Antepartum period

Calcium homeostasis during pregnancy is interrelated with changes in extracellular fluid volume, renal function, and fetal needs. The mother meets the fetal requirement for calcium primarily by increasing intestinal calcium absorption. These change are mediated by increased production of 1,25-(OH)₂D and PTHrP and under the influence of hormones and growth factors such as estrogens, prolactin (PRL), human placental lactogen (hPL), placental growth factor, and insulin-like growth factor-1.^51,56 These substances increase intestinal absorption of calcium in pregnancy, decrease urinary excretion, alter maternal bone calcium turnover, and stimulate synthesis of both PTHrP and 1,25-(OH)₂D.^35,56,65 Changes in calcium and phosphorus homeostasis during pregnancy are summarized in Table 17-2 and Figure 17-2.

Intrapartum period

Calcium is essential for activation of myosin light chain kinase in smooth muscle and thus myometrial contraction. Without calcium, much of which comes from extracellular sources, myometrial contraction does not occur. PTHrP levels in the myometrium and amnion decrease at the onset of labor. The role of calcium in uterine contraction is discussed in Chapter 4.

Postpartum period

Serum calcium, PTH, and calcitonin gradually return to prepregnant values by 6 weeks postpartum in nonlactating women.^36,62 Resumption of menses is associated with increases in calcium absorption, PTH, and, in most studies, 1,25-(OH)₂D.⁶⁵ In lactating women, changes in calcium metabolism continue in order for the mother to provide adequate calcium for infant growth and development.⁶⁵ Lactation is a greater challenge to calcium homeostasis than pregnancy. During lactation the woman must provide 280 to 400 mg/day of calcium.^44,56 Exclusive breastfeeding for 6 months leads to four times the calcium loss than in pregnancy.³⁶ In the lactating women, serum calcium levels are slightly decreased with a slight increase in ionized calcium (although still within normal limits), while phosphorus, PTH, PTHrP, and 1,25-(OH)₂D levels are all increased. PTH levels are low normal or slightly lower if the woman has adequate calcium and vitamin D intake.³⁶

PTHrP, primarily from mammary tissue, increases and plays an important role in controlling breast calcium content.^{6,32,44,51,56} PTHrP is important in regulating movement of calcium and phosphorus from maternal bone to breast milk, renal tubular calcium reabsorption, and suppressing PTH.⁵¹ Suckling and prolactin increase PTHrP, which in conjunction with low estradiol levels, up-regulates bone reabsorption of calcium.³⁶ PTHrP levels may show a pulsate pattern in response to suckling. Intestinal calcium absorption is not increased in lactation as it was during pregnancy. However, renal calcium excretion is reduced, conserving calcium for milk production.^44,51 Thus the calcium demands of lactation are met primarily through reabsorption of maternal skeletal calcium, probably mediated primarily by PTHrP, and reduction in renal excretion of calcium.³⁶ Changes in calcium metabolism during lactation are summarized in Figure 17-2.

Markers of bone turnover are increased in early lactation but decrease after 6 to 12 months, even with continuation of lactation.⁶⁵ Maternal bone density decreases during lactation, with up to 7% of the maternal bone mass lost by 9 months’ lactation.³⁹ These changes are most prominent in the trabecular bones of the axial skeleton and hip (e.g., pregnancy and lactation are associated with a 2% to 10% loss of bone mass in the spine and hip), in the first six months of lactation, with wide individual variation.^{3,18,51,56,65} Calcium losses do not continue beyond 6 months even with continued lactation.⁵¹ Calcium supplementation during lactation does not prevent these losses.¹⁸ These are reversible changes with no long-term adverse effects in most women as the maternal skeleton recovers the calcium within 3 to 6 months of weaning (with a regain of bone mineral density of 0.5% to 2% per month).^18,36,56,65 Very rarely bone reabsorption may be excessive, with fractures and a clinical diagnosis of osteoporosis.^35,44,65

Changes in the maternal skeleton are reversed in the later stages of lactation and with weaning. Markers of bone reabsorption increase in the first 5 to 12 months of lactation and then decrease.⁶⁵ During weaning, there is decreased suckling and milk volume and increase in estradiol levels. PTHrP levels decrease.⁵⁶ After weaning, PTHrP and PTH levels are elevated, intestinal absorption increases, and urinary calcium losses decrease.^44,65 These changes may help the woman regain her stores. By 3 to 5 months after lactation, bone mineral status is similar or higher in lactating women than in nonlactating women, regardless of the length of lactation.⁶⁵ Increases in PTH and 1,25-(OH)₂D after weaning help restore the maternal skeleton.⁶⁵ Lactation physiology is discussed further in Chapter 5.

