Calcium and phosphorus metabolism
Calcium and phosphorus are critical in cardiovascular, nervous, homeostatic, and muscular processes and in the function of many hormones and enzyme systems. Maternal calcium metabolism during pregnancy and lactation undergoes a series of hormone-mediated adjustments to enhance transport of this mineral to the fetus without long-term alterations in the maternal skeleton.35 Calcium serves as a second messenger; this calcium signaling is important in many reproductive processes, including fertilization, implantation and placental development and function.5
Calcium, phosphorus, and other minerals are transported across the placenta for fetal bone mineralization and skeletal growth. After birth the neonate loses the placental supply of calcium and must quickly establish homeostasis of this system to avoid metabolic derangements. This chapter discusses alterations in these substances and related hormones during pregnancy and the neonatal period. Calcium and phosphorus homeostasis in nonpregnant individuals is summarized in Box 17-1 on page 590 and in Figure 17-1. The roles of the major calcitropic hormones (parathyroid hormone, calcitonin, and vitamin D) are summarized in Table 17-1.
Table 17-1
Hormonal Actions Controlling Calcium and Phosphorus Levels
| HORMONE | BONE | INTESTINE | KIDNEY |
| Parathyroid hormone | Increased calcium release | Increased calcium reabsorption | |
| Increased phosphorus release | Decreased phosphorus reabsorption | ||
| Calcitonin | Decreased calcium release | May inhibit calcium and phosphorus reabsorption | Increased calcium excretion |
| Decreased phosphorus release | Increased phosphorus excretion | ||
| Vitamin D | Increased calcium release | Increased calcium absorption | Increased calcium reabsorption |
| Increased phosphorus absorption | Increased phosphorus reabsorption |
Maternal physiologic adaptations
Calcium and phosphorus metabolism is altered during pregnancy, with an increase in the amount and efficiency of intestinal calcium absorption. During pregnancy, absorption increases to 50%, versus 20% to 25% in nonpregnant individuals.56,65 The increased absorption is mediated primarily by increased 1,25-dihydroxyvitamin D (1,25-[OH]2D).62 Calcium accumulation in the fetus by term totals 28 to 30 g.36,51,59 Most of this accretion (approximately 25 g) occurs in the third trimester and is used for fetal bone formation and mineralization.56 Maternal calcium metabolism undergoes further changes during lactation to meet the calcium needs of the growing infant. Understanding of changes in maternal calcium metabolism in pregnancy and lactation has grown in recent years with improved assay techniques and recognition of the roles of parathyroid hormone–related peptide (PTHrP) (see Box 17-2 on page 591).44 PTHrP increases in the first trimester and is critical for placental calcium transport and thought to help protect the maternal skeleton from excess bone loss.47 PTHrP may also help mediate changes in vitamin D and PTH.73
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.
Table 17-2
Minerals and Hormones Involved in Calcium Homeostasis
| MINERAL/HORMONES | MOTHER | FETUS | NEWBORN |
| Total calcium* | Low | High | Falls‡ |
| Ionized calcium* | Low normal | High | Falls |
| Magnesium* | Low normal | High normal | Falls |
| Phosphorus* | Low | High | Rises‡ |
| Parathyroid hormone | Low | Low | Rises |
| Calcitonin | Normal/High | High | Falls |
| 25(OH)D* | Variable | Variable | Variable |
| 1,25(OH)2D | High | Low | Rises |
| Parathyroid hormone–related protein | High† | High |
‡Toward nonpregnant adult values.
From Nader, S. (2004). Other endocrine disorders of pregnancy. In R.K. Creasy, R. Resnik, & J.D. Iams (Eds.), Maternal-fetal medicine: Principles and practice (5th ed.). Philadelphia: Saunders.
Calcium
Maternal total serum calcium levels fall progressively beginning soon after fertilization and decrease by an average of 1 to 1.5 mg/dL (0.25 to 0.38 mmol/L). Calcium reaches its lowest levels at 28 to 32 weeks, followed by a plateau or slight rise to term.62,85 Serum calcium levels during pregnancy average 9 to 10 mg/dL (2.3 to 2.5 mmol/L)—a decrease of 5% to 6%.62 The decrease in serum calcium is a relative decrease, in that it is primarily related to and parallels the fall in serum proteins, especially albumin, with a decrease in both total and bound calcium.36,51,56 Other factors that contribute to alterations in serum calcium include increased plasma volume and hemodilution, increased urinary calcium excretion, and fetal transfer (primarily in the third trimester).44,62 Ionized calcium (physiologically active form) does not change significantly and is stable or in the low normal range.35,36,44,51
Calcium absorption occurs by active transport in the duodenum and proximal jejunum and by passive mechanisms in the distal jejunum and ileum. Intestinal absorption of calcium doubles during pregnancy, with a positive calcium balance noted by as early as 12 weeks’ gestation that continues to the third trimester.18,35,51 The early increase allows the mother to store calcium throughout pregnancy to meet the high fetal demands in the latter part of the third trimester.44 The rise in calcium absorption parallels the rise in 1,25-(OH)2D, which is the primary mediator of this change. However, since the increased intestinal absorption begins prior to the increase in 1,21,25-(OH)2D, there are likely other as yet unknown mechanisms.40 Estrogens and other hormones may up-regulate intestinal calcium transporter genes independent of the influence of vitamin D.80 Prolactin also has a calcitropic role during pregnancy as well as during lactation.17
