1

INTRODUCTION
Prematurity causes neonatal
mortality and morbidity. Nearly half
of neonatus who are survive will
have
congenital
neurological
disability including cerebral palsy
(CP). The incidence of CP and
cognitive impairment associated with
periventricular white matter damage,
which is often found in infants who
are born before pregnancy of 32
weeks or acquired corticosubcortical
abnormalities in term newborns
(Degos V et al .2008). Proinflammatory cytokines is known
significantly increased in the
amniotic fluid and fetal brain of
neonatus with infection, including
local inflammatory response that
causes damage to the fetal brain.
Microbial infections in the amniotic
fluid can cause premature labor and
result
to
a
fetal
infection.
Microorganisms produce a product
that can trigger mononuclear cells to
produce IL-1 and TNF-, which can
increase the permeability of the
blood brain barrier so that the
products of microorganisms and proinflammatory cytokines that can
enter the brain and cause tissue
damage to the brain's white matter
(white matter damage) of fetus. The
latest hypothesis states that the cause
of pre-eclampsia is more in focus to
the immune response. Cytokines are
regulator of immune substances that
involved in the pathogenesis of preeclampsia. Successful pregnancy is a
Th2 phenomenon, in which the Th1 /
Th2 shift to a Th2-type response.
Type
1
cytokines
including
interleukin-2, interferon (IFN) and
tumor necrosis factor alpha (TNF-)
are occured in pre-eclampsia caused
by inflammation (Mirahmadian et al,

2008). Plasma concentration of proinflammatory cytokines such as

tumor necrosis factor alpha (TNF-)
and interleukin 1 (IL-1) in patients
with pre-eclampsia compared to
normal pregnant women.
Cytokine TNF- is a 17kd
peptide, which is a soluble mediator
of cellular immunity. (Gulti et al,
2005). Some researchers have
demonstrated that TNF levels serum
are significantly higher in first
trimester and second trimester among
pregnant women who developed into
pre-eclampsia compared to the group
of control. Based on research
conducted by Kocyigit et al,
concentration of TNF- is higher in
pre-eclampsia. (Kocyigit et al, 2004).
Some
studies
suggested
that
infections
and
inflammatory
processes are associated with preeclampsia. IL-1 secretion initiated
pro-inflammatory cascade, including
the production of TNF-, interferon
gamma (IFN-), IL-2, and IL-12. IL1 gene family located on
chromosome 2q13-14. IL-1 gene is
the most high polymorphic and
several polymorphisms diallelic have
also been researched. In preeclampsia,
pro-inflammatory
cytokine IL-1 and TNF- as the
mediator of inflammatory response
by
attracting
and
activating
leukocytes in tissues and stimulates
the secretion of lymphocytes
cytokines and catabolic enzymes
which involved in oxidative stress
associated
with
pre-eclampsia.
Mechanisms of inflammation and
infection in the pathogenesis of preeclampsia is very significant in
developing countries, where the
highest incidence of subclinical
chronic infections may be one cause

of the high incidence of preeclampsia. (Tavakol et al, 2005).

Pathologic lesion that is
most common associated with
Cerebral Palsy (CP) in premature
infants is Periventricular White
Matter
Injury
(PWMI).
Oligodendrocyte gather most in
White Matter glia in the brain. Nmethyl-D-aspartic acid (NMDA)
receptors on oligodendrocyte is very
important in the process of damage
to the Glia. Antagonist receptor of Nmethyl-D-aspartic acid (NMDA)
become potential neuroprotective
agent in some animal models of brain
damage in pregnancy. Mediator of
inflammation cause damage to the
developing brain by different way, as
TNF-1, plays an important role in
the immune process which causes
damage to periventricular White
Matter in fetus/ neonatus. Cytotoxic
and inflammation processes of TNF occurs through the membrane
among the TNF-R1 receptors. TNFR1 has intracellular areas which have
been dead and the activation
regulates cell apoptosis. Aberrant
signal of TNF-/ TNF-R1 has a
potential rule
in the
early
pathogenesis of brain damage, in
which oligodendrocytes that have
been dead and demyelination is the
primary pathology factor in this
process. TNF-R1 expression in
oligodendrocytes
significantly
increased in Perivetrikular White
Matter of the brain that is growing. It
is paired with the increase of death
cell caused by apoptosis and necrosis
in the Periventricular White Matter.
So it appears that the production of
TNF- by microglial cells in hypoxic
conditions induces apoptosis of
oligodendrocytes through TNF-R1.

