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16 Calcium, Vitamin D, and Magnesium Calcium and magnesium are both present in the diet and the body at levels much higher than those of trace minerals such as iron. Approximately 99% of the calcium and magnesium in the human body is located in the skeleton. For many years, women have been advised to increase their calcium intake substantially during pregnancy, and there has been concern that many pregnant women do not ingest enough calcium to maintain their own skeletons while providing for fetal needs. Vitamin D is discussed in this chapter since calcium metabolism is dependent on this vitamin. Although calcium and phosphorus metabolism are closely linked, phosphorus is not discussed in this report, since usual intakes of the nutrient are well above the Recommended Dietary Allowance (RDA). Neither inadequate nor excessive intake appears to be a problem in pregnant women (NRC, 1989), and phosphorus is not ordinarily contained in multivitamin- mineral supplements. CALCIUM Metabolism Several changes in calcium metabolism associated with pregnancy facil- itate the transfer of calcium from mother to fetus while protecting calcium levels in maternal serum and bone. These include changes in calcium- regulating hormones, which affect intestinal absorption, renal reabsorption, and bone turnover of calcium. 318

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CALCIUM, VITAMIN D, AND MAGNESIUM 319 Total serum calcium decreases gradually throughout pregnancy. This is associated with and parallels the drop in serum albumin (to which 60% of the serum calcium is attached) that results from expansion of the extracellular fluid volume. When adjustments are made for changes in serum albumin or protein concentration, little or no change in the total serum calcium level is apparent during pregnancy. Serum ionic calcium changes are minimal (Pitkin et al., 1979~. Early studies indicated that the level of parathyroid hormone (PTH) in- creases progressively; in late pregnancy, it was reported to be approximately 50% higher than prepregnancy levels (Pitkin et al., 1979~. However, more recent research indicates that the previously reported hyperparathyroidism of pregnancy may be an artifact of earlier radioimmunoassay methods. A relatively new immunoradiometric assay that is highly specific for the intact, and presumably biologically active, form of PTH indicated that the mean serum PTH level in 81 pregnant women was 14.4 ~ 6.3 compared with 24.8 it 9.0 (standard deviation) ng/ml in 11 nonpregnant women (Davis et al., 1988), indicating a decline during pregnancy. A calcium-mobilizing peptide that is similar to PTH has been identified in both rat and human mammary tissue and milk (Budayr et al., 1989; Thiede and Rodan, 1988~. The partially purified peptide stimulates calcium transport in the sheep placenta (Rodda et al., 1988), but its role in human pregnancy remains to be determined. Changes in maternal calcitonin have been reported to be inconsistent (Pitkin et al., 1979) or increased in early pregnancy and then stable throughout the remainder of pregnancy (Whitehead et al., 1981~. A rise in calcitonin may protect the maternal skeleton against resorption. A substantial amount of the calcium needed by the fetus is provided by the increased maternal efficiency of dietary calcium absorption. Elevated 1,25-dihydroxycholecalciferol levels account for some of this increase, but other as yet unidentified factors may be involved (Halloran and DeLuca, 19804. Placental transfer of calcium is an active process that occurs against a concentration gradient and involves placental calcium-binding protein (Lester, 1986; Umeki et al., 1981~. Total and ionized serum calcium levels in the fetus and newborn are substantially higher than those in the mother. Calcium Balance Calcium and phosphorus are deposited in the fetus mainly in the last trimester, but the efficiency of maternal intestinal absorption is increased by at least the second trimester (Heaney and Skillman, 1971; Shenolikar, 1970~. In a balance study, true absorption of calcium increased from 27% in nonpregnant women to 54% at 5 to 6 months of gestation and 42% at term (Heaney and Skillman, 1971~. Urinary calcium increases during

