Magnesium supplementation affects metabolic status and pregnancy

outcomes in gestational diabetes: a randomized, double-blind,

placebo-controlled trial1
Zatollah Asemi,2 Maryam Karamali,3 Mehri Jamilian,3 Fatemeh Foroozanfard,4 Fereshteh Bahmani,2 Zahra Heidarzadeh,2

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Sanaz Benisi-Kohansal,6 Pamela J Surkan,5 and Ahmad Esmaillzadeh6*
2
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran; 3Department of Gynecology and
Obstetrics, School of Medicine, Arak University of Medical Sciences, Arak, Iran; 4Department of Gynecology and Obstetrics, School of Medicine, Kashan University
of Medical Sciences, Kashan, Iran; 5Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; and 6Food Security
Research Center and Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran

ABSTRACT Keywords: magnesium, supplementation, gestational diabetes,

Background: To our knowledge, prior research has not examined
the effects of magnesium supplementation on metabolic status and
pregnancy outcomes in maternal-child dyads affected by gestational
diabetes (GDM).
Objective: This study was designed to assess the effects of mag-
nesium supplementation on metabolic status and pregnancy out-
comes in magnesium-deficient pregnant women with GDM.
Design: A randomized, double-blind, placebo-controlled clinical trial
was performed in 70 women with GDM. Patients were randomly
assigned to receive either 250 mg magnesium oxide (n = 35) or
a placebo (n = 35) for 6 wk. Fasting blood samples were taken at
baseline and after a 6-wk intervention.
Results: The change in serum magnesium concentration was
greater in women consuming magnesium than in the placebo group
(+0.06 6 0.3 vs. 20.1 6 0.3 mg/dL, P = 0.02). However, after
controlling for baseline magnesium concentrations, the changes in
serum magnesium concentrations were not significantly different
between the groups. Changes in fasting plasma glucose (29.7 6
10.1 vs. +1.8 6 8.1 mg/dL, P , 0.001), serum insulin concentration
(22.1 6 6.5 vs. +5.7 6 10.7 mIU/mL, P = 0.001), homeostasis
model of assessment-estimated insulin resistance (20.5 6 1.3 vs.
+1.4 6 2.3, P , 0.001), homeostasis model of assessment–
estimated b-cell function (24.0 6 28.7 vs. +22.0 6 43.8, P =
0.006), and the quantitative insulin sensitivity check index
(+0.004 6 0.021 vs. 20.012 6 0.015, P = 0.005) in supplemented
women were significantly different from those in women in the
placebo group. Changes in serum triglycerides (+2.1 6 63.0 vs.
+38.9 6 37.5 mg/dL, P = 0.005), high sensitivity C-reactive protein
(2432.8 6 2521.0 vs. +783.2 6 2470.1 ng/mL, P = 0.03), and plasma
malondialdehyde concentrations (20.5 6 1.6 vs. +0.3 6 1.2 mmol/L,
P = 0.01) were significantly different between the supplemented
women and placebo group. Magnesium supplementation resulted in
a lower incidence of newborn hyperbilirubinemia (8.8% vs. 29.4%,
P = 0.03) and newborn hospitalization (5.9% vs. 26.5%, P = 0.02).
Conclusion: Magnesium supplementation among women with GDM
had beneficial effects on metabolic status and pregnancy outcomes. This
trial was registered at www.irct.ir as IRCT201503055623N39.
Am J Clin Nutr 2015;102:222–9.
pregnant women, pregnancy outcomes
INTRODUCTION
Gestational diabetes mellitus (GDM),7 defined as impaired
carbohydrate metabolism during pregnancy (1), affects 3–10%
of pregnant women (2). Increased hormones, including estrogen
and progesterone produced during pregnancy, can lead to ele-
vated inflammatory factors and biomarkers of oxidative stress
(3, 4), resulting in glucose intolerance and impaired insulin
metabolism (5). GDM has important health consequences for the
mother and the fetus (6). It is associated with increased sub-
sequent risk of developing diabetes, metabolic syndrome, and
cardiovascular events (7).
In addition to strategies focused on diet (8, 9), vitamin sup-
plementation (10–12), and pharmaceutical interventions (13),
some studies have shown a significant inverse relation between
dietary magnesium intake and glucose homeostasis in patients
with GDM (2, 14). Bardicef et al. (15) showed that intracellular
magnesium depletion can occur in pregnancy, especially in
pregnant women affected by GDM. Current data have suggested
a beneficial effect of magnesium supplementation on the
metabolic status of pregnant women (16) as well as dia-
betic and hypertensive subjects (17). Rodríguez-Moran and
1
Supported by a grant from the Kashan University of Medical Sciences.
The financial support for conception, design, data analysis, and development
of the manuscript comes from the Research Center for Biochemistry and
Nutrition in Metabolic Diseases, Kashan University of Medical Sciences,
Kashan, Iran.
7
Abbreviations used: FPG, fasting plasma glucose; GDM, gestational di-
abetes mellitus; GSH, total glutathione; HOMA-B, homeostasis model of
assessment–estimated b-cell function; hs-CRP, high-sensitivity C-reactive
protein; NO, nitric oxide; QUICKI, quantitative insulin sensitivity check
index; TAC, total antioxidant capacity; T2DM, type 2 diabetes mellitus.
*To whom correspondence should be addressed. E-mail: esmaillzadeh@
hlth.mui.ac.ir.
Received August 28, 2014. Accepted for publication April 16, 2015.
First published online May 27, 2015; doi: 10.3945/ajcn.114.098616.