Unlike TNF-, IL-1 is not toxic to

the oligodendrocytes, but it can block
the proliferation of oligodendrocytes.
This has been researched about the
significant increase in production of
IL-1 by microglial cells coincide
with the expression of IL-1 receptor
in
oligodendrocytes
in
the
periventricular white matter of
neonatal brain. It is estimated that the
activation and orientation of proinflammatory of the production of
IL-1 by microglial cells in hypoxic
conditions inhibit the development of
white matter and the improvement of
the hypoxic condition. (Berger et al
2012).
In human, magnesium is
very important in cellular processes,
including
glycolysis,
oxidative
phosphorylase, synthesis of proteins,
DNA and RNA aggregation and
maintain the plasma membrane.
Magnesium has a beneficial effect on
cell death by reducing cytokine proinflammation or free radicals formed
during the process of hypoxicischemia
reperfusion
and
inflammatory
processes
in
pregnancy.
Magnesium
keep
excitotoxic calcium which causes
tissue damage, by non competative
voltage-dependent inhibition of Nmethyl-D-aspartate
(NMDA)
glutamate receptors to reduce the
influx of calcium into the cell. Infant
and fetal brains are more susceptible
to damage by glutamate. Agents
block the glutamate receptors such as
magnesium sulfate may reduce the
risk of tissue damage in the perinatal
period. Magnesium has a beneficial
hemodynamic effects including
stabilize the blood pressure during
the first two days in the life of
preterm fetus and can increase

cerebral blood flow by reducing

constriction of the cerebral arteries.
Transfer
of
transplacental
magnesium can happen quickly, will
increase the concentration of
magnesium in the blood serum of
fetal just within an hour after
administration of magnesium to the
mother. (Crowther et al .2013)
In another study showed
that
levels
of
intracellular
magnesium increased when given
MgSO4 therapy. MgSO4 will pass
through the placenta so that its
concentration in maternal and fetal
become
equivalent.
Its
antiinflammatory effects are reversible,
magnesium will reduce cytokine
production and is not associated with
the changes of osmotic pressure.
MgSO4 also decrease cytokine and
gene expression IB. In addition, it
also reduces the phosphorylation
level of NF-B P56 and NF-B
nuclear location following the TLR4
stimulation.
And
reduce
the
production of cytokines will cancel
the function of NF-B inhibitors, this
proves that MgSO4 affects cytokine
production in NF-B dependent
behavior. MgSO4 reduce the
presentation of monocyte TNF
production and IL-6 following the
TLR2 / 6 agonist exposure.
Magnesium suplement increases the
level of IB, thus reducing NF-B
activation and cytokine production.
(Sugimoto et al, .2012)
MATERIALS AND METHODS
This research is an analytic
research using cross sectional with
clinical trials approach the levels of
TNF and IL-1 in preterm pregnant

women using MgSO4 and without

MgSO4 by using ELISA method.
This study was conducted
on 40 pretem pregnant women, a
single fetus with good nutritional
status who delivered in Dr.
Moewardi Surakarta hospital were
divided into 2 groups: 20 pretem
pregnant women were given MgSO4
and 20 pretem pregnant women were
not given MgSO4, which all these
samples are qualified with the
inclusion and exclusion criterias.
Blood sampling performed
in the umbilical vein 10 ml, then
each of it 5 ml for examination of
serum IL-1 and TNF-. Given lable
to the blood sample tube, name and
register, then centrifuge at a speed of
2000-3000 rpm for 15 minutes, then
serum was stored in a refrigerator at
a temperature of -20 C and later sent
to Jakarta using ice packs and being
worked in the PRODIA Laboratory
at Jakarta. The examination of serum
level of IL-1 and TNF- is done by
using the quantitative ELISA
method.
Data obtained from the
serum levels of TNF and IL-1 in
premature pregnancy who are given
MgSO4 and who are not given
MgSO4
were
collected
and
statistically compared using the t test
by using SPSS for windows version
17:00.
RESULTS
From the data obtained that
the average maternal age variable is
4:20 24.82 + years with the mean of
gestational age 33.52 + 1:50 weeks,
the mean of hemoglobin levels 10.61
+ 1:09 gr / dl, the mean of albumin
levels 1,361.16 12,682.50 + (103 /