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320 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS pregnancy, probably because of the higher glomerular filtration rate (Pitkin, 1985~. Fetal calcium levels suggest that ionized calcium is transferred from the mother to the fetus at a rate of 50 mg/day at 20 weeks of gestation to a maximum of 330 mg/day at 35 weeks of gestation (Forbes, 1976~. The few calcium balance studies that have been conducted in pregnant women fail to show a positive balance this large, suggesting that calcium may be withdrawn from maternal bone or that there are inaccuracies in the studies. Ashe et al. (1979) studied healthy pregnant white women who consumed an average of 1,390 mg of calcium per day from self-selected diets and reported that they had sufficient calcium intake to balance urinary and fecal losses over the course of pregnancy but not to achieve the anticipated positive balance. Young women with a daily intake of approximately 800 mg of calcium retained an estimated 14 g of calcium during pregnancy only half the amount needed for the fetus (Heaney and Skillman, 1971~. In the third trimester, Scottish women had a positive balance of 142 mg/day when intake was 1 g and 305 mg/day when intake was 2 g (Duggin et al., 1974~. Interpretation of these balance data is difficult due to the different levels of calcium intake, stage of pregnancy, and duration of the various studies. Maternal Bone Loss It is unclear whether the increased efficiency of intestinal calcium absorption during pregnancy prevents a net loss of calcium from the mother. Calcium balance would be expected to be strongly positive in late pregnancy, but as discussed above, the amount of calcium retained has been reported to be insufficient to supply the estimated total fetal needs (Duggin et al., 1974; Heaney and Skillman, 1971), suggesting that some is withdrawn from the mother's bones. Substantial increases in absorptive efficiency and positive balance begin in the first trimester. This must represent maternal accumulation of calcium, since the fetal calcium content is negligible at this time. It is possible that calcium added to maternal bone during early pregnancy is transferred to the fetus in later gestation. Perhaps because of their inability to detect small changes in skeletal calcium, measurements of maternal bone mineral changes have failed to support this possibility. An increase in the amount of bone alkaline phosphatase activity that is apparent by 10 to 12 weeks of gestation provides indirect evidence that maternal bone formation may be increased (Valenzuela et al., 1987~. Evidence of bone loss during pregnancy is negative in most studies (Christiansen et al., 1976; Frisancho et al., 1971; Goldsmith and Johnston, 1975; Walker et al., 1972~. X-ray spectrophotometry of the forearm showed a 4.2% average loss of trabecular bone and a 2% gain in cortical bone

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CALCIUM, VITAMIN D, AND MAGNESIUM 321 over the course of gestation (Lamke et al., 1977~. Measurement of bone mineral density by the photon absorption method applied to the distal radius revealed a significant positive association (R = .77) between parity and bone density in 1,053 black and white women in California who were uncontrolled for the extent of lactation (Goldsmith and Johnston, 1975~. In a retrospective study conducted in New York State, a 1.1% decrease in femoral neck density per live birth was found, but no association was ob- served between lumbar spine density and parity (Hreshchyshyn et al., 1988~. In Bantu and Caucasian South African women, cortical bone thickness in those with seven or more children was similar to that of women with zero to two children, even though the Bantu's daily intake of calcium averaged less than 400 mg (Walker et al., 1972~. Bone density of these two groups was not compared. Since the total amount of calcium transferred to the fetus is 30 g, which is equivalent to only 2.5% of maternal skeletal calcium, bone loss would be difficult to detect even with more precise techniques such as dual photon beam absorptiometry. Severe calcium and phosphorus restriction in rats increases maternal PTH synthesis, plasma 1,25-dihydroxycholecalciferol, and intestinal calcium absorption and reduces urinary calcium excretion. Consequently, the fetal mineralization process remains normal (Verhaeghe et al., 1988~. There are few data on the effect of maternal calcium intake on bone mineralization in human fetuses. In malnourished women in India, either 300 or 600 mg of supplemental calcium administered daily from week 20 of gestation significantly increased the density of fetal bones (Reman et al., 1978~. The clinical importance of this is not clear, however, because