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INTRODUCTION

In adult life, adaptation to acute and subacute alterations in calcium homeostasis is largely accomplished through the actions of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D. During the pregnancy and lactation other, "nonclassical" hormones, such as parathyroid-hormone-related protein (PTHrP) appear to contribute to the alterations in calcium and skeletal homeostasis which occur in this setting. Maternal calcium homeostasis is geared to provide sufficient calcium flux across the placenta during pregnancy and into breast milk during lactation to ensure normal fetal and neonatal skeletal mineralization. These requirements are substantial and cannot be met solely by augmented intestinal calcium absorption, so pregnancy and lactation are typically accompanied by increased rates of bone resorption and declines in bone density. As a consequence of these changes, the clinical course of diseases associated with hyper or hypocalcemia, is altered during pregnancy. Recognizing this is critical to successful management of these diseases and to ensuring good maternal and fetal outcomes.

Reviewed below are the physiologic alterations that occur in mineral and skeletal metabolism during pregnancy and lactation. This is followed by a discussion of common clinical disorders of mineral homeostasis that can occur during this period and their appropriate management. Although there is an extensive literature on experimental animal models of pregnancy and lactation, the focus of this review is solely human physiology and pathophysiology.

MATERNAL CALCIUM HOMEOSTASIS DURING PREGNANCY AND LACTATION

Pregnancy

As a consequence of hemodilution, the total serum calcium concentration falls during a normal pregnancy. This fall largely reflects the fall in serum albumin and the albumin-bound fraction of the total calcium (1). Ionized calcium levels, when measured directly, are not different from values in nonpregnant women (2-11). Serum concentrations of phosphate are normal throughout pregnancy (5,8,12,13).The normal fetus accumulates approximately 21 grams of calcium (range, 13-33 g) (14) prior to delivery with 80% of this accruing to the rapidly mineralizing skeleton in the third trimester (14,15). A key adaptive change in response to this dramatic strain on maternal calcium metabolism is an increase in maternal 1,25 dihydroxyvitamin D production. 1,25 dihydroxyvitamin D is the active form of vitamin D and has, as it's main site of action, the proximal intestine where it increases calcium absorption. Pregnancy is associated with an approximate 2-fold increase in circulating levels of 1,25 dihydroxyvitamin D (3,11,12,16-21). This increase occurs early in the first trimester and is sustained throughout pregnancy. The source and regulatory events that mediate this increase in 1,25-dihydroxyvitamin D production has been the topic of much debate. The principal site of increased production appears to be the maternal kidney, with contributions from maternal decidua, placenta, and fetal kidneys (22). Parathyroid hormone which is the primary regulator of 1,25 dihydroxyvitamin D synthesis in the nonpregnant state, plays little role in mediating this increase since several prospective studies have shown that the level of immunoreactive PTH is in a low normal range early in pregnancy when 1,25(OH)2vitamin D levels are high and PTH levels only reach the mid-normal range by the end of pregnancy (5-7,11,12,23). Further, women without functioning parathyroid glands still evidence a rise in circulating 1,25(OH)2vitamin D during pregnancy.

Increased 1, 25 dihydroxyvitamin D production during pregnancy leads to a marked increase in intestinal calcium absorption and as a consequence, hypercalciuria. The increase in intestinal calcium absorption has been demonstrated as early as week twelve of gestation, well before fetal skeletal mineralization is maximal (12,24,25). This suggests that the increase in 1,25 dihydroxyvitamin D is an independent phenomenon and may allow the maternal skeleton to store calcium in advance of peak fetal demands later in pregnancy. Urinary calcium excretion rates in the hypercalciuric range (i.e. > 4mg/kg body weight) are not uncommon (3,5,11,12,27).

A role for calcitonin and PTHrP in mediating mineral metabolism in pregnancy has also been suggested. Serum calcitonin levels during pregnancy are generally higher than values in nonpregnant women with at least 20% of values exceeding the normal range (22). It has been speculated that elevated calcitonin protects the maternal skeleton from excessive bone resorption but there are scant experimental data that address this issue and it deserves further study.

