- Email: [email protected]
Serum ionized magnesium levels in normal and preeclamptic gestation
Serum Ionized Magnesium Levels in Normal and Preeclamptic Gestation CYNTHlA A. STANDLEY, DAVID B. COTTON, MD
PhD, JANICE E. WHITTY,
Objective: To compare serum levels of ionized and total magnesium with those of ionized calcium, total calcium, sodium, and potassium over the course of pregnancy in normal women and in women who develop preeclampsia. Methods: We collected venous serum samples from 31 pregnant women during their first, second, and third trimesters. Gestational ages ranged from 6 to 37 weeks. Samples were analyzed for ionized and total magnesium, ionized and total calcium, sodium, and potassium using a biomedical chemistry analyzer. Data were analyzed with repeatedmeasures analysis of variance and two-way repeatedmeasures analysis of variance. Results: In 22 normal pregnant women, both serum ionized and total magnesium levels decreased significantly with increasing gestational age. No changes in sodium, potassium, or ionized or total calcium were observed. Nine of the 31 subjects developed preeclampsia by term; serum total magnesium levels decreased significantly by the second trimester in these women compared with those of normal pregnant women. Conclusion: Our results provide evidence of decreases in ionized and total magnesium levels with increasing gestational age during normal pregnancy, as well as evidence of a magnesium disturbance in women who later develop preeclampsia. Future studies of magnesium balance in women at risk for developing complications of pregnancy are indicated. (Obstet Gynecol 1997;89:24-7. Copyright 0 1997 by The American College of Obstetricians and Gynecologists.)
Pregnancy-induced hypomagnesemia has been reported previously. *J However, the status of ionized magnesium during pregnancy and its relation to other important cations such as ionized calcium, sodium, and potassium have not been described adequately. It is the “free” or ionized magnesium that exerts biologic activ-
24
002%7844197/$17.00 PI1 SOO29-7844(96)00380-X
MD, BRIAN A. MASON,
MD, AND
ity. Data on cation patterns during pregnancy are conflicting, and most reports have examined only a few of the cations present in biologic fluidsid The aim of this
study
was
to measure
serum
levels
of ionized
magnesium, total magnesium, ionized calcium, total calcium, sodium, and potassium longitudinally in normal pregnant women. We compared these values with those obtained from otherwise normal primigravid women who later developed preeclampsia.
Materials and Methods The Wayne State University Institutional Review Board approved the study protocol, and informed consent was obtained. The study population consisted of normal primigravid women who were receiving prenatal care at Hutzel Hospital in Detroit, Michigan between June 1993 and January 1995. Subjects were selected if they had no history of medical complications. Women experiencing complications such as chronic hypertension, gestational diabetes, asthma, preterm labor, or multiple gestation were excluded. Thirty-one of 60 women completed the study. The others had missing samplesand were excluded. Nine of the 31 subjectshad no overt symptoms of preeclampsia during the study period, but developed preeclampsia at term; these women were examined as a separate group and were compared with the remaining 22 women who remained healthy throughout pregnancy. Of the nine women with preeclampsia, six had mild preeclampsia and three had severe preeclampsia, as defined by standard blood pressure and proteinuria criteria. Venous serum samples were collected anaerobically during the first, second, and third trimesters. Gestational agesranged from 6 to 37 weeks. In addition, some women returned for a postpartum visit, and blood was drawn to establish nonpregnant values. At the time of blood collection, urine protein, edema, and deep tendon reflexes were assessed.Urine protein was measured by