there was no evidence of skeletal abnormalities in infants born to the placebo group. Usual calcium intakes of the women were reported as low but were not quantified. Supplementation and Hypertension An inverse relationship between calcium intake and blood pressure has been found in recent studies of nonpregnant adults. Recently, this finding has been extended to pregnant women in small-scale randomized clinical trials conducted in the United States (Maryland) and Argentina (Belizan et al., 1988) as well as in Ecuador (Lopez-Jaramillo et al., 1987~. Daily calcium supplementation ranging from 1,500 to 2,000 mg reduced the incidence of pregnancy-induced hypertension in the two South American countries but not in Maryland. A dose-response relationship was suggested by one of the studies (Belizan et al., 1988~. In further support of a possible relationship between calcium metabolism and preeclampsia (pregnancy- induced hypertension with proteinuria) are data demonstrating that the presence of hypocalciuria is a diagnostic aid in differentiating preeclampsia

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322 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS from other forms of gestational hypertension (Taufield et al., 1987~. The pathophysiologic basis for these associations is unclear, as is the effect of calcium supplementation on pregnancy outcome. More extensive clinical trials are needed to explore this relationship further. Supplementation and Leg Cramps Leg cramps in pregnant women are sometimes attributed to calcium deficiency or disturbances in calcium metabolism. The effectiveness of calcium therapy for treating this complaint is doubtful. Treatment with 2 g of calcium per day for 3 weeks produced no improvement in the incidence of leg cramps compared with that in a placebo group given 2 g of ascorbic acid per day (Hammer et al., 1987~. Recommendations Although pregnant women, on average, drink more milk than those who are neither pregnant nor lactating, the amounts of calcium recom- mended for pregnancy are often not achieved by dietary sources alone, especially in blacks, Hispanics, and American Indians (see Chapter 13~. No adverse consequences of low calcium intake during pregnancy have been documented. However, there is justifiable concern about the possible effects of inadequate calcium intake by pregnant women under age 25 in whom some mineral is most likely still being added to their bones. The subcommittee defined a low calcium intake to be less than 600 mg/day; below this level of intake the average U.S. adult develops a negative cal- cium balance (Marshall et al., 1976~. This is approximately the amount of calcium in a diet that includes only one small serving of a calcium-rich food in addition to nondairy foods. The subcommittee recommends, therefore, that younger women with low calcium intakes should either increase their intake of food sources of calcium, such as milk or cheese, or, less preferably, add a supplement that provides 600 mg of calcium per day. In the United States, however, there have been no reports on the effect of maternal calcium supplementation on bone mineralization of the mother or the fetus. Women with lactose intolerance need careful assessment of their cal- cium intake because they tend to drink little milk and to have relatively low calcium intakes. This condition is most prevalent among women of black, Hispanic, American Indian, and Asian background. These women can usually tolerate sufficient milk to meet their calcium requirements if taken in amounts less than one glass at a time. Alternative strategies are to consume calcium in yogurt, cheese, or low-lactose milk foods that contain

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CALCIUM, VITAMIN D, AND MAGNESIUM 323 relatively low amounts of lactose. A glass of mild and a slice of hard cheese each contain approximately 300 mg of calcium. The adsorbability of calcium from the most commonly used supple- ments is similar to that from dairy products. Absorption is improved by consuming calcium supplements with or at the end of a light meal (Heaney et al., 1989), although the possible inhibitory effects of a meal high in phy- tate or fiber on calcium absorption have not been adequately investigated. It is unlikely that pregnant women over age 35 would benefit from calcium supplementation to a greater extent than younger women would. Accelerated bone loss does not occur until menopause. VITAMIN D Metabolism Most vitamin D is synthesized from a precursor