Early Roots of Cardiovascular, Skeletal
and Renal Abnormalities

Mildred S. Seelig, M.D., M.P.H., F.A.C.N.

Goldwater Memorial Hospital
New York University Medical Center
New York, New York

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| Jacket | Preface | Contents | Introduction (Chapter 1) |
Chapter: | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 |
| Appendix | Bibliography (A-D), (E-K), (L-R), (S-Z) |

*All figures and tables for Chapter 2*

Part I: Chapter 2




The Role of Magnesium in Normal and Abnormal Pregnancy

2.1. Magnesium Balance in Pregnancy

The formation of new tissue (maternal and fetal) during pregnancy requires higher magnesium intakes than that of the normal nonpregnant woman of comparable age. The most recent recommended dietary allowances in the United States and Canada is 450 mg/day (Food and Nutrition Boards, 1968), a figure that is probably based largely on magnesium balance determinations and calculations done with adult pregnant women from 1914-1942. The general statement that the dietary magnesium during pregnancy should substantially exceed the amount required by other adults has led to the selection of 450 mg/day as reasonable, exceeding that recommended for adolescent and young adult women in the United States by 100 mg/day and exceeding the amount recommended in Canada for women over 22 by 150 mg/ day. Since adolescent children require much higher magnesium intakes to meet their own growth and maturation needs, it is questionable whether the same amount deemed necessary for the mature pregnant woman is sufficient for a teenaged pregnant girl. Even the amount generally considered sufficient, but rarely met by the American woman, whether or not she is pregnant (Seelig, 1964; N. Johnson and Phillips 1976/1980; Ashe et al., 1979), should be reevaluated.

Examination of magnesium retention by pregnant women on different dietary intakes (Table 2-1, Seelig, 1971) shows marked differences in retentions, ranging from negative to strongly positive. The first detailed metabolic balance studies of pregnant women (in Germany) that gave magnesium, calcium, and phosphorus intakes and retentions (Table 2-2, Landsberg, 1914) showed strongly positive balances of all these elements. The magnesium contents of the self-selected diets of 14 women ranged from 338-512 mg/day, and their calcium and phosphorus intakes were usually between 2 and close to 3 g a day. Hoffstrom's long-term study of a Finnish pregnant woman's metabolic balances during the last 23 weeks of pregnancy (Table 2-3, Hoffstrom, 1916) showed that on her much lower magnesium intakes, she was in negative magnesium balance during nine of the periods and retained less than 50 mg/day in eight more. Despite her adequate calcium and phosphorus intakes in all but four periods (never falling below 1 daily) she was in negative calcium balance during seven periods. She rarely retained as much calcium or phosphorus as did the women in the German study (Landsberg, 1914).

The emphasis in the United States was largely on the problem of calcium retention, and Coons and Blunt (1930) at first studied magnesium balances of pregnant women to see whether taking milk of magnesia as a laxative would unfavorably influence calcium retention. They found no interference with calcium retention, even on magnesium intakes as high as 810 mg/day. Toward the end of pregnancy, there was a tendency toward more and larger negative magnesium balances, even on daily magnesium intakes of 400 mg/day. They subsequently compared their findings with those obtained by other investigators (Fig. 2-1, Coons, 1935). The composite curve, and the scatter diagrams, show weakly positive and even negative magnesium balances on daily intakes of less than 300 mg/day. In their own study of eight women in Chicago (Coons and Blunt, 1930), half of the metabolic balance periods showed net losses of magnesium. There was a preponderance of positive balances in their Oklahoma studies of six women (Coons et al. . 1934, 1935); they speculated that the greater exposure to sunlight in Oklahoma might have been responsible for the better magnesium retention in their 1935 studies. To test the possibility that vitamin D was responsible, they studied the effect of cod liver oil on the magnesium retention of a primiparous woman who had also been tested before pregnancy (Coons and Coons, 1935), and whose intakes of magnesium and phosphorus were kept fairly constant. This was a long-term investigation that included 18 metabolic periods of 4 days each on a continuously regulated diet, from the 21st to 30th weeks of pregnancy. Despite an apparently adequate intake of magnesium (369-561 mg/day), three negative balances occurred during three of the metabolic periods, and the woman's average daily retention of magnesium was only 18 mg. Exposure to sunshine was avoided and cod liver oil supplements were provided only during 25th, 26th, 34th, and 35th weeks of study. The investigators concluded, from the slightly lower calcium and magnesium retentions during the first two weeks of cod liver oil administration at five months gestation, and the minimal changes in calcium retention and slight increase in magnesium retention during the second two weeks of supplementation during the eighth month of gestation, that vitamin D from cod liver oil was not equivalent (in its effects on calcium and magnesium retention) to that from reasonable exposure to sunlight (Coons and Coons, 1935). Table 2-4 includes the above data, and the balance data from the study of Toverud and Toverud (1931), from women whose mineral intakes were kept fairly constant before and while on vitamin D supplementation. The Norwegian study (Toverud and Toverud, 1931) shows that the magnesium balances improved on addition of vitamin D supplements, even when the magnesium intake was low (case 8). In that instance, the vitamin D converted a negative calcium balance on an adequate calcium intake to positive, but did little to correct the negative phosphorus balance, the phosphorus intake also being low. The women whose calcium and magnesium intakes were fairly low, but whose phosphorus intakes were adequate (cases 1,6), responded to vitamin D with more retention of magnesium, much less negative calcium balance in one (case 1) but no significant diminution of the strongly negative calcium balance in the other (case 6), whose phosphorus balances remained strongly positive. Not included in this table are the data from women given diets with and without added calcium as salt and milk, which showed that they required at least 1.6 g of calcium and phosphorus daily to maintain positive balances of those elements. The effects of the increased intake on magnesium retention cannot be determined from that study because the magnesium intake was not constant. In a subsequent study, in which the daily dietary intakes of calcium and phosphorus were kept at 1.5-2 g and that of magnesium between 313 to 504 mg (Table 2-5), the three women whose magnesium intakes exceeded 430 mg/day all obtained strongly positive magnesium balances. The one with the highest intake, whose intakes of calcium and phosphorus were over 2 g, retained slightly less magnesium than did those with slightly lower calcium and phosphorus intakes. Another woman whose magnesium/calcium/ phosphorus intakes were 392/1625/1843 also showed high retentions of all three elements. One with comparable magnesium intake (380) but calcium and phosphorus intakes above 2 g retained only 31 mg of magnesium daily. There are exceptions to these findings; individual differences and variations in intakes of effective elements no doubt influenced the metabolic balances. These data are suggestive that the dietary ratios of magnesium, calcium, and phosphorus, and a requisite amount of vitamin D, all influence the retention of these elements during pregnancy.