222 Am J Clin Nutr 2015;102:222–9. Printed in USA. Ó 2015 American Society for Nutrition
 MAGNESIUM SUPPLEMENTATION AND GDM
Guerrero-Romero (18) reported that consumption of 382 mg
magnesium per day resulted in a significant decrease in fasting
glucose, serum triglyceride concentrations, and HOMA-IR
in normal-weight subjects; however, no significant effect was
observed on HDL cholesterol concentrations. In another
study among healthy middle-aged overweight women with
adequate magnesium concentrations, administration of 250 mg
magnesium as magnesium oxide per day did not influence
inflammatory factors (19). Metabolic abnormalities found in
gestational diabetes are similar to those of metabolic syndrome
in nonpregnant individuals.
Magnesium is an essential cofactor in the enzymatic process of
high-energy phosphate (20), acts as a calcium channel antagonist,
223
[865 women were excluded for not having GDM and 15 women
were excluded after being diagnosed with GDM class A2
and needed insulin therapy: fasting plasma glucose (FPG)
.105 mg/dL and blood sugar 2 h postprandial .120 mg/dL).
These 70 pregnant women were randomly assigned to either
magnesium supplementation (n = 35) or a placebo (n = 35) for 6 wk.
Before random assignment, patients were stratified based on BMI
(in kg/m2; ,30 and $30) and weeks of gestation (,26 or $26 wk).
Study design
Participants were randomly assigned to consume either 250 mg
magnesium supplements/d as magnesium oxide or a placebo for
6 wk. Although the duration of the intervention was 6 wk, we