in the skin after ex- posure to ultraviolet light from the sun. Relatively few foods are good sources of this vitamin; the major source in the United States is vita- min D-fortified milk. After vitamin D is ingested or synthesized in the skin, the liver converts it to 25-hydroxycholecalciferol, which is the major circulating form and the best indicator of vitamin D nutritional status. In the kidney, it is converted into 1,25-dihydroxycholecalciferol, the bio- logically active form of the vitamin. Levels of the active metabolite are not highly correlated with 25-hydroxycholecalciferol levels in the physio- logic range. The 1,25-dihydroxycholecalciferol circulates both bound to a protein and in a free form; both forms are elevated during pregnancy (Paul- son and DeLuca, 1986~. Total levels are approximately doubled at term (Markestad et al., 1986~. The extent to which the increase is stimulated by PTH, prolactin, or other hormones is unclear. Levels of the precursor 25-hydroxycholecalciferol have been reported as both unchanged (Hillman et al., 1978) and decreased (Reiter et al., 1979) in pregnant women, but in animal studies they have been found to be lower when diet and exposure to ultraviolet light were controlled (Danan et al., 1980~. Both of these metabolites, as well as 24,25-dihydroxycholecalciferol, which has no known function, are able to cross the placenta. Fetal vitamin D status may be influenced by maternal vitamin D status, placental transfer and synthesis, or fetal synthesis of the vitamin. The rela- tive importance of each to fetal vitamin D status has not been determined in humans. Maternal plasma 25-hydroxycholecalciferol levels are higher than levels in the umbilical vein or in the newborn, although levels of the free hormone may be higher in the fetus (Bouillon et al., 1981~. Mater- nal and fetal levels of 25-hydroxycholecalciferol are positively correlated (Delvin et al., 1982), since the fetus obtains this form of the vitamin from its

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324 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS mother. In rats, a placental transport mechanism transfers vitamin D, 25- hydroxycholecalciferol, and 24,25-dihydroxycholecalciferol in similar pro- portions to the fetus, especially in the third trimester (Clements and Fraser, 1988~. In the fetus, the vitamin is stored mainly as 25-hydroxycholecalciferol in muscle. Clements and Fraser (19~) demonstrated that the vitamin D molecules obtained in utero, rather than from maternal milk, are the main source of the vitamin during the first 10 days postpartum in the rat. This implies that, at least in rats, the vitamin D status of the neonate is affected by the maternal vitamin D status during gestation. Although 1,25-dihydroxycholecalciferol levels are higher in pregnant than in nonpregnant women, this may have little effect on fetal levels, since this metabolite is produced by both the placenta and the fetal kidneys (Delvin et al., 1985~. Although most investigators have found no relation- ship between maternal and fetal levels of 1,25-dihydroxycholecalciferol, a positive correlation has been reported by Gertner et al. (1980~. Deficient maternal levels of 1,25-dihydroxycholecalciferol impair placental calcium transport to the fetus in sheep (Lester, 1986) but not in rats (Brommage and DeLuca, 1984~. Human placental calcium-binding protein is believed to facilitate placental calcium transport but is not very responsive to 1,25- dihydroxycholecalciferol (Bruns and Bruns, 1983~. Thus, the extent to which maternal vitamin D status regulates the placental transport of cal- cium is not clear, although the vitamin is necessary for the maintenance of maternal calcium status. Requirements The dietary requirement for vitamin D is highly dependent on exposure of the skin to ultraviolet light. In winter, the ultraviolet light reaching the earth's surface is insufficient for vitamin D synthesis in the skin at the latitudes of Britain (51N; Lawson, 1981~; Edmonton, Alberta, Canada (52N; Webb et al., 1988~; and Massachusetts (42N; Webb et al., 1988~. Further south (e.g., in Los Angeles; 34N), some synthesis does occur in winter, but not as much as it does in Puerto Rico (18N; Webb et al., 1988~. Prevalence of Deficiency Only a few studies have provided evidence relevant to the prevalence of vitamin D deficiency in the United States. Because of differences in exposure to ultraviolet light, there are seasonal differences in susceptibility to and prevalence of deficiency.