The long-term studies of a 37-year-old multiparous woman with a history of three prior successful pregnancies and healthy babies (Table 2-6, Hummel et al. 1936), and of an 18-year-old primipara with a suboptimal nutritional background but on a good diet during pregnancy (Table 2-7, Hummel et al., 1937), provide some data that might be germane to the lower magnesium levels of young primiparas and of their infants at birth. The healthy woman, whose metabolic studies encompassed 28 metabolic balance periods from the 135th to 280th day of pregnancy, was on an unusually rich diet that included two quarts of milk, each of which contained 400 units of vitamin D as cod liver oil. This provided an excess of calcium and phosphorus over that considered desirable, and exceeded that shown by Toverud and Toverud (1931) to decrease the retention of magnesium to +31 mg/day in the woman (case 10, Table 2-5) receiving 380 mg magnesium daily, but not to decrease its retention in the woman (case 13, Table 2-5) who ingested about 500 mg of magnesium daily. Neither received vitamin D supplements. Similarly, the patient reported by Hummel et al. (1936, Table 2-6) had high average daily magnesium intakes of 590-615 mg/day during the last two months of pregnancy, the month in which Toverud and Toverud did their metabolic studies (Table 2-5, 2-6), and then retained an average daily amount of magnesium of 85-104 mg. The poorly nourished primipara whose metabolic balance determinations were performed from 60 to 5 days antepartum (the length of gestation was not specified) exhibited greater daily calcium retention and lesser daily magnesium retentions during most of the metabolic balance periods. Only during two of the periods did she retain more than100 mg of magnesium daily. Calculations of the retention of the well-nourished quadripara during the 65 days up to 5 days before delivery, to obtain figures comparable to those for the 65-day period during which the young primipara was studied, show that the total gains during the last two months of pregnancy up to five days before birth were:

Element (g) Primipara Quadripara
Magnesium 4.2 8.0
Calcium 46.3 25.3
Phosphorus 16.3 12.7

Provocative is the finding that the primipara retained about half as much magnesium and almost twice as much calcium as did the healthy thirty-seven-year-old mother of three healthy children. The greater magnesium retention of the older woman is readily understandable on the basis of her having regularly ingested almost 200 mg more magnesium daily than did the young girl. Her lesser retention of calcium is surprising in view of her having regularly ingested extremely high amounts of calcium (about 3 g daily), in contrast to the acceptable intakes of close to 2 g daily by the young girl.

The magnesium intake of the woman who had had successful pregnancies and healthy offspring (Hummel et al., 1936) is reminiscent of the early metabolic studies by Landsberg (1914). In both, all of the metabolic balance determinations showed retentions of magnesium, as well as of calcium and phosphorus. Since Landsberg's 1914 study in Germany, analysis of self-selected diets of pregnant women have shown that daily intakes of magnesium ranged from 260 mg to below 400 mg in 9 out of the 12 studies evaluated (Coons and Coons, 1935). Two subjects ingested 413-422 mg daily; only one selected a diet that delivered 500 mg/day. The calcium and phosphorus intakes were usually close to the recommended amounts. A recent study of 47 pregnant women residing in Wisconsin (N. Johnson and Phillips, 1976/1980) showed that their daily intake was even less adequate than had been cited in the 1935 study. Their magnesium intakes ranged from 103-333 mg/day, averaging 204 mg± 54 S.D. daily. None ingested the recommended 450 mg/day; 98% ingested less than 70% of the recommended daily allowance; and 79% ingested less than 55%. The lower magnesium intakes were correlated with low birth weights. Ashe et al. (1979) have recently shown similarly low intakes in middleclass pregnant women. They had an average daily loss of 40 mg of magnesium.

