Question

Discuss the special importance of calcium and phosphorus to children and to pregnant women.

Also, explain the relationship of sodium and potassium in the body.

Answer 1

Pregnancy and lactation require women to provide calcium to the fetus and neonate in amounts that may exceed their normal daily intake. Specific adaptations are invoked within each time period to meet the fetal, neonatal, and maternal calcium requirements. During pregnancy, intestinal calcium absorption more than doubles, and this appears to be the main adaptation to meet the fetal demand for mineral. During lactation, intestinal calcium absorption is normal. Instead, the maternal skeleton is resorbed through the processes of osteoclast-mediated bone resorption and osteocytic osteolysis, in order to provide most of the calcium content of breast milk. In women this lactational loss of bone mass and strength is not suppressed by higher dietary intakes of calcium. After weaning, the skeleton appears to be restored to its prior bone density and strength, together with concomitant increases in bone volumes and cross-sectional diameters that may offset any effect of failure to completely restore the trabecular microarchitecture. These maternal adaptations during pregnancy and lactation also influence the presentation, diagnosis, and management of disorders of calcium and bone metabolism such as primary hyperparathyroidism, hypoparathyroidism, and vitamin D deficiency. Pregnancy and lactation can also cause pseudohyperparathyroidism, a form of hypercalcemia that is mediated by parathyroid hormone-related protein, produced in the breasts or placenta during pregnancy, and by the breasts alone during lactation. Although some women may experience fragility fractures as a consequence of pregnancy or lactation, for most women parity and lactation do not affect the long-term risks of low bone density, osteoporosis, or fracture.

INTRODUCTION

During gestation the average fetus requires about 30 g of calcium, 20 g of phosphorus, and 0.8 g of magnesium to mineralize its skeleton and maintain normal physiological processes. The suckling neonate obtains more than this amount of calcium in breast milk during six months of exclusive lactation. The adaptations through which women meet these calcium demands differ between pregnancy and lactation (Figure 1). Although providing extra calcium to the offspring could conceivably jeopardize the ability of the mother to maintain calcium homeostasis and skeletal mineralization, as this review will make clear, pregnancy and lactation normally do not cause any adverse long-term consequences to the maternal skeleton. The reader is referred to several comprehensive reviews for more details and extensive reference lists for the material covered in this chapter

Schematic illustration contrasting calcium homeostasis in human pregnancy and lactation, as compared to normal. The thickness of arrows indicates a relative increase or decrease with respect to the normal and non-pregnant state. Although not illustrated, the serum (total) calcium is decreased during pregnancy, while the ionized calcium remains normal during both pregnancy and lactation. Adapted from ref. (8), © 1997, The Endocrine Society.

MINERAL PHYSIOLOGY DURING PREGNANCY

Calcium provided from the maternal decidua aids in fertilization of the egg and implantation of the blastocyst; from that point onward the rate of transfer from mother to offspring increases substantially. About 80% of the calcium and phosphate present in the fetal skeleton at the end of gestation crossed the placenta during the third trimester and is mostly derived from the maternal diet during pregnancy. Intestinal calcium and phosphate absorption doubles during pregnancy, driven by 1,25-dihydroxyvitamin D (calcitriol) and other factors, and this appears to be the main adaptation through which women meet the mineral demands of pregnancy.

Mineral Ions

There are several characteristic changes in maternal serum chemistries and calciotropic hormones during pregnancy (Figure 2), which can easily be mistaken as indicating the presence of a disorder of calcium and bone metabolism, especially since it is not common for clinicians to measure calcium, phosphate, and calciotropic hormones during pregnancy (1). The serum albumin and hemoglobin fall during pregnancy due to hemodilution; the albumin remains low until parturition. In turn that fall in albumin causes the total serum calcium to decline to values that can be well below the normal range. The total calcium includes albumin-bound, bicarbonate-and-citrate-complexed, and ionized or free fractions of calcium. The ionized calcium, the physiologically important fraction, remains constant during pregnancy, which confirms that the fall in total calcium is but an artifact that can usually be ignored. However, that artifactual decline in total calcium means that the serum calcium cannot be relied upon to detect hypercalcemia or hypocalcemia. The ionized calcium should be measured or the albumin-corrected total calcium should be calculated to resolve any uncertainty about what the true serum calcium level is in a pregnant woman. Serum phosphate and magnesium concentrations remain normal during pregnancy.