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and stimulates production of prostacyclins and nitric oxide (NO)
followed patients until delivery. However, we did not continue
(21). Magnesium seems to have anti-inflammatory effects due to
magnesium supplementation until delivery because assessment
its antagonism to calcium that play an important role in in-
of compliance to supplements through blood samples was very
flammation as well as in protein synthesis and transmembrane ion
difficult in the final weeks of pregnancy. Furthermore, because we
transport (22). Considering inadequate dietary magnesium intake
wanted to examine the effects of supplementation on metabolic
among pregnant women (23) as well as a relatively high prev-
profiles, we were concerned that a large number of women would
alence of hypomagnesemia in the urban Iranian population (24),
drop out if they were asked to provide blood near the end of their
we hypothesized that magnesium supplementation might help
pregnancies. Magnesium supplements and the placebo were
patients with GDM to control their metabolic profile and preg-
manufactured by 21st Century Pharmaceutical Company and
nancy outcomes. The objective of this study was to examine the
Barij Essence Pharmaceutical Company, respectively. All mag-
effects of magnesium supplementation on metabolic status and
nesium and placebo tablets were provided by Barij Essence
pregnancy outcomes of pregnant women with GDM.
Pharmaceutical Company in prepackaged bottles that were
numbered for each patient according to a randomization se-
quence. Each patient was assigned to a number to establish
METHODS
participant order and received the magnesium or placebo in the
Participants corresponding prepackaged bottles. The placebo and magnesium
tablets were the same in size, weight, color, and taste. All pa-
This randomized, double-blind, placebo-controlled, parallel
tients, clinical investigators (including the person administering
clinical trial was done in Kashan, Iran, from February 2014 to
demographic and food recall questionnaires), and other health
July 2014 in accordance with the Declaration of Helsinki and
care personnel were blinded to treatment assignment. Participants
Good Clinical Practice guidelines. The Ethics Committee of Arak
were asked not to alter their routine physical activity or usual
University of Medical Sciences reviewed and approved the study
dietary intakes during the study and not to consume any sup-
protocol (registered in the Iranian registry of clinical trials as
plements other than those provided to them by the investigators.
IRCT201503055623N39). Written informed consent was ob-
All pregnant women also consumed 400 mg folic acid/d starting
tained from all participants before the intervention. To estimate
at the beginning of pregnancy and 60 mg ferrous sulfate/d as
the sample size, we used a randomized clinical trial sample size
of the second trimester. Compliance to the magnesium supple-
formula in which type I (a) and type II errors (b) were 0.05 and
mentation was assessed through quantification of serum mag-
0.20 (power = 80%), respectively. On the basis of a previous
nesium concentrations. The use of magnesium supplementation
study (10), we used an SD of 2.04 and a difference in mean (d)
and the placebo during the study was checked by asking par-
of 1.50, considering HOMA-IR as the key variable. The calcu-
ticipants to return the medication containers. To increase com-
lation indicated 30 subjects were needed in each group. As-
pliance, all patients received brief daily cell phone reminders to
suming a dropout of 5 participants per group, the final sample
take the supplements. All participants provided 3 dietary recalls
size was determined to be 35 patients per group. We chose
(once during the weekend and on 2 weekdays) and 3 physical
HOMA-IR to estimate sample size because it was the most
activity records to verify that they maintained their usual diet
important variable under consideration in patients with GDM.
and physical activity during the intervention. Both dietary re-
Furthermore, the largest sample size was obtained when we used
calls and physical activity records were taken at weeks 2, 4, and
this variable. Eligible participants were aged 18–40 y (at weeks
6 of the intervention. To obtain information on participant nu-
24–28 of gestation) who were diagnosed with GDM by a “one-
trient intake based on these 3-d food diaries, we used Nutri-
step” 2-h 75-g oral glucose tolerance test. Gestational age was
tionist IV software (First Databank) modified for Iranian foods.
assessed from the date of last menstrual period and concurrent
clinical assessment (25). A diagnosis of GDM was based on the
American Diabetes Association criteria (26). Women whose Assessment of anthropometric variables
plasma glucose met one of the following criteria were diagnosed Data on prepregnancy weight and height (measured values)
with GDM: fasting, $92 mg/dL; 1 h, $180 mg/dL; or 2 h, were obtained from the women’s clinical records. A trained
$153 mg/dL. After screening 950 pregnant women in the Na- midwife at the maternity clinic took anthropometric measure-
ghavi maternity clinic affiliated with Kashan University of Medical ments at baseline and 6 wk after the intervention. Height and
Sciences, Kashan, Iran, 70 subjects were eligible for enrollment weight (Seca) were measured while the participants wore light
224 ASEMI ET AL.
clothing and no shoes. BMI was calculated as weight (in kilo-
grams) divided by height (in meters) squared. Infant length and
weight were measured by using standard methods (Seca 155
Scale) during the first 24 h after birth and were recorded to the
nearest 1 mm and 10 g, respectively. Infant head circumference
was measured to the nearest 1 mm with a Seca girth measuring
tape. We also collected data on infants’ 1- and 5-min Apgar
scores. Macrosomic babies were defined as those whose birth
weight was .4000 g (27).
Biochemical and polyhydramnios assessment
Before the onset and after the end of intervention, 10-mL blood
samples were taken from each patient at the Kashan reference
laboratory. Blood was collected in 2 separate tubes: 1) one
without EDTA to separate the serum, to quantify serum mag-
nesium, insulin, lipid profiles, and high-sensitivity C-reactive
protein (hs-CRP) concentrations and 2) another one containing
EDTA to examine plasma NO and biomarkers of oxidative
stress. FPG concentrations were measured on the day blood was
collected. Blood samples were immediately centrifuged (D-
78532; Hettich) at 1465 3 g for 10 min to separate the serum.
Serum lipid profiles were also quantified on the day of blood
collection. The samples were then stored at 2708C until ana-
lyzed at the Kashan University of Medical Sciences reference
laboratory. Commercial kits were used to measure serum mag-
nesium, FPG, serum cholesterol, triglycerides, and VLDL, LDL,
and HDL cholesterol concentrations (Pars Azmun). All inter-
and intra-assay CVs for magnesium, FPG, and lipid profile
measurements were ,5%. Serum insulin concentrations were
assayed by ELISA (Monobind). The intra- and interassay CVs
for serum insulin were 2.9% and 5.8%, respectively. HOMA-IR
and homeostasis model of assessment–estimated b-cell function
(HOMA-B) and quantitative insulin sensitivity check index
FIGURE 1 Summary of the patient flow.
(QUICKI) were calculated based on suggested formulas (28).
Serum hs-CRP was quantified by using an ELISA kit (LDN)
with intra- and interassay CVs of 2.8% and 4.4%, respectively.
The plasma NO concentration was determined by the Griess
method (29). Plasma total antioxidant capacity (TAC) was as-
sessed by the use of the ferric reducing antioxidant power
method developed by Benzie and Strain (30). Plasma to-
tal glutathione (GSH) was examined by using the method of
Beutler and Gelbart (31). The plasma malondialdehyde con-
centrations were determined by the thiobarbituric acid reactive
substance spectrophotometric test (32). CVs for plasma TAC,
GSH, and malondialdehyde were 0.8%, 2.6%, and 3.4%, re-
spectively. Hyperbilirubinemia was defined as total serum bili-
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rubin concentrations $15 mg/dL (257 mol/L) in infants 25–48 h
old, 18 mg/dL (308 mol/L) in infants 49–72 h old, and 20 mg/dL
(342 mol/L) in infants older than 72 h (33). Polyhydramnios was
diagnosed by using sonographic estimation at postintervention.
On the basis of this measurement, polyhydramnios was defined
as an amniotic fluid index in excess of 25 cm (34).
Statistical analysis
We used the Kolmogorov-Smirnov test to examine if variables
were normally distributed. Intention-to-treat analysis of the
primary study endpoint was performed for all the randomly
assigned participants. To determine the effects of magne-
sium supplementation on insulin metabolism, lipid profiles, in-
flammatory factors, and biomarkers of oxidative stress, we used
mixed-model repeated-measures ANOVA. Because the mixed-
model analysis without any ad hoc imputation has been shown to
provide equal or more power than does analysis using mixed
models with missing values imputed by ad hoc imputation
methods, we did not impute missing values by considering the
assumption that these values are missing at random (35). To
 MAGNESIUM SUPPLEMENTATION AND GDM 225
assess if the magnitude of the change in dependent variables TABLE 2
depended on the baseline maternal age and weight, we controlled Dietary intake of pregnant women with GDM who received either
all analyses for baseline values of maternal age and weight to magnesium supplements or a placebo1
avoid potential bias. To identify the effect of magnesium sup- Placebo group (n = 35) Magnesium group (n = 35)
plementation on pregnancy outcomes of maternal-child dyads,
Energy, kcal/d 2381 6 194 2451 6 186
we applied a x2 test for categorical variables and 1-factor Carbohydrates, g/d 321.6 6 45.2 335.7 6 42.2
ANOVA for continuous variables (newborns’ weight, length, and Protein, g/d 86.3 6 19.8 86.6 6 9.2
head circumference and Apgar score). To examine if prepreg- Fat, g/d 86.8 6 17.8 88.9 6 13.8
nancy BMI, maternal FPG at baseline, and maternal age influ- SFAs, g/d 25.4 6 7.0 25.3 6 5.3
enced these findings, we applied ANCOVA controlling for these PUFAs, g/d 27.5 6 6.1 29.7 6 8.1
variables. P , 0.05 was considered statistically significant. All MUFAs, g/d 24.3 6 7.7 23.3 6 4.8
statistical analyses were done by using the Statistical Package Cholesterol, mg/d 237.3 6 152.7 208.3 6 116.0
Crude fiber, g/d 5.5 6 1.7 5.6 6 1.6
for Social Sciences version 17 (SPSS Inc.).
6 6

