Research www.AJOG .

org

OBSTETRICS
Maternal magnesium supplementation reduces intrauterine
growth restriction and suppresses inflammation
in a rat model
Amanda Roman, MD; Neeraj Desai, MD; Burton Rochelson, MD; Madhu Gupta, MBBS;
Malvika Solanki, MBBS, MPH; Xiangying Xue, MD; Prodyot K. Chatterjee, PhD; Christine N. Metz, PhD

OBJECTIVE: Intrauterine growth restriction (IUGR) is associated
with increased inflammatory responses. We sought to investigate
whether magnesium (Mg) attenuates inflammation and IUGR in a rat
model.
STUDY DESIGN: Pregnant Wistar rats (12 weeks, gestational day 18)
were randomly assigned to 1 of 4 groups: normal diet with bilateral
uterine artery ligation (BL) (n 6) or sham surgery (SH) (n 5);
and Mg chloride (MgCl2) 1% (wt/vol) in the drinking water
throughout gestation BL (MgBL) (n 6) or SH (MgSH) (n 5).
Dams were euthanized 24 hours postsurgery (gestational day 19).
Maternal plasma, fetal plasma (pooled), individual amniotic fluid (AF)
samples, and placentas (PL) were collected and assessed from live
fetal pups only (BL, n 36; SH, n 20; MgBL, n 20; MgSH,
n 20). All samples were analyzed for cytokines/chemokines
(interleukin [IL] 6, IL 1b, chemokine [C X C motif] ligand 1 [CXCL1],
chemokine [C C motif] ligand 2 [CCL2], and tumor necrosis factor
[TNF a] sensitivity <3 pg/mL) using a multiplex platform. Data were
analyzed using Mann Whitney, analysis of variance, and Fisher exact
tests.
RESULTS: The incidence of IUGR (pup weight <10th percentile of SH)
in the MgBL group was significantly lower (31%) than the BL group
(86.3%) (relative risk, 0.36; 95% confidence interval, 0.2 0.6;
P < .0001). BL significantly increased AF levels of IL 6, IL 1b, TNF a
(P < .05), and CCL2 (P < .001) vs SH and PL levels of IL 6, IL 1b,
CCL2 and CXCL1 (P < .001), and TNF a (P < .05) vs SH. Maternal
MgCl2 supplementation significantly decreased IL 1b, TNF a, and
CCL2 levels in AF and IL 1b in PL tissues of MgBL vs BL rats
(P < .0001).
CONCLUSION: Maternal oral MgCl2 supplementation reduced BL
induced IUGR by 64% and suppressed cytokine/chemokine levels in
the AF and PL.
Key words: cytokines, inflammation, intrauterine growth restriction,
magnesium supplementation, rat model

Cite this article as: Roman A, Desai N, Rochelson B, et al. Maternal magnesium supplementation reduces intrauterine growth restriction and suppresses inflammation in
a rat model. Am J Obstet Gynecol 2013;208:383.e1-7.