Maternal nutritional needs

During pregnancy an additional 400 mg/day of both calcium and phosphorus is recommended, especially during the second and third trimesters. This results in a total calcium intake of 1200 mg/day in the pregnant woman (or 1600 mg/day in the pregnant adolescent).⁴⁴ The effect of supplemental calcium intake on bone density during pregnancy is unclear, since changes in bone metabolism occur even with increased calcium intakes.^65,83 There is no consistent correlation between dietary calcium intake or 1,25-(OH)₂D bioavailability and intestinal calcium absorption. Hoskings notes that because the fetal skeleton contains only 28 to 30 g of calcium (far less than the average 1000 g of calcium in the adult skeleton), it is unlikely that fetal calcium needs cause clinical bone disease in the mother, but these needs may exacerbate the effects of existing low peak bone mass.²⁷

Most studies have not shown significant increase in maternal bone mineral density with use of calcium supplements, although neonatal bone mineral density may be improved.^36,51,75,77 However, women with low calcium intakes (less than 600 mg/day), adolescents, or women with multiple pregnancy may benefit from increased calcium intake or supplementation during pregnancy.^1,37,56,65 Calcium supplementation during pregnancy has been associated with a reduced risk of preeclampsia (see Maternal Calcium Metabolism and Pregnancy Complications), increased birth weight, decreased risk of preterm delivery, decreased fetal lead exposure (calcium decreases circulating lead in the mother), and lower infant blood pressures.^6,26,77,82 Calcium and phosphorus needs during lactation are discussed further in Chapter 5.

Vitamin D intake is critical in maintaining calcium homeostasis. Vitamin D intakes of 400 international units (10 mcg) per day are recommended in pregnancy, although some question whether these values are too low.⁶ Vitamin D helps ameliorate fluctuations in the calcium-to-phosphorus ratio and enhances calcium absorption. Five percent to 29% of pregnant women in the United States may have an inadequate vitamin D status.¹⁵ Alterations in calcium and bone metabolism, including increased risk of maternal osteomalacia and neonatal hypocalcemia, tend to occur primarily in women who have diets that are low in both calcium and vitamin D.⁴⁴ Supplementation is recommended for women with low levels prior to pregnancy, low dietary intakes, and minimal sunlight exposure, although studies of the efficacy of supplementation are limited.^36,40,50,58 Low intake of vitamin D during pregnancy has been associated with preeclampsia, gestational diabetes, increased cesarean section, bacterial vaginosis, preterm delivery, and lower weight gain and altered fetal mineral accretion, although some data for these effects are contradictory.^{2,6,12,15,36,38,40,82}

Milk is an excellent source of calcium, vitamin D, and phosphorus. Alternatives for women who are lactose intolerant include cheese, yogurt, lactose-free milks, sardines, whole or enriched grains, and green leafy vegetables. Some substances alter calcium absorption. For example, lactose increases calcium absorption, possibly by decreasing luminal pH or through chelate formation. Excessive fats, phosphate, phytates (found in many vegetables), or oxalates interfere with calcium absorption by forming insoluble calcium salts within the intestinal lumen. High sodium concentrations may also decrease calcium absorption by interfering with active transport mechanisms.

Adequate intake of phosphorus is as important as that of calcium because these two minerals exist in a constant of solubility in the blood (see Box 17-1 on page 590). Excess dietary phosphorus binds calcium in the intestine, limiting absorption; excess blood phosphorus leads to increased urinary excretion of calcium. Therefore it is essential for the diet of pregnant and lactating women to be balanced in regard to these substances. Foods such as processed meats, snack foods, and cola drinks have high phosphorus but low calcium levels.

Leg cramps

Sudden tonic or clonic contraction of the gastrocnemius muscles and occasionally the thigh and gluteal muscles is experienced by 25% to 50% of all pregnant women.^25,63,79 These cramps are felt most frequently at night or on awakening and are most common after 24 weeks’ gestation.⁸⁹ Leg cramps are also more common in sedentary versus active pregnant women.

Cramps may be associated with a lower threshold for increased neuromuscular irritability due to decreased serum ionized calcium levels combined with increased serum inorganic phosphate levels, along with the hormonal and biochemical alterations of pregnancy.^62,63 Systemic relaxin may decrease calcium movement into muscle, increasing the risk of leg cramps.⁶³ The incidence of leg cramps is not correlated with ionized calcium levels. Muscular irritability in pregnancy also arises from the lowered calcium levels and mild alkalosis caused by changes in the respiratory system (see Chapter 10).⁶³ Interventions have included reducing milk intake (although milk is rich in calcium, it also contains large amounts of phosphate); supplementation with magnesium lactate or citrate; or use of aluminum hydroxide antacids to promote formation of insoluble aluminum phosphate salts in the gut, thus reducing absorption of phosphorus.⁶² Young and Jewell found the best evidence for treatment with magnesium lactate or citrate.⁸⁹ Calcium supplements have often been used although data to support their efficacy are weak.^25,89 Thus the specific basis for leg cramps in pregnant women and the most effective interventions remain unclear.