2.2. Fetal Magnesium Requirements

Coons et al. (1935) tabulated the mineral constituents of fetuses by lunar month, obtained from the literature. Table 2-8 provides their magnesium, calcium, and phosphorus data. It should be kept in mind that human fetuses available for such analyses are usually obtained as a result of abnormalities during pregnancy or labor. Thus, their constituents cannot be considered indicative of those of normal fetuses or full-term infants. As an example, among the analyses by Givens and Macy (1933) were twins born after eight lunar months: one died in three hours and had a total magnesium content of 670 mg; the other died after four days and had a total magnesium content of 1443 mg, far more than might be retained in those few days. Magnesium balance data tabulated for newborn infants (Duckworth and Warnock, 1942), suggest total daily retentions of magnesium of 10-18 mg). Thus, the mineral contents of fetuses and neonates have a wide range at any given age, possibly reflecting maternal stores and intake and placental integrity. Widdowson and Spray (1951) analyzed the mineral content of fetuses, tabulating the data by body weight. The data on magnesium, calcium, and phosphorus are given in Table 2-9. The increments of minerals reflect both the growth and changing chemical composition of the fetus as it develops. Widdowson and Dickerson (1962) have illustrated the changes by comparing the composition of a fetus weighing 175 g with its composition at 3.5 kg, were its chemical composition to be increased proportionally twentyfold, and the actual composition of a 3.5-kg infant (Table 2-10). Infants born prematurely have considerably less of these minerals than do full-term infants, with relatively lesser amounts of calcium and phosphorus than of magnesium, indicating the lesser bone calcification, most of which occurs in the third trimester. The magnesium content of neonates has been as low as 277 mg and as high as 886 mg; similarly, the calcium content of the newborn has been from 13.08 to 33.27 g, and that of phosphorus, 8.96-18.68 g (Coons et al. 1935).

2.3. Magnesium Serum Levels in Normal and Abnormal Pregnancy

2.3.1. Normal Pregnancy: Magnesium Levels

When the dietary intake of magnesium is not sufficient to meet the demands of gestation, the maternal stores are mobilized and magnesium deficiency can develop. Although under most circumstances the body maintains plasma magnesium levels within very narrow limits, the pregnant woman tends to develop lower than normal magnesium levels, even in the absence of toxemia. Since the homeostasis of calcium and phosphorus is intimately related to that of magnesium, brief note is taken here of the tendency also toward declining calcium levels during pregnancy (Newman, 1957; Hardy, 1956; E. Dawson et al., 1969; Watney et al., 1971). It has been shown that phosphorus levels also fall somewhat during pregnancy, so calcium supplements have often been given in the form of the phosphate, with resultant increase in leg cramps of pregnancy. Hardy (1956) and Kerr (et al. (1962) demonstrated that when the phosphate salt is given, with or without vitamin D (viosterol), the serum total and ionized calcium levels were actually depressed, as compared with the rises seen in pregnant women given calcium carbonate or lactate. Even the serum phosphate levels increased when the nonphosphate calcium salts were given (Kerr et al., 1962). Since high phosphate intake interferes with magnesium, as well as calcium absorption, it is possible that calcium phosphate salts also lowered magnesium levels, and that this might have contributed to the muscle cramps.