I ntrauterine growth restriction

(IUGR), is dened as fetal weight
<10th percentile of a given population at
fetuses are the result of placental (PL)
insufciency.1,2 IUGR is associated
with increased preterm birth, fetal and
intracranial hemorrhage, necrotizing
enterocolitis, and respiratory complica-
tions.5-7 In addition, IUGR impacts fetal
the same gestational age. Approximately neonatal death, low Apgar scores, hyp- programming and is associated with
25-30% of all nonanomalous IUGR oxemia, acidosis at birth,3,4 sepsis, numerous long-term health sequelae,
including cognitive disabilities, schizo-
phrenia, cerebral palsy,8,9 broncho-
From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Hofstra pulmonary dysplasia,10 and an increased
North ShoreeLIJ School of Medicine (Drs Roman, Desai, and Rochelson), and the Center for risk for cardiovascular, metabolic, and
Immunology and Inammation, Feinstein Institute for Medical Research (Drs Gupta, Solanki, Xue, renal diseases in adulthood.11 To date
Chatterjee, and Metz), Manhasset, NY.
there are no antenatal treatments that
Received Nov. 28, 2012; revised Feb. 21, 2013; accepted March 1, 2013.
improve neonatal outcomes once IUGR
Financial support was provided by the Oxenhorn family and the Feinstein Institute for Medical is diagnosed. The only current recom-
Research.
mendation is close antenatal surveillance
The authors report no conict of interest.
to determine the optimal timing of
Data from this manuscript were presented, in part, at the 32nd annual meeting of the Society for delivery.12
Maternal Fetal Medicine, Dallas, TX, Feb. 6 11, 2012, and, in part, in oral format at the 33rd annual
meeting of the Society for Maternal Fetal Medicine, San Francisco, CA, Feb. 13 16, 2013.
The excessive production of inam-
matory cytokines and chemokines dur-
The racing ag logo above indicates that this article was rushed to press for the benet of the scientic
community. ing hypoxic events may lead to tissue
Reprints: Christine N. Metz, PhD, Center for Immunology and Inammation, Feinstein Institute for
injury. Elevated cytokine levels have
Medical Research, 350 Community Dr., Manhasset, NY 11030. cmetz@nshs.edu. been found in both the amniotic
0002 9378/$36.00  2013 Mosby, Inc. All rights reserved.  http://dx.doi.org/10.1016/j.ajog.2013.03.001 uid (AF) and umbilical cord serum
(interleukin [IL]-6, IL-1b, and tumor

