Premature Brain Protection

Neurological and developmental outcome in extremely preterm children born in England in
1995 and 2006 : the EPICure studies Moore T. Marlow N. et al BMJ. 2012
The study demonstrate

improvements in survival at
extremely low gestational ages
and in the proportion of
survivors who not have
disability. These improvements
are only statistically significant
at 24 and 25 weeks gestation.
Preterm birth
5%
15%
60% 20%
Extreme Very Late Term

24 28 32 34 37 40
Gestational Age: weeks
OUTCOME
OF EXTREME PRETERM NEONATE

LATE PT BIRTH
34-36
28-31
32-33
< 28
EG wks
Carrie K. Sem Fetal and Neonatal Medicine,2012 2012,

Late Preterm Birth
Definition
Infants between 34 and 35

completed wks of gestation
Loftin RW Rev Obstet Gynecol. 2010

Late Preterm
PER SINTETIZZARE
Longer hospitalisation
More frequent admission to NICU
Inappropriate neuro-developmental achievement
Increased medical-legal litigation
Higher mortality
RESULTS: of 2693 late preterm deliveries
32.3% (872/2693) were iatrogenic:

56.7% were delivered for NEB indications.
Gyamfi-Bannerman C. Non spontaneous late preterm birth: etiology and

outcomes.. Am J Obstet Gynecol. 2011 Nov;205(5):456.e1-6.
Seminars in Perinatology Volume 30, Issue 2, April 2006
Late Preterm SNC
Mc Gowan JE et al. Early Childood Development of late Preterm infants : A systematic

Review. Pediatrics 2011
- 6300 at term 1200 late preterm
- age : 24 m (chronological age)
Mental developmental index (MDI)
Psychomotor developmental index (PDI)
Bayley Scale of Infant Development Short Form-Research Edition (BSF-R)
Seminars in Fetal and Neonatal Medicine 2012

Late Preterm neurodevelopmental impairment
School performance scores
.
Late Preterm neurodevelopmental impairment
School performance scores
behaviour
relationship
writing /composition
fine motor coordination
mathematics
language
phisical education
Effect of magnesium sulfate on cerebral palsy
Antenatal magnesium sulfate and
neuroprevention
5 RCTs (in 4 neuroprevention was primary aim)

Meta-analysis:
RR
Cerebral Palsy 0.69 (CI 0.54-0.87)
Motor dysfunction 0.61 (CI 0.44-0.85)
No effects on mortality or on other neurological impairments or

disabilities in the first years of life
Doyle LW, Current Opinion in Pediatrics 2012;24:154-159

Magnesium sulphate
To prevent one case of moderate/severe CP:

<28 wks, number needed to treat : 30
<32 wks, number needed to treat : 63
Dosage:
4 g i.v. loading dose; 1-2g/h maintenance for 12-24 h*
Maternal side effects:

Vasodilatation
Neuromuscular blocking agent Prevent overdosing
*Guidelines Australian & Canadian COG

Pathophysiology of
Perinatal Brain Damage
Is Multifactorial
Cardiovascular instability and hypoxia-ischemia are the sole culprits
Prenatal, Perinatal, and Postnatal Factors are encountered
Preoligodendrocytes are highly vulnerable to oxidative stress, leading to
Periventricular White Matter Damage (PWMD)
Peranan Faktor Antenatal, Perinatal dan Postnatal pada
patogenesis Brain Injury pada Cerebral Palsy
Mekanisme seluler dan molekuler akibat kelebihan Glutamat dan sitokin proinflamasi
Yang berakhir pada kerusakan otak. (PWMD = Periventricular White Matter damage)
( NMDA-R : N-methyl-D-aspartate-Receptor ; AMPA : alpha-3-Amino-Hydroxy-5-Methyl-4