Urinary calcium excretion parallels the rise in intestinal calcium absorption.35,36 Urinary excretion increases by 12 weeks, with an average increase from the nonpregnant value of 160 to 240 mg/dL (40 to 60 mmol/L) in the third trimester.56,62 This change is due to up-regulation of 1α-hydroxylase (enzyme involved in 1,25-[OH]2D synthesis) activity by PTHrP, estrogens, prolactin, and human placental lactogen as well as the increased glomerular filtration rate, and occurs even when the maternal diet is calcium deficient.18,65 After 36 weeks, urinary calcium excretion decreases by about 35%, increasing calcium availability by approximately 50 mg/day. Because fetal needs at this point are approximately 350 mg/day, however, other maternal calcium sources (i.e., dietary sources or the maternal skeleton) are essential.62
Parathyroid hormone
PTH levels fall to low-normal in the first trimester and may become undetectable in women with adequate calcium and vitamin D intake, and increase to mid-normal ranges by term in these women.18,36,44 Newer assays suggest PTH levels decrease to 10% to 30% of prepregnant values before increasing to term.51 The initial decrease is due to the increased 1,25-(OH)2D in response to increased PTHrP, which may contribute to changes in parathyroid function during pregnancy.6,27,35,36,51,87
Vitamin D
Both free and bound levels of 1,25-(OH)2D rise early in pregnancy, double by 10 to 12 weeks’ gestation, and remain high to term.6,35,36,44,51,65 Maternal serum levels of 1,25-(OH)2D are 50% to 100% higher by the second trimester and up to 100% higher in the third trimester.40 Vitamin D–binding protein also increases, possibly due to the increased estrogen.6,61 Changes in 1,25-(OH)2D are not mediated by PTH, because levels of this hormone are low-normal during the first trimester, but are under the influence of estrogens, PRL, hPL, and especially PTHrP, which increases levels of the enzyme 1α-hydroxylase needed for production of 1,25-(OH)2D and suppresses maternal PTH.6,18,40,51 The increased 1,25-(OH)2D comes primarily from increased production by the maternal kidney, with some from the decidua and fetoplacental unit.6,35,36,40,44,65,87 1,25-(OH)2D opens voltage-dependent calcium channels in intestinal cells to increase calcium absorption.51 Thus the doubling of 1,25-(OH)2D is paralleled by a twofold increase in intestinal calcium absorption. Serum 25-hydroxyvitamin D (25-[OH]D) levels (stored form) do not change significantly during pregnancy. The increase in 1,25-(OH)2D after 34 to 36 weeks has been associated with an increase in a vitamin D–binding protein and bound vitamin D. Thus intestinal absorption of vitamin D is enhanced throughout gestation. Renal clearance of 1,25-(OH)2D does not change during pregnancy.6
Calcitonin
Calcitonin levels are generally reported to be normal to high during pregnancy, particularly in the latter half, with about 20% of women having values outside the normal range.35,51 During pregnancy calcitonin is synthesized by the breasts and placenta in addition to the usual synthesis by the C cells of the thyroid gland. The increase in calcitonin with advancing pregnancy may stimulate the proximal renal tubule to increase 1,25-(OH)2D production.27 Increased calcitonin inhibits calcium and phosphorus release from the bones, counteracting the action of PTH (see Table 17-1). This may help prevent excessive reabsorption of bone calcium and conserve the maternal skeleton while simultaneously permitting the intestinal and renal actions of PTH and 1,25-(OH)2D to provide the additional calcium needed by the fetus.
Changes in bone formation and density
Uncoupling of bone reabsorption and formation is seen during pregnancy, with increased reabsorption during the first two trimesters and increased formation in the third trimester.51 For example, markers of bone reabsorption are reported to increase through 28 weeks’ gestation, whereas bone formation markers remain stable to 28 weeks and then increase to term.18,36,51 Maternal bone formation increases early in pregnancy with increased storage of calcium in maternal bones. Maternal bone growth is associated with increases in bone formation and reabsorption markers such as bone alkaline phosphatase and procollagen peptides in the blood.53,56,65 Osteocalcin, which normally increases with bone formation, is lower in pregnancy, although some increase is noted in late pregnancy. This may be due to increased placental calcium uptake.44,87 Bone turnover increases in the third trimester at the time of peak calcium transfer to the fetus. During this time, maternal bone stores are mobilized to meet fetal demands.35,62 However, the fetal calcium accumulation of 28 to 30 g represents only a small proportion of maternal skeletal stores. The changes in maternal bone are transient.31,56
Studies of bone mineral density during pregnancy have been inconsistent with small sample sizes and other methodological problems, including time of follow-up and other confounding factors.18,22,30,31,49,53 However, most indicate that bone mineral density decreases by 2% to 5% during pregnancy and lactation, especially in the trabecular bone sites (lumbar spine and hips).11,18,40,53,55 This is balanced by increases in the periosteal and endosteal surfaces of cortical bones (arms, legs).53,56,65,86 Individual variations are seen with an increased risk of loss with frequent pregnancies, short time between pregnancies, adolescent women, lower calcium intake during pregnancy, multiple gestation, and heparin use.56,65 There do not appear to be any long-term effects of maternal skeletal mass or bone density changes during pregnancy, and bone mineral density has been found to be similar in postmenopausal women who have or have not been pregnant.31,56 A decrease in hip fractures has been reported in several studies in women who have had children, perhaps because pregnancy-associated changes in calcium and phosphorus metabolism may improve mechanical resistance of the upper femur.56,57,61.
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.
Clinical implications for the pregnant woman and her fetus
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
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,