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TDF, g/d 18.0 4.7 18.8 4.8
Magnesium, mg/d 282.1 6 72.3 301.5 6 76.0
Manganese, mg/d 2.3 6 0.7 2.3 6 0.8
RESULTS 1
Values are means 6 SDs. There were no significant differences between
As demonstrated in the study flow diagram (Figure 1), during the groups. GDM, gestational diabetes mellitus; TDF, total dietary fiber.
the intervention phase of the study, 3 patients were excluded from
the magnesium group [withdrawn due to personal reasons (n = 2) 0.31 vs. 20.11 6 0.29 mg/dL, P = 0.02) (Table 3). In addition,
and hospitalization (n = 1)] and 3 [withdrawn due to personal magnesium-supplemented women had a significant reduction in
reasons (n = 2) and insulin therapy (n = 1)] from the placebo FPG (29.7 6 10.1 vs. +1.8 6 8.1 mg/dL, P , 0.001), serum
group. Finally, 64 participants [magnesium (n = 32) and placebo insulin concentrations (22.1 6 6.5 vs. +5.7 6 10.7 mIU/mL,
(n = 32)] completed the trial. However, because the analysis was P = 0.001), HOMA-IR (20.5 6 1.3 vs. +1.4 6 2.3, P , 0.001),
based on the intention-to-treat principle, all 70 women (35 in each and HOMA-B (24.0 6 28.7 vs. +22.0 6 43.8, P = 0.006) and
group) were included in the final analysis. On average, the an increase in QUICKI (+0.004 6 0.021 vs. 20.012 6 0.015,
compliance rate in our study was high, such that 100% of cap- P = 0.005) compared with women in the placebo group. Changes
sules were taken during the course of the study in both groups. No in serum triglycerides (+2.1 6 63.0 vs. +38.9 6 37.5 mg/dL,
side effects were reported after consumption of magnesium sup- P = 0.005), serum hs-CRP (2432.8 6 2521.0 vs. +783.2 6
plements in patients with GDM or in their infants. 2470.1 ng/mL, P = 0.03) and plasma malondialdehyde con-
Participants’ mean age, prepregnancy weight, and BMI were centrations (20.5 6 1.6 vs. +0.3 6 1.2 mmol/L, P = 0.01)
29.3 6 3.9 y, 70.1 6 11.5 kg, and 27.2 6 4.0, respectively. differed significantly between the 2 groups. We also observed
Baseline demographic characteristics of patients in the 2 groups a trend toward a significant effect of magnesium supplementation
were not clinically and statistically different (Table 1). on increasing plasma NO concentrations (+15.9 6 37.0 vs. +1.1 6
Based on the 3-d dietary recalls obtained throughout the in- 39.0 mmol/L, P = 0.05). There were no significant differences
tervention, no significant differences were observed between the between the magnesium and placebo groups in terms of changes
2 groups in terms of dietary intakes of energy, carbohydrates, in other lipid profiles and plasma TAC and GSH concentrations.
proteins, fats, SFAs, PUFAs, MUFAs, cholesterol, crude fiber, Baseline concentrations of magnesium differed significantly
total dietary fiber, magnesium, and manganese (Table 2). between the 2 groups. Therefore, baseline concentrations were
The change in serum magnesium concentrations after 6 wk controlled for in the analyses. However, after this adjustment, no
of supplementation was greater in magnesium-supplemented substantial changes in our findings occurred, except for mag-
women compared with women in the placebo group (+0.06 6 nesium (P = 0.89) and total cholesterol concentrations (P =
0.01). Additional adjustments for age and baseline weight did
TABLE 1 not affect our findings, except for serum magnesium (P = 0.89)
General characteristics of pregnant women with GDM who received either
and total cholesterol concentrations (P = 0.01) (Table 4).
magnesium supplements or a placebo1
Taking magnesium supplements resulted in a lower incidence
Placebo group Magnesium group of newborn hyperbilirubinemia (8.8% vs. 29.4%, P = 0.03) and
(n = 35) (n = 35) lower newborn hospitalization rate (5.9% vs. 26.5%, P = 0.02)
Maternal age, y 29.4 6 3.1 29.1 6 4.6 (Table 5). We did not observe significant differences in the
Height, cm 160.6 6 3.9 160.1 6 7.1 cesarean delivery rate, need for insulin therapy after the in-
Prepregnancy weight,2 kg 70.3 6 8.1 70.0 6 14.2 tervention, polyhydramnios, maternal hospitalization, preterm
Weight at study baseline, kg 73.1 6 9.5 73.6 6 14.8 delivery, gestational age, newborn birth size, Apgar score, and
Weight at end of trial, kg 75.1 6 9.4 76.0 6 12.4 newborn hypoglycemia between the 2 groups. Adjustment for
Weight change, kg 2.1 6 1.1 2.4 6 2.3 prepregnancy BMI, baseline maternal FPG, and age did not alter
Prepregnancy BMI,2 kg/m2 27.2 6 2.9 27.3 6 4.9
the findings.
BMI at study baseline, kg/m2 28.3 6 3.5 28.7 6 5.3
BMI at end of trial, kg/m2 29.1 6 3.5 29.6 6 5.4
BMI change, kg/m2 0.8 6 0.4 0.9 6 0.9
DISCUSSION
1
Values are means 6 SDs. GDM, gestational diabetes mellitus.
2
Based on participants’ measured weight and height from maternity On the basis of serum magnesium concentrations at base-
clinic records. line, all patients with GDM in our study were magnesium
226 ASEMI ET AL.
TABLE 3
Metabolic profiles, inflammatory factors, and biomarkers of oxidative stress at baseline and after a 6-wk intervention in pregnant women with GDM who
received either magnesium supplements or a placebo1
Placebo group (n = 35) Magnesium group (n = 35)