The first reports of blood magnesium levels during pregnancy were in 1923. Krebs and Briggs (1923) reported a range of 1.7-2.2 mEq/liter among 17 women in their 8th to 40th weeks of pregnancy. Bogert and Plass (1923) compared the serum levels of 40 pregnant women at different stages of pregnancy with those of nonpregnant women and found that the average value 2.0 mEq/liter at the outset (which equaled the control average) fell to an average of 1.7 by the end of pregnancy. Watchorn and McCance (1932) found that half of the 12 pregnant women in their series had serum magnesium levels below 1.99 mEq/liter (which was below the values they found in normal nonpregnant subjects), and that the percentage of the total magnesium in the ultrafiltrable fraction was increased. They were dubious that the difference was due to diminished quantities of serum protein, this not being a constant finding, and speculated that an unidentified change in the physicochemical equilibria must have taken place that allowed for more ready passage of magnesium across the placental barrier. Such a change might allow, too, for more ready urinary excretion and might partially explain the need for high magnesium intake during pregnancy to maintain the degree of positive balance necessary for successful gestation without prejudicing the health of the mother. Another group of investigators reported that the blood magnesium of 75 women was higher especially in the sixth month of gestation (range during pregnancy 1.95-2.78 mEq/liter mean = 2.41) than it was four nonpregnant women (2.11 mEq/liter) (Zaharescu-Karaman et al., 1936a). However, they found that the level dropped markedly at the end of labor, to a range of 0.35-2.35 mEq/liter and a mean of 1.5 (Zaharescu-Karaman et al., l936b). Extremely low serum magnesium levels (1.0-1.1 mEq/liter) were reported in a small series of cases by Wolff and Jorrand Bourquard (1937) in the second month of pregnancy which increased slightly (to 1.25-1.41 mEq/liter) at the end of gestation. Their control (nonpregnant) mean value was 1.7 mEq/liter. Haury and Cantarow (1942) included four normal pregnant women in their tabulation of 108 subjects, and reported a range of 1.4-2.1 mEq/liter; most of their normal controls had serum magnesium levels of 1.8-2.4 mEq/liter. Köberlin and Mischel (1958) also reported lower Mg levels in the first trimester than later in pregnancy. A more extensive report by Newman (1957) has shown the range of serum magnesium levels in 27 normal pregnant women to be very wide in each of the trimesters, at delivery, and at 3-5 days and 6 weeks postpartum (Table 2-11). Newman also reported an unusually wide normal range of serum magnesium (1.34-2.4) in non- pregnant women. The calcium and phosphorus levels also dropped slightly.

Hall (1957) graphed values, obtained from 30 pregnant patients who were followed from 11 weeks to term and at six weeks postpartum (Fig. 2-2), as well as values from 294 normal and toxemic (11.9%) women. Their work illustrates that the normal pregnant woman tends to have serum magnesium levels that remained at the low limit for the nonpregnant range (1.69-2.0 mEq/liter) with the broadest range (about 1.6-2.1) in the second trimester. The lowest values that were recorded in this study, which started in the 11th week, were in the 12th-18th week of pregnancy (1.45-1.8 mEq/liter. Archari et al. (1961) found no difference in serum magnesium levels of normal pregnant and nonpregnant women; both groups had a range of 1.5-1.9 mEq/liter. DeJorge (1965a,b) found that serum magnesium levels fell continuously in 99 pregnant women from about 1.6 mEq/liter in the second month to about 1.2 mEq/liter in the eighth month, as compared to their nonpregnant range of 1.70-2.25 mEq/liter. Correcting for the dilution of plasma that occurs during pregnancy, in a study of 139 pregnant women (Table 2-12), they concluded that the hypomagnesemia is real only during the first half of pregnancy and during the last month (DeJorge, 1965b). Comparable conclusions were reached by Dawson et al. (1969) in their study of 244 adolescent (ages 13-19) pregnant women. The mean plasma magnesium levels declined slightly from 2.6-2.2 mEq/liter as pregnancy progressed, but showed no change when expressed as a ratio to hematocrit values.

Celli Arcella (1965) reported lower serum magnesium levels (1.9 mEq/liter) during the third trimester than in normal nonpregnant women (2.2 mEq/liter). Lim et al. (1969b) similarly reported significantly lower serum (and erythrocyte) levels in normal pregnant women in the third trimester than in normal nonpregnant women. In the latter study, the average of 105 serum samples from normal pregnant women was 1.43 ± 0.05 mEq/liter, with a range of 1.28-1.73, as compared to the normal nonpregnant value of 1.60 ± 0.17. The average value for erythrocyte Mg was also lower than for nonpregnant women. The authors suggest that these differences, taking into account the increasing demands of the rapidly growing fetus, may indicate an occult magnesium deficiency. In contrast, Mahran and Hanna (1968) reported a higher mean (1.83 ± S.D = 0.28) among normal pregnant women in the third trimester, as compared with their control mean magnesium value of 1.66 mEq/liter ± S.D = 0.01. They expressed concern about the magnesium deficiency early in pregnancy, at a time when hyperemesis gravidarum can lead to loss of minerals, including magnesium. They stressed the importance of repairing the magnesium deficit, as well as that of the fluids and more commonly considered electrolytes. This observation recalls the work of Hall (1957), who showed the lowest serum magnesium levels in the early weeks of his study, and that of DeJorge (l965b), who considered the magnesium deficit real only in the first half of pregnancy and the final month.