dipstick (Miles Inc., Elkhart, IN) from a random urine sample and was graded on a scale of 0 to 4+ (0 = none; I+ = 30 mg/dL; Zf = 100 mg/dL; 3+ = 300-1999 mg/dL; 4+ = at least 2000 mg / dL). Pedal and pretibial edema were assessed by palpation and rated on a scale of 0 to 4+ (0 = none; l- = generalized puffiness; 2- = indentation depth up to 1 cm with immediate recovery; 3+ = indentation depth l-l.5 cm with slow recovery; 4= indentation depth greater than 1.5 cm). Deep tendon reflexes were assessed by striking the patellar tendon and grading the response on a scale of 1’ to 4+ (l+ = slight movement of the foot; 2+ = mild leg withdrawal; 3+ = marked leg and foot movement; 4+ = abrupt leg jerk and extension). Blood samples were allowed to clot at room temperature and then were centrifuged at 2000 rpm for 15 minutes. Serum aliquots in 1.5-mL polypropylene tubes were stored at -70°C until analysis. Samples were analyzed for ionized magnesium, ionized calcium, sodium, and potassium using a Nova 8 Biomedical Stat Profile chemistry analyzer (Nova Biomedical, Inc., Waltham, MA). In addition, serum total magnesium and total calcium levels were measured using a Nova Nucleus chemistry analyzer. Internal control sera of three different levels were used to calibrate the chemistry analyzers. The coefficient of variation for all electrolytes assessed with all three serum controls was less than 1%. Repeated-measures analysis of variance was used for statistical comparisons, followed by univariate analysis for individual group comparisons. Two-way repeatedmeasures analysis of variance with contrast analysis was used to compare data between women who developed preeclampsia and controls. In addition, correlations were made using Statistical Package for Social Sciences, Version 5.0 software (SPSS, Inc., Chicago, IL) and Pearson product coefficient. Finally, Friedman nonparametric analysis of variance and 2 were used to analyze urine protein, edema, and reflex data. All data are presented as mean t standard error of the mean unless otherwise noted. Statistical significance was established at P < .05.
Results Subject demographics according to pregnancy outcome are given in Table 1. The study population consisted of 22 African American women, eight white women, and one Hispanic woman. In normal pregnant women, ionized magnesium decreased significantly with increasing gestational age (first trimester 1.17 + 0.02, second trimester 1.10 t 0.03, third trimester 1.04 2 0.03 mg/dL; P < .Ol). Ionized magnesium also decreased in women who developed preeclampsia (first trimester
VOL.
89,
NO
1, JANUARY
19Y7
Table
1.
Pregnancy Outcome According Characteristics
Variable Primigravida Race African American White Hispanic Gestational age (MW Maternal age (y) Gestational age at delivery (wk) Delivery Vaginal Cesarean Birth weight (g) Birth length (cm) Data are presented mean.
to Subject
Controls
Preeclamptics
22
9
13
2 0 8-33.5
6-36.3 20.1 + 0.5 39.6 2 0.6
22.0 2 0.8 38.9 % 0.8
19
5
3107.5 ? 89.2 49.4 2 0.7
3097.4 i 91.5 50.1 = 1.2
as n, range,
or mean
2 standard
error
of the
1.16 -C0.03, second trimester 1.10 + 0.05, third trimester 1.07 -C0.04 mg/dL; P < .Ol), but the absolute levels did not differ significantly from those of normal pregnant women. First-trimester levels of ionized magnesium did not differ from postpartum levels (first trimester 1.17 -C 0.02, postpartum 1.19 + 0.03 mg/dL). Like ionized magnesium, total magnesium decreased significantly during gestation in normal pregnant women (first trimester 1.77 ? 0.03, second trimester 1.75 z 0.04, third trimester 1.58 + 0.05 mg/dL; P < .Ol), with the greatest decline during the third trimester. Regression analysis revealed the following correlation coefficients for total magnesium in each trimester: first, Y = -0.34; second, Y= -0.20; third, Y = -0.30; overall, r = -0.38 (P < .05). First-trimester levels of total magnesium did not differ significantly from postpartum levels (first trimester 1.77 -+ 0.03, postpartum 1.83 2 0.09 mg/dL). In women who eventually developed preeclampsia, total magnesium levels were significantly lower by the second trimester compared with the normal women (first trimester 1.73 2 0.06, second trimester 1.53 2 0.04, third trimester 1.55 + 0.04 mg/dL; P < .05). Thus, total magnesium levels were significantly reduced during gestation (P < .Ol), but they decreased earlier in women who developed preeclampsia than in those who remained healthy. No changesin sodium, potassium, or ionized calcium levels were observed (Table 2). Total calcium tended to decrease over the course of pregnancy in normal women, and decreased significantly during pregnancy in women who developed preeclampsia (P < .05). We calculated the ratio of ionized calcium to ionized magnesium and the ratio of total calcium to total magnesium in controls and in preeclamptic women.