Several recent studies have documented elevated levels of PTHrP as early as the first trimester of pregnancy (23,28). PTHrP, parathyroid hormone-related protein, was discovered in the early 1980s when it was found to be overexpressed by tumors that cause hypercalcemia, so called humoral hypercalcemia of malignancy (29-31). It is a product of gene distinct from that for PTH. It is processed to multiple forms including an amino-terminal fragment with structural similarity to the amino-terminus of PTH, and structurally unique mid and c-terminal segments. Unlike PTH, PTHrP does not normally circulate in detectable concentrations. It is widely expressed and appears to be an important paracrine signal in several tissues. Absence of PTHrP leads to a failure of normal skeletal development due to accelerated mineralizing of cartilage. PTHrP can relax smooth muscle and stretch induces its expression in the bladder, vascular smooth muscle and uterus. Potential sources of PTHrP production during pregnancy include the placenta, decidua, amnion, fetal parathyroid glands and umbilical cord (32-35). PTHrP is also produced by breast tissue (36,37). Elevations in N-terminal fragments of PTHrP may contribute to the increase in 1,25-dihydroxyvitamin D and to the suppression of PTH, noted during pregnancy. It has also been suggested that amino-terminal forms of PTHrP may play a role in regulating the onset of labor since PTHrP levels decline in myometrium at the onset of labor (32). A midmolecular form of PTHrP stimulates placental calcium transport (38) and may be important in ensuring that adequate calcium gets to the developing fetus. The carboxyl-terminal portion of PTHrP, termed "osteostatin," is able to inhibit osteoclastic bone resorption in some in vitro assays and in rats in vivo. Therefore, this fragment of PTHrP could have a role in protecting the maternal skeleton from excessive bone loss during pregnancy (22).

Lactation

Although accurate estimates of the calcium loss during lactation are difficult to quantify precisely due to inherent variations in the calcium content of breast milk as well as other factors (39,40), the daily loss of calcium in breast milk has been estimated to range from 280-400 mg (40). Losses up to 1000 mg calcium/day have been reported (42). In contrast to the pregnant state, lactation is not associated with intestinal calcium hyperabsorption and the skeleton appears to be the primary source from which lactating women meet these requirements. The underlying mechanisms responsible for this demineralization are not fully understood but a prominent role for PTHrP in mediating this process has been proposed. Total and ionized calcium (43-47) and serum phosphate (5,13,45,48-51) are high normal or slightly elevated in lactating women. The majority of studies have found that PTH levels are low in lactating as compared to nonlactating women with levels rising to normal or just above normal after weaning (12,45-50,52-55). The post weaning increase in PTH levels may be sustained for up to 3 months (12,45) and whether this increase contributes to rebuilding of bone after weaning remains unknown. Elevated levels of 1,25-dihydroxyvitamin D seen in pregnancy fall into the normal range within days of delivery and remain normal during lactation (11,12,18,21,44,49,55-57). As a consequence of this, the intestinal calcium hyperabsorption and hypercalciuria seen during pregnancy resolve within days after delivery. In addition, the renal excretion of calcium has been reported to be low during lactation (3,5,12,13,23,26,49,58). After weaning, there is an increase in intestinal absorption of calcium (51), while low urinary calcium excretion persists (49). These changes likley contribute to rebuilding the maternal skeleton after weaning.

