Placental Transport

During pregnancy, calcium is actively transferred from the mother to the fetus. The normal fetus accumulates about 25 to 30 g of calcium by the end of gestation. Approximately 80% of this calcium accumulates during the third trimester, when the fetal skeleton is rapidly mineralized. To meet the high demand for mineral requirements of the developing skeleton, the fetus maintains higher serum calcium and phosphorus levels than the maternal levels. This process is the result of the active transport of calcium across the placenta by a calcium pump in the basal membrane that maintains a gradient of maternal-to-fetal calcium of 1 : 1.4.

The main regulator of fetal ionized calcium appears to be parathormone-releasing protein (PTHrP), which is produced by the placenta as well as by the fetal parathyroid glands. Animal data suggest that both PTH and PTHrP act in the regulation of fetal mineral metabolism. PTH-ablated mice showed significant abnormalities in fetal bone formation, including decreased mineralization of the cartilage matrix and decreased vascular invasion of the growth plate, suggesting a role of PTH beyond simply regulating serum mineral ion concentration.⁶⁰ In contrast to the relatively mild phenotype of PTH ablated mice, animals that lack PTHrP show major developmental abnormalities, particularly a significant acceleration of chondrocyte differentiation in the growth plates leading to a lethal skeletal dysplasia characterized by the premature mineralization of all bones that are formed through an endochondral process.^46,51

Although vitamin D is critical for mineral ion homeostasis and bone development during adult life, fetal mineral ion homeostasis appears to be mostly independent of this hormone. 1,25(OH)₂D₃ is produced by the fetal kidney, and the vitamin D receptor is present in many fetal tissues, including the placenta. However, neonates deficient in 1-alpha-hydroxylase are grossly normal from birth until weaning.²⁸ Additionally, the absence of the vitamin D receptor (VDR) either in the mother or the fetus does not affect placental calcium transfer or fetal serum levels of calcium, phosphorus, or magnesium during the first days after delivery, indicating that the VDR in either side of the placenta, on the maternal or at the fetal side, is not critical for placental calcium, phosphorus, or magnesium transfer.^52,89 Cord concentrations of 25(OH)D and 1,25(OH)₂D₃ correlate significantly with those found in the maternal circulation, suggesting that the vitamin D pool of the fetus depends entirely on that of the mother. 1,25(OH)₂D₃ found in fetal plasma is a result of fetal kidney and placental hydroxylation activity. The placenta is able to synthesize and metabolize 1,25(OH)₂D₃ through the activity of 25-hydroxyvitamin D-1α hydroxylase and 1,25-dihydroxyvitamin D-24 hydroxylase, two key enzymes for vitamin D metabolism. Bone mass of neonates may be partially related to the vitamin D status of the mother, although this relationship is not consistently found in either the United States or in developing countries.⁷⁹

After the umbilical cord has been cut, the neonate loses the transplacental supply of calcium and must adapt rapidly to ensure normal calcium homeostasis and skeletal growth and mineralization. The neonate is dependent on intestinal absorption to supply calcium and therefore must quickly stimulate the synthesis of PTH and 1,25(OH)₂D₃, which had been suppressed in utero. Total and ionized calcium levels decrease significantly within 24 to 48 hours after birth. Calcium concentrations usually return to normal by 5 to 8 days after birth. Serum PTH levels, which are low at birth, increase within the first 24 to 48 hours, probably in response to the decrease in serum calcium. Subsequently, 1,25(OH)₂D₃ levels rise to adult levels within a few days. Serum calcitonin rises two- to tenfold over cord blood levels within the first 48 hours. Hypocalcemic premature and asphyxiated newborns have the highest levels of postnatal calcitonin.⁶⁴

Intestinal Absorption

Calcium absorption occurs primarily in the small intestine by both active and passive processes. Ionization of calcium compounds, which requires an acidic pH, develops in the stomach and is a prerequisite for absorption. Vitamin D is essential for the active absorption of calcium, which involves carriers such as calcium-binding proteins. However, the role of vitamin D and active transport early in life is uncertain.