Table
2. Serum
Electrolyte
by Trimester
Normal
Electrolyte (mmol/L) Potassium Ionized calcium Sodium Total calcium
Concentrations
Pregnant
1st 4.28 1.17 139.5 2.44
Data are presented as mean * P < .05 vs first trimester.
2 i 2 t
Women
Preeclamptic
2nd 0.06 0.01 1.2 0.06
4.09 1.15 139.0 2.40
i standard
error
2 f t -c
3rd 0.08 0.01 1.1 0.07
4.14 1.13 140.1 2.28
Discussion We found a decrease in both total and ionized magnesium over the course of gestation in normal pregnant women, but no change in sodium, potassium, or ionized calcium levels. The levels of the cations studied are within the ranges reported previously.2-4 Several studies 2,3,5,6 have reported hypomagnesemia associated with pregnancy. Although the reason for this is not clear, it is not likely to be due solely to hemodilution. Serum magnesium levels are still observed to decrease when correcting for protein dilution.’ An increase in renal clearance during pregnancy may contribute to the reduction in serum magnesium,7 since the kidney is the main regulator of total body magnesium. The most common cause of magnesium deficiency is renal wasting.8 Extracellular fluid volume expansion, such as that occurring in pregnancy, decreases magnesium resorption,’ and this finding suggests an increased renal clearance of this electrolyte during pregnancy. Other factors that may contribute to hypomagnesemia in pregnancy include poor dietary
Standley et al
Longitudinal
Ionized
0.07 0.01 0.9 0.05
4.21 1.14 137.8 2.65
% 2 2 2
2nd 0.09 0.02 2.0 0.13
4.27 1.14 141.3 2.34
t i + 2
3rd 0.20 0.03 1.6 0.09
4.10 1.17 142.1 2.26
i ? f 2
0.02 0.03 3.9 0.07*
of the mean.
The ratio of ionized calcium to ionized magnesium increased significantly during pregnancy in both the controls (first trimester 2.44 -t 0.05, second trimester 2.57 t- 0.07, third trimester 2.75 -C 0.16; P < .05) and in women who developed preeclampsia (first trimester 2.41 -C 0.05, second trimester 2.54 + 0.07, third trimester 2.68 -+ 0.08; P < .05). The total calcium to total magnesium ratio did not change significantly during pregnancy in either the controls or the preeclamptic women. Urine protein and deep tendon reflexes did not change significantly during gestation in controls or preeclamptic women. The degree of edema was not altered in controls, but increased with gestational age in the women who developed preeclampsia (first trimester 0, second trimester 0.33 -t 0.50, third trimester 1.11 2 0.78; P < .05). In the third trimester, the level of edema was significantly higher in preeclamptic women than in healthy controls (control 0.32 ? 0.48, preeclamptic 1.11 2 0.78; P < .Ol [mean t standard deviation]).