MAY 2013 American Journal of Obstetrics & Gynecology 383.e1

Research Obstetrics
necrosis factor [TNF-a])13,14 and in-
creased PL cytokine messenger RNA
expression (IL-8, IL-6, interferon-g,
and TNF-a)15-17 has been observed
among small-for-gestational-age (SGA)
neonates. These inammatory media-
tors are believed to contribute, in part, to
the short- and long-term adverse con-
sequences of IUGR.
Magnesium (Mg) is reported to have
a neuroprotective effect on preterm
fetuses. A randomized clinical trial by
Rouse et al18 showed a signicantly lower
rate of cerebral palsy among infants
born to women at 24-32 weeks gestation
who received Mg sulfate (MgSO4) before
delivery. A more recent metaanalysis
conrmed the neuroprotective effects
of maternal MgSO4 administration.19
While the exact mechanism for the
benecial effect of Mg is not known,
numerous studies support its antiin-
ammatory and vasodilatory activities.
Research in our laboratory revealed that
MgSO4 attenuates cytokine production
by lipopolysaccharide (LPS)-stimulated
endothelial cells20 and PL explants.21
Further studies by our group22 and by
Burd et al23 demonstrated the potent
antiinammatory and fetal neuro-
protective effects of maternal MgSO4
using rodent models of maternal infec-
tion. The vasodilatory effect of Mg has
been investigated in several vessels. Both
in vivo and in vitro studies have shown
vasorelaxation on rat aortic rings,24
mesenteric vessels and cerebral micro-
circulation,25 human PL,26 and uterine
arteries (UAs)27 after MgSO4 exposure.
Animal models of IUGR by UA liga-
tion have been used to study IUGR-
related metabolic,28 behavioral, and
neurological conditions.29 While little
is known regarding the maternal and
fetal inammatory responses follow-
ing UA ligation, we hypothesized that
the production of numerous proin-
ammatory mediators would ensue
within the maternal and fetal com-
partments following ligation. Further-
more, given the antiinammatory and
vasodilatory activities of Mg, we exam-
ined the effects of maternal oral Mg
supplementation on maternal and fetal
inammation, as well as on fetal and
PL weights using a rat model of IUGR
383.e2 American Journal of Obstetrics & Gynecology MAY 2013
induced following bilateral UA ligation
(BL).
M ATERIALS AND M ETHODS
Animal
The Institutional Animal Care and Use
Committee approved all animal studies
prior to animal experimentation. Female
Wistar rats (12-15 weeks old) (Taconic
Farms, Germantown, NY) were initially
acclimatized under normal environ-
mental conditions and allowed free ac-
cess to standard rat chow and tap water
for at least 72 hours prior to mating with
normal male Wistar rats (Taconic
Farms). Pregnancy was assessed by a
positive vaginal plug and/or sperm in
vaginal lavage uids. On gestational day
(GD) 1, dams were randomly assigned
to 1 of 4 treatment groups: normal
chow/tap water with BL (n 6) or
sham surgery (SH) (n 5); and normal
chow/tap water containing Mg chloride
(MgCl2) 1% (wt/vol) BL (MgBL)
(n 6) or SH (MgSH) (n 5). Dams
were individually housed and normal
chow and tap water 1% MgCl2 were
provided throughout gestation. Oral
MgCl2 supplementation given early and
throughout pregnancy was chosen to
mimic human prophylactic therapy.
MgCl2, was administered at 1% (wt/vol)
because in a pilot trial this was the best
tolerated dose (ie, it did not cause diar-
rhea and resulted in maternal weight
gain and pup weights that were similar to
dams given normal tap water). Rats were
weighed immediately prior to mating
and then on GD1, GD5, GD11, GD18,
and GD19. On GD18 dams were anes-
thetized using inhaled isourane and
underwent laparotomy for the BL pro-
cedure under sterile conditions. The
uterine horns were exteriorized and
the numbers of pups were determined;
the UAs were identied and sterile steel
wire (0.1-mm diameter) was placed
parallel along the top of the both UAs to
achieve consistent arterial occlusion
upon ligation using 3-0 Vicryl suture
material. Following occlusion, the wires