The absorption rate of calcium is higher than that during other periods of life except for during pregnancy in populations with low mineral intake. The average reported absorption of calcium from human milk in small infants is approximately 50% to 60% of its intake. The absorption of calcium added to human milk with commercially available fortifiers generally parallels that of the calcium endogenous to human milk.³⁶

Studies in vitamin D receptor-knockout (VDR-KO) mice have underscored the importance of an intact VDR for intestinal calcium absorption. The VDR-KO mice exhibit decreased calcium absorption with a concomitant reduction in the expression of transcellular calcium transport proteins. Vitamin D-dependent transcellular calcium transport involves three major components: transient receptor potential vanilloid type 6 (TRPV6), calbindin D_9k, and Ca⁺²ATPase. VDR-KO mice exhibit decreased calcium absorption with a concomitant reduction in the expression of transcellular calcium transport proteins. However, recent studies revealed that TRPV6/calbindin D_9k double KO mice do not demonstrate impaired intestinal calcium transport when they have usual dietary calcium intake, indicating that other compensatory factors are involved in intestinal calcium transport. Several studies underscored the importance of the paracellular route and suggested that 1,25(OH)₂D₃ regulates tight junction proteins such as Caludin-2,3, Caludin-12, and Cadherin-17, which lead to increased paracellular calcium transport.²⁵

Passive calcium transport is driven by chemical gradients that represent movement of calcium among the cells (paracellular transport). It may account for most of the calcium absorption very early in life, particularly in premature infants in whom the transport, which is transcellular and dependent on vitamin D, is not completely expressed.18,19 In addition to vitamin D status, various other factors affect calcium absorption. Ionization of calcium compounds, which requires an acidic pH, occurs in the stomach and is a prerequisite for absorption. Therefore, low availability could be the result of an insoluble fraction of calcium intake or the precipitation of calcium in the gut. The quantity and quality of fat intake may influence calcium absorption through the formation of calcium soaps. It has been suggested that the free palmitate content in the gastrointestinal tract after the hydrolysis of triglyceride may impair calcium absorption.²⁰ Human milk contains a bile salt-stimulated lipase that is not specific to the Sn-1 and Sn-3 positions. The improvement of calcium absorption with the use of medium-chain triglycerides may be the result of the reduction of total saturated long-chain fatty acid content in formula. Relatively low gastrointestinal pH content or the lactose and casein content of the formula may also have an additional positive effect on calcium absorption.

Medications may also interfere with calcium absorption. For example, glucocorticoids inhibit intestinal absorption, and some anticonvulsants can also inhibit calcium absorption either directly (phenytoin) or indirectly through interference with vitamin D metabolism (phenobarbital and phenytoin). The clinical consequences of the use of these anticonvulsants in the neonatal period is not known, but is unlikely to be a common major risk factor for low bone mineral accumulation in early life.

In infants, a significant amount of calcium is secreted in the intestinal lumen through digestive fluid. With the use of stable isotopes, endogenous fecal calcium excretion and true calcium absorption may be evaluated. Numerous metabolic balance studies have been performed in preterm infants fed human milk or a formula to evaluate apparent calcium absorption. In preterm infants fed human milk with or without fortification, calcium absorption ranges from 50% to 70%. In formula-fed infants, the percentage of calcium absorption may be slightly less than that with human milk although the difference does not appear to be large.³

Renal Excretion

Under normal circumstances, calcium status is maintained by a balance between its intestinal absorption and renal and endogenous fecal excretion with a small component of skin losses, especially with sweating. Although it is responsible for only 5% to 10% of Ca²⁺ reabsorption, the major regulation of Ca²⁺ reabsorption occurs in the distal convoluted tubule by a mechanism independent of Na⁺ reabsorption, but regulated by PTH and 1,25(OH)₂D₃. Calcium reabsorption is increased by both PTH and 1,25(OH)₂D₃. It is also regulated by ionized calcium concentration, phosphate concentration, and acid-base status. It increases with Ca²⁺ depletion and alkalosis but decreases with hypercalcemia, phosphate depletion, and acidosis. The effects of diuretics on renal calcium excretion vary considerably. Furosemide markedly increases renal calcium losses and is a risk factor for neonatal nephrocalcinosis. Thiazides increase renal tubular calcium reabsorption, thereby reducing calciuria. However, the clinical consequences of this process on neonatal physiology have not been fully investigated.⁸⁴

Nearly all filtered calcium (98%) is reabsorbed in the renal tubule. However, preterm and term infants differ from adults in three main aspects: (1) renal function is far from being completely developed; (2) mineral requirements for growth are very high; (3) renal calcium load results solely in the difference between net absorption and net bone and soft tissue retention. Considering that calcium soft tissue retention is negligible, renal calcium load is highly dependent on bone calcium deposition associated with phosphorus in the form of hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂] containing a molar calcium-to-phosphorus ratio of 1.67 (2.15 wt/wt). Therefore, the main determinant of the urinary loss of calcium in preterm and term neonates is phosphorus depletion and urinary excretion. When human milk is provided exclusively, there is an increase in the urinary excretion of calcium associated with very low urinary phosphate excretion.⁸⁴ In contrast, when human milk is supplemented with phosphate, significant phosphaturia appears at the same time that calciuria decreases to a minimum level. Therefore, hypercalciuria can primarily be explained by a relative phosphate depletion that cannot meet the phosphate demand necessary for skeletal mineralization (Figure 96-2).