Maternal calcium metabolism and pregnancy complications

Women with acute and chronic hypertension during pregnancy tend to have lower serum calcium and higher magnesium levels.^35,51 Decreased calcium increases vascular resistance.⁶⁴ The incidence of preeclampsia has been reported to vary inversely with calcium intake, primarily in women at high risk for low calcium intake.²⁶ A recent meta-analysis of 12 studies of calcium supplementation and preeclampsia found that the risk for preeclampsia decreased by 50% (range 31% to 67% reduction) and concluded that the “reduction in preeclampsia, and in maternal death or severe morbidity, support the use of calcium supplementation, particularly for those with low dietary intake.²⁶ Calcium supplementation during pregnancy was also found in this meta-analysis to reduce the risk of preterm birth; another more recent meta-analysis also found a significant protective benefit of calcium supplementation in the prevention of preeclampsia, but found no additional benefit in preventing preterm birth or low birthweight.^16,26

Women on long-term heparin therapy for thromboembolism during pregnancy may occasionally develop heparin-induced osteopenia. Heparin inhibits 1α-hydroxylation of 25-(OH)D, decreasing levels of 1,25-(OH)₂D; altering calcium homeostasis; and increasing bone calcium absorption.^44,51 Calcium status should be monitored carefully in women receiving this therapy.

Disorders of the parathyroid glands are rare. The diagnosis of primary hyperparathyroidism may be obscured by pregnancy changes in calcium metabolism. Pregnancy may provide some protection to women with this disorder, with 39% to 80% becoming asymptomatic during pregnancy. This is often followed by an acute exacerbation postpartum. Moderate to severe forms of this disorder may lead to maternal hypercalcemia with fetal parathyroid suppression and hypocalcemia and risk for neonatal tetany.^35,44,51,64 In women with hypoparathyroidism the normal replacement dose of vitamin D may need to be increased due to the increased vitamin D–binding hormone in pregnancy.^35,44,51,64

Osteoporosis is a rare complication of pregnancy and seems to be associated with various factors—such as chronic heparin, anticonvulsant, or steroid use, low bone mineral density prepregnancy, skeletal abnormalities, or excessive reabsorption secondary to chronic inadequate calcium intake, low 1,25-(OH)₂D stores, or excessive parathyroid hormone–related peptide (PTHrP)—rather than pregnancy-induced alteration in calcium metabolism.^18,35,44 Similarly the also rare pregnancy-associated osteoporosis of the hip is thought to be unrelated to alterations in mineral balance in pregnancy.^14,35 This condition, seen primarily in primigravida lactating women with small body builds, is self-limiting and usually resolves by 6 to 12 months postpartum.³¹

Maternal-fetal interactions

Maternal-placental-fetal calcium metabolism is interrelated. As noted earlier, fetal calcium accumulation is mediated by increased maternal absorption of calcium. Calcium is actively transported across the placenta, mediated primarily by PTHrP to maintain a 1:1.4 maternal to fetal calcium gradient.^{28,35,62,69,87} Calcium transport increases from 50 mg/day (20 weeks) to greater than 150 mg/day (mean 200-300 mg/day) at term.^{5,17,31,35,36,46} About 80% of fetal mineral accretion occurs after 25 weeks, with peak accretion occurring from 34 to 38 weeks’ gestation coinciding with bone development.^18,29,33,34 Total fetal calcium accretion increases during pregnancy from 100 mg (4 months) and averages 25 to 30 g (generally 28-30) at term.^{36,51,59,64,69} Fetal serum calcium (10 to 11 mg/dL [2.5 to 2.8 mmol/L]) is about 1 mg/dL (0.25 mmol/L) above maternal values.⁴⁴ The higher fetal values are primarily due to increased ionized calcium.