were gently removed and the abdominal
wound was closed with 3-0 Vicryl. Sham
rats underwent the same surgical pro-
cedures without ligation of the UAs.
Rats recovered within a few minutes
www.AJOG.org
and had ad libitum access to food and
water (MgCl2). Dams were euthanized
24 hours after the surgical procedure
by carbon-dioxide inhalation followed
by exsanguination via cardiac punc-
ture using heparinized needles/syringes.
Fetuses, delivered by cesarean section,
were euthanized by decapitation and
fetal blood was collected into heparin-
ized capillary tubes. PL weights, litter
number, fetal weight, and fetal mortality
were assessed. PL and fetal samples were
collected from live fetuses only. Maternal
blood and fetal blood were centrifuged
to obtain plasma. Maternal plasma (MP)
and fetal plasma (FP) (pooled), AF
(from individual sacs), and PL samples
were ash frozen in liquid nitrogen and
stored at 80 C until processing for
analysis of inammatory mediators.
Preparation of biological samples
and assessment of inflammatory
mediators
After an initial centrifugation step, MP,
FP, and AF were analyzed for inam-
matory mediators using a multiplex
platform (described below). Frozen PL
samples were homogenized using freshly
prepared lysis buffer (150 mmol/L
sodium chloride [NaCl], 20 mmol/L
Tris [pH 7.5], 0.25% Triton X-100,
10 mmol/L sodium uoride [NaF], and
phosphatase/protease inhibitor cocktail
[Thermo Scientic, Waltham, MA]).
After centrifuging, cell-free homoge-
nates were analyzed for inammatory
mediators using a multiplex platform
(described below). Inammatory medi-
ator levels in the maternal and fetal
samples were determined using cus-
tomized rat cytokine 5-plex kits for
TNF-a, IL-6, chemokine (C-X-C motif)
ligand 1 (CXCL1), IL-1b, and chemo-
kine (C-C motif) ligand 2 (CCL2), with
sensitivity <3 pg/mL (purchased from
Meso Scale Discovery, Rockville, MD),
according to the manufacturers di-
rections. The Meso Scale Discovery plate
was analyzed using the Meso Scale Dis-
covery Sector Imager 2400 plate reader.
The raw data were measured as electro-
chemiluminescence signals detected by
photodetectors and analyzed using Dis-
covery Workbench 3.0 software (Meso
Scale Discovery). A 4-parameter logistic
www.AJOG.org Obstetrics Research
t curve was generated for each cytokine
using the standards and used to deter- TABLE 1
mine the concentration of the individual Pregnancy outcomes at gestational day 19
cytokines in each sample. PL cytokine P value
data were normalized for protein con- ANOVA
MSH, MBL, Aa: SH vs BL
centrations (as determined using the
Variable SH, n [ 56 BL, n [ 51 n [ 60 n [ 42 Ba: BL vs MBL
Bradford method, Bio-Rad Laboratories,
Hercules, CA). For analyses, fetal sam- Pups, g 1.22  0.08 0.933  0.2 1.2  0.06 1.24  0.27 A: < .001
B: < .001
ples from the BL and MgBL groups
(except fetal blood, which was pooled) Placenta, g 0.42  0.08 0.32  0.05 0.35  0.04 0.36  0.05 A: < .001
were selected from fetal pups weighing B: < .01
10th percentile of the SH group; SH Fetal mortality 0/56 (0%) 31/82 (38%) 0/60 (0%) 32/74 (43%) A: .52b
and MgSH samples were selected from Pregnancy outcomes following BL induced intrauterine growth restriction in presence or absence of maternal oral magnesium
fetal pups weighing >10th percentile. A (M) supplementation throughout pregnancy: pup weight (g), placental weight (g), and fetal mortality were assessed on 24 h
after either SH or BL performed on gestational d 18. Data are shown as mean  SD (pup weight and placental weight) or
larger number of AF and PL samples percentage (fetal mortality).
were evaluated in the BL group (n 36) ANOVA, analysis of variance; BL, bilateral uterine artery ligation; MBL, magnesium chloride 1% bilateral uterine artery
to assess the impact of fetal position ligation; MSH, magnesium chloride 1% sham surgery; SH, sham surgery.
a
within the uterine horn (with respect to Kruskal Wallis (nonparametric ANOVA) with post hoc test; b Fisher exact test.