Intake

Mature human milk contains approximately 260 mg of calcium per liter.⁴² Considering the possibility of a lower efficiency (fraction) of calcium absorption from infant formulas compared with human milk, the guidelines of the Food and Drug Administration, the Life Sciences Research Office (LSRO),⁴⁷ and those of the Scientific Committee on Food of the European Commission for full-term infants during the first 6 months of life recommended a content of 50 to 140 mg of calcium per 100 kcal.⁶ It should be noted that there are no comparisons of calcium absorption performed in the United States for infant formulas and human milk at the same calcium content, as the calcium content of human milk is uniformly less than the minimum mandated for infant formulas by the Infant Formula Act.⁴² Typical 24-hour intake and retention values for human milk-fed infants is shown in Figure 96-3.

The requirements for enteral calcium intake in preterm infants were reconsidered in a recent American Academy of Pediatrics (AAP) statement.³ The AAP recommended a range of calcium intake of 150 to 220 mg/kg per day consistent with the LSRO recommendations for infants receiving 120 kcal/kg per day of feeding.⁴⁷ The AAP recommendations are slightly above those of the European authorities (Table 96-2).⁶ In the United States, fortified human milk or preterm formula generally provides about 180 to 230 mg/kg per day of calcium at usual intakes (Table 96-3). There is no evidence that small variations among formulas within a class (e.g., different brands of preterm formulas marketed in the United States) in amount or source of calcium have a biologically meaningful impact on preterm infants.

Phosphorus Physiology

Unlike calcium, phosphorus is present in the soft tissues, mainly in the form of phosphate esters, and in extracellular fluid in the form of inorganic phosphate ions. This represents about 15% of the whole-body content. Given its widespread distribution, phosphorus plays a critical role in many biologic processes, including energy metabolism, membrane composition, nucleotide structure, cellular signaling, and bone mineralization. It is therefore not surprising that a deficiency of phosphorus results in clinical disease, including muscle weakness, impaired leukocyte function, and abnormal bone metabolism.

Renal Excretion

The three major factors that control phosphorous reabsorption are high PTH activity, high FGF (fibroblast growth factor)23 activity, and renal defects that lead to inorganic phosphate (Pi) wasting. Hallmarks of high PTH activity are hypophosphatemia, phosphaturia, disturbance in vitamin D metabolism, and low calcium. The hallmarks of high FGF23 activity are hypophosphatemia and phosphaturia with inappropriately low 1,25-OH₂D, and the hallmarks of renal rickets are hypophosphatemia and phosphaturia with high circulating 1,25-OH₂D.

The kidney contributes to a positive phosphate balance during growth by the reabsorption of a relatively high fraction of filtered inorganic phosphate (99% in neonates, 95% in infants fed human milk, and 80% in adults). Preterm infants have an increased fractional excretion of phosphate and are at a greater risk for developing signs and symptoms of phosphate deficiency. The bulk of filtered phosphate is reabsorbed in the proximal tubule through sodium-dependent transporters, the Na-phosphate cotransporters 2A and 2C. A change from human milk with a low phosphate content to a formula with a higher content is associated with a rapid down-regulation of Na-phosphate cotransporters mRNA and protein in the brush border membrane.

Because intestinal phosphorus absorption is very efficient and fairly unregulated, renal phosphorus excretion plays an important role in maintaining its balance. Filtered load depends on the plasma phosphorus level and glomerular filtration rate (GFR). Tubular reabsorption is an active and saturable process that gives rise to a maximal rate of tubular reabsorption (Tm). There is a plasma minimal threshold below which phosphorus reabsorption is almost complete and urinary excretion close to zero, and a maximal threshold above which all tubular reabsorptive systems are saturated, so each additional increment in filtered load is associated with a parallel increment in excretion.⁵⁴ In preterm infants, the minimal and maximal threshold levels are 1.75 mmol/L (5.4 mg/dL) and 2.45 mmol/L (7.6 mg/dL), respectively (Figure 96-4). The three main factors responsible for Pi readsorption by the sodium/Pi cotransporter in the proximal tubule are urinary phosphorus, PTH, and FGF23. Renal handling of Pi is regulated by hormonal and nonhormonal factors. Changes in urinary excretion of Pi are almost invariably mirrored by changes in the apical expression of NaPi-IIa and NaPi-IIc in proximal tubules. Phosphate deprivation increases NaPi-IIa and NaPi-IIc expression in the proximal tubule. Both NaPi-IIa and NaPi-IIc, the main sodium/Pi cotransporters, are regulated in a similar fashion by PTH, FGF23, and dietary phosphate. Both PTH and FGF23 accelerate the cotransporter endocytosis and FGF23 also accelerates cotransporters’ degradation in the lysosome.⁶³