26
2 ? I 5
1st
Women
Magnesium
intake and consumption of minerals by the growing fetal skeletal system. We also found an increasing ionized calcium-ionized magnesium ratio during pregnancy. In a previous report,5 the molar ratio of total calcium to total magnesium remained constant throughout pregnancy. However, ionized magnesium can be altered independent of total magnesium concentrations.4 A high calciummagnesium ratio has been associated with increasing Our data suggest that although the total vasospasm.” calcium-magnesium ratio is maintained during pregnancy, the ionized ratio of these cations is increased. Increased intracellular calcium and decreased magnesium have been reported in women with hypertension and diabetes.” Thus, electrolyte abnormalities may contribute to altered blood pressure. Although serum ionized calcium remained constant during gestation, most likely because of parathyroid hormone responses, ionized magnesium was decreased. The implications of the calcium-magnesium ratio during pregnancy, especially of the ionized fraction, deserve further investigation. The relation between serum total and ionized magnesium with intracellular magnesium has not been defined clearly. In a previous study,12 there was no significant difference in red blood cell magnesium levels in teenagers with pregnancy-induced hypertension, whereas plasma magnesium tended to decrease with increasing gestation in this same group. However, recent evidence suggests that extracellular magnesium may modulate intracellular magnesium in vascular smooth-muscle cells.13 The relative importance of these factors as determinants of smooth-muscle irritability and vasospasm remains to be determined. The implications of magnesium deficiency during pregnancy include the speculation that lower magnesium levels increase uterine contractility? Evidence suggests that serum magnesium levels are lower in women with preterm labor. Magnesium levels are also lower in cases of spontaneous abortion in the first trimester5 and in pregnant diabetic women.14 It is possible that an electrolyte imbalance may predispose
Obstefvics
b Gynecology
these women to the devastating complications of preterm delivery and preeclampsia. The decrease in magnesium levels in the present study suggests that magnesium therapy may be especially appropriate in disease states that exaggerate this physiologic hypomagnesemia of pregnancy. Our study showed that total magnesium levels decrease early during pregnancy in women who develop preeclampsia. This phenomenon may be related to the development of insulin resistance. Pregnancy is associated with a decrease in peripheral insulin sensitivity, primarily by the third trimester.‘” In women with preeclampsia, an “insulin-resistant syndrome” is apparent. 16,*7Magnesium deficiency can induce insulin resistance.ra Plasma magnesium is correlated inversely with glycemic control in non-insulin-dependent diabetes mel1itus.i” In addition, magnesium can influence peripheral tissue responsiveness to insulin”; in turn, insulin regulates magnesium transport in platelets2’ Thus, the relation between magnesium and insulin in the development of preeclampsia merits further study.
References
89. NO.
11.
12.
13.
14.
15.
16.
17.
18.
1. Se&g MS. Magnesium deficiency in the pathogenesis of disease. New York: Plenum, 1980. 2. Kurzel RB. Serum magnesium levels in pregnancy and preterm labor. Am J Perinatol 1991;8:119-27. 3. Handwerker SM, Altura BT, Royo B, Altura BM. Ionized serum magnesium levels in umbilical cord blood of normal pregnant women at delivery: Relationship to calcium, demographics and birth weight. Am J Perinatol 1993;10:392-7. 4. Brookes CIO, Fry CH. Ionized magnesium and calcium in plasma from healthy volunteers and patients undergoing cardiopulmonary bypass. Br Heart J 1993;69:404-8. 5. Borella I’, Szilagyi A, Than G, Csaba I, Giardino A, Facchinetti F. Maternal plasma concentrations of magnesium, calcium, zinc, and copper in normal and pathological pregnancies. Sci Total Environ 1990;99:67-76. 6. Seydoux J, Luc Paunier EG, Beguin F. Serum and intracellular magnesium during normal pregnancy and in patients with preeclampsia. Br J Obstet Gynaecol 1992;99:207-11. 7. Hytten FE. Renal physiology in normal pregnancy. In: de Alvarez RR, ed. The kidney in pregnancy. New York: John Wiley and Sons, 1976:23-43. 8. Ryan Ml’, Whang R. Interrelationships between potassium and magnesium. In: Whang R, ed. Potassium: Its biologic significance. Boca Raton, Florida: CRC Press, 1983:97-107. 9. De Rouffignanc C, Morel F, Moss N, Roinel N. Micropuncture study of water and electrolyte movements along the loop of Henle
VOL.
10.
1, JANUARY
I997
19.
20.