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CALCIUM, VITAMIN D, AND MAGNESIUM 325 Seasonal Differences In New York City, a low vitamin D intake (2.5 to 5 fig, or 100 to 200 IU, per day) combined with a lack of sunlight exposure in winter resulted in reduced plasma levels of 25-dihydroxycholecalciferol in both the mother and the umbilical cord (Rosen et al., 1974~. In St. Louis, Missouri, maternal serum 25-hydroxycholecalciferol concentrations were three times higher in August than they were in February (42.1 compared with 15.4 ng/ml) in both black and white women (Hillman and Haddad, 1976~. Studies from outside of the United States are more informative. In autumn, both maternal and fetal 25-hydroxycholecalciferol concentrations are substantially higher than they are in spring in Finland (Kuoppala et al., 1986), England (Verity et al., 1981), and even Israel (Nehama et al., 1987~. Reported maternal levels in the fall and spring averaged 17.7 and 10.6 ng/ml in Finland, 25.1 and 16.7 ng/ml in England, and approximately 25 and 16.9 ng/ml in Israel, respectively. Respective newborn levels were 11.5 and 7.5 ng/ml, 16.7 and 10.6 ng/ml, and 18.1 and 11.3 ng/ml. These were positively correlated with maternal values (Nehama et al., 1987; Verity et al., 1981~. The prevalence of deficiency (<6.8 ng/ml) in the Israeli women was 7% in spring and zero in fall. No British women had levels this low. A much higher prevalence of maternal deficiency (defined as <5 ng/ml) occurred in Finland 47% in spring and 33% in fall. In all countries, the reported prevalence of borderline values, i.e., between 5 and 8 ng/ml, was relatively high after winter. Racial, Ethnic, and Dietary Differences In Cleveland, Ohio, vitamin D levels were higher in white mothers and their infants than they were in their black counterparts (Hollis and Pittard, 1984), probably because the rate of vitamin D synthesis is slower in the skin of blacks (Clemens et al., 1982~. On the other hand, a study by Hillman and Haddad (1976) in St. Louis, Missouri, showed no differences in the 25-hydroxycholecalciferol levels in black and white pregnant women in either summer or winter. There are numerous examples of low 25- hydroxycholecalciferol levels resulting from clothing that restricts exposure to ultraviolet light, e.g., in Bedouin (Biale et al., 1979) and Saudi Arabian (Serenius et al., 1984) pregnant women. A disturbingly high prevalence of vitamin D deficiency has been re- ported among pregnant Asian (mainly Indian and Pakistani) women living in Britain (Maxwell et al., 19814. Vitamin D deficiency was indicated by low plasma 25-hydroxycholecalciferol levels, osteomalacia, elevated alka- line phosphatase levels, and a high incidence of neonatal hypocalcemia. On average, 35% of the women and 32% of the infants had undetectable levels of 25-hydroxycholecalciferol in the first week postpartum (Maxwell et

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326 DIETARY INTAKE AND NUTRIENT SUPPl AMENS al., 1981~. Vegetarian women in this group were at a special disadvantage: 71% of them had undetectable levels of 25-hydroxycholecalciferol in the first week postpartum. This, together with a lack of seasonal fluctuation in the prevalence of deficiency, suggests that diet was a major factor in the etiology of their deficiency. Effects of Deficiency Maternal vitamin D deficiency has been associated with neonatal hypocalcemia and tetany in Europe (Paunier et al., 1978), tooth enamel hypoplasia that is more prevalent in British infants born in late winter or spring (Cockburn et al., 1980; Purvis et al., 1973), and maternal osteoma- lacia (Brooke et al., 1980~. Evidence for Supplementation Although there are no concomitant seasonal changes in maternal or fetal 1,25-dihydroxycholecalciferol, calcium, or alkaline phosphatase, the evidence of strong seasonal fluctuations in serum 25-hydroxycholecalciferol has provoked suggestions that pregnant women in northern latitudes should receive vitamin D supplementation during pregnancy, at least during winter months (Kuoppala et al., 1986; Nehama et al., 1987; Verity et al., 1981~. Supplementation of British women with approximately 10 fig (400 IU) of vi- tamin D per day increased maternal and newborn 25-hydroxycholecalciferol levels in both spring and fall (Verity et al., 1981~. In Finland, supplementa- tion given because of low 25-hydroxycholecalciferol levels quickly improved plasma levels of the vitamin (Kuoppala et al., 1986~. Maternal and fetal 25-hydroxycholecalciferol but not 1,25-dihydroxycholecalciferol levels were increased by supplementation of pregnant