Parathyroid hormone-related protein is expressed in lactating mammary tissue and plays a key role in mammary gland development (59, Chapter 5 - Endocrinology of pregnancy, by John Wysolmerski). In it's absence the mammary gland does not develop. PTHrP is secreted into milk in large quantities (60-62). In fact, the concentration of PTHrP in milk is 1,000-fold higher than that measured in hypercalcemic cancer patients (60). The role of PTHrP in milk remains unclear. It is possible that, like in the placenta, it augments transport of calcium into breast milk although this has not been established. In support of this notion, PTHrP concentrations in the milk have been found to correlate positively with a total milk calcium content (63). PTHrP like PTH stimulates bone resorption through the PTH receptor expressed in bone (64) and emerging evidence suggests that breast derived PTHrP may reach the maternal circulation and be an important mediator of maternal skeletal resorption during lactation. Consistent with this PTHrP levels have been found to correlate positively with serum ionized calcium levels (47,48,70) as well as with the degree of bone loss during lactation (65). Hypercalcemia associated with low PTH levels has been reported in lactating women, which has resolved after weaning (66) or reduction mammoplasty (67) suggesting breast derived PTHrP may be responsible. Calcitonin is also secreted into breast milk at concentrations significantly higher then in the maternal serum (68) but it's functions if any are not known.

In summary, maternal calcium homeostasis is geared to provide sufficient calcium flux across the placenta during pregnancy and into breast milk during lactation to ensure normal fetal and neonatal skeletal mineralization. These requirements are substantial and are met by alterations in calcitropic hormone profile and effects of "nonclassical" hormones, such as parathyroid-hormone-related protein (PTHrP) on calcium homeostasis as summarized in Table 1.

Table 1. Summary of calcitropic hormone profile during pregnancy and lactation
	serum Ca total	serum Ca ionized	serum P	urinecalcium	1,25 vit D	PTH	PTHrP
PREGNANCY		NL	NL			Low NL
LACTATION	NL	NL	High NL		NL	Low NL

FETAL-PLACENTAL UNIT

Among the many functions of the fetal-placental unit is to provide sufficient calcium for the fetal skeleton to mineralize and to maintain the fetal extracellular calcium concentration in the appropriate range. Serum calcium levels are higher in the fetus than in the mother. Human cord blood calcum levels exceed maternal values by 1 and 0.5 mEq/L for total and ionized calcium, respectively (69). Therefore, placental calcium transport occurs against a concentration gradient, especially at the end of gestation when the difference between maternal and fetal blood calcium is greatest. As noted there is evidence that the active placental transport mechanism for calcium is regulated by a midmolecule portion of PTHrP (22,75). Fetal hypercalcemia is also maintained by the effects of PTrP, in this instance, the amino-terminal fragment of PTHrP which stimulates fetal renal tubular calcium reabsorption thereby helping to maintain a high serum calcium. Unlike calcium, PTH, 1,25-dihydroxyvitamin D, and calcitonin apparently do not cross the placenta in appreciable amounts. Circulating 25-hydroxyvitamin D freely crosses the placenta, where placental 1a-hydroxylases convert it to the active 1,25-dihydroxyvitamin D.

The fetal-placental unit functions relatively independently of the maternal calcium needs. For example the fetal skeleton will mineralize normally and the fetal calcium concentration is unaffecteted even in the presence of moderate hypocalcemia and vitamin deficiency in the mother (71-73). The ciculating concentration of intact PTH in the fetus has been reported to be one fourth that of maternal values (74) presumably secondary to the relative hypercalcemia of the fetus. At birth, the neonate has relatively elevated serum levels of total and ionized calcium, calcitonin, and PTHrP, and suppressed levels of PTH. Serum calcium levels fall by about 1 mEq/L and reach a nadir at 1 or 2 days of age. In normal infants, secretion of PTH is stimulated at this point and recovery of normal serum calcium levels generally occurs by 1 week of age.

