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

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

383.e2 American Journal of Obstetrics & Gynecology MAY 2013

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.
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.


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

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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.

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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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1. Resnik R. Intrauterine growth restriction.
Oral maternal Mg supplementation suppresses cytokine and chemokine Obstet Gynecol 2002;99:490 6.
levels in AF and IL-1b in PL tissues following BL-induced intrauterine 2. Salaa CM, Minior VK, Pezzullo JC,
growth restriction Popek EJ, Rosenkrantz TS, Vintzileos AM.
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IL-6, IL-1b, TNF-a, CXCL1, and CCL2 levels were measured in A, AF and B, PL tissues 24 hours 204 9.
8. Wu YW, Escobar GJ, Grether JK, Croen LA,
after SH or BL surgery (maternal oral Mg chloride supplementation [M]). Data are shown as
Greene JD, Newman TB. Chorioamnionitis and
mean  SEM. cerebral palsy in term and near term infants.
AF, amniotic fluid; BL, bilateral uterine artery ligation; CCL2, chemokine (C C motif) ligand 2; CXCL1, chemokine (C X C motif) ligand 1; JAMA 2003;290:2677 84.
IL, interleukin; MBL, magnesium chloride BL; Mg, magnesium; MSH, magnesium chloride SH; PL, placental; SH, sham surgery; 9. Jarvis S, Glinianaia SV, Torrioli MG, et al.
TNF, tumor necrosis factor.
Cerebral palsy and intrauterine growth in single
*P < .05; **P < .001 when comparing SH with BL; P < .001 when comparing BL with MBL (Mann Whitney test). births: European collaborative study. Lancet
Roman. Maternal magnesium reduces IUGR. Am J Obstet Gynecol 2013. 2003;362:1106 11.
10. Zeitlin J, El Ayoubi M, Jarreau PH, et al.
Impact of fetal growth restriction on mortality
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point(s) (which we did not assess). restriction) potentially mediated through 11. Simmons RA. Developmental origins of
Similarly, the absence of increased the antiinammatory effects of maternal adult disease. Pediatr Clin North Am 2009;56:
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