French women (Mallet et al., 1986~. The ability of supplements to increase maternal and fetal plasma levels of 25-hydroxycholecalciferol is not sufficient justification to recommend their use. However, other beneficial effects of such supplements have been reported. In Britain, for example, daily supplementation of vitamin D- deficient pregnant women of Asian background with 10 fig (400 IU) per day lowered (but did not eliminate) the incidence of neonatal hypocalcemia and convulsions, and it reduced maternal osteomalacia (Brooke et al., 1980~. The women supplemented with 25 fig (1,000 IU) per day gained weight faster (63 g/day) than did unsupplemented controls (46 g/day) (Maxwell et al., 1981~. Reported effects of supplementation on birth weight range from nonexistent in France (Mallet et al., 1986) to a halving of the incidence of low birth weight among Asian immigrants in London (Maxwell et al., 1981) and an increase in birth weight of 100 to 300 g among infants born

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CALCIUM, VITAMIN D, AND MAGNESIUM 327 in India (Marya et al., 1981~. Infants born to Asian women in Britain given 25 fig (1,000 IU) per day during the last trimester weighed significantly more between 3 and 12 months after birth, and they were taller between 9 and 12 months, (Brooke et al., 1981) compared with those born to similar women given placebos. Dosage If supplementation with vitamin D is indicated, careful consideration should be given to selecting a dose that is safe and effective. An excessive vitamin D intake can result in hyperabsorption of calcium, hypercalcemia, and calcification of soft tissues. It is not possible to define a minimal toxic dose (Food and Nutrition Board, 1975) because interindividual sensitivity to excess vitamin D intake is quite variable. Toxicity in nonpregnant adults has been reported after repeated 15-mg (600,000-IU) doses (von Beuren et al., 1966~. In human pregnancy, high maternal intakes of vitamin D were impli- cated as the cause of a syndrome that included mental and physical growth retardation and hypercalcemia in British infants between 1953 and 1957 (Seelig, 1969~. In an animal model, Friedman and Mills (1969) gave high amounts of vitamin D to pregnant rabbits and induced fetal hypercalcemia, aortic stenosis, and abnormal skull development. These symptoms are similar to those caused by excessive vitamin D intake in pregnant women (Friedman and Roberts, 1966~. However, high doses of vitamin D given to pregnant women with hypo- parathyroidism produced no fetal abnormalities (Goodenday and Gordan, 1971~. Very high doses of 1,25-dihydro~ycholecalciferol 17 to 36 mg (680,000 to 1,444,000 IU) per day produced no harmful effects in a pregnant woman with vitamin D-resistant rickets, although her infant had hypercalcemia (Marx et al., 1980~. Thus, it is clear that vitamin D is potentially toxic to the fetus if given in large doses during pregnancy, but the level of intake at which this occurs is uncertain. The relative efficacy of maternal supplementation with vitamin D is greatest during the third trimester (Clements and Fraser, 1988~. Supple- ments of vitamin D2(ergocalciferol) and D3 (cholecalciferol) are processed similarly by the mother and fetus (Markestad et al., 1984~. Daily 10- to 12.5-,ug (400- to 500-IU) vitamin D supplements have been reported to be adequate and safe (Cockburn et al., 1980; Markestad et al., 1986; Paunier et al., 1978~. In Britain, therapeutic use of 25 ,ug (1,000 IU) per day administered in the last trimester reduced signs of deficiency without toxicity (Brooke et al., 1980; Heckmatt et al., 1979~. In other countries, a few large doses rather than small daily doses have been provided to reduce the need for patient compliance. In northern

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328 DIETARY INTAKE AND NUTRIENT SUPPLEMENTS France, for example, a single 5-mg (200,000-IU) oral dose of vitamin D2 in the seventh month of pregnancy increased maternal and umbilical cord levels of 25-hydroxycholecalciferol to the same extent that 25 fig (1,000 IU) of vitamin D2 daily throughout the last trimester did (Mallet et al., 1986~. In India, 30 fig (1,200 IU) per day given to women in their third trimester was less effective than two very large doses of 15 mg (600,000 IU) given in the seventh and eighth months, based on increased serum calcium, reduced alkaline phosphatase, and increased birth weight (Marya et al., 1981~. There is a higher risk of overdose when a few large doses are used in place of daily small doses, and there has been insufficient study of when