BONE PHYSIOLOGY AND DISEASE STATES IN PREGNANCY AND LACTATION

Effect of pregnancy on markers of bone turnover

Studies examining the effects of pregnancy on bone turnover markers in human are limited but the existing evidence suggests that bone turnover is low in the first half of pregnancy and increases towards the end of pregnancy which coincides with the increased demands of the mineralizing fetal skeleton. Markers of bone resorption (pyridinoline and deoxypyridinoline crosslinks and hydroxyproline) are low in the first trimester and increase steadily throughout pregnancy peaking at about twice normal in the third trimester (12,23,52,76). Markers of bone formation, such as osteocalcin and procollagen I carboxypeptides, are low or undetectable in early pregnancy but rise to a normal levels by the end of pregnancy (6,12,52,76-78). Alkaline phosphatase, which is routinely used to evaluate bone turnover in a nonpregnant patient, is not a helpful marker during the pregnancy due to the contribution of placental alkaline phosphatase to maternal levels.

Effect of pregnancy on bone density

Despite several studies and case reports describing changes in bone mineral density (BMD) during pregnancy, controversy exists regarding the time course and extent of BMD changes during and after gestation. Due to concerns about radiation exposure to the fetus few studies have been done examining BMD during the pregnancy by precise techniques like DEXA (dual energy x-ray absorptiometry). Older prospective studies using either SPA or DPA (single or dual photon absorptiometry) did not find a significant change in BMD during pregnancy (13,26,79,80). One study found a significant decrease in bone mineral density of the femoral neck and radial shaft, but no change in lumbar bone density, by comparing preconception SPA and DPA measurements to those 6 weeks postpartum (81). More recent studies using DEXA measurements before and after pregnancy reported conflicting results with two studies showing declines in lumbar bone density ranging from 3.5% to 4.5% (82,83) while a third study reported no change in bone density during pregnancy (84). These divergent results may be related to the fact that in the first two studies, bone density was measured 4-6 weeks postpartum and lactation-induced bone loss may have confounded the results (see discussion below). A few studies have used ultrasonography to measure bone density and have reported a decrease in BMD by this technique during pregnancy (76,85,86). Whether parity has any long term effect on the maternal skeleton is unclear although the majority of studies have found no effect of parity on bone density or fracture risk (22) and several other studies, have found increased parity to have a beneficial effect on bone mass. Few studies have linked parity to decreased bone density (87-89). In summary, it has not been clearly established whether the increased bone turnover seen in late pregnancy has any long-term effects on the maternal skeleton. The discrepancies in data are attributable to a number of factors including small sample sizes in study populations, differences in gestational weight gain, body composition, pattern of physical activity, and whether or not the mothers breast fed. On balance, the existing evidence suggests either no effect or a very small negative effect of pregnancy on bone density long term.

Osteoporosis and pregnancy

Osteoporosis with accompanying fragility fracture is extremely rare in pregnancy. When it does occur it is usually assumed that the woman's bone density was very low prior to conception and that the additional physiologic and physical stress of pregnancy (i.e. back strain) unmasks rather than causes the osteoporosis. There are rare cases of women presenting in the third trimester with transient osteoporosis of the knee or hip (90-94). The pathophysiology in these unusual cases is unkown but the normal calcitropic hormone profile in these patients and the fact that this condition is usually localized suggests mechanisms other then generalized bone loss are the underlying cause. Local factors, such as reflex sympathetic dystrophy, ischemia, trauma, viral infections, marrow hypertrophy, immobilization, and fetal pressure on the obturator nerve have been proposed. These patients typically present with hip pain and/or insufficiency fractures of the hip (90,92,95,96). Osteopenia is seen on plain films (91,97) and DEXA measurements of the symptomatic femoral head and neck document reduced bone mass (95). Magnetic resonance imaging (MRI) of the affected femoral head has demonstrated joint effusions and increased water content of the femoral head and marrow cavity (98). The condition is typically self limiting and requires no treatment except for analgesia. The decreased BMD and MRI findings usually resolve within 2 to 6 months postpartum (90,95,96,98).

Effect of lactation on bone turnover

In the aggregate studies examining the rate of bone turnover indicate that both bone resorption and formation are increased during lactation. Markers of bone resorption are elevated 2- to 3-fold during lactation and are higher than values observed during pregnancy (12, 13,47,49,52,53,76,99). Similarly, markers of bone formation have been reported to be high during lactation and increased over the levels observed during pregnancy with the exception of alkaline phosphatase which typically falls immediately postpartum following delivery of the placenta (13,47,49,52,53,76,99).

