Skeletal Development and Mineral Requirements of the Fetus
The growing fetus must be supplied with sufficient calcium for the formation and growth of a mineralizing skeleton. In addition, the physiologic milieu of the fetus must be maintained in an environment appropriate for normal cellular function. Thus, adequate extracellular calcium must be provided for normal function of the clotting factors, and avoidance of neuromuscular hyperexcitation. Yet at the same time, the supply must be appropriately limited to prevent soft tissue calcification or other toxicity to the developing fetus. A critical calcium dependent process in fetal life is skeletal accrual of mineral. Most of the skeleton is formed by the com plex process referred to as endochondral ossification. Cartilage templates are organized in concert with the transition of undifferentiated mesenchymal cells to differentiated chondrocytes. The cartilage templates serve as a nidus for eventual development into the skeleton. A system of chondrocyte maturation and proliferation oc curs at what will become the ends of long bones, allowing for the continued linear growth of the skeleton. Regulation of this early formative process is dependent upon a variety of local and systemic factors, such as insulin- like growth factors (IGFs), fibroblast growth factors (FGFs), parathyroid hormone- related peptide (PTHrP), and Indian hedgehog protein. Once mature cartilage forms, chondrocytes hypertrophy, and blood vessels penetrate the region, with the appearance of marrow stroma and osteoblasts soon to follow. Mineralization of the newly established skeleton begins, and growth results in an increasing mineral demand in order to effectively mineralize the newly formed tissue. Indeed, the fetus has substantial mineral demands: approximately 26– 30 grams of calcium accumulate in the human through a term gestation, and accretion of more than three- fourths of this amount occurs in the third trimester. Calcium supply from the maternal circulation must be regulated by specific mechanisms in order to meet these demands throughout the later weeks of gestation.
The Fetal Calcium Regulating System
The maternal circulation is the source of calcium provided to the fetus. An abundance of calcium occurs in the mother primarily as a result of a pregnancy- induced doubling of maternal circulating 1,25- dihydroxyvitamin D [1,25 (OH)2D] levels, which in turn increases fractional absorption of calcium at the intestine. This occurs in the absence of significant increases in circulating levels of parathyroid hormone (PTH) in the mother.
The placenta is the site of nutrient transfer from the maternal circulation to the fetus. Calcium may be transported by several mechanisms across the placenta; the dominant direction of flow is from maternal to the fetal circulation, requiring active transport. A Ca++- ATPase located in the fetus- directed basement membrane of the syncytial trophoblast cells appears to mediate this important function. Although it is not clear exactly when in gestation active calcium transport begins, it is present by the beginning of the third trimester. The fetal circulating calcium level is maintained at a slightly higher concentration (1.2– 2.0 mg/ dl) than the maternal circulation as early as 15 weeks of gestation. Active placental calcium transfer plays an important role in determining fetal circulating calcium level, but other factors may play a role, including PTH and PTHrP. The relative hypercalcaemia in the fetus appears to be necessary for complete skeletal growth and mineralization.
Placental calcium transfer seems to be mainly regulated by PTHrP, and to a lesser extent by PTH. The mid- and carboxy- terminal portions of the PTHrP molecule are required, whereas the amino- terminus (most related to PTH in sequence) does not have activity in this regard. PTHrP plays an important role in embryonic growth and development of many tissues, and is produced by multiple tissues. Major sources of PTHrP production are the placenta, and to a lesser extent, the parathyroid glands. In a fetal mice model, disruption of PTHrP results in hypocalcaemia and severe chondrodysplasia. Fetal circulating PTH levels are low, probably due to Ca- sensing receptor (CaSR) mediated suppression of PTH secretion by fetal parathyroid glands. Nevertheless, aparathyroid fetal mice develop hypocalcaemia and defective bone mineralization, pointing towards a role for PTH in maintaining normal serum calcium, and thereby perhaps supporting normal bone mineralization. PTH may also exert its effect on bone formation, to some extent, via direct interaction with osteoblasts.