Fetal calcium accretion and active transport across the placenta are independent of maternal calcium levels and stores. Calcium movement across the placenta involves three phases: (1) passive bidirectional movement across the maternal-facing microvillous trophoblast membrane into the syncytiotrophoblast cytosol; (2) binding of calcium to calcium-binding proteins such as calmodulin for transport through the syncytiotrophoblast cytosol (binding buffers the calcium so that it does not disrupt cellular processes in the trophoblast); and (3) active transport across the fetal-facing basolateral trophoblast membrane into fetal circulation via several calcium channels and transporters.^5,7,27,29 Placental transport of both calcium and phosphorus also involves insulin–like growth factor-1, which also stimulates 1,25-(OH)₂D synthesis.⁶⁹

PTHrP (see Box 17-2 page 591) regulates control of calcium transport across the placenta.²⁸ PTHrP is the major factor in maintaining the fetal calcium level higher than maternal levels. PTHrP is also important for bone development.³⁶ PTHrP is produced by the fetal parathyroid glands, skeletal growth plate, umbilical cord, amnion, chorion, and placenta.^27,87 PTHrP levels are higher in the fetus than in adults.⁸⁷ Fetal calcium levels are set at a specific level and appear to be maintained at that level regardless of maternal calcium level, even with maternal hypocalcemia.³⁵ Although fetal calcium levels are maintained primarily by PTHrP-mediated placental calcium transport, movement of calcium in and out of fetal bone, fetal renal tubular reabsorption and excretion of calcium, and swallowing of amniotic fluid also have a role in maintaining fetal homeostasis.³⁵ Lack of adequate PTHrP and PTH can lead to fetal growth restriction since both substances are critical for skeletal mineral accretion.⁶⁹

The fetus accumulates 16 g of phosphorus, primarily in the third trimester, and 0.75 g of magnesium (with a peak of 60-75 mg/kg/day in the third trimester).^46,69,70 Most of the fetal phosphorus is used for bone mineralization.⁶⁹ Fetal phosphorus and magnesium levels are higher than maternal levels; these minerals are actively transported across the placenta.^39,62,69,72 Magnesium is transported to the fetus in increasing amounts after the fifth month.²⁰ Fetal magnesium levels depend on adequate placental function and maternal stores. Placental insufficiency and inadequate nutritional intake increase the risk of neonatal hypomagnesemia. Transplacental passage of magnesium is influenced by maternal level; for example, administration of large amounts of magnesium sulfate to the mother leads to elevated magnesium in both mother and fetus.²³

Fetal mineral homeostasis is not heavily dependent on vitamin D.⁴⁶ Placental transport of 1,25-(OH)₂D is low and the fetus is a main source of this substance.^4,40,62,75 The placenta also synthesizes 1,25-(OH)₂D and contains 1,25-(OH)₂D receptors and key enzymes such as 1-hydroxylase needed for vitamin D metabolism.⁴ The fetus is dependent upon maternal 25-(OH)D, which is readily transported across the placenta, because fetal hepatic enzyme processes are limited. The 25-(OH)D is 1α-hydroxylated to 1,25-(OH)₂D in the fetal kidneys.^35,44 Maternal vitamin D deficiency is associated with an increased incidence and severity of neonatal hypocalcemia. PTH and calcitonin do not appear to cross the placenta.^44,62,75 Vitamin D is an important factor in the regulation of cellular differentiation and apoptosis.⁴¹ Insufficient vitamin D during gestation can affect development of the fetal skeleton, immune system, and brain and may alter fetal programming, increasing the risk of adult-onset disorders.⁴¹ Maternal vitamin D deficiency during pregnancy has been associated with neonatal hypocalcemia, impaired growth, and later problems in offspring including skeletal problems, type 1 diabetes, altered immunotolerance, risk of autoimmune disease, food allergies, and altered programming of long bone development.^{6,13,36,40,41,42,71,82}

Parathyroid glands

Many structures of the head and neck—the maxillary process, mandibular arch, several muscles of the jaw, hyoid and ear bones, thyroid, and cricoid cartilage—develop from the branchial or pharyngeal arches. These are bars of mesenchymal tissue separated by pharyngeal clefts. The pharyngeal pouches are outpouchings along the lateral walls of the pharyngeal gut. Structures that develop from these pouches include the palatine tonsils, thymus, primitive tympanic cavity, and (from the third and fourth pouches) the parathyroid glands (Figure 17-3).⁴⁸

The third and fourth pharyngeal pouches develop bulbar and ventral portions. The inferior parathyroid glands differentiate from the dorsal bulbar portion of the third pharyngeal pouch during the sixth week. The ventral portion of this pouch forms the thymus. The parathyroid glands initially migrate caudally and medially with the thymus, later separating and attaching to the inferior portion of the dorsal surface of the descending thyroid gland (see Chapter 19). The superior parathyroid glands develop from the dorsal bulbar portion of the fourth pharyngeal pouch by the sixth week and attach to the superior portion of the dorsal side of the caudally migrating thyroid gland (see Figure 17-3).⁴⁸ Parathyroid glands are active by 12 weeks, but function is suppressed by the high serum calcium concentrations in the fetus.^23,51,69 

