calcitonin lowers serum calcium and phosphorus concentrations mainly by inhibiting bone resorption and increasing calcium excretion in the kidneys ( Table 83.1 ).

Table 83.1

Other Hormones

	Serum Calcium Concentration	Intestinal Calcium Absorption	Renal Calcium Excretion	Bone Effects
Glucocorticoids	Increase	Decrease	Increase
Growth hormone		Increase
Insulin-like growth factor 1				Protein synthesis in bone
Insulin				Bone loss
Thyroid hormone excess	Increase		Increase	Osteoporosis

Glucocorticoids lower serum calcium concentration by inhibiting osteoclast formation and activity but use for a long time causes osteoporosis by decreasing bone formation and increasing bone resorption. They also decrease intestinal absorption and increase renal excretion of calcium and phosphorus. Because of these mechanisms, glucocorticoids depress hypercalcemia in vitamin D intoxication and subcutaneous fat necrosis (SFN).

Growth hormone increases calcium excretion in the kidney and intestinal absorption. Insulin-like growth factor 1, generated by growth hormone action, stimulates protein synthesis in bone. Insulin increases bone formation, with observed bone loss in patients with uncontrolled diabetes mellitus.

Thyroid hormone excess has been described to be associated with hypercalcemia, hypercalciuria, and osteoporosis. The mechanism of these findings is not entirely clear.

Currently, there is no compelling evidence that the calcitonin-like calcium-lowering hormones are critical regulators of calcium homeostasis in nonpregnant adult humans, perhaps because the low prevailing rate of bone turnover blunts the impact of the antiresorptive actions. However, calcitonin may have important calcitropic functions in pregnant and lactating women and in the fetus and neonate, and in other mammals, particularly rodents, whose bones are constantly growing. In human newborns, the parafollicular C-cell population and serum calcitonin concentrations are much greater than in adults.

Perinatal Mineral Metabolism

During human pregnancy, approximately 30 g of calcium and more than 16 g of phosphorus are transferred transplacentally from the maternal circulation to the growing fetus during the third trimester, when fetal calcium accretion is approximately 140 to 150 mg/kg/day. In humans, a doubling of maternal intestinal calcium absorption and a net increase of calcium accretion into bone compensate for the formidable demand on maternal calcium. A mid-molecule PTHrP hormone expressed principally by the placenta regulates this transplacental calcium pump. TRPV6, a member of the transient receptor potential channel superfamily, may be the primary calcium channel at the trophoblast apical membrane. Calcium flux across the placenta in Trpv6 -null mice is reduced by approximately 40%.

Pregnancy

Pregnancy constitutes a unique hormonal milieu that promotes a state of “physiologic absorptive hypercalciuria.” Maternal total serum calcium concentration declines slightly during pregnancy, reaches a nadir in the middle of the third trimester, and then increases slightly toward term. The maternal serum phosphorus and magnesium profiles are similar to that of calcium. Maternal serum 25(OH)D concentration varies seasonally and with vitamin D intake, but the vitamin D transport protein concentration increases during pregnancy. Serum 1,25(OH) ₂ D concentrations increase early in pregnancy and continue to rise throughout gestation. The calculated concentration of free 1,25(OH) ₂ D also rises. For many years it was believed that PTH levels also increased steadily throughout pregnancy. However, the use of newer immunometric “sandwich” assays indicates that PTH concentration declines during pregnancy. PTHrP levels, in contrast, may be higher in pregnant than in nonpregnant women. The role of circulating calcitonin in pregnancy is uncertain.

1,25(OH) ₂ D drives enhanced maternal intestinal mineral absorption (reviewed in Kovacs, 2008). After parturition, 1,25(OH) ₂ D concentrations and calcium absorption rates decrease to prepregnancy levels. The interplay of calcitropic and progestational hormones in pregnancy protects the maternal skeleton from demineralization. In contrast, during the relatively low estrogen state of lactation, calcium is mobilized from bone stores, possibly under the influence of PTHrP.

Fetal plasma PTH concentration is low, and calcitonin and PTHrP levels are relatively high. Even these low circulating PTH levels may be functionally important in fetal calcium and magnesium metabolism. There is also a close correlation between maternal and fetal serum 25(OH)D levels, consistent with the transplacental transfer of this metabolite. Hypocalcemia is commonly found in infants born to women with low circulating 25(OH)D levels resulting from poor dietary intake of vitamin D and lack of sunlight exposure. Fetal plasma 1,25(OH) ₂ D concentration is also relatively low, despite robust renal 25(OH)D 1α-hydroxylase activity, whereas the concentrations of 24,25(OH) ₂ D are high. The major function of the fetal kidneys in calcium homeostasis may be the production of 1,25(OH) ₂ D rather than renal tubular regulation of calcium excretion. The high circulating concentrations of calcitonin may support this stimulated fetal 25(OH)D 1α-hydroxylase activity. In contrast, the relatively low circulating fetal 1,25(OH) ₂ D concentrations are a consequence of enhanced placental clearance. Constitutively activated placental 24-hydroxylase activity also preferentially hydroxylates maternally derived 25(OH)D to 24,25(OH) ₂ D. This placental capacity to metabolize 25(OH)D and 1,25(OH) ₂ D accounts for the enhanced clearance of fetal 1,25(OH) ₂ D, limits access of placenta-synthesized 1,25(OH) ₂ D to the fetal and maternal circulations, and, in effect, partitions the maternal and fetal vitamin D pools.