ml), random blood sugar 103.40 +

13:17 (mg / dL), the mean of AST
8:09 28.27 + U / I, SGPT with mean
26.60 + 7:59 U / I, the mean of TNFalpha 2:52 + 0.76 ng / mL and the
mean of IL-1 beta 0.60 + 0:27 ng /
mL.
Statistical analysis using the
Kolmogorov-Smirnov normality test
for research variable of maternal
age, gestational age, hemoglobin,
albumin, random blood sugar, SGOT
and SGPT in preterm pregnant group
given MgSO4 and preterm pregnant
group without given MgSO4 do not
have
significant
differences/
homogeneous
(KolmogorovSmirnov> 0.05). Table 1.
From the results of mean
difference test of preterm pregnant
given MgSO4 group and preterm
pregnant group without given
MgSO4, it is found that maternal
age, gestational age, albumin,
number of platelets, random blood
sugar and SGPT are significantly
different in statistis (p <0.05), while
hemoglobin levels and SGOT do not
have significant difference / normal
(homogeneous) (p> 0.05). Table 2.
Normality Test of TNF-alpha and
IL-1 beta
Variable analysis of TNF-
and IL-1 by using normality test
(Kolmogorov-Smirnov) in group of
preterm pregnant women given
MgSO4 and group of preterm
pregnant women without MgSO4
normally distributed with TNF- p
value = 0.71 (p> 0.05) and IL-1 p =
0.95 (p> 0.05) for group of pregnant
women given MgSO4. TNF- p =
0:39 (p> 0.05) and IL-1 p = 0.76
(p> 0.05) for preterm pregnant

women group who were not given

MgSO4, so TNF-alpha and IL-1 in
the group of preterm pregnant
women given MgSO4 and preterm
pregnant women group without given
MgSO4 are homogeneous.
Results of the mean
distribution of TNF-alpha appears
lower in the group of preterm
pregnant women given MgSO4 (2:24
+ 0:56 ng / mL), compared to
preterm pregnant group without
given MgSO4 (2.80 + 0.85 ng / mL).
The interpretation of the graph shows
that the decreased levels of TNFalpha in preterm pregnant group
given MgSO4 having a lower peak
than the levels of TNF-alpha in
preterm pregnant group without
given MgSO4. (Figure 1.) Table 3
T test analysis using =
0:05 proves that TNF-alpha levels
between preterm pregnant group
without given MgSO4 and preterm
pregnant group given MgSO4 have
there are significant differences with
p = 0:01 (<0.05).
Results of the average
distribution of IL-1beta appears
lower in the group given perterm
pregnant MgSO4 (0:49 + 0:22 ng /
mL), compared with non-pregnant
preterm given MgSO4 (0.71 + 0:28
ng / mL). The interpretation of the
graph shows that the decreased levels
of IL-1beta in preterm pregnant
group were given MgSO4 having a
lower peak than the levels of IL1beta in preterm pregnant group
were not given MgSO4. (Figure 1.)
Table 4.
T test analysis using =
0:05 prove that the levels of IL-1beta
between pregnant group were not
given MgSO4 preterm and preterm
pregnant group were given MgSO4