The change in serum magnesium that takes place during labor and in the parturient period are not clear. Wallach et al. (1962) found the concentrations of plasma Mg to be below normal in three normal parturient women (1.57-1.70 mEq/ liter), as compared with the normal value of 2.0 ± 0.15, obtained from 75 men and women 19-68 years of age. Celli Arcella (1965) reported that serum magnesium levels rose to normal levels during labor, after the low values they had noted during the third trimester. Lupi et al. (1967) noted low serum magnesium levels (1.4 mEq/liter) at the beginning of labor, but observed a further decline during the final stage of labor (1.1 mEq/liter). Manta et al. (1967) also found serum magnesium levels to decrease during labor, reaching the lowest point at the stage of expulsion and then rising. These findings confirm the early report that the mean serum magnesium levels drop at the end of labor to 1.5 [ range = 0.35-2.35 mEq/liter (Zaharescu Kamman, 1936b)], and those of Rusu et al. (1971/1973), who found that the mean serum magnesium levels dropped slightly at the outset of labor in 38 women to 2.0 mEq/liter from 2.3 just before labor began. During active labor there was a further drop (in 88 women) to 1.5 ± 0.3 mEq/liter. Ten women with imminent premature labor had a mean serum level of 1.4 ± 0.3 mEq/liter. The values depicted in Table 2-13 indicate that most investigators have found low maternal serum levels at delivery, cord blood values being significantly higher

Caddell et al. (1973a) have evaluated the magnesium status of postpartum, well-fed women in Thailand (where the magnesium intake is greater than it is in the United States), and found that the postpartum plasma magnesium levels were significantly lower than they were in young nulliparous women. When they were tested by a parenteral magnesium load, the postpartum women retained a mean of 15% more magnesium than did the nulliparous women (borderline significance). Some apparently normal, asymptomatic postpartum patients had moderately high magnesium retention, but 37% retained only 0-25%. In a study of 198 moderate-income American mothers assessed by an intravenous magnesium load test, the mean postpartum magnesium retention was 51% (Caddell et al. 1975). Over 90% of the magnesium load was retained by biologically immature (under 17 years of age) multiparas and in young mothers of twins. Most primiparous mothers showed little retention of the load, but 6 who had had prolonged labors retained 78% of the load. Multiparous mothers with a long interval since the previous pregnancy had the lowest magnesium retention. However, among the 46 patients who retained less than 40% of the load, the mean plasma magnesium was 1.58, and among the 81 who retained more than 40%, the plasma magnesium was 1.45 mEq/liter. Only plasma levels below 1.2 mEq/liter could be matched with high retention of magnesium.

2.3.2. Preeclampsia and Eclampsia: Magnesium Levels and Treatment

The use of magnesium salts parenterally for control of manifestations of acute eclampsia long antedated the demonstration that serum levels of magnesium tend to be lower in women with toxemic pregnancies (especially early in the course of pregnancy) than they are during normal pregnancies. Less reliable as an index of magnesium deficiency of toxemic pregnancy is the serum level toward the end of gestation, when renal damage can interfere with magnesium excretion, as it does in patients with nephritis. The first published reports of the anticonvulsant properties of magnesium sulfate in eclampsia appeared in Europe (Einar, 1907; Kaas, 1917). It became a favored treatment of convulsions of pregnancy in the United States from the time Lazard (1925) and McNeile and Vruwink (1926) recommended its use intravenously, Dorsett (1926) described its use intramuscularly, and Alton and Lincoln (1925) reported its use intrathecally. Hirschfelder (1934) first reported a markedly low serum magnesium level (0.8 mEq/liter) in a 47-year-old patient with eclampsia, who then responded favorably to high dosage oral magnesium sulfate therapy. Among eight eclamptic women, Haury and Cantarow (1942) reported three with serum magnesium levels of 0.8-1.0 mEq/liter and three with levels of 2.7-3.2 mEq/liter. Their stages of pregnancy were not given. Achari et al. (1961) reported that 21 eclamptic women had a mean serum magnesium level of 0.83 mEq/liter (range = 0.25-1.84). Eclamptic women frequently have higher plasma or serum magnesium levels toward the end of pregnancy than do normal pregnant women at term (Pritchard, 1955; Hall, 1957; Kontopoulos et al. 1976/1979), but such normal or even elevated levels are not considered a contraindication to the use of large doses of magnesium salts, which are administered parenterally for their pharmacodynamic neurosedative, antihypertensive effects and not to correct a deficiency. As much as 200 mg of magnesium an hour, given intravenously as the sulfate, was recommended in the early studies (Lazard, 1925, 1933; McNeile, 1934; Winkler et al., 1942). This route is recommended by many either as the sole approach (Zuspan and Ward, 1964, 1965; Zuspan, 1966, 1969; Harbert et al., 1968; Hutchinson et al., 1963), or in combination with intramuscular injections (Pritchard, 1955; Flowers et al. 1962; Flowers, 1965, 1975; Kontopoulos et al., 1976/1980, Weaver, 1976/1980; Flowers et al., 1962, Fig. 2-3). Pritchard (1955) observed that administration of large doses of epsom salts orally exerted no effect on the plasma magnesium levels. Since only 5% of the administered dose appeared in the urine, the possibility that only a small percentage of the administered dose was absorbed was considered. However, even after administration of 150 g of magnesium sulfate intramuscularly over a five-day period, he found that the plasma levels were maintained between 3.5 and 7 mEq/liter. When treatment was initiated with 4 g of MgSO 4 intravenously, there was an initial peak, followed by a prompt rapid fall and then a gradual decline. He found that the cerebrospinal fluid magnesium levels did not reflect the high plasma levels induced by therapy. Flowers (1965) found it necessary to use a mean of 70 g of magnesium sulfate over a three-thy period to control eclampsia. Similarly, Harbert et al. (1968) found it necessary to use 40-60 g of magnesium sulfate per 24 hours to maintain neurosedative serum levels of magnesium of 6-8 mEq/liter. Perhaps the failure to develop hypermagnesemia more frequently toward the end of an eclamptic pregnancy and the difficulty in maintaining pharmacologic blood levels may reflect not only repletion of maternal stores but high fetal requirements, which might not have been supplied during the abnormal pregnancy. Possible Contribution of Magnesium Deficiency to Eclamptic Pregnancy