Isoxasole Propinic Acid ; ROS : Reactice Opxygen Species ; RNS : Reactice Nitrogen Species ;
KA-R : Kainate Glutamatergic Receptor ; Pre-oligos : Preoligodendrocyte )
Hypoxic-Ischemic Insult
PATHOPHYSIOLOGY OF NEURONAL CELL DEATH
Hypoxiaischemia (Fig. 3) induced by oxygen and glucose deprivation is followed by a severe decrease in adenosine
triphosphate content, causing failure of the sodiumpotassiumadenosine triphosphate pump that maintains the polarity of
the neuronal membrane.
Membrane depolarization induces excessive glutamate release, leading to a massive influx of sodium and calcium via the
NMDA receptor.
The increase in intracellular calcium activates several enzymes including phospholipases, proteases, and endonucleases, and
neuronal nitric oxide (NO) synthase.
Further deleterious effects occur at the reperfusion phase as a result of excessive production of superoxide (which damages
the mitochondria and produces peroxynitrate by forming a
complex with NO and generation of free radicals.
Reactive oxygen species cause oxidation of lipids and proteins and damage to DNA. Neuronal cell death was shown in animal
models to be a combination of necrosis, apoptosis, and intermediate mechanisms.
Mitochondrial damage, caspase activation, and apoptosis-inducing factor play key roles in perinatal neuronal cell death.
Of particular interest, the delayed phase of neuronal cell death was protracted in rodents, lasting several weeks after the initial
insult.
Apoptosis and caspase activation have been documented in the developing brain subjected to hypoxiaischemia.
Key factors involved in apoptosis, such as caspase 3, bcl-2, and bax, are up-regulated in
the immature brain compared with the adult brain.
Definition
A neuroprotectant is generally defined as an agent that

prevents neuronal death by
inhibiting one or more of the pathophysiolo-gical steps in the
processes that follow injury to the nervous system or ischemia
due to occlusion of an artery or hypoxia due to any cause.
This definition has now been extended to include protection against neurodegeneration and neurotoxins. The extended
definition includes interventions that slow or halt the progression of neuronal degeneration
Table 1.1 Historical landmarks in the development of neuroprotection
Year/era Landmark, comments
Ancient Greek physicians used hypothermia and originated the concept
Greeks of neuroprotection
1900 Recognition of organic free radicals by Gomberg led to the speculation that
free radicals may be involved in the living systems (Reid 1957)
1943 Hypothermia used as a protection for the brain as a part of the treatment
of head injury (Fay 1943)
1943 Use of oral glutamate for treatment of petit mal seizures (Price et al. 1943).
Other reports suggested that it enhanced intelligence in mentally retarded
children. None of these claims were substantiated later but indicate that
glutamate had some effect on the central nervous system (CNS)
1959 Glutamate was demonstrated to excite neurons throughout the CNS (Curtis
et al. 1959)
1962 First demonstration of the use of barbiturates for neuroprotection (Arnfred
and Secher 1962)
1964 Profound hypothermia used in head injury (Lazorthes and Campan 1964)
1968 Application of the concept of reperfusion disturbance (originally described
for the myocardium in 1960) to injury of the neurons in cerebral
ischemia (Ames et al. 1968)
1976 Concept of penumbra a zone of potentially viable neurons at the junction
of infarcted and noninfarcted brain (Symon 1976). This provided the
basis for neuroprotection in stroke
1980 F irst use of hyperbaric oxygen for neuroprotection in acute cerebral
ischemia (Neubauer and End 1980)
1980s Increasing recognition of the role of free radicals in human disease and use
of free radical scavengers in various diseases including neurological
disorders
1990s Improved knowledge of molecular basis of neurological diseases and
extensive investigation of neuroprotective therapies in controlled
clinical trials. Use of neurotrophic factors and gene therapy
Brain Protection
Prevention or amelioration of neuronal damage evidenced by
abnormalities in cerebral metabolism, histopathology or neurologic
function occurring after a hypoxic or an ischaemic event.
( Messick JM, Middle LM. Brain protection. Advances in anethesiology