Effect of lactation on bone density

Several recent longitudinal studies of bone density during lactation, have documented 3-8.0% declines in trabecular bone mass (i.e. at sites like the lumbar spine) after 2 to 6 months with smaller losses at cortical sites when lactating women are compared to women who are bottle-feeding their infants (13,26,47,49,52,53,55,81,99-108). It is not clear whether the lactation-induced bone loss is due to the relative estrogen deficiency that occurs during lactation or to the combined effects of estrogen deficiency and PTHrP-induced skeletal resorption. Several studies have suggested that estrogen withdrawal and the intensity and duration of lactation are factors that predict the degree of bone loss during lactation (54,95,107,109,110). Early resumption of menses or use of supplemental estrogen can reduce skeletal losses during lactation (107,109). Conversely bone density may continue to decrease during extended lactation, even after resumption of menses (95,110) which suggests that estrogen deficiency alone can not fully account for lactation-induced bone loss. In selected studies, PTHrP levels were found to correlate with loss of bone mineral density at the lumbar spine and femoral neck in lactating women, even after controlling for serum estradiol and PTH levels (65). PTHrP has also been reported to be elevated in patients with hyperprolactinemia (48,111) and in these patients, PTHrP correlated negatively with bone density of the lumbar spine lending further support to the notion that PTHrP is a mediator of lactation-induced bone resorption. The majority of studies have reported that the bone loss associated with lactation is completely reversed during weaning (49,52,55,110). Recovery of skeletal mass occurs quickly since women who breast-feed for at least 6 months, and had a second pregnancy within 18 months of their prior delivery, did not have lower bone density after the second pregnancy (108,112). Further extended lactation was not associated with lower BMD in a cross-sectional study of 30 multiparous women who had breast fed as compared to a control population (113). There is no convincing evidence in the literature that increasing dietary calcium intake will prevent lactation-induced bone loss (114,115). In addition, the majority of epidemiological studies of pre- and postmenopausal women have found that a history of lactation has no adverse or salutory effect on peak bone mass or hip fracture risk.

Osteoporosis of lactation

Osteoporosis with accompanying fragility fractures have occasionally been described during lactation. As is the case for osteoporosis during pregnancy it is difficult to separate patients with preexisting low bone mass from those with significant pregnancy and lactation-induced bone loss. Typically women with lactation associated osteoporosis present several months postpartum with vertebral crush fractures, bone pain, loss of height, and rarely hypercalcemia (66,116). Histologic evaluation of bone shows either normal cellular activity or evidence for increased resorption (116). Serum PTH levels have been reported to be normal or reduced, and 1,25-dihydroxyvitamin D levels are normal (66,116). It has been postulated that PTHrP released from the lactating breast into the maternal circulation contributes to the excessive bone resorption, osteoporosis, and fractures in these cases (66,117).

HYPERCALCEMIA DURING PREGNANCY

Hypercalcemia during pregnancy poses a risk to both the mother and fetus and can present a complex management issue. Although hypercalcemia from any cause can occur during pregnancy (Table 2) given that women of childbearing years are young and healthy, primary hyperparathyroidism is the most common cause. The specific causes and management of hypercalcemic diseases have been reviewed in detail elsewhere (Diseases of Bone and Calcium Metabolism, Chapter 4 by Goltzman and Chapter 5 by Bilezikian ).