the BL procedure) and proximity to fetal Roman. Maternal magnesium reduces IUGR. Am J Obstet Gynecol 2013.

demise.

Assessment of MP and AF Mg2D
levels
MP and pooled AF samples (for each
dam) were assayed for total Mg2 levels
by the Core Laboratories of the North
Shore-LIJ Health System, Manhasset, NY.
Statistical analysis
Maternal and fetal outcome data (weight
gain, fetal weight, PL weight, and Mg
levels), presented as means and SD, were
compared using the Kruskal-Wallis test
(nonparametric analysis of variance)
with post hoc testing. Fetal mortality
and incidence of IUGR (pups <10th
percentile of normal SH pups), pre-
sented as rates, were analyzed using the
Fisher exact test. Cytokine data are
shown as means and SEM and analyzed
with Student t test. Maternal and fetal
cytokine data were analyzed rst by
comparing the SH vs BL groups. Subse-
quently, to test the efcacy of the MgCl2
treatment, BL cytokine data were
compared to the MgBL group. Statistical
signicance was set at P < .05.
R ESULTS
Maternal Mg supplementation in an
IUGR model improves fetal pup
weight
Dams given normal drinking water and
those given MgCl2 1% (wt/vol) in their
drinking water throughout gestation
(GD1-GD18) gained similar weights
(83.54  13 g vs 79.26  14.48 g,
respectively; P .52). There were no
signicant differences in litter sizes
among the 4 groups (11.25  1.7 [SH],
11.8  1.3 [MgSH], 12.1  1.7 [BL},
and 12  2.3 [MgBL]; P .6). The
average fetal weight among BL dams was
signicantly lower than the SH dams
(0.93  0.2 g [BL] vs 1.22  0.08 g [SH],
P <.001) (Table 1). Likewise, PL weights
obtained from the BL dams were signif-
icantly lower than those obtained from
the SH dams (0.32  0.05 g [BL] vs
0.42  0.08 g [SH], P < .001) (Table 1).
By contrast, there were no differences
in fetal pup weights (1.24  0.27 g vs
1.20  0.06 g, P .8) or PL weights
(0.35  0.04 g vs 0.36  0.05 g, P .4)
between the MgBL vs MgSH groups,
respectively (Table 1). Overall fetal
mortality was not signicantly different
between the BL vs MgBL groups (31/82
[38%] vs 32/74 [43%], respectively)
and no fetal mortality was observed in
either the SH (0/56 [0%]) or MgSH
(0/60 [0%]) groups (Table 1). The po-
sition of the fetal pups within the uterine
horn had no impact on fetal or PL weight
following BL or SH procedures. The
10th percentile for fetal pup weight
among the control (SH) group was
1.127 g. The incidence of IUGR (fetal
pup weight 10th percentile of the
control group) among the BL vs MgBL
groups was 86.3% vs 31%, respectively
(relative risk, 0.36; condence interval,
0.2 0.6; P < .0001]). Total Mg2 con-
centrations, according to 2 methods,
found in the MP and AF were similar
among all groups (Table 2).
Maternal Mg supplementation blocks
BL-induced inflammatory mediator
levels in the AF and IL-1b in the PL
First, we examined the effect of BL on
inammatory mediator levels in the MP
and FP 24 hours postsurgery. Interest-
ingly, we found that even though IL-1b,
IL-6, TNF-a, CCL2, and CXCL1 levels in
the MP and FP levels were not signi-
cantly different between the SH vs
BL groups, all inammatory mediator
levels (with the exception of IL-6) were
signicantly decreased by maternal Mg
supplementation (Figure 1). In contrast,
IL-6 levels in the FP and PL were signif-
icantly higher in the MgBL group
compared to SH and MgSH groups.
Next, we examined the effect of BL (vs
SH) on inammatory mediator pro-
duction in the AF and PL 24 hours
postsurgery. Levels of IL-6, IL-1b,
TNF-a, CCL2, and CXCL1 were signif-
icantly increased in both the BL-AF
and BL-PL tissues when compared to
the SH-AF and SH-PL tissues, respec-
tively (Figure 2). Maternal oral Mg
supplementation signicantly decreased
BL-induced IL-1b, TNF-a, and CCL2
(P < .001) levels in the AF and