During early postnatal life, the phosphate response to PTH is blunted, whereas PTH increases tubular calcium reabsorption. Together, these actions result in the retention of both calcium and phosphate in infants, which is favorable for growth and bone mineralization.

The level of FGF23 in cord blood is low, which might be caused by the low expression of FGF23 in fetal tissues. Measuring soluble α-Klotho and FGF23 levels in the cord blood reveals a negative correlation between the two.⁶⁶ The low FGF23 levels promote a relative hyperphosphatemia and the relative increase in 1,25(OH)₂D₃ promotes bone mineralization during early rapid growth in the neonatal period.

FGF23 functions principally as a phosphaturic factor. It is secreted by osteocytes and osteoblasts in response to high serum phosphate levels and 1,25(OH)₂D₃. In the osteoblast, FGF23 post-translation undergoes O-glycosylation by GALNT 3. The glycosylation protects the molecule from degradation. Nonglycosylated FGF23 may be targeted for degradation by subtilisin/furin-like endopeptidases. Impaired FGF23 synthesis or action, owing to FGF23 gene mutations; mutations in GALNT 3; or mutations in Klotho, which is required for the conversion of FGFR1(IIIc) into the FGF23 receptor, leads to severe hyperphosphatemia and tumoral calcinosis.⁹¹

FGF23 accelerates NaPi-2a and NaPi-2c cotransporters’ endocytosis to reduce renal phosphate reabsorption and thereby increases urinary phosphate excretion. Furthermore, FGF23 suppresses the expression of 1-α-hydroxylase to reduce the production of the active vitamin D metabolite 1,25(OH)₂D₃. The hallmark of all clinical entities that share high FGF23 activity is rickets or osteomalacia with hypophosphatemia owing to renal phosphate wasting and inappropriately low serum 1,25(OH)₂D₃ levels. Moreover, FGF23 can also induce 24-hydroxylase, which degrades 1,25(OH)₂D₃.

Absorbed phosphate enters the extracellular phosphate pool, which is in equilibrium with bone and soft tissue. In growing infants, the amount of phosphorus excreted is less than the net amount absorbed owing to the deposition of phosphorus in soft tissues and bone. In infants, phosphorus will preferentially go to soft tissue with a weight-to-weight nitrogen-to-phosphorus ratio of 15 : 1 and to bone with a weight-to-weight calcium-to-phosphorus ratio of 2.15 : 1. The residual phosphorus constitutes the renal phosphorus load influencing plasma concentration and urinary excretion. In the face of a limited total phosphorus supply, bone mineral accretion may be limited, leading to significant calcium excretion associated with very low urinary excretion of phosphorus. This particular situation is illustrated in Figure 96-2, showing calcium and phosphorus metabolism in term infants fed human milk or formula.

Because the amount of Pi filtered through the glomeruli greatly exceeds intestinal absorption, it is the tubular reabsorption that determines Pi serum level. Bedside assessment of Pi renal handling is done by fasting spot urine and serum measurements of Pi and creatinine, calculating the tubular reabsorption of phosphate (TRP), or the renal threshold for Pi (TmPO₄/GFR). The first is based on the concept that:

TRP (%)=(1−Pi clearance/creatinine clearance)×100

By dividing clearance / clearance, the time and volume are redundant, and

TRP (%)=(1−Up×Scr/Sp×Ucr)×100.