The Neonate

Placental transfer of calcium ceases abruptly at birth. In healthy term newborns, total calcium concentration and Ca ²⁺ concentration decline from nearly 11 mg/dL and 6 mg/dL, respectively, in umbilical cord blood to serum levels of 8 to 9 mg/dL and 5 mg/dL, respectively, by 24 to 48 hours. The nadir of Ca ²⁺ concentration may range from 4.4 to 5.4 mg/dL. Concomitant rises in the concentrations of PTH and 1,25(OH) ₂ D stabilize serum calcium concentration as the newborn adapts to extrauterine mineral homeostasis and dietary calcium intake. In preterm infants, calcium absorption from the intestine is nonsaturable and may be vitamin D independent. Serum calcitonin levels increase sharply during the first day and remain elevated compared with those in adults. In the mother, prolactin helps stimulate PTHrP expression in lactating breast tissue. PTHrP is secreted into milk at concentrations 10,000-fold higher than in serum. It is possible that the abundant milk PTHrP content ingested by the neonate is important for mineral regulation. By 2 weeks of life, serum calcium concentration rises to the mean values observed in older children and adults.

During the first week of life, urinary phosphate excretion is significantly higher in preterm newborns than in term newborns but then approximates that of term newborns, possibly owing to accelerated postnatal renal maturation. Calcium excretion is low during the first week when the newborn must compensate for the postpartum fall in serum calcium concentration. After the first several days, calcium excretion increases with a magnitude inversely proportional to gestation. The high urinary calcium-to-creatinine ratio (UCa/Cr) of young infants then steadily declines with age. However, in preterm breastfed infants who are more than 2 weeks old, the UCa/Cr can exceed 2.0. These changes may reflect the relative phosphate deficiency in many preterm infants, which results in an adaptively low urinary phosphate excretion, decreased bone mineralization, and, consequently, relatively high urinary calcium excretion.

Neonatal Hypocalcemia

The definition of hypocalcemia depends on gestational age and birthweight. A precise definition of hypocalcemia, like hypoglycemia, in preterm infants is particularly difficult to formulate. Neonatal hypocalcemia has been defined as a serum calcium level below 8 mg/dL (2 mmol/L) or Ca ²⁺ level less than 4.4 mg/dL (1.10 mmol/L) in term infants and preterm infants weighing >1500 g. Hypocalcemia in very low birthweight (VLBW) infants has been defined as a serum calcium level below 7 mg/dL (1.75 mmol/L) or Ca ²⁺ level less than 4 mg/dL (1 mmol/L). Under conditions of normal acid-base status and normal serum albumin concentration, total serum calcium and Ca ²⁺ levels are linearly correlated, so total serum calcium measurements remain useful as a screening test. However, because Ca ²⁺ is the physiologically active fraction in sick infants, it may be preferable to assay Ca ²⁺ directly in freshly obtained blood samples. The causes of neonatal hypocalcemia are classified by the timing of onset. Early hypocalcemia occurs in the first 2 to 3 days of life. “Early” and “late” occurring hypocalcemias ( Box 83.1 ) have different causes, usually occur in different clinical settings, and should prompt different approaches to evaluation and management.