during pregnancy to administer large doses of vitamin D for maximum effectiveness and safety. This approach to the prevention of vitamin D deficiency is not recommended for use in the United States. Recommendations The subcommittee does not recommend routine supplementation with vitamin D during pregnancy. The preceding discussion illustrates that vita- min D deficiency is common among pregnant women in Europe and that the consequences are harmful. In most regions of the United States, however, exposure to sunlight is greater than in Europe, and unlike the milk in most European countries, most milk in the United States is fortified with the vi- tamin. Nevertheless, daily supplementation with 10 fig of vitamin D should be considered for complete vegetarians, whose 25-hydroxycholecalciferol levels are low due to their avoidance of milk, eggs, and fish (Dent and Gupta, 1975; Maxwell et al., 1981~. Supplementation with 5 fig of vitamin D per day should be considered for pregnant women whose consumption of vitamin D-fortified mild is low. This concern is compounded during low exposures to ultraviolet light in winter at the most northern latitudes. MAGNESIUM Metabolism The metabolism of magnesium is not regulated by any known hormone. Magnesium is essential for the release of PTH and its action on the intestine, bone, and kidney. A mild magnesium deficiency increases PTH secretion; administration of large doses of PTH stimulates the intestinal absorption and renal retention of magnesium. Magnesium participates in the 25-hydroxylation of cholecalciferol to form 25-hydroxycholecalciferol. The maternal serum magnesium concentration rises slightly in early pregnancy, returning to nonpregnant levels by late pregnancy (Reitz et al., 1977~. Maternal levels are slightly below and correlated with those of the

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CALCIUM, VITAMIN D, AND MAGNESIUM 329 infant at delivery (Cockburn et al., 1980~. Seasonal fluctuations (e.g., 5% lower in summer) in maternal blood levels were reported in some studies (Hillman and Haddad 1976), but not in others (Kuoppala et al., 1986; Verity et al., 1981~. Vitamin D supplementation has no effect on maternal or umbilical cord blood magnesium concentrations (Cockburn et al., 1980; Verity et al., 1981~. Magnesium is probably actively transported to the fetus (Reitz et al., 1977~. The normal fetus contains 1 g of magnesium, which is acquired primarily during the last two trimesters at a rate of about 6 mg/day. Adequacy of Intake Magnesium is widely distributed among foods, especially grains, sea- food, and green vegetables. The average U.S. diet contains approximately 120 mg/1,000 kcal. When magnesium intake is low, the efficiency of its absorption increases and relatively more of the mineral is retained by the kidneys. As indicated in Chapter 13, usual magnesium intakes by pregnant women in the United States are substantially lower than the RDA of 300 mg (NRC, 1989~. In one study, 10 healthy, white pregnant women living at home consumed 269 mg/day from their usual diet. For only 6% of 47 one- week-long balance periods were they in a positive magnesium balance (Ashe et al., 1979~. On average, balance was negative ~-40 mg/day). Intake may have been underestimated, however, since magnesium in drinking water was not measured and there were no signs of magnesium deficiency. In fact, magnesium deficiency has never been reported to occur in healthy individuals consuming ordinary diets (Shils, 1988~. On the basis of a medical records study, Conradt et al. (1984) reported that magnesium supplementation during pregnancy was associated with lower frequencies of fetal growth retardation and preeclampsia. This was reevaluated in a double-blind prospective study in Switzerland (Spading and Spatting, 1988~. Before 16 weeks of pregnancy, women were randomly allocated to either an aspartic acid placebo group or to a group receiving a magnesium supplement providing 360 mg/day as magnesium-aspartate- hydrochloride. The investigators reported that the supplemented group had 30% fewer hospitalizations (for any cause), approximately 50% as many premature births and cases of incompetent cervix, and 25% more perinatal hemorrhages than the placebo group. The rate of infant referral to the neonatal intensive care unit was half as high for infants of magnesium- supplemented mothers as for infants of the placebo group. These results were obtained only when the analysis was limited to women who followed the protocol (thus the sample was no longer random), and they require confirmation from other investigators.