(Up, Urinary phosphorus; Scr, serum creatinine; Sp, serum phosphorus; Ucr, urine creatinine; Pi, inorganic phosphate)

The normal range for TRP is 80% to 90%; low values indicate phosphaturia, such as in hyperparathyroidism or hypophosphatemic rickets; high values designate enhanced Pi reabsorption, such as in hypo- or pseudohypoparathyroidism. In the presence of abnormally high or low serum Pi, renal reabsorption decreases or increases, respectively. The TRP becomes therefore a lesser value in such conditions, and TmPO₄/GFR is calculated. TmPO₄, the tubular threshold for Pi reabsorption, reflects the highest serum Pi levels that will result in complete reabsorption of the filtrated Pi load. The nomogram developed for that purpose almost four decades ago is still a useful bedside tool (Figure 96-5).⁹⁴

Magnesium Physiology

The skeleton represents the largest magnesium store (60%), which is divided into two compartments: one firmly bound to apatite and nonmobilizing, and the other absorbed to the surface of the mineral crystals and contributing to magnesium homeostasis. The remaining magnesium is distributed in skeletal muscle, the nervous system, and other organs with a high metabolic rate. Magnesium is the second most abundant intracellular cation, playing a crucial role in many physiologic functions. It is critical in energy-requiring metabolic processes, protein synthesis, membrane integrity, nervous tissue conduction, neuromuscular excitability, muscle contraction, hormone secretion, and intermediate metabolism.

Effects

Parathyroid hormone increases serum calcium concentrations directly by increasing bone resorption and renal calcium reabsorption and indirectly by increasing renal synthesis of 1,25(OH)₂D₃, thereby increasing intestinal calcium absorption. In addition, PTH lowers serum phosphorus concentrations through its phosphaturic action on the renal proximal tubule. This action minimizes the possibly adverse effect of hyperphosphatemia related to bone resorption on calcium homeostasis.

Regulation of Hormonal Secretion

Serum calcium concentration regulates PTH secretion; high concentrations inhibit the secretion of PTH, and low concentrations stimulate it. Low or falling serum calcium concentrations act within seconds to stimulate PTH secretion, initiated by means of a calcium-sensing receptor on the surfaces of parathyroid cells. This receptor is expressed in the parathyroid glands where it regulates PTH secretion and in the kidneys where it regulates tubular calcium reabsorption. Decreases in ionized calcium of as little as 0.4 mmol/L stimulate PTH secretion, and increases suppress it. Acute decreases in magnesium concentrations also stimulate PTH secretion, and increases depress it. However, chronic magnesium deficiency paradoxically decreases PTH secretion, probably by altering the calcium-sensitive, magnesium-dependent adenylate cyclase involved in PTH secretion.

Vitamin D and its metabolites 25-OHD and 1,25-OH₂D, acting through vitamin D receptors, decrease the level of PTH mRNA. The human calcium receptor gene contains six exons and is located at 3q13.3-21 (Online Mendelian Inheritance in Man, OMIM, 601199). In the parathyroid gland, the calcium receptor mediates inhibition by extracellular Ca²⁺ concentration of PTH secretion, of PTH gene expression, and of parathyroid cellular proliferation. In the kidney, the receptor mediates the direct inhibition of the reabsorption of divalent cations in the thick cortical ascending limb of the loop of Henle.⁷⁸ Inactivating or activating mutations of this receptor cause inherited human conditions.

Both activating and inactivating calcium-sensing receptor (CaSR) mutations have been identified. Loss-of-function CaSR mutations lead to familial hypocalciuric hypercalcemia, which is an autosomal dominant condition usually characterized by mild degrees of hypercalcemia, inappropriately normal PTH levels, and low (or inappropriately low) urinary calcium excretion.⁷⁰ Gain-of-function CaSR mutations are associated with dominant hypocalcemic hypercalciuria. Some cases of nonfamilial idiopathic hypoparathyroidism may also be caused by gain-of-function CaSR mutations.

Fetal Parathyroid Function

Maternal immunoreactive PTH, like other polypeptide hormones, does not cross the placenta. Concentrations of PTH increase from the first to the second trimester, declining again in the third trimester to the levels of the first trimester. However, PTH is significantly increased postpartum.¹² In contrast, PTHrP concentrations increase continuously throughout pregnancy and lactation. Human parathyroid glands are functionally active as early as 12 weeks of gestation. However, fetal parathyroid glands are functionally suppressed by high intrauterine calcium concentrations, and PTH levels in cord blood are frequently below the detection limit.⁸⁰ Loss of PTH has no effect on overall fetal growth (crown-rump length, weight); loss of PTHrP has a modest effect on fetal growth; loss of PTH and PTHrP has a more pronounced effect on fetal growth; loss of the PTH1 receptor causes the most marked fetal growth restriction.