Week 0 Week 6 Change Week 0 Week 6 Change P value2

Magnesium, mg/dL 1.62 6 0.33 1.51 6 0.33* 20.11 6 0.29 1.32 6 0.34** 1.35 6 0.31 0.06 6 0.31 0.02
FPG, mg/dL 91.4 6 9.0 93.7 6 11.0 1.8 6 8.1 95.1 6 12.6 85.8 6 6.1* 29.7 6 10.1 ,0.001
Insulin, mIU/mL 14.1 6 5.7 19.9 6 12.6* 5.7 6 10.7 13.1 6 7.1 10.7 6 3.1 22.1 6 6.5 0.001
HOMA-IR 3.2 6 1.6 4.7 6 3.1* 1.4 6 2.3 3.1 6 1.8 2.7 6 0.6* 20.5 6 1.3 ,0.001
HOMA-B 52.0 6 20.8 74.1 6 50.8* 22.0 6 43.8 46.5 6 31.3 42.4 6 14.1 24.0 6 28.7 0.006
QUICKI 0.351 6 0.022 0.338 6 0.028* 20.012 6 0.015 0.343 6 0.023 0.349 6 0.019 0.004 6 0.021 0.005
Total cholesterol, mg/dL 198.8 6 51.4 204.1 6 44.8 6.3 6 20.6 188.1 6 42.8 182.2 6 31.8 23.8 6 33.0 0.10
Triglycerides, mg/dL 166.5 6 73.7 201.5 6 91.2* 38.9 6 37.5 173.1 6 97.9 171.0 6 96.7 2.1 6 63.0 0.005