21.
in psammomys with special reference to magnesium, calcium and phosphate. I’flugers Arch 1973;344:309-26. Altura BM, Altura BT, Carella A. Magnesium deficiency-induced spasms of umbilical vessels: Relation to preeclampsia, hypertension, growth retardation. Science 1983;221:376-8. Resnick LM, Gupta RK, Bhargave KK, Grunespan H, Alderman MH, Laragh JH. Cellular ions in hypertension, diabetes and obesity. Hypertension 1991;17:951-7. Boston JL, Beauchene RE, Cruikshank DP. Erythrocyte and plasma magnesium during teenage pregnancy: Relationship with blood pressure and pregnancy-induced hypertension. Obstet Gynecol 1989;73:169-74. Zhang A, Cheng TI’O, Altura BT, Altura BM. Extracellular magnesium regulates intracellular free Mg” in vascular smooth muscle cells. Pflugers Arch 1992;421:391-3. Cruikshank DP, Pitkin RM, Reynolds WA, Willams GA, Hargis GK. Altered maternal calcium homeostasis in diabetic pregnancy. J Clin Endocrinol Metab 1980;50:264-7. Catalan0 PM, Tyzbir ED, Roman NM, Amini SB, Sims EAH. Longitudinal changes in insulin resistance in nonobese pregnant women. Am J Obstet Gynecol 1991;165:1667-72. Kaaja R, Tikkanen MJ, Viinikka L, Ylikorkala 0. Serum lipoproteins, insulin, and urinary prostanoid metabolites in normal and hypertensive pregnant women. Obstet Gynecol 1995;85:353-6. Ferrannini E, Haffner SM, Mitchell DB, Stern Ml’. Hyperinsulinaemia: The key feature of a cardiovascular and metabolic syndrome. Diabetologia 1991;34:416-22. Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 1993;21:1024-9. Fujii S, Takemura T, Wada M, Akai T, Okuda K. Magnesium levels in plasma, erythrocyte and urine in patients with diabetes mellitus. Horm Metab Res 1982;14:161-2. Yajnik CS, Smith RF, Hockaday TDR, Ward NI. Fasting plasma magnesium concentrations and glucose disposal in diabetics. BMJ 1984;288:1032-4, Hwang D, Yen CF, Nadler JL. Insulin increases intracellular magnesium transport in human platelets. J Clin Endocrinol Metab 1993;76:549-53.
Address reprint requests to: Cynthia A. Sfnndley, PhD Midwesfenz University 29555 North 59th Avenue Glendale, AZ 85308
Received March 6, 1996. Received in revised form August Accepted September 19, 1996.
23, 1996
Copyright 0 1997 by The American College of Obstetricians Gynecologists. Published by Elsevier Science Inc.
Standley
et al
Longitudinal
Ionized
Magnesium
and
27
PhD, JANICE E. WHITTY,
Objective: To compare serum levels of ionized and total magnesium with those of ionized calcium, total calcium, sodium, and potassium over the course of pregnancy in normal women and in women who develop preeclampsia. Methods: We collected venous serum samples from 31 pregnant women during their first, second, and third trimesters. Gestational ages ranged from 6 to 37 weeks. Samples were analyzed for ionized and total magnesium, ionized and total calcium, sodium, and potassium using a biomedical chemistry analyzer. Data were analyzed with repeatedmeasures analysis of variance and two-way repeatedmeasures analysis of variance. Results: In 22 normal pregnant women, both serum ionized and total magnesium levels decreased significantly with increasing gestational age. No changes in sodium, potassium, or ionized or total calcium were observed. Nine of the 31 subjects developed preeclampsia by term; serum total magnesium levels decreased significantly by the second trimester in these women compared with those of normal pregnant women. Conclusion: Our results provide evidence of decreases in ionized and total magnesium levels with increasing gestational age during normal pregnancy, as well as evidence of a magnesium disturbance in women who later develop preeclampsia. Future studies of magnesium balance in women at risk for developing complications of pregnancy are indicated. (Obstet Gynecol 1997;89:24-7. Copyright 0 1997 by The American College of Obstetricians and Gynecologists.)
Pregnancy-induced hypomagnesemia has been reported previously. *J However, the status of ionized magnesium during pregnancy and its relation to other important cations such as ionized calcium, sodium, and potassium have not been described adequately. It is the “free” or ionized magnesium that exerts biologic activ-
24
002%7844197/$17.00 PI1 SOO29-7844(96)00380-X
MD, BRIAN A. MASON,
MD, AND
ity. Data on cation patterns during pregnancy are conflicting, and most reports have examined only a few of the cations present in biologic fluidsid The aim of this
study
was
to measure
serum
levels
of ionized
magnesium, total magnesium, ionized calcium, total calcium, sodium, and potassium longitudinally in normal pregnant women. We compared these values with those obtained from otherwise normal primigravid women who later developed preeclampsia.