Primary hyperparathyroidism

The incidence of hyperparathyroidism during the pregnancy is not known but it is uncommon with less then 200 cases reported in the literature (118). This may reflect a failure to recognize all cases or be due to underreporting. Further, it is possible that pregnancy-related changes in calcium and PTH physiology (as outlined above) with a physiologic fall in total serum calcium as well as the pregnancy-related hypercalciuria obscures the diagnosis of mild primary hyperparathyroidism in some women. As noted, calcium easily crosses the placenta and hypercalcemia in a pregnant woman with hyperparathyroidism may be further masked by the ability to "dispose" of calcium in the mineralizing fetus. Up to 80% of pregnant women with hyperparathyroidism are asymptomatic (119-122), and are detected on routine prenatal biochemical tests or postpartum when the newborn develops symptomatic hypocalcemia. Although most patients with hyperparathyroidism are asymptomatic this disease can be associated with a significantly increased risk of maternal and fetal complications. Earlier studies (largely conducted before automated blood sampling of calcium) reported maternal complication rates as high as 67% in patients with hyperparathyroidism (123). Because the hypercalciuria of pregnancy can be exacerbated by hyperparathyroidism nephrolithiasis is the most common symptomatic presentation of hyperparathyroidism during pregnancy with an estimated incidence of 24% to 36% (119,124). Pancreatitis, which poses a significant risk, occurs in 7-13% of pregnant women with hyperparathyroidism (119,123,125-128). Hyperemesis gravidarum also occurs with a significantly increased frequency in pregnant patients with primary hyperparathyroidism.

In the past fetal complications have occurred with a frequency as high as 53% (129-131) and the incidence of neonatal death has been reported to be as high as 27%-31% (129,130,132). Fortunately, neonatal death is rarely seen now. Non fatal complications of hyperparathyroidism in pregnancy have included intrauterine growth retardation, low birth weight, and preterm delivery (119,129,130,132-134).

Although less serious, neonatal hypocalcemia. and, if unrecognized hypocalcemic tetany, are common in offspring of women with hyperparathryiodism and may be seen in up to 50% of infants (131,135-138). Even mild asymptomatic hypercalcemia in the mother has been reported to cause neonatal parathyroid suppression and tetany (135-137). This can largely be avoided if calcium supplementation is started promptly after birth. Neonatal hypocalcemia is usually transient but it can persist for several months, and cases of permanent neonatal hypoparathyroidism have been reported (132,139,140).

Because of the potential for serious complications, women diagnosed with hyperparathyroidism who wish to conceive should be treated surgically prior to pregnancy. When the hyperparathyroidism is discovered during the pregnancy, management is influenced by the degree of hypercalcemia, gestational age and presence of complications. Surgical correction of primary hyperparathyroidism during the second trimester, to prevent fetal and neonatal complications, has been recommended in older studies (141-144). However, many of the women in those early cases were symptomatic and had nephrocalcinosis or renal insufficiency. Available evidence although limited suggests that the typical mildly hypercalcemic asymptomatic pregnant woman with primary hyperparathyroidism, can be safely managed conservatively (145-148) provided neonatal hypocalcemia is sought for and treated. A proposed algorithm for managing pregnant women with primary hyperparathyroidism is presented in Figure 1. In general, it is reasonable to follow patients with mild asymptomatic primary hyperparathyroidism conservatively simply by discontinuing the use of calcium supplements and encouraging good hydration. Medications often used to treat nonpregnant hypercalcemic patients such as loop diuretics, (e.g.furosemide) and bisphosphonates readily cross the placenta and should be avoided during pregnancy (122,128). As noted, in the conservatively managed patient the neonate must be monitored closely for the development of hypocalcemia. In patients who fail conservative management or present with complications during pregnancy, surgical therapy is indicated. To limit the extent and duration of surgery, non-invasive preoperative localization studies can be helpful. Radionueclide localizing studies (sestamibi scan) are contraindicated during the pregnancy but in experienced hands ultrasonography can be helpful in localizing a parathyroid adenoma (149,150). In selected cases ultrasound guided biopsy of a suspected lesion with measurement of PTH in the aspirate can confirm the diagnosis. Such fine needle aspirates carry minimal risk, and if successful provide the opportunity to limit surgery to a minimally invasive parathyroidectomy. Intraoperative measurement of serum PTH, available in most major centers doing parathyroid surgery, should be done to ensure the success of the procedure (151). If required a pregnant patient should undergo parathyroid adenomectomy during the second trimester when the rate of surgical complications and risk of pre-term labor are generally considered to be low (152).