Maternal hyperparathyroidism results in maternal hypercalcemia, which leads to fetal hypercalcemia and suppression of fetal and neonatal parathyroid glands. Conversely, untreated maternal hypoparathyroidism leads to maternal hypocalcemia, fetal hypocalcemia, and secondary fetal and neonatal hyperparathyroidism.

Neonatal Parathyroid Function

After birth, with the abrupt termination of the maternal calcium supply, serum calcium in the newborn decreases, and serum PTH increases correspondingly. Both term and preterm infants may show a PTH response to falling serum calcium. Infants with VLBW have a decreased PTH surge compared with full-term infants. Infants of diabetic mothers may have impaired PTH production during the beginning days of life. Infants with severe perinatal depression may also have decreased PTH responses to hypocalcemia.

Parathyroid Hormone Reference Values

Current assays for serum PTH are conducted at two sites that are designed to detect both amino-terminal and carboxy-terminal epitopes of the peptide. PTH molecules that are reactive in these two-site immunoassays are considered intact.

In full-term newborn infants, serum PTH concentrations tend to be low in cord blood, but increase within the first 48 hours of life in response to the decrease in serum calcium. In preterm infants, PTH concentrations increase immediately after birth, indicating that, in them, the secretion of the hormone responds physiologically to the hypocalcemic stimulus. This increase in PTH concentration could be blunted when premature infants receive calcium by infusion, with the calcium load buffering the postnatal depression of serum calcium. By day of life 10, the serum concentrations of intact PTH return to euparathyroid values (Table 96-4). The multiplication factor for serum PTH from picograms per deciliter to picomoles per liter (pg/dL to pmol/L) is 0.11.

Vitamin D is synthesized endogenously in the skin (cholecalciferol or vitamin D₃) after sunshine exposure to high-energy ultraviolet photons (ultraviolet B, 290 to 315 nm) or is absorbed from dietary sources in the duodenum and jejunum as either vitamin D₃ (from animal sources) or vitamin D₂ (ergocalciferol, from vegetable sources). Regardless of its origin, vitamin D₂ and D₃ are transported bound to the vitamin D–binding protein to the liver, where it is hydroxylated at carbon 25 to form vitamin D₃ (25(OH)D₃, or calcidiol), the most abundant vitamin D metabolite. The generation of calcidiol is regulated by CYP2R1.²² Circulating concentrations of 25(OH)D₃ provide a useful index of vitamin D status (reflecting both dietary intake and sunshine exposure). Subsequently, 25(OH)D₃ is further hydroxylated at carbon 1 to form the final active metabolite, 25-hydroxyvitamin D₃-1α-hydroxylase (1α-hydroxylase), which is classically expressed in the kidney. However, 1,25(OH)₂D₃ can also be synthesized by various cells, including monocytes and skin cells, as well as by the placenta during pregnancy.⁹⁷

Neonatal Vitamin D Function and Recommendations

Serum or plasma 25(OH)D concentration is a useful vitamin D biomarker reflecting vitamin D supply (exposure) over a period of time. Nevertheless, several surveys show a high rate of poor maternal vitamin D status throughout the world, particularly in countries without vitamin D supplementation, with poor sun exposure, extensive clothing, or with deeply pigmented skin. Thus, the rate of cord blood vitamin D deficiency (<20 nmol/L; <8.3 ng/mL) may reach up to 70% in European populations.⁶⁸

Vitamin D content in human milk is usually low.38,42 A daily intake of up to 400 IU (10 micrograms/day) of vitamin D is recommended by the Institute of Medicine and endorsed by the American Academy of Pediatrics for all infants beginning soon after birth.¹¹ In addition, vitamin D is metabolized in the liver, and anticonvulsants such as phenobarbital and diphenylhydantoin increase its hepatic catabolism and requirements. There are some questions about what is meant in terms of timing of initiation by the available statements. In most practices, it is considered ideal to begin healthy full-term infants who are being partly or wholly breastfed, on vitamin D supplements prior to their hospital discharge or not later than a week of age for those with longer initial hospitalizations.

In preterm infants, as a result of the decrease in serum calcium during the first days of age, the postnatal surge in PTH induces increased synthesis of 1,25(OH)₂D₃ during the first days of life. Provision of vitamin D₃ increases the 25(OH)D pool of the newborn infant at birth, followed by rapid renal synthesis of 1,25(OH)₂D during the early postnatal days. In preterm infants, immaturity of the vitamin D activation pathway, either alone or in combination with other abnormalities, particularly transient hypoparathyroidism, hypercalcitoninemia, and end-organ resistance to its hormonal effects, may promote late neonatal hypocalcemia.

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