Materials and Methods The Wayne State University Institutional Review Board approved the study protocol, and informed consent was obtained. The study population consisted of normal primigravid women who were receiving prenatal care at Hutzel Hospital in Detroit, Michigan between June 1993 and January 1995. Subjects were selected if they had no history of medical complications. Women experiencing complications such as chronic hypertension, gestational diabetes, asthma, preterm labor, or multiple gestation were excluded. Thirty-one of 60 women completed the study. The others had missing samplesand were excluded. Nine of the 31 subjectshad no overt symptoms of preeclampsia during the study period, but developed preeclampsia at term; these women were examined as a separate group and were compared with the remaining 22 women who remained healthy throughout pregnancy. Of the nine women with preeclampsia, six had mild preeclampsia and three had severe preeclampsia, as defined by standard blood pressure and proteinuria criteria. Venous serum samples were collected anaerobically during the first, second, and third trimesters. Gestational agesranged from 6 to 37 weeks. In addition, some women returned for a postpartum visit, and blood was drawn to establish nonpregnant values. At the time of blood collection, urine protein, edema, and deep tendon reflexes were assessed.Urine protein was measured by
dipstick (Miles Inc., Elkhart, IN) from a random urine sample and was graded on a scale of 0 to 4+ (0 = none; I+ = 30 mg/dL; Zf = 100 mg/dL; 3+ = 300-1999 mg/dL; 4+ = at least 2000 mg / dL). Pedal and pretibial edema were assessed by palpation and rated on a scale of 0 to 4+ (0 = none; l- = generalized puffiness; 2- = indentation depth up to 1 cm with immediate recovery; 3+ = indentation depth l-l.5 cm with slow recovery; 4= indentation depth greater than 1.5 cm). Deep tendon reflexes were assessed by striking the patellar tendon and grading the response on a scale of 1’ to 4+ (l+ = slight movement of the foot; 2+ = mild leg withdrawal; 3+ = marked leg and foot movement; 4+ = abrupt leg jerk and extension). Blood samples were allowed to clot at room temperature and then were centrifuged at 2000 rpm for 15 minutes. Serum aliquots in 1.5-mL polypropylene tubes were stored at -70°C until analysis. Samples were analyzed for ionized magnesium, ionized calcium, sodium, and potassium using a Nova 8 Biomedical Stat Profile chemistry analyzer (Nova Biomedical, Inc., Waltham, MA). In addition, serum total magnesium and total calcium levels were measured using a Nova Nucleus chemistry analyzer. Internal control sera of three different levels were used to calibrate the chemistry analyzers. The coefficient of variation for all electrolytes assessed with all three serum controls was less than 1%. Repeated-measures analysis of variance was used for statistical comparisons, followed by univariate analysis for individual group comparisons. Two-way repeatedmeasures analysis of variance with contrast analysis was used to compare data between women who developed preeclampsia and controls. In addition, correlations were made using Statistical Package for Social Sciences, Version 5.0 software (SPSS, Inc., Chicago, IL) and Pearson product coefficient. Finally, Friedman nonparametric analysis of variance and 2 were used to analyze urine protein, edema, and reflex data. All data are presented as mean t standard error of the mean unless otherwise noted. Statistical significance was established at P < .05.
Results Subject demographics according to pregnancy outcome are given in Table 1. The study population consisted of 22 African American women, eight white women, and one Hispanic woman. In normal pregnant women, ionized magnesium decreased significantly with increasing gestational age (first trimester 1.17 + 0.02, second trimester 1.10 t 0.03, third trimester 1.04 2 0.03 mg/dL; P < .Ol). Ionized magnesium also decreased in women who developed preeclampsia (first trimester
VOL.
89,
NO
1, JANUARY
19Y7
Table
1.