Figure 1.

Familiar Hypocalciuric hypocalcemia (FHH)

Familial hypocalciuric hypercalcemia (FHH), is an autosomal dominant disorder due to heterozygous inactivation of the calcium sensing receptor gene. This receptor is expressed in the parathyroid gland and kidney and loss of function leads to a failure of the parathyroid gland to appropriately sense serum calcium and to suppress secretion of the hormone when serum calcium rises. Therefore, patients with FHH evidence mild elevations in serum calcium with concomitant elevations in serum PTH. Urine calcium is paradoxically low because the kidney cannot sense the level of calcium in the blood and inappropriately reclaims excessive amounts of filtered calcium. It is important not to confuse FHH with primary hyperparathyroidism as parathroidectomy is not indicated in patients with FHH. Although usually posing no risk to the mother, infants of mothers with the disease can have suppressed parathyroid glands, and are at risk for neonatal hypocalcemia, and seizures or tetany. Neonatal hypocalcimia can have a delayed presentation in this setting and require prolonged treatment while parathyroid function recovers (140).

HYPOCALCEMIA DURING PREGNANCY

The many causes of hypocalcemia are summarized in Table 3. Most of these have been reported in pregnancy. The specific causes and management of these diseases have been reviewed in detail elsewhere (153,154, hyperlink to Chapter 7 by Fitzpatrick in Diseases of Bone and Calcium Metabolism). However, since pregnancy and lactation can alter the clinical course and management of some of these diseases a selected few are discussed below.

Hypoparathyroidism

Hypoparathyroidism results from inadequate secretion of PTH. Absent or diminished action of PTH in the kidney and in bone leads to hypocalcemia and hyperphosphatemia. Multiple causes of hypoparathyroididsm have been described (154) with autoimmune causes and inadvertent removal of the parathyroids during thyroid surgery being relatively more common. Patients with mild hypoparathyroidism may be asymptomatic or may experience only subtle manifestations of the disease. In more severe forms of the disorder, symptoms and signs related to decreased serum ionized calcium concentrations may occur. Increased neuromuscular excitability with a positive Chvostek's or Trousseau's signs can be observed. Muscle weakness and paresthesias can progress to the development of seizures, tetany, or laryngospasm. Papilledema, elevated cerebrospinal fluid pressure, and neurologic signs that mimic a cerebral tumor may be found. A spectrum of mental status changes, from irritability to psychosis, can also occur. Abnormalities in cardiac conduction, particularly prolongation of the QT interval and T wave changes, may be present. Radiographs of the skull may demonstrate intracranial calcifications. Uncorrected hypocalcemia in pregnancy can lead to maternal, fetal, and neonatal complications (155). As a consequence of decreased availability of maternal calcium, the fetus of a hypocalcemic woman develops compensatory secondary hyperparathyroidism (with measurable elevations of serum PTH). Generalized skeletal demineralization can result (156). Although the secondary hyperparathyroidism is usually transient and resolves in the neonatal period, the infant may not achieve normal bone mineralization until age 6 months (155). These complications can be avoided if the maternal serum calcium is maintained in a low normal range during pregnancy. Because of PTH-independent production of 1,25(OH)2vitamin D during pregnancy, hypoparathyroid women have fewer hypocalcemic symptoms, and reduced requirements for supplemental calcitriol [1,25(OH)2vitamin D] to maintain a serum calcium in the desired range. (157-165). Despite a few reports to the contrary (166-168), there is general agreement that in late pregnancy the dose of calcitriol needs to be reduced or discontinued, altogether to avoid the appearance of hypercalcemia (22,157,158,161,166,167,169).