have significant differences with p =

0:01 (<0.05).
DISCUSSION
The high numbers of
premature birth both in the world and
in Indonesia particularly, of course
become concern to us. In addition to
the high number of neonatal deaths
due to prematurity, permanent
complications such as Cerebral Palsy
(CP) is a frightening specter even for
obstetricians
and
experts
perinatology.
Prematurity
has
demonstrated causes results in
neuronal injury both through
hypoxic-ischemic
process
or
inflammation-infection
process.
Therapeutic action against neuronal
injury will not help much. Proper
prevention is required. The concept
of obstetrics prevention is the
concept of the latest obstetrics in the
hope of maternal quality and
neonatal outcomes are optimal and
not avoid only the incidence of
death.
Cytokines associated with
preterm delivery include IL-1, IL-6,
IL-8, and TNF-. Activation of
immune cells including circulating
neutrophils,
macrophages
phagocytes, T cells, NK cells, CNS
astrocytes and microglia produce
biological mediators such as
cytokines, chemokines, adhesion
molecules and growth factors
involved
in
the
complex
intermolecular
interactions
that
participate in the process of dealing
with
the
damage
immunoinflamationthat is correlated with
brain damage. (Adams et al, 2011)
This study was conducted
on 40 preterm pregnant women, a

single fetus with good nutritional

status who delivered in Dr.
Moewardi Surakarta hospital were
divided into 2 groups: 20 preterm
pregnant women who were given
MgSO4 and 20 preterm pregnant
women who were not given MgSO4,
which all samples are qualified with
the inclusion and exclusion criterias.
From the results, the tabulation of
calculation
results
the
mean
distribution of IL-1beta, showed a
decreasing in the mean distribution
of IL-1beta between preterm
pregnant group who were not given
MgSO4 and the pretem pregnant
group given MgSO4. T test analysis
using = 0:05 prove that the levels
of IL-1beta between pretem pregnant
group were not given MgSO4 and
preterm pregnant group were given
MgSO4 are found significant
difference with p = 0:01 (<0.05).
Tabulation of the calculation results
of mean distribution of TNF-alpha,
showed a decreasing of mean
reduction of TNF-alpha between the
preterm pregnant group who were
not given MgSO4 and preterm
pregnant group given MgSO4. T test
analysis using = 0:05 proves that
TNF-alpha levels between pregnant
group were not given MgSO4
preterm and preterm pregnant group
were given MgSO4 are found
significant differences with p = 0:01
(<0.05).
Although many researchers
are trying to find the truth about the
causes and treatment of brain
damage, until now we do not really
know the exact mechanism of why
magnesium sulfate can protect
neuronal cells from hypoxiaischemia process. However, data
from this study clearly indicates that

the administration of MgSO4 can

significantly reduce the levels of
TNF- and IL-1.
Researchers Burd in 2010
also mentioned that magnesium
reduces the amount of free radicals
oxygen and there is also opinion
stated that magnesium reduces the
amount of inflammatory cytokines,
because some studies proved that
mice which lack of magnesium
would have a lot of inflammatory
cytokines and brain damage. (Burd et
al.2010)
Ever conducted research on
the mechanisms of the cause of nerve
damage and it is found that beside
mice fetus nerve damage, also it that
may be occured damage to the other
normal nerves. (Burd et al.2009).
They also found that the brains of
fetal
mice
exposed
to
lipopolysaccharide,
bacterial
antigens can cause intrauterine
inflammation, indicating abnormal
neural morphology with decreased
dendritic
processes,
thereby
disrupting
the
communication
between sypnatic nerves. (Burd et
al.2009). One of the studies that have
been conducted with animals
suggested that the fetal brain which
are underwent the inflammatory
process and then given MgSO4, do
not showed nerve damage associated
with dendritic process. (Breen et
al.2009).
Research Limitations
This study has many
limitations
including
preterm
gestational age that is used, which is
gestational age of 28-35 weeks, so it
does not cover the fetus at the age
less than 28 weeks or more than 35

weeks. Therefore, the data can be

more accurate and more valid. It is
remembered
to
notice
about
sampling technique, endurance of
serum in the storage, also much time
needed to wait for the ordered
reagents to come, as well as its
durability of the reagent itself,
moreover, there is human error in the
laboratory. In the end, this
magnesium sulfate administration
would be expected to be able to
decrease the incidence of cerebral
palsy (CP) and further studies with
more details about this research are
still needed and in a long time
period.

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