Skeletal development and growth

Skeletal growth occurs in two phases. During fetal life a cartilage anlage (primordium) is formed that is later replaced by bone. Bone formation also occurs by differentiation of mesenchyme directly into bone cells. Later linear growth depends on cartilaginous growth in the endochondral ossification centers at the epiphyses; appositional growth of the skeleton depends on the laying down of new bone by bone-forming cells with subsequent remodeling (reabsorption of existing bone followed by formation of new bone). Bone formation and remodeling are a cyclic process that occurs continuously throughout life. During growth, bone formation is greater than remodeling. Once maximal growth is achieved, the skeletal mass is stable for 10 to 15 years, and remodeling and bone formation occur at the same rate. With aging, remodeling is greater than bone formation, with a gradual loss of bone mass. Excessive differences between bone formation and remodeling can lead to osteoporosis and compromised skeletal integrity. Stress, such as subjecting bone to heavy loads, or stress that occurs with strenuous exercise, stimulates osteoblastic deposition of new bone, leading to thickening of bones.^24,67

Skeletal development begins in early embryonic life (apparent by the eighth week) and continues well into postnatal life.⁵¹ Bone consists primarily of organic matrix and bone salts. Compact bone is 30% organic matrix and 70% bone salts; newer bone has a more organic matrix. The organic matrix is composed primarily of collagen fibers that give the bone its tensile strength. The rest of the matrix is ground substance, consisting of extracellular fluid and proteoglycans, which may assist in controlling deposition of calcium salts. Crystalline bone salts (hydroxyapatites) give bone compressional strength and consist primarily of calcium and phosphorus with small deposits of sodium, potassium, magnesium, and carbonate salts.^24,67

Bone is formed by either intramembranous or endochondral ossification. Intramembranous ossification is the process involved in formation of bones such as the skull, mandible, and maxilla.^67,69 With intramembranous ossification, the fibrous mesenchyme condenses to form a collagenous membrane in which some cells differentiate into osteoblasts. Osteoblasts produce a collagenous material and ground substance to fill the extracellular spaces. The collagen polymerizes to form collagen fibers and the tissue becomes osteoid and similar to cartilage.^67,69 Osteoblasts later secrete alkaline phosphatase, which leads to deposition of calcium salts in the form of calcium hydroxyapatite crystals, with gradual conversion of the osteoid to bone. Some osteoblasts are trapped within lacunae in the bone matrix and develop into osteocytes. The bone matrix grows in all directions as spicules and ossification centers are established.

The osteoblasts deposit spongy bone first, followed by plates of compact bone (periosteal ossification). Spongy bones are filled with fibrous and cellular mesenchymal derivatives that later differentiate into elements characteristic of red bone marrow (reticular tissue, fat cells, sinusoids, and developing blood cells). Bone growth is accompanied by remodeling in which much of the original matrix is reabsorbed by osteoclasts simultaneously with formation of new bone by osteoblasts. During this process the osteoclasts project villi that secrete proteolytic enzymes to dissolve the organic matrix and citric, lactic, and other acids that cause solution of bone salts.²⁴

The long bones of the appendicular and axial skeleton form by endochondral ossification in which the condensed mesenchymal cells give rise to hyaline cartilage models that are shaped like the eventual bone. This cartilage is eroded locally and destroyed as bone is formed. Endochondral ossification involves the progressive destruction of cartilage, deposition of calcium salts, and formation of a central area of spongy bone (that will later develop a red marrow matrix) surrounded by compact bone. This process begins in the middle of the bone shaft and progresses toward the epiphysis. At birth the long bones consist of central ossification centers and bony shafts with cartilaginous ends. Secondary areas of ossification later appear in the epiphyses.^48,67

Bone growth and mineralization are mediated by a variety of regulating hormones and growth factors including calcitropic hormones (e.g., PTH, vitamin D, calcitonin); parathyroid hormone–related peptide (PTHrP); systemic growth-regulating hormones (e.g., growth hormone, insulin, glucocorticoids, thyroid hormones, sex steroids); circulating growth factors (e.g., somatomedin, insulin-like growth factor [IGF], epidermal growth factor, platelet-derived growth factor, fibroblast growth factor); and local factors (e.g., osteoclast activity factor, cartilage-derived growth factor).^67,69,72 In addition, maternal diet (especially vitamin D), physical activity, and smoking during pregnancy may also influence fetal bone mineral acquisition.¹⁹

Functional development

Fetal mineral requirements are met by transport of calcium, phosphorus, magnesium, and other minerals across the placenta (see Maternal-Fetal Interactions). Eighty percent of calcium and phosphorus accretion occurs in the third trimester.⁷² From 25 weeks’ gestation to term, bone mineralization increases fourfold and fetal calcium acquisition ranges from 92 to 119 mg/kg/day or higher (up to 350 mg/day or a mean of 200 mg/day at term) and phosphorous from 2.51 to 3.44 mg/kg/day (Figure 17-4).^33,35 In contrast, calcium accretion immediately after birth increases from 15 mg/kg on day 1 to 45 mg/kg on day 3.²⁰ Phosphate levels peak at midgestation (15 mg/dL [4.8 mmol/L]) and then decrease to 5.5 to 7 mg/dL (1.8 to 2.3 mmol/L) by term.