Box 83.1

Causes of Neonatal Hypocalcemia

Early-Onset Hypocalcemia (<48 h of Age)
- Prematurity
- Perinatal distress/asphyxia
- Infants of diabetic mothers
- Intrauterine growth restriction
Late-Onset Hypocalcemia (First Week of Life)
- High phosphate load with or without hypoparathyroidism or vitamin D deficiency
Neonatal Hypoparathyroid Syndromes
- Parathyroid agenesis
- DiGeorge syndrome (22q11.2 deletions)
- Familial isolated hypoparathyroidism
  - PTH mutations
Autosomal Dominant Hypocalcemic Hypocalciuria
- Activating mutations of Ca ²⁺ -sensing receptor
Neonatal Hypoparathyroidism Secondary to Maternal Hyperparathyroidism
Autoimmune Polyglandular Syndrome Type 1 (Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy)
Hypoparathyroidism Associated With Skeletal Dysplasias
- Kenny-Caffey syndrome
- Hypoparathyroidism-retardation-dysmorphism (Sanjad-Sakati) syndrome
- Osteogenesis imperfecta type II
Parathyroid Hormone Resistance (Transient Neonatal Pseudohypoparathyroidism)
Hypomagnesemia With or Without Distal Renal Tubular Acidosis
- Primary hypomagnesemia
- Renal tubular acidosis type 1
Abnormal Vitamin D (1,25-Dihydroxyvitamin D) Production or Action (“Hypocalcemic Rickets”)
- Vitamin D deficiency (secondary to maternal vitamin D deficiency)
- Acquired or inherited disorders of vitamin D metabolism
- Resistance to the actions of vitamin D
Hyperphosphatemia
- Excessive dietary phosphate
- Phosphate-containing enemas
- Rhabdomyolysis-induced acute renal failure
- Hyperphosphatemic renal insufficiency
“Hungry Bones Syndrome” (Mineralization Outpacing Osteoclastic Bone Resorption)
Other Causes
- Metabolic or respiratory alkalosis
- Phototherapy
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency
- Pancreatitis
- Sepsis, septic shock
- Rotavirus gastroenteritis
- Osteopetrosis and other skeletal dysplasias
- Pseudohypocalcemia (hypoalbuminemia)
- Medications
  - Bicarbonate
  - Rapid transfusion or plasmapheresis with citrated blood
  - Furosemide induced
  - Lipid infusions

Clinical Presentation

Most infants with hypocalcemia are asymptomatic. Hypocalcemic signs in neonates are variable and may not correlate with the magnitude of the decline in calcium level. Calcium ions couple excitation and contraction in skeletal and cardiac muscle, so increased neuromuscular excitability (tetany) is a cardinal feature of hypocalcemia. Such infants are jittery and hyperactive and frequently exhibit muscle jerks and twitches induced by environmental noise or other stimuli. Generalized or focal clonic seizures may occur. Other signs of neonatal tetany include poor feeding, hypotonia, apnea, tachycardia, tachypnea, high-pitched cry, and irritability. Occasionally, respiratory or gastrointestinal rather than neurologic signs predominate. Rare presentations include inspiratory stridor caused by laryngospasm, wheezing caused by bronchospasm, or vomiting possibly resulting from pylorospasm, which may cause hematemesis or melena. At times the gastrointestinal signs are severe enough to mimic those of intestinal obstruction. Carpopedal spasm and the Chvostek sign are not as reliably elicited in hypocalcemic newborns as in older children or adults. Hypocalcemia characteristically causes prolongation of the QT interval in the electrocardiogram.

Early Neonatal Hypocalcemia

Hypocalcemia occurring during the first 3 days of life, usually between 24 and 48 hours postpartum, is termed early neonatal hypocalcemia . It is an exaggeration of the normal decline in circulating calcium concentration. Early neonatal hypocalcemia is typically encountered in any of four circumstances: prematurity, severe perinatal stress or asphyxia, maternal diabetes, or significant intrauterine growth restriction (IUGR). In addition, phototherapy, maternal hyperparathyroidism, maternal anticonvulsant use, and iatrogenic causes (e.g., transfusion with citrated blood, furosemide use) have also been implicated with early neonatal hypocalcemia.

In preterm infants, there is a steeper and more rapid postnatal decline in serum calcium concentration. The magnitude of the depression is inversely proportional to gestational age. Approximately one-third of premature infants and most VLBW infants have low total serum calcium levels (<7.0 mg/dL) during the first 2 days after birth. However, the fall in Ca ²⁺ concentration is not proportional to the fall in total calcium concentration. The ratio of ionized to total calcium in these newborns is higher than at term. This “sparing” of Ca ²⁺ may be related to the lower serum protein concentration and pH in prematurity. Multiple factors contribute to the fall in total serum calcium concentration, including low milk intake, impaired response to PTH, and hypoalbuminemia, which does not lower the Ca ²⁺ concentration. The sparing effect on Ca ²⁺ concentration explains the frequent absence of hypocalcemic signs in preterm infants.

The neonatal parathyroid glands, regardless of the degree of prematurity, can mount an appropriate PTH response to hypocalcemia. Hypocalcemia in extremely preterm newborns or infants undergoing cardiac bypass stimulates increases in serum PTH at least as great as those seen in adults during citrate-induced hypocalcemia. PTH resistance plays an uncertain role in early neonatal hypocalcemia. A several-day delay in the phosphaturic and renal cAMP responses to PTH has inconsistently been reported, suggesting that there might be a maturational delay in renal responses to PTH. Calcitonin usually peaks in 12 to 24 hours of life. Preterm infants’ exaggerated rise in calcitonin may also promote hypocalcemia.