Pregnancy Outcome According Characteristics
Variable Primigravida Race African American White Hispanic Gestational age (MW Maternal age (y) Gestational age at delivery (wk) Delivery Vaginal Cesarean Birth weight (g) Birth length (cm) Data are presented mean.
to Subject
Controls
Preeclamptics
22
9
13
2 0 8-33.5
6-36.3 20.1 + 0.5 39.6 2 0.6
22.0 2 0.8 38.9 % 0.8
19
5
3107.5 ? 89.2 49.4 2 0.7
3097.4 i 91.5 50.1 = 1.2
as n, range,
or mean
2 standard
error
of the
1.16 -C0.03, second trimester 1.10 + 0.05, third trimester 1.07 -C0.04 mg/dL; P < .Ol), but the absolute levels did not differ significantly from those of normal pregnant women. First-trimester levels of ionized magnesium did not differ from postpartum levels (first trimester 1.17 -C 0.02, postpartum 1.19 + 0.03 mg/dL). Like ionized magnesium, total magnesium decreased significantly during gestation in normal pregnant women (first trimester 1.77 ? 0.03, second trimester 1.75 z 0.04, third trimester 1.58 + 0.05 mg/dL; P < .Ol), with the greatest decline during the third trimester. Regression analysis revealed the following correlation coefficients for total magnesium in each trimester: first, Y = -0.34; second, Y= -0.20; third, Y = -0.30; overall, r = -0.38 (P < .05). First-trimester levels of total magnesium did not differ significantly from postpartum levels (first trimester 1.77 -+ 0.03, postpartum 1.83 2 0.09 mg/dL). In women who eventually developed preeclampsia, total magnesium levels were significantly lower by the second trimester compared with the normal women (first trimester 1.73 2 0.06, second trimester 1.53 2 0.04, third trimester 1.55 + 0.04 mg/dL; P < .05). Thus, total magnesium levels were significantly reduced during gestation (P < .Ol), but they decreased earlier in women who developed preeclampsia than in those who remained healthy. No changesin sodium, potassium, or ionized calcium levels were observed (Table 2). Total calcium tended to decrease over the course of pregnancy in normal women, and decreased significantly during pregnancy in women who developed preeclampsia (P < .05). We calculated the ratio of ionized calcium to ionized magnesium and the ratio of total calcium to total magnesium in controls and in preeclamptic women.
Table
2. Serum
Electrolyte
by Trimester
Normal
Electrolyte (mmol/L) Potassium Ionized calcium Sodium Total calcium
Concentrations
Pregnant
1st 4.28 1.17 139.5 2.44
Data are presented as mean * P < .05 vs first trimester.
2 i 2 t
Women
Preeclamptic
2nd 0.06 0.01 1.2 0.06
4.09 1.15 139.0 2.40
i standard
error
2 f t -c
3rd 0.08 0.01 1.1 0.07
4.14 1.13 140.1 2.28
Discussion We found a decrease in both total and ionized magnesium over the course of gestation in normal pregnant women, but no change in sodium, potassium, or ionized calcium levels. The levels of the cations studied are within the ranges reported previously.2-4 Several studies 2,3,5,6 have reported hypomagnesemia associated with pregnancy. Although the reason for this is not clear, it is not likely to be due solely to hemodilution. Serum magnesium levels are still observed to decrease when correcting for protein dilution.’ An increase in renal clearance during pregnancy may contribute to the reduction in serum magnesium,7 since the kidney is the main regulator of total body magnesium. The most common cause of magnesium deficiency is renal wasting.8 Extracellular fluid volume expansion, such as that occurring in pregnancy, decreases magnesium resorption,’ and this finding suggests an increased renal clearance of this electrolyte during pregnancy. Other factors that may contribute to hypomagnesemia in pregnancy include poor dietary
Standley et al
Longitudinal
Ionized
0.07 0.01 0.9 0.05
4.21 1.14 137.8 2.65
% 2 2 2
2nd 0.09 0.02 2.0 0.13
4.27 1.14 141.3 2.34
t i + 2
3rd 0.20 0.03 1.6 0.09
4.10 1.17 142.1 2.26
i ? f 2
0.02 0.03 3.9 0.07*
of the mean.