1,25-(OH)₂D and PTH levels are low in the fetus and probably have a limited role in fetal calcium physiology.^35,46 The parathyroid gland contains PTH by 10 to 12 weeks and actively secretes PTH by 25 to 26 weeks in response to decreased extracellular fluid calcium.^6,48 The fetal parathyroid is less responsive to decreased serum calcium, perhaps because of suppression of the parathyroid by the relative fetal hypercalcemia or placental PTH production.^6,28,62 The predominant hormone regulating fetal calcium homeostasis is PTHrP (see Box 17-2 on page 591) rather than PTH as occurs after birth and in adults, although PTHrP and PTH act synergystically.^27,69

Cord concentrations of vitamin D metabolites are only about 20% of maternal levels.^6,36 25-(OH)D is transferred from the mother since fetal liver processes for vitamin D metabolism are limited.³⁵ Renal 1α-hydroxylation to form 1,25-(OH)₂D occurs in the fetal kidneys, placenta, and decidua.⁴⁶ The fetus needs to store vitamin D to cope with the relatively high calcium requirements of the early postbirth period. Vitamin D deficiency during fetal development can alter bone growth and development as well as other areas of development in the infant and child and has implications for the development of other disorders.^1,46 These implications and fetal vitamin D synthesis are described further in Maternal-Fetal Interactions on pp. 595-596.

Calcitonin-containing cells appear in the thyroid at about 14 weeks’ gestation and secrete immunoreactive calcitonin from 28 weeks.⁴⁶ Calcitonin levels are high in the fetus, with increasing concentrations during the third trimester. The role of calcitonin in the fetus is unclear; however, animal evidence suggests that calcitonin does not have a major role in fetal bone metabolism.^35,46

Transitional events

At birth, maternal supplies of calcium and other minerals are no longer available to the infant. Within 24-48 hours of birth, the infant moves from the hypercalcemic, peptide PTHrP-dominated calcium metabolism to a parathyroid hormone (PTH) and 1,25-(OH)₂D environment. In this environment, the infant must mobilize bone calcium and increase intestinal absorption to maintain serum calcium levels.³⁵ Total and ionized calcium levels are higher in cord blood than in maternal serum; PTH is decreased, but PTHrP is increased.^{21,23,35,62,70} Cord blood magnesium levels are slightly increased and related to maternal levels, whereas phosphorus levels are low.^21,69 Cord blood levels of calcitonin are reported to be 68% to 108% of maternal levels and correlate with maternal levels.²³

Maternal serum 25-(OH)D levels at term correlate with cord blood levels, although cord blood values are about 20% lower; 1,25-(OH)₂D levels are about half maternal values.^6,46 At birth serum osteocalcin levels are two to three times higher than in adults. This reflects the rapid rate of fetal bone formation in the last weeks of pregnancy. Osteocalcin is a noncollagenous bone-specific protein that is released into the blood in proportion to the amount of bone formation. Levels increase from birth to 1 to 5 days and then decrease. Markers of bone formation decrease and markers of bone reabsorption increase for a few days after birth due to the transition to dependence on intestinal mineral absorption and the relatively low intake immediately after birth. After that time, both types of markers increase over the next few weeks.¹⁸

Calcium

The relative hypercalcemia at birth is followed by a physiologic hypocalcemia as both total and ionized calcium fall to levels lower than those found in older infants and about 1 mg/dL (0.25 mmol/L) lower than birth values.^23,46,62 There is a rapid decrease in ionized calcium, especially in the first 4 to 6 hours after birth, reaching a nadir of 4.4 to 5.4 mg/dL (1.1 to 1.4 mmol/L) by 16 to 24 hours.^35,37,46,54 Calcium levels generally stabilize in the next 24 to 48 hours and then increase along with increases in PTH and 1,25-(OH)₂D.^23,35 The fall in calcium is thought to be due to parathyroid suppression in late gestation (from elevated fetal calcium levels), loss of placental transport of calcium, and an increased PTH response.^35,46 This nadir is more pronounced in infants who are preterm or born to mothers with diabetes or vitamin D deficiency.³⁶ In term infants, total calcium values average 8 to 9 mg/dL (2 to 2.2 mmol/L), with a range of 8 to 11 mg/dL (2 to 2.8 mmol/L), and are slightly lower in preterm infants. Ionized calcium levels are 4 to 4.6 mg/dL (1 to 1.5 mmol/L).^28,69 Calcium levels at birth correlate inversely with gestational age.^33,62,69 The length and degree of the postbirth physiologic hypocalcemia are also correlated inversely with gestational age.^23,69 In very low–birth weight (VLBW) infants this hypocalcemia may persist despite increasing levels of PTH and 1,25-(OH)₂D.^23,36