Severe hypomagnesemia, in the setting of diabetes mellitus, alcoholism, aminoglycoside use, or malabsorptive syndrome, may cause an acquired hypoparathyroidism. Hypomagnesemia is thought to impair release of PTH from the parathyroid gland, although impaired PTH bioactivity or end-organ resistance may contribute to the hypocalcemia in some hypomagnesemic patients. Calcium and vitamin D supplementation may not be effective in treating hypocalcemia associated with hypomagnesemia and correction of the hypomagnesemia is the preferred approach. Magnesium supplementation is safe and effective in pregnancy.

Women with hypocalcemia (regardless of cause) are at increased risk of tetany during labor, presumably because of the frequent occurrence of hyperventilation leads to an acute fall in ionized calcium. Intravenous calcium should be available at the bedside of women with documented hypocalcemia or who are at risk for developing hypocalcemia.

Pseudohypoparathyroidism

Pseudohypoparathyroidism is a heterogeneous group of genetic syndromes characterized by hypocalcemia due to PTH resistance (154). Pseudohypoparathyroidsim has been described in pregnancy and Breslau and Zerwekh (170) in their report of pregnant patients with pseudohypoparathyroidism noted a normalization of serum calcium levels as pregnancy progressed. These patients remained normocalcemic without the use of supplemental calcium or vitamin D. During pregnancy the circulating level of 1,25 dihydroxyvitamin D increased two- to three-fold while PTH levels fell to nearly half the pre-pregnancy values (171). Again, this is due in large part to the PTH-independent rise in circulating levels of 1,25(OH)2vitamin D. Therefore, the requirement for vitamin D and calcium supplementation should be reevaluated frequently in pregnant patients with pseudohypoparathyroidism to avoid hypercalcemia.

In both patients with hypoparathyroidism and pseudohypoparathyroidism following delivery the requirement for supplemental calcitriol and calcium will rapidly increase as placental 1,25(OH)2vitamin D production ceases.

Magnesium therapy

Parenteral magnesium sulfate, used in the treatment of women with eclampsia, pre-eclampsia, or preterm labor, can cause alterations in calcium homeostasis. In women treated for as little as 24 hours, hypocalcemia, hyperphosphatemia, and hypercalciuria, can occur. The mechanism by which magnesium sulfate causes hypocalcemia is unclear, although a plausible explanation is that magnesium ions compete with calcium for common reabsorptive sites in Henle's loop. A loading dose of 4 to 6 g intravenously, followed by infusion of 1 to 2 g/hr, can cause serum ionized calcium concentrations to fall. A compensatory secondary hyperparathyroidism develops with a rise in circulating levels of PTH and 1,25-dihydroxyvitamin D, which tends to limit the degree of hypocalcemia (172). Umbilical venous levels of 1,25-dihydroxyvitamin D and PTH are also found to be elevated during maternal treatment with magnesium sulfate. The elevated levels of 1,25-dihydroxyvitamin D may be caused by placental transport of maternal 1,25(OH)2D; however, the PTH is of fetal origin. These hormonal changes, in addition to other placental protective mechanisms, somewhat shield the fetus from the hypermagnesemia and hypocalcemia experienced by the mother. However, at birth these infants can be mildly hypermagnesemic and hypocalcemic. Usually neither is clinically significant and typically both resolve during the first 2 days of life.

Although the effects of short-term magnesium sulfate therapy on calcium homeostasis appear benign and reversible, more recent use of long-term, higher-dose magnesium sulfate for tocolysis has raised safety issues . A prospective study of women treated with magnesium sulfate for a mean of 26 days revealed alterations in calcium homeostasis that parallel those described above with short-term magnesium therapy (173). The frequency of significant side effects in neonates born to mothers receiving long-term magnesium sulfate therapy are largely unknown. There are however a few case reports of neonatal hypocalcemia, osteopenia, and rickets (174,175) although it appears that these are rare complications.