Hall (1957), because of the experimental and clinical evidence that magnesium deficiency is associated with neuromuscular irritability and convulsions, and because of the long-recognized efficacy of magnesium in the management of preeclampsia and eclampsia, considered the possibility that magnesium deficiency might contribute to toxemia of pregnancy. He found that the mean of plasma magnesium levels had been somewhat lower among toxemic than among normal pregnant women from the 12th through the 25th week. He charted a tendency of the magnesium levels to rise slightly toward the end of pregnancy in toxemic women (Fig. 2-2, Hall, 1957), a finding that might be related to increasing renal damage in that group. The percentage variations from the normal nonpregnant levels were as great as 50%-90% below the mean at different times during pregnancy. However, since the differences between the levels in the normal and toxemic pregnant women were not statistically significant, Hall questioned whether the low magnesium levels contributed to the symptoms of toxemia. Two years earlier a preeclamptic woman with pseudohypoparathyroidism (serum calcium of 4-6 mg percent and lack of response to PTH), and hypomagnesemia (1.1 mEq/liter) associated with mental aberrations, had been reported from the same medical center (Suter and Klingman, 1955). The possibility was considered that lowered serum magnesium levels during pregnancy might predispose to seizures during pregnancy in susceptible women, such as those with a tendency toward epilepsy (Suter and Klingman, 1957). Flowers et al. (1965) suggested that depletion of tissue stores of magnesium might explain eclamptic patients' tolerance and requirement for such large doses of magnesium. McGanity (1965) proposed that dietary magnesium deficiency might be etiologic in preeclampsia.

In France, where latent tetany had long been recognized as a manifestation of subacute magnesium deficiency (Durlach and LeBrun, 1959; 1960; Durlach, l969a) uterine cramps and abnormal contractility during pregnancy have been shown to be responsive to treatment with magnesium, and have been proposed as a manifestation of its deficiency (Dumont, 1965; Muller, 1968; Muller et al., 1971/l973).It was observed that patients with this complaint frequently also exhibited latent tetany and often had marginal hypomagnesemia (1.5 mEq/liter or lower levels), with and without hypocalcemia (Dumont, 1965). Uterine hypercontractility has been added to the signs of toxemia of pregnancy and has also responded to intravenous magnesium therapy (Hutchinson et al., 1963; Cobo, 1964).

The efficacy of pharmacologic doses of magnesium in the treatment of manifestations of toxemias of pregnancy has led to consideration of magnesium as a drug, in that condition, far more commonly than consideration of the fact that it is a nutrient, the supply of which must be increased substantially during gestation. Two years before hypomagnesemia was first reported in an eclamptic woman (Hirschfelder, 1934), magnesium deficiency was associated with abnormalities of pregnancy and during early lactation in cows (Sjollema, 1932). Neuromuscular manifestations in pregnant and lactating herbivores included tetany and convulsions; cardiovascular lesions were found at autopsy (Sjollema, 1932; Rook and Storry, 1962; Storry and Rook, 1962; Rook, 1963; Herd, 1966a,b; Hjerpe, 1971). Magnesium deficiency has been accepted as contributory to toxemia of pregnancy in grazing animals, and magnesium recognized as protective.

The possibility is increasingly being considered that magnesium deficiency can also contribute to major and lesser manifestations of toxemias of pregnancy (Dumont, 1965; McGanity, 1965; Lim et al., 1969b; Muller, 1968; Muller et al., 1971/1973; Hurley, 1971; Seelig, 1971; Seelig and Bunce, 1972; Kontopoulos et al., 1976/1980; Weaver, 1976/1980). There is evidence that the magnesium intake during pregnancy is likely to be suboptimal (Review: Seelig, 1971). That it might be sufficiently low to contribute to early and late abnormalities of pregnancy is suggested by the survey that showed magnesium intakes during pregnancy that are low (N. Johnson and Philipps, 1976/1980), even by standards for nonpregnant women (Seelig, 1964). The women with the lowest magnesium intakes gave birth to low-birth- weight infants, a finding that suggests intrauterine growth retardation. Mahran and Hanna (1968) expressed concern about the magnesium deficit, early in gestation, that might be caused by hyperemesis gravidarum. When one considers how frequently lesser degrees of nausea and vomiting (i.e., "morning sickness") interfere with proper nutrition in the first trimester, and one recalls the evidence that hypomagnesemia is encountered at that time (de Jorge et al., 1965a,b) and shortly thereafter (Hall, 1957), the possibility of early magnesium deficiency being etiologic in abnormalities of pregnancy, placental abnormalities, intrauterine malnutrition, and fetal abnormalities should be seriously entertained. That hyperemesis can precipitate acute hypomagnesemia later in pregnancy was demonstrated in a report by R. Fraser and Plink (1951) of a 33-year-old woman who developed hypochloremic, hypokalemic alkalosis in association with hypomagnesemia a few days before delivery of her eighth child. It should be noted that so young a woman, completing her eighth pregnancy, would be expected to be magnesium depleted. Possible Contribution of Magnesium Deficiency to Placental and Coagulation Abnormalities