Intestinal absorption of calcium is correlated with both gestational and postbirth age, but the major factor in determining absorption is postnatal age.²³ Immature intestinal function and decreased intake may limit calcium absorption. Much of the intestinal transport is primarily passive (via paracellular transport) in preterm infants since transcellular active transport, which is vitamin D dependent, is not yet mature.⁶⁹ Renal calcium excretion is relatively efficient in both term and preterm infants, although increased renal sodium losses in VLBW infants may also increase calcium loss.^23,69 Renal calcium excretion increases with gestational and postbirth age, ranging from 60 to 88 mg/day during the first 2 weeks to 180 mg/day by 3 to 12 weeks in the term infant and from less than 8 to 80 mg/day to 120 mg/day by 2 weeks of age in the preterm infant.²⁰

Phosphorus

Phosphorus levels may decrease slightly during the first 1 to 2 days after birth but remain higher than those of adults.⁶² Renal excretion of phosphorus is delayed because of a decreased glomerular filtration rate and increased tubular reabsorption of phosphorus. Increased energy demands during birth with conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) lead to additional phosphorus release. Delayed feeding further elevates phosphorus levels because of tissue catabolism. Phosphorus levels are lower in small-for-gestational-age (SGA) infants and correlate with the degree of growth restriction. Levels are higher in formula-fed than breastfed infants and inversely related to serum calcium concentrations.⁶⁹ The fractional excretion of phosphorus is increased in preterm infants, increasing the risk of phosphate deficiency.⁶⁹

Parathyroid hormone

As serum calcium levels decrease over the first few days after birth, PTH levels gradually increase by about 24 to 48 hours.³⁷ Levels are higher in hypocalcemic preterm infants.²³ Preterm infants may have a transient pseudohypoparathyroidism for the first 72 hours secondary to immature bone and renal responses to PTH.²³ By 3 to 4 days of age, the preterm infant’s parathyroid gland generally responds effectively to calcium. The infant of a diabetic mother may also have impaired PTH production initially; infants following perinatal hypoxic ischemic events may have a decreased PTH response to low calcium.⁶⁹ PTH levels do not appear to change with oral administration of calcium supplements, but intravenous bolus administration of calcium can suppress parathyroid function.²³ PTHrP decreases rapidly after birth to the low levels normally seen in adults. Its role in neonatal calcium homeostasis is unclear, but PTH is the major calcitropic hormone by 48 hours of age.³⁵ The response of the neonatal kidneys to PTH is not well understood, although both term and preterm infants do respond to exogenous PTH.²⁸ The amount of calcium excreted by the kidneys increases over the first 2 weeks after birth, perhaps mediated by the increasing glomerular filtration rate (see Chapter 11).²⁸

Vitamin D

Plasma concentrations of 25-(OH)D are lower than and correlate with maternal serum values and remain stable in both term and preterm infants in the first week.²³ Term infants are able to effectively metabolize vitamin D in the liver and kidneys. The kidneys can convert 25-(OH)D to 1,25-(OH)₂D by 28 to 32 weeks’ gestational age. However, vitamin D metabolism remains limited in the preterm infant because 25-hydroxylation by the liver does not occur at significant rates until 36 to 38 weeks’ gestation.⁷⁵ In VLBW infants born at less than 28 weeks gestation the vitamin D activation pathway may remain immature.⁶⁹ Absorption of exogenous vitamin D may also be limited because of immature fat absorption. Serum 1,25-(OH)₂D levels increase during the first 48 hours, probably because of decreased serum calcium or increased PTH, and elevated levels persist for the first week.⁵⁶ The increase parallels the decrease in serum calcium and increase in PTH in both term and preterm infants.²³ This helps maintain calcium levels within physiologic limits by stimulating bone and intestinal reabsorption.^23,35 In preterm infants, levels may remain higher for up to 7 to 9 weeks, reflecting rapid prenatal growth.²³ 