Schematic illustration of the longitudinal changes in calcium, phosphate, and calciotropic hormone levels that occur during pregnancy and lactation. Normal adult ranges are indicated by the shaded areas. PTH does not decline in women with low calcium or high phytate intakes, and may even rise above normal. Calcidiol (25OHD) values are not depicted; most longitudinal studies indicate that the levels are unchanged by lactation, but may vary due to seasonal variation in sunlight exposure and changes in vitamin D intake. PTHrP and prolactin surge with each suckling episode, and this is represented by upward spikes. FGF23 values cannot be plotted due to lack of data. Very limited data suggest that calcitriol and PTH may increase during post-weaning, and the lines are dashed to reflect the uncertainty. Adapted with permission from (1).

Parathyroid Hormone

Parathyroid hormone (PTH) was first measured with assays that reported high circulating levels during pregnancy. The finding of a low total serum calcium and an apparently elevated PTH led to the concept of “physiological secondary hyperparathyroidism in pregnancy.” This erroneous concept persists in some textbooks even today. Those early-generation PTH assays measured many biologically inactive fragments of PTH. When measured with 2-site “intact” assays or the more recent “bio-intact” PTH assays, PTH falls during pregnancy to the low-normal range (i.e. 0-30% of the mean non-pregnant value) during the first trimester, and may increase back to the mid-normal range by term. Most of these recent studies of PTH during pregnancy have examined women from North America and Europe who also consumed calcium-replete diets. In contrast, in women from Asia and Gambia who have very low dietary calcium intakes (and often high intakes of phytate that blocks dietary calcium absorption), the PTH level does not suppress during pregnancy and in some cases it has been found to increase above normal (1).

Vitamin D Metabolites

25-hydroxyvitamin D or calcifediol (25OHD) readily crosses the rodent hemochorial placenta (9) and appears to cross hemochorial human placentas just as easily because cord blood 25OHD levels generally range from 75% to near 100% of the maternal value (1,5). A common concern is that the placenta and fetus might deplete maternal 25OHD stores, but this does not appear to be the case. Even in severely vitamin D deficient women there was no significant change in maternal 25OHD levels during pregnancy (1,4,10,11).

Total calcitriol levels increase two to five-fold early in pregnancy and stay elevated until parturition, whereas measured free calcitriol levels were reported to be increased only in the third trimester (12). However, when the 20-40% increase in vitamin D binding protein and the decline in serum albumin during pregnancy are considered, that calculated free calcitriol should be increased in all three trimesters (11,13-16).There are several unusual aspects about this situation. PTH is normally the main stimulator of the renal 1alpha-hydroxylase; consequently, elevated calcitriol values are usually driven by high PTH concentrations. An exception to this is the ectopic expression of an autonomously functioning 1alpha-hydroxylase by such conditions as sarcoidosis and other granulomatous diseases. Another exception is pregnancy because the rise in calcitriol occurs when PTH levels are typically falling or quite low. Moreover, this increase in calcitriol occurs despite the ability of high levels of fibroblast growth factor-23 (FGF23) to suppress the synthesis and increase the catabolism of calcitriol, as shown in animal models of X-linked hypophosphatemic rickets (17-19). Evidence from additional animal models suggest that it is not PTH but other factors, such as PTH-related protein (PTHrP), estradiol, prolactin and placental lactogen, which drive the 1alpha-hydroxylase to synthesize calcitriol (1).

The placenta expresses 1alpha-hydroxylase and it is often assumed that autonomous placental production of calcitriol explains why the maternal calcitriol level doubles; other sources such as maternal decidua and the fetus itself could conceivably contribute to the maternal value. However, it appears that any contributions of placenta and other extra-renal sources to the maternal calcitriol level are trivial. Animal studies indicate that the maternal renal 1alpha-hydroxylase is markedly upregulated during pregnancy (20,21) and that placental expression of 1alpha-hydroxylase is many-fold less than in the maternal kidneys (17). Clinical studies have revealed that anephric women on dialysis have very low circulating calcitriol levels before and during pregnancy (1,22), confirming that maternal kidneys must be the main source of the normal 2 to 5-fold increase in calcitriol during normal pregnancy. Rodent studies, including pregnancies in mice that lack the 1alpha-hydroxylase, have confirmed that there is a small contribution of fetal or placental calcitriol to the maternal circulation (1,23,24). However, it is not enough to account for the marked increase in maternal calcitriol that normally occurs during pregnancy.

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