1987;4:47-88 )
Brain Protectants can exert their protective
effects at 3 basic levels :
1. Reduction in oxygen demand
2. Increase in oxygen delivery
3. Arresting deleterious pathological intracellular processes
Brain Protectants
Barbiturates
Isoflurane
Lidocaine
Benzodiazepines
Calcium entry blockers (Nimodipine, Nifedipine, Magnesium sulfate)
Ketamine and NMDAS receptor antagonist (MK-801)
Phenytoin
Agents with potential but unproven efficacy :
- corticosteroids
- Free radical scavengers (barbiturate, vit C and E, mannitol, 1-
methiamine, glutathione-SH), catalase, SOD.
- Prostaglandine inhibitors : indomethacin
- Iron chelators : Deferoxamine
Richard Hall. MD FRCPC; John Murdoch. BSc
Can J Anaesth 1990; 37-7: 762-77
Can J Anaesth 1990; 37-7: 762-77
Can J Anaesth 1990; 37-7: 762-77
Can J Anaesth 1990; 37-7: 762-77
Can J Anaesth 1990; 37-7: 762-77
Can J Anaesth 1990; 37-7: 762-77
POTENTIAL TARGETS FOR NEUROPROTECTION
Glutamate Receptors
Conventional Anesthetics
Inflammation and Cytokines
Oxidative stress
GLUTAMATE RECEPTOR
MK-801, a potent non competitive NMDA-R antagonist led to massive
cell death by apoptosis
Topiramate, blocks AMPA and kainate Receptors. Currently used as well
tolerated antiepileptic drug.
Conventional anticonvulsants (Phenytoin, Phenobarbital, Diazepam,
Clonazepam, Vigabatrin and Valproate) cause apoptotic
neurodegeneration
Magnesium Sulfate
Others ; Riluzole, Amantadine, Memantine
Conventional Anesthetics
NMDA-R blockers: nitrous oxide, ketamine, opioid analgesic

Gama-amnibutyric acidergic transmission enhancer : injectables and
volatile anethetics
Xenon
Inflammation and Cytokines
Tianapectine
IL-10, a Th2 antiinflammatory cytokine.
Enbrel (recombinant human soluble-receptor fusion protein etanercept)
Chloroquine alone or with Colchicines
Tetracycline
Minocycline
NSAID (Indomethacin, Ibuprofen), Cox-2 inhibitor (Nimesulide), Steroids
Oxidative Stress
Allopurinol
Reduce exposure to pro-oxidative agents, (O2 and Iron).
Erythropoietin (Epo)
Prevention of Delayed Neuronal Cell Death
Hypotermia (target body temperature, mode of hypotermia

induction, duration and rate of rewarming)
Growth Factors: IGF-1, BDNF= Brain Derived Neurotrophic factor, have
antiapoptotic properties.
NEP (neutral endopeptidase) or Neprilysin
Tiorfan (NEP inhibitor racecadotril)
Epo
PLASTICITY AND REPAIR
Melatonin (agomelatine, Valdoxan, amelteon, Rozerem)
Ampakines (positive allosteric modulators of AMPA receptors)
Stem cells (multipotent embryonic stem cells, and neural stem cells)
Vaccins and gene therapy are now fit in with the concepts of
personalized approach in the era of Personalized Medicine
Effect of Magnesiaum Sulfate given for Neuroprotection
before Preterm Birth
A Randomized Controlled Trial
Caroline A. Crowther
Janet E. Hiller
Lex W. Doyle
Ross R. Haslam
JAMA 2003 ; 290: 2669-76.

RECOMMENDATIONS
( J Obstet Gynaecol Can 2011;33(5):516-529 )
Volume 42, Issue 1 (Jan 2014)
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Influence of antenatal magnesium sulfate application on cord blood