Calcitonin

Calcitonin levels may be normal or slightly elevated at birth, followed by a surge that is reported to peak anywhere from two- to 10-fold over cord blood levels by 24 to 48 hours of age.⁶⁹ Levels then plateau and decrease to childhood levels by 1 month.^23,52 Calcitonin levels are inversely correlated with gestational age.⁵² Increased calcitonin may protect the infant from excessive bone reabsorption and promote mineralization during a period of active bone growth in the face of increased PTH and 1,25-(OH)₂D. High calcitonin levels may contribute to the lower serum calcium levels and increased risk of hypocalcemia seen in preterm infants. Calcitonin levels remain high in preterm infants for a longer period of time, slowly decreasing over the first 2 to 3 months to reach normal levels by about 40 weeks’ postmenstural age.⁵²

Magnesium

Serum magnesium levels increase initially after birth and then fall to levels similar to those in adults (range, 1.5 to 2.8 mg/dL [0.6 to 1.2 mmol/L]) by 2 weeks. Urinary excretion of magnesium may be low for the first few days after birth.

Bone mineralization

After birth the neonatal skeleton continues to accrete calcium at a rate of approximately 150 mg/kg/day.^35,37 To accomplish this, the infant must have adequate vitamin D and intestinal absorption of calcium. This may be difficult to achieve in VLBW and ELBW infants. Rigo and colleagues note that the goal for VLBW infants is postnatal growth similar to the intrauterine rate, with a slightly higher rate in ELBW infants.⁶⁷ To reach this goal, these infants need not only adequate supplies of calcium, phosphorus, and other minerals, but also protein and energy for formation of the collagen matrix.^67,69 VLBW infants have decreased postnatal bone mineralization and a significant delay in completing bone development in comparison with intrauterine rates.¹⁰ Prolonged (greater than 5 days) maternal magnesium sulfate administration has been reported to alter neonatal bone mineralization.⁸⁸

Preterm infants are at risk for both rickets and osteopenia (reduction of bone mass with demineralization of the bone with or without signs of rickets). By term-corrected age, VLBW infants are still of lower weight and length than term infants with linear growth restriction and lower bone mineral mass and density seen in up to 22% of AGA preterm infants.^8,37 Land and Schoenau suggest that one reason for this difference is that the fetus in utero experiences higher mechanical resistance to extremity movement than occurs after birth. Thus the preterm infant’s movements occur against lower resistance, which provides less stimulation for development.³⁷ Significant bone mineralization problems, ranging from osteopenia to rickets, are seen in more than 30% of ELBW infants.^33,67 Mineralization may also be delayed in SGA infants. Longitudinal follow-up is important after discharge to promote catch-up growth and optimal bone mineralization.⁶⁷ Factors leading to inadequate bone mineralization are illustrated in Figure 17-5.

The serum calcium level below which an infant is considered to be hypocalcemic varies in the literature from 7 to 8 mg/dL (1.75 to 2 mmol/L).^33,62,69,70 Most sources use a lower limit of 7 mg/dL (1.75 mmol/L) in preterm and 7.8 to 8 mg/dL (1.95 to 2 mmol/L) in term infants.^23,33 Ideally determination of hypocalcemia should be based on the ionized calcium fraction (less than 4.4 mg/dL [1.1 mmol/L]) because this is the biologically active form.^8,20,23,33 In preterm infants the relationship between total and ionized calcium is atypical, so infants may have a greater decrease in total serum calcium than in ionized calcium.²⁸

Hypoproteinemia or acid-base changes can alter calcium levels. Serum calcium is either ionized (physiologically active form) or undissociated and bound to protein or complexed to anions. Because these two forms of serum calcium are in equilibrium, hypoproteinemia lowers serum calcium levels. This equilibrium is influenced by acid-base status. Acidosis increases the movement of calcium from bone and decreases the amount of protein-bound calcium. As a result, levels of ionized calcium increase. Opposite effects are seen during alkalosis.²⁰

Infants at greatest risk for hypocalcemia are preterm infants, those born to diabetic mothers, and those born after perinatal hypoxic-ischemic events. Possible pathogenic mechanisms are discussed below and are summarized in Table 17-4. Hypocalcemia due to decreased ionized calcium may occur after exchange transfusion, with renal dysfunction, after furosemide therapy, or with magnesium deficiency. Hypocalcemia with a decrease in ionized calcium but without a decrease in total calcium can occur with alkalosis, after exchange transfusion with citrated blood, or with elevated serum free fatty acids after lipid infusion.²⁰ Alkalosis leads to a decreased affinity of albumin for calcium and thus less ionized calcium. A rapid shift in the amounts of ionized versus albumin-bound calcium can lead to significant hypocalcemia.⁶⁹ Hypocalcemia in infants with fetal growth restriction is usually associated with prematurity or perinatal hypoxic-ischemic events.³³