The abnormalities of placentas of eclamptic women which range from functional insufficiency (secondary to arteriolar spasm) to small size, scarring, and infarction (Warkany et al., 1961: Holman and Lipsitz, 1966; Wigglesworth, 1966) are associated with intrauterine growth retardation (IUGR) and hypoxia. There is insufficient evidence to implicate magnesium deficiency in eclamptic pregnancy as a direct contributory factor in placental abnormalities, but there are some findings that suggest the need for further study of this question. Charbon and Hoekstra (1962) tabulated the magnesium and calcium contents of placentas from women with normal single and twin pregnancies and with preeclampsia or eclampsia. The decreased magnesium and increased calcium levels of the placentas from eclamptic women are especially striking (Table 2-14). Magnesium-deficient pregnant rats had placental calcification and bore low-weight young (Cohlan et al., 1970; Dancis et al., 1971). An excess of vitamin D, which is known to cause net loss of magnesium (to be discussed later in this volume) has caused reduction in placental size in rats, placental damage, and birth of small for gestational-age young (Potvliege, 1962; Ornoy et al., 1968). Whether the peroxidized cod liver oil, or its fractions, that were used to produce experimental eclampsia in rats, with intravascular coagulation and damaged placental trophoblast (McKay et al., 1967) also cause magnesium loss has yet to be investigated. Changes similar to those caused by an excess of vitamin D or peroxidized vitamin D have been reported in placentas of women with eclampsia, and thrombocytopenia that reflects intravascular platelet aggregation of eclampsia has long been recognized (Review: McKay et al., 1967).

The initiating factor that damages the syncytial trophoblast in human preeclampsia is not known. Hyperreactivity to vitamin D, possible formation of toxic derivatives of that sterol (Seelig and Mazlen, 1977), and the evidence that high Ca/Mg and Na/K ratios increase arterial resistance (Haddy and Seelig 1976/1980) are factors that should be considered. It remains to be resolved whether the observation that magnesium administration to preeclamptic women produced highly significant increased coagulation time and decreased platelet adhesiveness (Weaver, 1976/1980) indicates only a direct effect of magnesium on coagulopathy, or whether it plays a role in correcting a deficit that intensifies placental damage.

The coagulation abnormalities of eclampsia (McKay et al., 1967; Howie et al., 1976), the significant risk of antenatal thromboembolism (Editorial, Brit. Med., 1:249-250, 1970), and the hypercoagulability of the blood of eclamptic patients who have responded to magnesium therapy (Weaver, 1980) are provocative observations pointing toward a possible etiologic role of early magnesium deficiency. Perhaps the clinician is in error when he assumes that the hypomagnesemia seen during normal pregnancy is necessarily normal. It would have been useful had serum magnesium levels been obtained from the thriving mother whose sustained positive magnesium balance throughout pregnancy has been described by Hummel et al. (1936). Her daily intake of magnesium had exceeded the generally recommended 400 mg/day by 200 mg daily; she had retained 15½ g of magnesium during the last half of her pregnancy. If the magnesium requirements during pregnancy are as great as those suggested by the early Landsberg (1914) study and those of Hummel et al. (1936, 1937), and if magnesium deficiency contributes to toxemia, why is toxemia not more common? The answer may lie in the possibility that unlike the magnesium-deficient pregnant rats that sustain their own magnesium levels, with fetal loss, the normal less depleted woman draws more on her own reserves of magnesium to meet fetal demands. Her declining blood levels may reflect the drain, but need not be associated with maternal pathologic changes unless concomitant abnormalities are present. If the rat studies are relevant to pregnant women, it may be that in some women with insufficient magnesium deficiency to cause overt maternal changes, there can be fetal damage, in view of high fetal cellular demands for magnesium (McCance and Widdowson, 1961).