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VLDL cholesterol, mg/dL 33.1 6 14.5 39.9 6 18.3* 6.3 6 7.0 34.1 6 19.4 33.9 6 18.8 0.51 6 11.7 0.005
LDL cholesterol, mg/dL 108.1 6 37.4 107.2 6 31.6 21.5 6 15.0 98.8 6 31.1 96.9 6 25.3 23.2 6 22.3 0.41
HDL cholesterol, mg/dL 58.1 6 15.7 59.5 6 11.7 0.8 6 6.0 53.1 6 12.0 54.7 6 9.2 1.7 6 6.0 0.61
Total/HDL cholesterol ratio 3.4 6 0.8 3.8 6 0.8 0.3 6 0.5 3.7 6 0.8 3.4 6 0.6 20.2 6 0.6 0.09
hs-CRP, ng/mL 6101.1 6 3715.0 6881.1 6 4007.0 783.2 6 2470.1 5731.3 6 3932.2 5305.5 6 4091.0 2432.8 6 2521.0 0.03
NO, mmol/L 101.1 6 36.4 101.7 6 54.6 1.1 6 39.0 100.2 6 27.7 116.1 6 36.8* 15.9 6 37.0 0.05
TAC, mmol/L 715.1 6 155.8 722.2 6 134.5 5.4 6 82.8 710.4 6 151.2 777.5 6 466.4 67.3 6 456.8 0.39
GSH, mmol/L 470.1 6 238.7 469.4 6 173.5 22.1 6 118.0 511.3 6 231.5 431.5 6 71.9 280.2 6 233.7 0.07
MDA, mmol/L 3.4 6 1.4 3.7 6 1.5 0.3 6 1.2 4.0 6 1.1 3.5 6 1.5 20.5 6 1.6 0.01
1
Values are means 6 SDs. Values in this table were not adjusted for baseline concentrations, maternal age, or baseline weight. Baseline values of magnesium
differed between the 2 groups. *Significantly different from baseline, P , 0.05. **Significantly different from placebo group at week 0, P , 0.005. FPG, fasting plasma
glucose; GDM, gestational diabetes mellitus; GSH, total glutathione; HOMA-B, homeostasis model of assessment–estimated b-cell function; hs-CRP, high-sensitivity
C-reactive protein; MDA, malondialdehyde; NO, nitric oxide; QUICKI, quantitative insulin sensitivity check index; TAC, total antioxidant capacity.
2
P values represent the time 3 group interaction (computed by mixed-model repeated-measures ANOVA).

deficient. Magnesium supplementation for 6 wk significantly that the acetyl-CoA carboxylase enzyme that catalyzes the formation
decreased FPG, insulin, HOMA-IR, HOMA-B, hs-CRP, and of malonyl-CoA, which is implicated in physiologic insulin secre-
malondialdehyde and increased QUICKI compared with the tion, is stimulated via magnesium in a concentration-dependent
placebo.
In interpreting the results, it is important to keep in mind that TABLE 4
women participating in the study were magnesium deficient, Adjusted changes in metabolic variables in pregnant women with GDM
explaining why we found an increase in serum magnesium who received either magnesium supplements or a placebo1
concentrations in the supplementation compared with the placebo Placebo group Magnesium group
group. However, after controlling for baseline magnesium con- (n = 35) (n = 35) P value2
centrations, the changes in serum magnesium concentrations
Magnesium, mg/dL 20.03 6 0.04 20.03 6 0.04 0.89
were not significantly different. This implies that baseline serum
FPG, mg/dL 0.4 6 1.2 27.8 6 1.4 ,0.001
magnesium concentrations were involved in the response to Insulin, mIU/mL 6.3 6 1.4 22.5 6 1.4 ,0.001
magnesium supplementation. It is also important to note that HOMA-IR 1.7 6 0.4 20.9 6 0.4 ,0.001
serum magnesium concentrations do not thoroughly reflect di- HOMA-B 21.0 6 5.9 24.9 6 5.9 0.001
etary or supplemental magnesium intake. However, we were not QUICKI 20.018 6 0.003 0.008 6 0.003 0.001
able to assess intracellular magnesium concentrations in the Total cholesterol, mg/dL 9.1 6 4.3 24.9 6 4.2 0.01
current study. Some investigators have also recommended the use Triglycerides, mg/dL 34.8 6 8.0 2.0 6 8.1 0.005
VLDL cholesterol, mg/dL 7.7 6 1.4 0.4 6 1.4 0.005
of erythrocyte magnesium content to assess dietary intake. Others
LDL cholesterol, mg/dL 1.6 6 3.1 26.1 6 3.1 0.10
have shown that the magnesium content of white blood cells is HDL cholesterol, mg/dL 0.6 6 0.7 21.0 6 0.4 0.55
a better index of intracellular magnesium in skeletal and cardiac Total/HDL cholesterol ratio 0.1 6 0.1 20.1 6 0.1 0.06
muscle (36). hs-CRP, ng/mL 834.8 6 411.0 2482.2 6 414.7 0.02
Patients with GDM are susceptible to metabolic abnormalities, NO, mmol/L 21.9 6 6.0 16.9 6 6.1 0.05
inflammation, and oxidative stress (11). Our findings showed that TAC, mmol/L 22.1 6 53.1 67.0 6 52.1 0.28
the administration of magnesium supplements for 6 wk in women GSH, mmol/L 217.5 6 17.7 266.0 6 17.7 0.05
MDA, mmol/L 0.5 6 0.3 20.2 6 0.2 0.04
with GDM resulted in a significant decrease in FPG, serum insulin
concentrations, HOMA-IR, and HOMA-B and a significant rise in 1
Values are means 6 SEs. Values are adjusted for baseline values,
QUICKI compared with placebo. A growing body of evidence has maternal age, and baseline weight. FPG, fasting plasma glucose; GDM,
gestational diabetes mellitus; GSH, total glutathione; HOMA-B, homeostasis
suggested an inverse association between dietary magnesium in-
model of assessment–estimated b-cell function; hs-CRP, high-sensitivity
take (37) and serum magnesium concentrations (38) and the risk of C-reactive protein; MDA, malondialdehyde; NO, nitric oxide; QUICKI, quan-
developing insulin resistance and type 2 diabetes mellitus (T2DM). titative insulin sensitivity check index; TAC, total antioxidant capacity.
Consistent with our study, reduced HOMA-IR has been observed 2
Obtained from mixed-model repeated-measure ANOVA (time 3 group
after intake of 2.5 g magnesium chloride/d (39). It has been reported interaction).
 MAGNESIUM SUPPLEMENTATION AND GDM 227
TABLE 5
Associations between magnesium supplementation and pregnancy outcomes1
Placebo group (n = 34) Magnesium group (n = 34) P value