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330 DIETARY INTAKE AA/D NUTRIENT SUPPLEMENTS Recommendations Data are insufficient to support a recommendation of magnesium supplementation for pregnant women. Because of the negative balances found in healthy women consuming usual diets and the potential beneficial effects of supplementation observed in one study, however, research on the effects of magnesium supplementation during pregnancy should receive high priority. Dosage There are no reported studies on the safety of different doses of magnesium supplements given during pregnancy. Large doses (e.g., 3 to 5 g) of magnesium salts cause catharsis, but there is no evidence of any other adverse effects in nonpregnant adults (Mordes and Wacker, 1978~. In studies of iron absorption in nonpregnant women who took vitamin-mineral supplements containing 60 mg of iron as ferrous fumarate, Seligman et al. (1983) report that 100 mg of magnesium as magnesium oxide added to supplements significantly reduced the absorption of the iron. SUMMARY There is no evidence that routine calcium, vitamin D, or magnesium supplementation is beneficial to pregnant women in the United States. Inadequate calcium intake by women under age 25 is more likely to affect maternal bone accretion than to cause inadequate calcification of the fetus. Increased intake of calcium-rich foods is preferred to supplementation because such foods are also a source of other valuable nutrients, e.g., riboflavin and vitamin D. The vitamin D status of pregnant women is influenced not only by dietary vitamin D (especially in winter) but also by geographic location and season because of the low amounts of ultraviolet radiation in winter months in northern latitudes. Consumption of vitamin D-fortified mild is especially important in winter since that is the main dietary source of vitamin D. CLINICAL IMPLICATIONS . Ill effects of low maternal calcium intakes on the mother or fetus have not been reported. Nevertheless, there is some concern that low calcium intakes during pregnancy might impair bone mineral deposition, especially in women under age 25.

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CALCIUM, VITAMIN D, AND MAGNESIUM 331 A pregnant woman whose calcium intake is less than 600 mg/day- the approximate amount provided by a diet that includes only one small serving of a calcium-rich food should be advised to increase her consump- tion of milk cheese, yogurt, or other food sources of calcium or to take a calcium supplement at mealtimes that provides 600 mg of calcium per day. The strategy of increasing dairy product intake is preferred since such products also supply energy, protein, minerals, and vitamins-all of which are needed in increased amounts by pregnant women. Special attention should be directed toward the adequacy of intake of black, Hispanic, and American Indian women and complete vegetarians. For pregnant women who are milk intolerant because of the lack of the enzyme lactase, strategies should be directed to increase calcium intake through the use of low-lactose, calcium-rich foods before supplementation is considered. Older pregnant women do not need higher calcium intakes than do those who are younger. Evidence does not support the practice of prescribing calcium for leg cramps during pregnancy. There is insufficient evidence to support routine supplementation with large amounts of calcium as a possible means of preventing pregnancy- induced hypertension. Women who avoid drinking milk have low dietary intakes of vitamin D, since fortified milk is one of the few dietary sources of this nutrient. This is of special concern in winter months, when there is less synthesis of the vitamin in the skin even at southern latitudes and no synthesis at northern latitudes. Based on the known adverse effects of vitamin D deficiency during pregnancy, such women should be counseled to increase their intake of vitamin D-fortified mink or to take supplements providing 10 ,ug (400 IU) of vitamin D per day. . There is no justification for routine supplementation with magne . . slum ~ urlng pregnancy. The subcommittee does not recommend routine supplementation of pregnant women in the United States with calcium, magnesium, or vitamin D. The subcommittee does not recommend the routine use of lab- orato~y tests to assess the calcium, magnesium, or vitamin D status in pregnant women. Assessment of vitamin D status using serum 25- hydroxycholecalciferol levels is recommended for research purposes and, specifically, to evaluate the prevalence of maternal vitamin D deficiency in the United States. .

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