Already mentioned is the possibility that agents (such as vitamin D or derivatives) that affect magnesium requirements, as well as presenting other toxic potential (Seelig and Mazlen, 1977), can participate. Additionally, in a study of the effect of vitamin D with and without calcium and phosphorus supplements on success of gestation in rats, Nicholas and Kuhn (1932) found that unlike the test rats the control rats were given fresh green vegetables, yeast, fruits, butter, and cod liver oil and had the best gestations. Thus, the controls received a balanced diet containing magnesium, trace elements, the B vitamins, and vitamin A, which were absent in the experimental groups that had significantly less successful gestations. This study calls to mind the studies implicating pyridoxine deficiency in the "morning sickness" syndrome and in later manifestations of toxemia (Sprince et al., 1951; Klieger et al., 1966). The extent to which magnesium and pyridoxine deficiencies might interrelate in pregnancy-both nutrients are involved in phosphorylation reactions and protein synthesis (Review: Durlach, 1969b)-remains to be determined,

Even such a seemingly minor abnormality as a smaller than normal placenta has been associated with a disproportionate reduction in birth weight (Wigglesworth, 1966). Placental infarction, such as occurs in toxemic pregnancy, interferes with placental transfer of nutrients and affects gaseous diffusion, leading to lowered oxygen levels in the fetus. Scarred placentas have impaired blood flow, with resultant retardation of intrauterine growth and oxygenation (Walker and Turnbull, 1953; Warkany et al., 1961; Gruenwald, 1961, 1963, 1964; Scott and Usher, 1964; Holman and Lipsitz, 1966; Wigglesworth, 1966). Even moderate maternal malnutrition has been shown to be associated with significantly smaller than normal placentas and a high prevalence of low-birth-weight infants (Lechtig et al., 1975). Scott and Usher (1966) analyzed the factors associated with fetal malnutrition and found that it occurred in 13.5% of the primipara (usually young), and in only 8.4% of multiparous births, but that the incidence rose with each successive pregnancy after the sixth pregnancy. There was also a higher incidence of fetal malnutrition when previous pregnancies had produced low-birth-weight infants, to as high as a ninefold increased incidence when there had been four or more low-birth-weight infants. Infants with IUGR had a higher incidence of fetal distress, asphyxia neonatorum, and congenital abnormalities than did normal-weight infants. Congenital anomalies were diagnosed in 17% of the 60 markedly underweight infants and in 31% of 35 who were markedly wasted. The incidence represents a 30-fold increase in major anomalies and a 16-fold increase in congenital heart disease in infants with marked fetal malnutrition.

Placental insufficiency, found not only in eclampsia and frequent pregnancies but in prolonged gestation, placenta praevia, and pregnancy in the elderly primigravida patient, is associated with fetal malnutrition and low calcium and glucose levels in the infant (Khattab and Forfar, 1971). There should be routine determinations of magnesium levels and retention during and after pregnancy in women at risk of placental pathology, and of their infants.

2.4. Magnesium Levels in Women with Recurrent or Imminent Abortion

Women who have experienced one spontaneous abortion not infrequently experience repeated abortions. Zigliara et al. (1971/1973) studied the magnesium levels of 294 women with imminent abortions and found that 50% had significantly lower than normal erythrocyte magnesium levels; 25% had hypomagnesemia as measured by serum determinations. The serum levels showed the existence of severe chronic magnesium deficiency in only 11% whereas low erythrocyte magnesium levels were seen in 40.8% of those with repeated abortions. The greater the number of abortions, the greater the degree of magnesium deficiency detected. Normal levels were reached three days after the abortion. Rusu et al. (1971/1973) also reported lower (than in normal pregnancy) magnesium levels among women with imminent abortions (1.4 ± 0.3 mEq/liter versus 2.0 mEq/liter). Treatment with magnesium doubled the serum levels and permitted some of the women to continue to term.

Whether the uterine hypercontractility, considered part of the preeclamptic syndrome (Hutchinson et al., 1963; Cobo, 1964) and found as a complication of pregnancy among women with latent tetany of marginal hypomagnesemia (supra vide), is related to the hypomagnesemia of recurrent aborters remains to be proved. Rusu et al. (1971-1973) found that as the serum magnesium level fell the uterine reactivity to oxytocin increased.

It may be relevant that magnesium-deficient animals have poor gestational success, with evidence of resorption at implantation sites in severely deficient animals, and smaller-than-control size of litters in less deficient animals.

The severity of postpartum uterine cramps has also been related to the drop in serum magnesium after delivery. Nicolas (1971/1973) reported that there was a slight decrease of magnesium levels during labor [1.74 (1.4-2.2 mEq/liter)] and 24 hours later [1.64 (1.4-2.2)]. A double-blind study in which one group was given magnesium therapy after delivery (500 mg magnesium lactate four times a day) or placebo resulted in a significant (p < 0.001) increase of magnesemia (from 1.6 to 1.9) in the magnesium-treated group, a change that was associated with improvement in uterine discomfort; there was no change in uterine cramps in the placebo-treated group.

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| Jacket | Preface | Contents | Introduction (Chapter 1) |
Chapter: | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 |
| Appendix | Bibliography (A-D), (E-K), (L-R), (S-Z) |

*All figures and tables for Chapter 2*