Early neonatal hypocalcemia with hyperphosphatemia is frequently observed in severely stressed or asphyxiated infants. Possible mechanisms include increased phosphate load caused by tissue catabolism, renal insufficiency, and acidosis. There is an exaggerated serum calcitonin response and decreased PTH secretion. Low serum Ca ²⁺ and elevated serum magnesium levels have been correlated with the severity of hypoxic–ischemic encephalopathy and poor outcome.

Hypocalcemia occurs in at least 20% to 50% of infants of diabetic mothers (IDMs). IDMs show an exaggerated postnatal drop in circulating calcium levels compared with gestational-age controls that typically occur between 24 and 72 hours after birth and are often associated with hyperphosphatemia. The course is usually similar to early neonatal hypocalcemia in preterm infants, although hypocalcemia sometimes persists for several additional days. The greater bone mass and relative undermineralization typical of macrosomic IDMs may increase the neonatal demand for calcium, producing a deeper and prolonged decline in postnatal serum calcium levels. In addition, magnesium deficiency leads to decreased PTH production and action. Maternal glycosuria is associated with urinary magnesium losses, which may lead to significant maternal magnesium deficiency followed by fetal magnesium deficiency.

Neonatal hypocalcemia in IDMs has been associated with the severity and duration of maternal diabetes and inadequate glycemic control. Not surprisingly, preterm IDMs who have sustained IUGR and asphyxia as a result of uteroplacental insufficiency invariably become quite hypocalcemic. Improved metabolic control for pregnant diabetic women can markedly diminish the occurrence and severity of early neonatal hypocalcemia. Healthy IDMs who can start milk feedings on the first day do not require serum calcium monitoring unless suspicious signs (e.g., jitteriness, stridor) are noted.

Hypocalcemia occurs with increased frequency in infants with IUGR. The mechanism is thought to involve a decreased transfer of calcium across the placenta due to uteroplacental insufficiency.

Late Neonatal Hypocalcemia

Late neonatal hypocalcemia develops after 3 to 5 days of life and typically occurs at the end of the first week. It occurs more frequently in term than in preterm infants and is not usually associated with maternal diabetes, birth trauma, or asphyxia. Historically, late-onset hypocalcemia is associated with ingestion of cow's milk or formula with a high phosphate load. The high phosphate level increases calcium deposition in bone and antagonizes PTH secretion and action, leading to hypocalcemia. However, the widespread use of high phosphorus formula in the United States and elsewhere contrasts with the rarity of this condition, which suggests that infants who develop phosphate-induced late neonatal hypocalcemia may have an otherwise undetected renal phosphate excretion problem.

The hyperphosphatemia may also result from varying combinations of immature renal tubular phosphate excretion, transiently low levels of circulating PTH, hypomagnesemia, and inadequate maternal vitamin D intake. A relatively high dietary phosphate load coupled with a low GFR leads to an increase in serum phosphate levels and a reciprocal decline in serum calcium levels. The physiologic response to hypocalcemia is an increase in PTH secretion, leading to increased urinary phosphate excretion and tubular calcium resorption. Serum calcium levels frequently increase when these infants are placed on a low-phosphate formula and supplemental calcium. After several days to weeks, serum PTH usually increases, and the infants then can tolerate more dietary phosphate. The pathogenesis of this “transient hypoparathyroidism” in late neonatal hypocalcemia is not readily apparent. Some of these infants show a persistent or recurrent inability to mount an adequate PTH response to a hypocalcemic challenge, indicating partial hypoparathyroidism.

In other infants, maternal vitamin D deficiency can cause late (or occasionally “early”) neonatal hypocalcemia. This possibility is checked by measuring maternal and neonatal serum 25(OH)D levels. Maternal vitamin D deficiency is implicated by the increased incidence of late neonatal hypocalcemia in winter due to inadequate sunlight. The high prevalence of enamel hypoplasia of incisor teeth reported in affected infants indicates that the mineralization defect begins during the third trimester of pregnancy.

Hypocalcemia and hyperphosphatemia after the first 3 to 5 days should always prompt a thorough investigation for the underlying causes (see Box 83.1 ). Hypocalcemia in this setting usually implies primary or secondary dysregulation of (1) the parathyroid-renal (PTH–-,25[OH] ₂ D) axis, (2) hypomagnesemia, or (3) renal insufficiency. The primary hormonal and end-organ disturbances that cause neonatal hypocalcemic syndromes are described later. As a cautionary note, observations of generally favorable neurologic outcomes in newborns with hypocalcemic or hypomagnesemic seizures may be valid for those with a nutritional cause but are less relevant to patients with associated medical conditions. In this group, the neurologic prognosis may be more closely related to the causative disorder.

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