levels of brain-derived neurotrophic factor in premature infants
Muhammad Adrianes Bachnas3 / Johanes Cornelius Mose1 / Jusuf Sulaeman Effendi1 / Wiku Andonotopo2
Fetomaternal Division, Department of Obstetrics and Gynecology, Medical Faculty of Padjadjaran University, Hasan
Sadikin Hospital, Bandung, Indonesia
Fetomaternal Division, Department of Obstetrics and Gynecology, Medical Faculty of Indonesia University, Tangerang
General District Hospital, Banten, Indonesia
Fetomaternal Division, Department of Obstetrics and Gynecology, Medical Faculty of Sebelas Maret University,
Moewardi Hospital, Solo, Surakarta, Indonesia
Corresponding author: Muhammad Adrianes Bachnas, MD, Fetomaternal Division, Department of Obstetrics and
Gynecology, Medical Faculty of Sebelas Maret University, Moewardi Hospital, Solo, Surakarta, Indonesia, Tel.:
+628122692928, E-mail: (email)
Citation Information: Journal of Perinatal Medicine. Volume 42, Issue 1, Pages 129134, ISSN (Online) 1619-3997,
ISSN (Print) 0300-5577, DOI: https://doi.org/10.1515/jpm-2013-0137, September 2013
Publication History
Received: 2013-06-13
Accepted: 2013-08-14
Published Online: 2013-09-24
Abstract
Aim: To investigate the influence of antenatal magnesium sulfate (MgSO4) application on cord blood brain-derived
neurotrophic factor (BDNF) levels the first-line neuroprotection for preventing cerebral palsy in prematurely born
infants.
Subjects and methods: A randomized controlled trial was conducted by observing 72 pregnant women who were
divided into three groups: group I (preterm pregnancy with MgSO4), group II (preterm pregnancy without MgSO4), and
group III (full-term pregnancy as control group). Groups I and II were selected by block permutation randomization on
subjects. Inclusion criteria consisted of preterm pregnancy at 34 weeks of gestation or less who were in labor or having
planned terminations and receiving antenatal corticosteroids. Exclusion criteria consisted of previous complications
caused by MgSO4, previous history of antenatal MgSO4 application in the current pregnancy infant was born before 4 h
administration of MgSO4 or unborn more than 72 h after maximum course of antenatal MgSO4 of 24 h, prolonged
antenatal MgSO4 treatment (>24 h), refusal to participate, and emergent adverse events during the study. Group I was
given intravenous MgSO4; initial dose was 4 g, which was maintained at 1 g/h up to maximum of 24 h. Meanwhile,
groups II and III were not given any special treatment. BDNF was examined by ELISA by taking 5 mL cord blood sample
shortly after birth. The result was statistically measured by ANOVA.
Volume 42, Issue 1 (Jan 2014)
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Influence of antenatal magnesium sulfate application on cord blood

levels of brain-derived neurotrophic factor in premature infants
Muhammad Adrianes Bachnas3 / Johanes Cornelius Mose1 / Jusuf Sulaeman Effendi1 / Wiku Andonotopo2
Fetomaternal Division, Department of Obstetrics and Gynecology, Medical Faculty of Padjadjaran University, Hasan
Sadikin Hospital, Bandung, Indonesia
Fetomaternal Division, Department of Obstetrics and Gynecology, Medical Faculty of Indonesia University, Tangerang
General District Hospital, Banten, Indonesia
Fetomaternal Division, Department of Obstetrics and Gynecology, Medical Faculty of Sebelas Maret University,
Moewardi Hospital, Solo, Surakarta, Indonesia
Corresponding author: Muhammad Adrianes Bachnas, MD, Fetomaternal Division, Department of Obstetrics and
Gynecology, Medical Faculty of Sebelas Maret University, Moewardi Hospital, Solo, Surakarta, Indonesia, Tel.:
+628122692928, E-mail: (email)
Citation Information: Journal of Perinatal Medicine. Volume 42, Issue 1, Pages 129134, ISSN (Online) 1619-3997,
ISSN (Print) 0300-5577, DOI: https://doi.org/10.1515/jpm-2013-0137, September 2013
Publication History
Received: 2013-06-13
Accepted: 2013-08-14
Published Online: 2013-09-24
Abstract
Aim: To investigate the influence of antenatal magnesium sulfate (MgSO4) application on cord blood brain-derived
neurotrophic factor (BDNF) levels the first-line neuroprotection for preventing cerebral palsy in prematurely born
infants.
Conclusion : Subjects and methods: A randomized controlled trial was conducted by observing 72 pregnant women who were
divided into three groups: group I (preterm pregnancy with MgSO4), group II (preterm pregnancy without MgSO4), and
group III (full-term pregnancy as control group). Groups I and II were selected by block permutation randomization on
subjects. Inclusion criteria consisted of preterm pregnancy at 34 weeks of gestation or less who were in labor or having
The application of antenatal MgSO4 in preterm delivery increased cord blood BDNF levels, which could
planned terminations and receiving antenatal corticosteroids. Exclusion criteria consisted of previous complications
caused by MgSO4, previous history of antenatal MgSO4 application in the current pregnancy infant was born before 4 h
have a potential role on fetal neuroprotection. Futher investigation is needed.
administration of MgSO4 or unborn more than 72 h after maximum course of antenatal MgSO4 of 24 h, prolonged
antenatal MgSO4 treatment (>24 h), refusal to participate, and emergent adverse events during the study. Group I was
given intravenous MgSO4; initial dose was 4 g, which was maintained at 1 g/h up to maximum of 24 h. Meanwhile,
groups II and III were not given any special treatment. BDNF was examined by ELISA by taking 5 mL cord blood sample
shortly after birth. The result was statistically measured by ANOVA.
Magnesium sulphate for women at risk of preterm birth for
neuroprotection of the fetus (Review)
D oyle LW, Crowther CA, M iddleton P, M arret S, Rouse D
T hisisa reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in TheCochraneLi brary
2010, I ssue 1
http:/ / www.thecochranelibrary.com
Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review)
Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[I ntervention Review]