Cesarean delivery, n (%) 16 (47.1) 11 (32.4) 0.212

Need for insulin therapy after intervention, n (%) 2 (5.9) 1 (2.9) 0.552
Preeclampsia, n (%) 0 (0) 1 (2.9) 0.312
Polyhydramnios, n (%) 1 (2.9) 2 (5.9) 0.552
Maternal hospitalization, n (%) 2 (5.9) 1 (2.9) 0.552
Preterm delivery, n (%) 1 (2.9) 2 (5.9) 0.552
Macrosomia .4000 g, n (%) 5 (14.7) 2 (5.9) 0.232
Gestational age, wk 38.7 6 0.23 39.1 6 0.2 0.252
Newborn weight, g
Crude 3417.0 6 91.2 3208.1 6 91.2 0.07
Model 14 3421.2 6 91.0 3209.5 6 90.8

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0.08
Model 25 3412.6 6 91.2 3214.5 6 90.9 0.13
Newborn length, cm
Crude 50.6 6 0.4 50.9 6 0.4 0.61
Model 14 50.6 6 0.4 50.9 6 0.4 0.60
Model 25 50.6 6 0.4 51.0 6 0.4 0.51
Newborn head circumference, cm
Crude 35.1 6 0.3 35.3 6 0.3 0.61
Model 14 35.1 6 0.3 35.3 6 0.3 0.62
Model 25 35.0 6 0.3 35.3 6 0.3 0.56
1-min Apgar score
Crude 8.8 6 0.03 8.8 6 0.03 0.99
Model 14 8.9 6 0.03 9.0 6 0.03 0.95
Model 25 9.0 6 0.03 9.0 6 0.03 0.91
5-min Apgar score
Crude 9.9 6 0.03 9.9 6 0.03 1
Model 14 9.9 6 0.03 9.9 6 0.03 0.99
Model 25 9.9 6 0.03 9.9 6 0.03 0.96
Newborn hyperbilirubinemia, n (%) 10 (29.4) 3 (8.8) 0.032
Newborn hospitalization, n (%) 9 (26.5) 2 (5.9) 0.022
Newborn hypoglycemia, n (%) 1 (2.9) 2 (5.9) 0.552
1
We excluded one patient and her newborn in each group because of intrauterine fetal death.
2
Obtained from x2 test.
3
Mean 6 SE (all such values).
4
Obtained from ANCOVA adjusted for prepregnancy BMI.
5
Obtained from ANCOVA adjusted for prepregnancy BMI, maternal fasting plasma glucose at baseline, and maternal
age.