Fetal circulating 1,25 (OH)2D levels are low, and derived from placenta and fetal kidney, and may be related to the concurrent low PTH and high serum phosphorus levels. 1,25 (OH)2D does not play a major role in placental calcium transfer or maintenance of serum calcium level as evidenced by the fully mineralized skeleton and normal fetal serum calcium levels at term in vitamin D receptor- null (vdr- null) mice. In human cases of maternal vitamin D deficiency, skeletal mineralization seems to be unaffected but the newborn will be at risk of developing hypocalcaemia. The presence of CaSR in both human and murine placenta suggests a possible role for this membrane receptor in fetal calcium homeostasis. Some insight has been provided by CaSR null mice: fetuses of this strain demonstrate increased PTH levels, reduced placental calcium transport, increased amniotic fluid calcium, and increased markers of bone resorption. This constellation of findings suggests that an increase in skeletal resorption can occur, when inadequate calcium levels are sensed by the fetus. The fetal kidneys may be in volved in regulation of fetal calcium levels as well, but is of limited impact in that fetal urine is excreted into the amniotic fluid and recycled with swallowing.
Limited data regarding FGF23 levels in the human fetus suggest that intact FGF23 levels are lower than levels in adults but that C- terminal levels are approximately twofold greater than in adults. Circulating levels of alpha- klotho are reported as elevated in the fetus, likely reflecting a placental source. Other relevant measures in the fetal circulation include relatively increased levels of phosphorus, magnesium, and relatively low concentrations of calcitonin compared to postnatal life.
Transition from Fetal Life to Infancy
At birth the generous supply of maternal calcium is abruptly with drawn from the fetus, as well as the placental sources of PTHrP and 1,25 (OH)2D, with a resultant acute decrease in serum calcium of approximately 1 mg/ dl in term infants, and slightly more in pre- term infants. One study indicates that the decrement in serum calcium and rise in PTH is greater in babies born by Caesarean section than in babies born spontaneously by the vaginal route. This de crease in calcium then stimulates secretion of PTH, suppressed during fetal life, which in turn, stimulates the kidney to generate adult normal levels of 1,25 (OH)2D within the next several days. Levels of PTHrP are reduced; this hormone likely plays a lesser role in postnatal calcium homeostasis than in utero. The serum calcium gradually increases to normal childhood levels within a few days of the acute postnatal decrement. The relative hypercalcaemia of the fetus likely protects the newborn infant from acute severe hypocalcaemia during the transition to the ex utero environment.
The intestine and kidney assume major roles in mineral homeo stasis with this transition. The neonatal skeleton continues to accrue calcium at rates close to that attained in late gestation (averaging 100– 150 mg/ kg/ day). Thus, the newborn infant becomes dependent upon exogenous nutritional sources of calcium. Renal excretion of calcium increases over the first few weeks of life, as glomerular filtration rate (GFR) increases. As the kidney matures, it begins to play a minor role in regulation of calcium. The newborn infant, however, becomes primarily dependent upon the intestine to maintain its calcium supply. In the first few days to weeks of neonatal life, passive or facilitated calcium transport (not vitamin D- mediated mechanisms) are the dominant means by which calcium is brought into the body. After several weeks, vitamin D appears to be useful in enhancing calcium absorption in term infants. Fractional calcium absorption can be relatively high in infancy particularly in very low birthweight children, who may develop hypercalcaemia during high calcium intake, as may occur with the administration of breast- milk fortifiers. This phenomenon may occur independently of vitamin D status (with normal circulating levels of 25-hydroxyvitamin D (25- OHD), and appropriately low circulating PTH and 1,25 (OH)2D), implying that passive or facilitated, non- vitamin D- mediated calcium transport in the immature intestine can be remarkably efficient. The relatively low phosphate content of breast milk likely contributes to the greater bioavailability of calcium from breast milk as compared to most infant formulas. Formation of calcium- phosphate complexes in the higher phosphate containing formulas limit the availability of calcium for intestinal absorption.