neuroprotection of the fetus
Lex W Doyle1 , Caroline A Crowther2, Philippa M iddleton2 , Stephane M arret 3 , D wight Rouse4
1
D epartment of Obstetrics and Gynaecology, University of M elbourne, Parkville, Australia. 2 ARCH : Australian Research Centre for
H ealth of Women and Babies, D iscipline of Obstetricsand Gynaecology, T heUniversity of Adelaide, Adelaide, Australia. 3 D epartment
of N eonatal M edicine, University H ospital, Rouen, Rouen cedex, France. 4 Center for Womens Reproductive H ealth, T he University
of Alabama, Birmingham, Alabama, USA
Contact address: Lex W Doyle, D epartment of Obstetrics and Gynaecology, University of M elbourne, The Royal Womens H ospital,
Locked Bag 300, 20 Flemington Rd, Parkville, Victoria, 3052, Australia. lwd@unimelb.edu.au.
Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: Edited (no change to concl usions), published in Issue 1, 2010.
Review content assessed as up-to-date: 5 N ovember 2008.
Citation: D oyle LW, Crowther CA, M iddleton P , M arret S, Rouse D . M agnesium sulphate for women at risk of preterm
birth for neuroprotection of the fetus. Cochrane Database of Systemati c Revi ews 2009, I ssue 1. Art. No.: CD004661. D OI :
10.1002/ 14651858.CD 004661.pub3.
Copyright 2010 T he Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Epidemiological and basic science evidence suggests that magnesium sulphate before birth may be neuroprotective for the fetus.
Objectives
To assess the effects of magnesium sulphate as a neuroprotective agent when given to women considered at risk of preterm birth.
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (31 August 2008).
Selection criteria
Randomised controlled trialsof antenatal magnesium sulphatetherapy in women threatening or likely to givebirth at lessthan 37 weeks
gestational age. For one subgroup analysis, studies were broadly categorised by the primary intent of the study into neuroprotective
intent , or other intent (maternal neuroprotective - pre-eclampsia) , or other intent (tocolytic) .
D ata collection and analysis
At least two authors assessed trial eligibility and quality, and extracted data.
M ain results
Five trials (6145 babies) were eligible for this review. Antenatal magnesium sulphate therapy given to women at risk of preterm birth
substantially reduced the risk of cerebral palsy in their child (relative risk (RR) 0.68; 95% Condence interval (CI ) 0.54 to 0.87; ve
trials; 6145 infants). There was also a signicant reduction in the rate of substantial gross motor dysfunction (RR 0.61; 95% CI 0.44
to 0.85; four trials; 5980 infants). No statistically signicant effect of antenatal magnesium sulphate therapy was detected on paediatric
mortality (RR 1.04; 95% CI 0.92 to 1.17; ve trials; 6145 infants), or on other neurological impairments or disabilities in the rst few
yearsof life. Overall therewereno signicant effectsof antenatal magnesium therapy on combined ratesof mortality with cerebral palsy,
Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus (Review) 1

neuroprotection of the fetus
Lex W Doyle1 , Caroline A Crowther2, Philippa M iddleton2 , Stephane M arret 3 , D wight Rouse4
1
D epartment of Obstetrics and Gynaecology, University of M elbourne, Parkville, Australia. 2 ARCH : Australian Research Centre for
H ealth of Women and Babies, D isci pline of Obstetricsand Gynaecology, T he University of Adelaide, Adelaide, Australia. 3 D epartment
of N eonatal M edicine, University H ospital, Rouen, Rouen cedex, France. 4 Center for Womens Reproductive H ealth, T he University
of Alabama, Birmingham, Alabama, USA
Contact address: Lex W Doyle, D epartment of Obstetrics and Gynaecology, University of M elbourne, The Royal Womens H ospital,
Locked Bag 300, 20 Flemington Rd, Parkville, Victoria, 3052, Australia. lwd@unimelb.edu.au.