MAY 2013 American Journal of Obstetrics & Gynecology 383.e3

Research Obstetrics www.AJOG.org

ndings were corroborated by a study in

TABLE 2 which fetal pups exhibited increased
Magnesium levels in maternal serum and amniotic fluid at 19 days circulating IL-6 and TNF-a levels and
gestation enhanced IL-6 and TNF-a messenger
P value RNA expression in the lungs, hearts, and
Variable SH, n [ 5 BL, n [ 6 MSH, n [ 5 MBL, n [ 6 ANOVA brains following exposure of pregnant
Maternal 2.7  0.25 2.58  0.24 2.64  0.18 2.76  0.56 .6223 guinea pigs to chronic hypoxemia.32
serum, mg/dL Additionally, increased levels of CCL2
Amniotic 3.02  0.13 3.08  0.23 2.92  0.24 3.18  0.23 .1637 were found in peripheral blood of SGA
fluid, mg/dL neonates and infants compared to
Magnesium (Mg2, mg/dL) levels in maternal serum and amniotic fluid were determined on gestational d 19, 24 hours after appropriate-for-gestational-age controls
either SH or BL performed on gestational d 18 after maternal administration of normal drinking water or drinking water in the absence of increased levels in
containing Mg chloride (1% [wt/vol], MSH and MBL) throughout pregnancy. Data are shown as mean  SD.
the maternal serum or umbilical cord
ANOVA, analysis of variance; BL, bilateral uterine artery ligation; MBL, magnesium chloride 1% bilateral uterine artery
ligation; MSH, magnesium chloride 1% sham surgery; SH, sham surgery. serum.35 Therefore, chronic hypoxia
Roman. Maternal magnesium reduces IUGR. Am J Obstet Gynecol 2013. fullls the criteria of fetal inammatory
response syndrome.34
In this study, the maternal oral Mg
supplementation given throughout the
signicantly reduced BL-induced IL-1b supplementation signicantly amelio- gestational period was accompanied by a
levels in the PL tissues (P < .001) rated BL-induced inammation in the signicant decrease (64%) in the inci-
(Figure 2). IL-1b, TNF-a, and CCL2 AF (IL-1b, TNF-a, and CCL2) and PL dence of IUGR following BL. In previous
levels in the AF and IL-1b, TNF-a, and (IL-1b) compartments and this was studies, Mg supplementation improved
CXCL1 levels in the PL tissues of the accompanied by improved fetal weight fetal weight in a rat model of IUGR/
MgBL group were not signicantly gain following BL. preeclampsia induced by N-nitro-L-
different when compared with AF and PL UA ligation in the rat has been arginine methyl ester administration.36
tissues obtained from the MgSH group, used extensively to produce fetal growth MgSO4 exerts vasodilatory effects on
respectively (Figure 2). IL-6 and CXCL1 restriction at different gestational ages both uterine and PL vasculature.26,27
levels were decreased in the AF samples (GD18-GD21) and reduced weight at Specically, Mg may improve utero-PL
obtained from the MgBL group when birth (which catches up by 7 weeks perfusion by acting as a calcium antag-
compared to the BL group; however, postpartum).28,30,31 While we suspect onist on most types of calcium channels
these differences were not statistically that maternal Mg supplementation in in vascular smooth muscle cells, and by
signicant (Figure 2). Fetal position this model would protect against re- reducing intracellular calcium levels,
within the uterine horn and proximity to duced birthweight our study did not resulting in decreased contraction and
fetal demise had no impact on inam- specically examine it. The incidence of increased arterial relaxation that may
matory mediator levels in the various IUGR (fetal weight 10th percentile) subsequently lower peripheral vascular
compartments (data not shown). using the rat BL model has not been re- resistance and relieve vasospasms.34,37
ported previously. Total Mg2 levels in the MP and AF
C OMMENT Enhanced levels of IL-6 and TNF-a were not signicantly different among
In this study, we found impaired fetal within the AF and PL in our IUGR rat groups. Total circulating Mg2 levels
growth 24 hours post-BL. Restricted model are consistent with ndings may not best reect an individuals Mg
fetal growth was accompanied by the in the AF13,32 and PL15-17,33 tissue of status because only approximately 1%
presence of numerous inammatory SGA neonates and in animal models of the bodys stores of Mg is in the
cytokines (IL-6, IL-1b, and TNF-a) and following chronic hypoxemia.34 In- plasma; approximately 99% is found
chemokines (CCL2 and CXCL1) in creased IL-6, TNF-a, C reactive-protein, intracellularly in tissues and bones.38
affected AF and PL 24 hours after BL and thrombopoietin levels have been Furthermore, numerous studies sup-
(Figure 2). It is important to note reported in the AF and umbilical cord port the concept that due to the high
that samples from only live fetal pups serum of SGA neonates when compared demands for Mg from the growing fetus,
were analyzed. Interestingly, enhanced with controls.13 Elevated inammatory there is an Mg gradient from the
inammation within the PL and AF mediator levels in the AF and cord maternal to the fetal side that increases
occurred in the absence of increased in- blood were accompanied by increased with gestation.39 Thus, maternal serum
ammatory mediators in the MP and FP levels of both IL-8 and IL-6 in PL Mg levels may appear normal even after
(Figure 1). To our knowledge, this is the tissue.12-14,30 Likewise, chronic hypoxia, low-dose Mg supplementation. Finally,
rst report describing increased cytokine in the absence of infection, increased the Mg responsible for the antiin-
levels in the AF and PL following BL IL-6 and TNF-a levels within FP and ammatory effects observed is likely
and increased CCL2 and CXCL1 levels AF, and was associated with IUGR, pre- intracellular Mg, which was not assessed
associated with IUGR. Maternal Mg term birth, and tissue injury.13,32 These in this study.