manner (40). In addition, magnesium may competitively inhibit the
voltage-dependent calcium channel, which is known to play a role in
insulin secretion (41).
Our study showed that in patients with GDM, magnesium
supplement intake led to a significant difference in changes in
serum triglycerides and VLDL cholesterol concentrations but did
not influence other serum lipid profiles. In line with our findings,
a significant reduction in serum triglyceride concentrations was
observed after intake of magnesium supplements (18, 42). In
addition, in a crossover study in healthy participants, taking
magnesium oxide reduced total and LDL cholesterol concen-
trations (43). However, magnesium supplementation has been
found to not affect lipid profiles among patients with T2DM (44).
Furthermore, no significant change in lipid concentrations was
seen after intake of 384 mg magnesium chloride/d among patients
with T2DM (45). This might be explained by the near-normal
concentrations of serum magnesium in the participants of that
study (44). Magnesium might suppress postprandial hyperlip-
idemia through promoting the formation of insoluble compounds
and the excretion of fat (46). Furthermore, VLDL cholesterol
lipolysis is facilitated by magnesium because this nutrient is
known to be a cofactor for lipoprotein lipase (47).
Findings from the current study showed that magnesium
supplementation in patients with GDM led to greater decreases in
serum hs-CRP concentrations compared with the placebo. Al-
though magnesium supplementation resulted in a significant
increase in plasma NO concentrations, the changes were not
significantly different from those of the placebo group. In
agreement with our results, Nielsen et al. (48) found that taking
magnesium supplements improved indicators of inflammation in
elderly people. However, cyclosporine and magnesium supple-
mentation did not change NO concentrations in rats (49). In
addition, research has shown that magnesium supplementation
does not significantly attenuate inflammatory markers (19, 50).
Anti-inflammatory effects of magnesium may be mediated via its
antagonism to calcium, the ion playing an important role in
inflammation (51). Inactivation of N-methyl-D-aspartate re-
ceptors and the inhibition of nuclear transcription factor kB by
magnesium have been considered potential mechanisms leading
to a decreased inflammatory response (52).
We found that magnesium supplementation was associated
with a significant reduction in plasma malondialdehyde con-
centrations but did not affect plasma TAC and GSH concen-
trations. Supporting our results, supplementation with vitamin
228 ASEMI ET AL.
combinations (vitamins C and E) and minerals (magnesium and
zinc) has led to decreased malondialdehyde concentrations
among patients with T2DM (53). These findings were also
reported by other investigators (54). Magnesium supplementation
increased GSH concentrations among atopic asthmatic children
(55). It has been suggested that when the concentrations of free
radicals are high, including GDM, magnesium supplementation
might reduce free radical production and lipid hydroperoxides
through decreasing reactive oxygen species production (56) and
increasing glutathione peroxidase activity (57).
Our study demonstrated that magnesium supplementation in
patients with GDM was associated with a decreased incidence of
newborn hyperbilirubinemia and hospitalizations but did not
affect other pregnancy outcomes. In line with our study, Misra
et al. (58) indicated that serum total magnesium concentrations in
30 newborns with hemolytic hyperbilirubinemia were signifi-
cantly lower than those of healthy subjects. However, others
observed no significant association of low dietary intake of
magnesium with preeclampsia, small-for-gestational age infants,
or preterm labor (59). However, Pintov et al. (60) showed no
significant association between umbilical cord magnesium
concentrations and newborns’ bilirubin concentrations in the
48th hour of life. It is speculated that gestational malnutrition
may cause maternal and neonatal hypomagnesemia by nega-
tively affecting enzymes in bilirubin metabolism and antioxidant
enzymes in erythrocytes, thus leading to newborns’ indirect
hyperbilirubinemia (61).
To interpret our findings, some limitations need to be taken into
account. Because of limited funding, we did not examine the effects
of magnesium supplementation on other biomarkers of systemic
inflammation or oxidative stress. The use of serum magnesium
concentrations to measure compliance, instead of intracellular or
urinary concentrations, may have led to less accurate assessment
(62). The dosage of magnesium supplements that can influence
serum or intracellular magnesium concentrations must also be
examined in future studies. Some investigators have used higher
dosages of supplemental magnesium than those used in this
study to increase plasma/serum magnesium concentrations (63).
However, supplements of #450 mg/d could result in increased
serum magnesium concentrations in magnesium-deficient sub-
jects (44). Furthermore, we demonstrated that 250 mg magne-
sium oxide/d for 6 wk resulted in increased serum magnesium
concentrations by 0.06 mg/dL. Future studies are needed to
further confirm these findings. Although we controlled for sev-
eral confounders in the analysis, it must be kept in mind that
even without any adjustment, the assessment of numerous out-
comes in the current study inflates the type I error. In addition,
multiple-comparison issues associated with comparing groups
on a large number of outcomes also must be taken into account.
In conclusion, magnesium supplementation in pregnant
women with GDM was associated with decreased insulin, hs-
CRP, malondialdehyde concentrations, newborn hyperbilirubinemia,
and hospitalization but did not influence other lipid profiles, NO,
TAC, GSH, or other pregnancy outcomes.
The authors’ responsibilities were as follows—ZA and AE: contributed to
the conception, design, statistical analysis, and drafting of the manuscript; MK,
MJ, FF, FB, ZH, and SB-K: contributed to the data collection and manuscript
drafting; PJS: contributed to the editing of the manuscript; AE: supervised the
study; and all authors: read and approved the final version of the manuscript.
None of the authors declared any personal or financial conflicts of interest.
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