The ratio of ionized calcium to ionized magnesium increased significantly during pregnancy in both the controls (first trimester 2.44 -t 0.05, second trimester 2.57 t- 0.07, third trimester 2.75 -C 0.16; P < .05) and in women who developed preeclampsia (first trimester 2.41 -C 0.05, second trimester 2.54 + 0.07, third trimester 2.68 -+ 0.08; P < .05). The total calcium to total magnesium ratio did not change significantly during pregnancy in either the controls or the preeclamptic women. Urine protein and deep tendon reflexes did not change significantly during gestation in controls or preeclamptic women. The degree of edema was not altered in controls, but increased with gestational age in the women who developed preeclampsia (first trimester 0, second trimester 0.33 -t 0.50, third trimester 1.11 2 0.78; P < .05). In the third trimester, the level of edema was significantly higher in preeclamptic women than in healthy controls (control 0.32 ? 0.48, preeclamptic 1.11 2 0.78; P < .Ol [mean t standard deviation]).
26
2 ? I 5
1st
Women
Magnesium
intake and consumption of minerals by the growing fetal skeletal system. We also found an increasing ionized calcium-ionized magnesium ratio during pregnancy. In a previous report,5 the molar ratio of total calcium to total magnesium remained constant throughout pregnancy. However, ionized magnesium can be altered independent of total magnesium concentrations.4 A high calciummagnesium ratio has been associated with increasing Our data suggest that although the total vasospasm.” calcium-magnesium ratio is maintained during pregnancy, the ionized ratio of these cations is increased. Increased intracellular calcium and decreased magnesium have been reported in women with hypertension and diabetes.” Thus, electrolyte abnormalities may contribute to altered blood pressure. Although serum ionized calcium remained constant during gestation, most likely because of parathyroid hormone responses, ionized magnesium was decreased. The implications of the calcium-magnesium ratio during pregnancy, especially of the ionized fraction, deserve further investigation. The relation between serum total and ionized magnesium with intracellular magnesium has not been defined clearly. In a previous study,12 there was no significant difference in red blood cell magnesium levels in teenagers with pregnancy-induced hypertension, whereas plasma magnesium tended to decrease with increasing gestation in this same group. However, recent evidence suggests that extracellular magnesium may modulate intracellular magnesium in vascular smooth-muscle cells.13 The relative importance of these factors as determinants of smooth-muscle irritability and vasospasm remains to be determined. The implications of magnesium deficiency during pregnancy include the speculation that lower magnesium levels increase uterine contractility? Evidence suggests that serum magnesium levels are lower in women with preterm labor. Magnesium levels are also lower in cases of spontaneous abortion in the first trimester5 and in pregnant diabetic women.14 It is possible that an electrolyte imbalance may predispose
Obstefvics
b Gynecology
these women to the devastating complications of preterm delivery and preeclampsia. The decrease in magnesium levels in the present study suggests that magnesium therapy may be especially appropriate in disease states that exaggerate this physiologic hypomagnesemia of pregnancy. Our study showed that total magnesium levels decrease early during pregnancy in women who develop preeclampsia. This phenomenon may be related to the development of insulin resistance. Pregnancy is associated with a decrease in peripheral insulin sensitivity, primarily by the third trimester.‘” In women with preeclampsia, an “insulin-resistant syndrome” is apparent. 16,*7Magnesium deficiency can induce insulin resistance.ra Plasma magnesium is correlated inversely with glycemic control in non-insulin-dependent diabetes mel1itus.i” In addition, magnesium can influence peripheral tissue responsiveness to insulin”; in turn, insulin regulates magnesium transport in platelets2’ Thus, the relation between magnesium and insulin in the development of preeclampsia merits further study.
References
89. NO.
11.
12.
13.
14.
15.
16.
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Address reprint requests to: Cynthia A. Sfnndley, PhD Midwesfenz University 29555 North 59th Avenue Glendale, AZ 85308
Received March 6, 1996. Received in revised form August Accepted September 19, 1996.
23, 1996
Copyright 0 1997 by The American College of Obstetricians Gynecologists. Published by Elsevier Science Inc.
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