383.e4 American Journal of Obstetrics & Gynecology MAY 2013

www.AJOG.org Obstetrics Research
This observation agrees with previous
studies revealing that intracellular Mg FIGURE 1
levels of cord blood platelets were Cytokine and chemokine concentrations in maternal and FP following
signicantly lower in SGA neonates BL-induced intrauterine growth restriction
than the appropriate-for-gestational-age
control group.40 Less than 40% of
women between 19-30 years of age in the
United States consume the recom-
mended daily intake of Mg.41 Mg de-
ciency in pregnant women is frequently
observed because of inadequate or
low Mg intakes despite prenatal supple-
mentation and increased Mg require-
ments associated with the metabolic
demands of pregnancy.42 The use of
antenatal maternal Mg administration
in pregnancy is further supported by
previous studies reporting reductions
in the risks of cerebral palsy and gross
motor dysfunction by 32% and 39%,
respectively, following antenatal MgSO4
treatment given to women experiencing
preterm labor.19 In this study, we ob-
served no adverse effects of maternal
Mg supplementation and together these
studies support further investigating
the use of maternal Mg supplementation IL-6, IL-1b, TNF-a, CCL2, and CXCL1 were measured in A, maternal plasma and B, FP (pooled from
in IUGR-complicated pregnancies. individual dams) 24 hours after SH or BL surgery (maternal oral magnesium chloride supple-
This is the rst report describing the mentation [M]). Data are shown as mean  SEM.
protective effect of Mg on IUGR, with BL, bilateral uterine artery ligation; FP, fetal plasma; IL, interleukin; MBL, magnesium chloride BL; MSH, magnesium chloride SH;
respect to fetal growth and/or inam- SH, sham surgery; TNF, tumor necrosis factor.

mation. The mechanism(s) of action for P < .05; P < .001 when comparing BL with MBL (Mann Whitney Test).
the fetal/PL protective effects of Mg are Roman. Maternal magnesium reduces IUGR. Am J Obstet Gynecol 2013.
not completely understood. There is
increasing evidence that MgSO4 exerts
antiinammatory effects in both animal the transcription factor, nuclear factor- and reduced NFkB activation, thereby
and cell-based models. We showed in a kappa B (NFkB). decreasing production of cytokines
rat model of maternal infection that Increased cytokine expression associ- and chemokines.20,21,46 In this study,
MgSO4 treatment signicantly attenu- ated with IUGR is poorly understood. maternal Mg administration reversed
ated LPS-induced IL-6, CCL2, and It is believed to be secondary to the IUGR-induced cytokine levels within
CXCL1 levels in maternal and fetal activation of NFkB, as NFkB activation is the feto-PL compartment supporting an
compartments.22 In a mouse model of increased in IUGR PL.44 NFkB is bound antiinammatory mechanism of action.
inammation-associated preterm birth, to its inhibitory subunit, inhibitor kappa Finally, we did not detect elevated
MgSO4 protected against brain inam- B alpha (IkBa), in the cytoplasm and levels of cytokines or chemokines in the
mation and prevented LPS-induced after IkBa degradation, free NFkB MP or FP following BL vs SH. Maternal
morphologic changes in neuronal cell translocates into the nucleus where it serum cytokine levels remained unaf-
cultures.23 Finally, in a rat model of stimulates the transcription of inam- fected when assessed 24 hours post-BL,
hypoxia-induced fetal brain damage, matory cytokines such as IL-1b, IL-6, even after controlling for number of
maternal MgSO4 administration reduced IL-8, TNF-a, chemokines, prostaglan- fetal demise per dam. Elevated IL-6
hypoxia-induced inammation on fetal dins, and other acute-phase proteins.45 in AF and PL was not reduced by
brain histopathology and size.43 Treat- Excessive cytokine production (IL-1b, Mg supplementation, Moreover, IL-6 in
ment of human umbilical vein endo- IL-6, and TNF-a) has been associated MgBL-FP was elevated when compared
thelial cells20 and human PL explants21 with preterm labor and poor pregnancy with MgSH. This does not exclude
with MgSO4 prior to LPS stimulation outcomes.6-14 Previous studies showed the possibility that BL induces maternal
inhibited inammatory mediator pro- that in vitro and in vivo Mg supple- and/or fetal inammation or Mg mod-
duction by suppressing the activation of mentation increased basal IkBa levels ulation of IL-6 at an earlier or later time

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