Publication status and date: Edited (no change to concl usions), published in Issue 1, 2010.
Review content assessed as up-to-date: 5 N ovember 2008.
Citation: D oyle LW, Crowther CA, M iddleton P , M arret S, Rouse D . M agnesium sulphate for women at risk of preterm
birth for neuroprotection of the fetus. Cochrane Database of Systemati c Revi ews 2009, I ssue 1. Art. No.: CD 004661. D OI :
10.1002/ 14651858.CD 004661.pub3.
Authors conclusions : A B S T R A C T
Background
Epidemiological and basic science evidence suggests that magnesium sulphate before birth may be neuroprotective for the fetus.
The neuroprotective role for antenatal magnesium sulfate therapy given to women at risk of preterm birth
Objectives
To assess the effects of magnesium sulphate as a neuroprotective agent when given to women considered at risk of preterm birth.
for preterm fetus is now established. The number of women needed to be treated to benefit one baby by
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trials Register (31 August 2008).
avoiding cerebral palsy is 63 (95% CI 43 to 155). Given the beneficial effects of magnesium sulfate on
Selection criteria
Randomised controlled trialsof antenatal magnesium sulphatetherapy in women threatening or likely to givebirth at lessthan 37 weeks
substantial gross motor function in early childhood, outcome later in childhood should be evaluated to
gestational age. For one subgroup analysis, studies were broadly categorised by the primary intent of the study into neuroprotective
intent , or other intent (maternal neuroprotective - pre-ecl ampsia) , or other intent (tocolytic) .
determine the presence of later potentially neurological effects, particularly on motor or cognitive
At least two authors assessed trial eligibility and quality, and extracted data.
function.
M ain results
Five trials (6145 babies) were eligible for this review. Antenatal magnesium sulphate therapy given to women at risk of preterm birth
substantially reduced the risk of cerebral palsy in their child (relative risk (RR) 0.68; 95% Condence interval (CI ) 0.54 to 0.87; ve
trials; 6145 infants). There was also a signicant reduction in the rate of substantial gross motor dysfunction (RR 0.61; 95% CI 0.44
to 0.85; four trials; 5980 infants). No statistically signicant effect of antenatal magnesium sulphate therapy was detected on paediatric
mortality (RR 1.04; 95% CI 0.92 to 1.17; ve trials; 6145 infants), or on other neurological impairments or disabilities in the rst few
yearsof life. Overall therewereno signicant effectsof antenatal magnesium therapy on combined ratesof mortality with cerebral palsy,
Analysis 1.4. Comparison 1 Magnesium versus no magnesium, Outcome 4 Cerebral palsy.
Review: Magnesium sulphate for women at risk of preterm bir th for neuroprotection of the fetus
Comparison: 1 Magnesium versus no magnesium
Outcome: 4 Cerebral palsy
Study or subgroup Magnesium N o magnesium Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 N europrotective intent: any CP

Crowther 2003 36/629 42/626 29.0 % 0.85 [ 0.55, 1.31 ]
Marret 2006 22/352 30/336 21.1 % 0.70 [ 0.41, 1.19 ]
Mittendorf 2002 3/30 0/29 0.3 % 6.77 [ 0.37, 125.65 ]
Rouse 2008 41/1188 74/1256 49.5 % 0.59 [ 0.40, 0.85 ]
Subtotal (95% CI ) 2199 2247 100.0 % 0.71 [ 0.55, 0.91 ]

Total events: 102 (Magnesium), 146 (N o magnesium)
Heterogeneity: Chi2 = 4.01, df = 3 (P = 0.26); I2 = 25%
Test for overall effect: Z = 2.74 (P = 0.0061)
2 N europrotective intent: mild CP
Crowther 2003 21/629 21/626 28.7 % 1.00 [ 0.55, 1.80 ]
Marret 2006 12/352 17/336 23.7 % 0.67 [ 0.33, 1.39 ]
Rouse 2008 21/1188 36/1256 47.7 % 0.62 [ 0.36, 1.05 ]
Subtotal (95% CI ) 2169 2218 100.0 % 0.74 [ 0.52, 1.04 ]

Heterogeneity: Chi2 = 1.47, df = 2 (P = 0.48); I2 = 0.0%
3 N europrotective intent: moderate CP
Crowther 2003 12/629 15/626 71.0 % 0.80 [ 0.38, 1.69 ]
Marret 2006 2/352 6/336 29.0 % 0.32 [ 0.06, 1.57 ]
Subtotal (95% CI ) 981 962 100.0 % 0.66 [ 0.34, 1.28 ]

4 N europrotective intent: moderate/severe CP
Crowther 2003 15/629 21/626 29.5 % 0.71 [ 0.37, 1.37 ]
Marret 2006 10/352 13/336 18.7 % 0.73 [ 0.33, 1.65 ]
Rouse 2008 20/1188 38/1256 51.8 % 0.56 [ 0.33, 0.95 ]
Subtotal (95% CI ) 2169 2218 100.0 % 0.64 [ 0.44, 0.92 ]

Heterogeneity: Chi2 = 0.47, df = 2 (P = 0.79); I2 = 0.0%
0.001 0.01 0.1 1 10 100 1000

Favours magnesium Favour s no magnesium
(Continued . . . )
(. . . Continued)
St udy or subgroup Magnesium N o magnesium Risk Ratio Weight Risk Ratio
5 N europrotective intent: severe CP
Crowther 2003 3/629 6/626 45.6 % 0.50 [ 0.13, 1.98 ]
Marret 2006 8/352 7/336 54.4 % 1.09 [ 0.40, 2.98 ]
Subtotal (95% CI ) 981 962 100.0 % 0.82 [ 0.37, 1.82 ]

Het erogeneit y: Chi2 = 0.81, df = 1 (P = 0.37); I2 = 0.0%
6 O ther intent: maternal neuroprotective (pre-eclampsia)
Magpie 2006 2/798 5/795 100.0 % 0.40 [ 0.08, 2.05 ]
Subtotal (95% CI ) 798 795 100.0 % 0.40 [ 0.08, 2.05 ]

Het erogeneit y: not applicable
7 O ther intent: tocolytic
Mittendorf 2002 0/55 3/51 100.0 % 0.13 [ 0.01, 2.51 ]
Subtotal (95% CI ) 55 51 100.0 % 0.13 [ 0.01, 2.51 ]

8 Any CP: any intent
Crowther 2003 36/629 42/626 27.5 % 0.85 [ 0.55, 1.31 ]
Magpie 2006 2/798 5/795 3.3 % 0.40 [ 0.08, 2.05 ]
Marret 2006 22/352 30/336 20.1 % 0.70 [ 0.41, 1.19 ]
Mittendorf 2002 3/85 3/80 2.0 % 0.94 [ 0.20, 4.53 ]
Rouse 2008 41/1188 74/1256 47.1 % 0.59 [ 0.40, 0.85 ]
Subtotal (95% CI ) 3052 3093 100.0 % 0.68 [ 0.54, 0.87 ]

0.001 0.01 0.1 1 10 100 1000

Favour s magnesium Favour s no magnesium
Analysis 1.6. Comparison 1 Magnesium versus no magnesium, Outcome 6 Substantial gross motor
dysfunction.
Comparison: 1 Magnesium versus no magnesium
O utcome: 6 Substantial gross motor dysfunction
Study or subgroup Magnesium N o magnesium Risk Ratio Weight Risk Ratio

1 N europrotective intent
Crowther 2003 18/629 34/626 36.2 % 0.53 [ 0.30, 0.92 ]
Marret 2006 18/352 22/336 23.9 % 0.78 [ 0.43, 1.43 ]
Rouse 2008 20/1188 38/1256 39.3 % 0.56 [ 0.33, 0.95 ]
Subtotal (95% CI ) 2169 2218 99.5 % 0.60 [ 0.43, 0.83 ]

2 O ther intent: maternal neuroprotective - pre-eclampsia)
Magpie 2006 1/798 0/795 0.5 % 2.99 [ 0.12, 73.26 ]
Subtotal (95% CI ) 798 795 0.5 % 2.99 [ 0.12, 73.26 ]

Total (95% CI ) 2967 3013 100.0 % 0.61 [ 0.44, 0.85 ]
0.01 0.1 1 10 100

Favour s magnesium Favour s no magnesium
Analysis 2.2. Comparison 2 Studies with lowest risk of bias only, Outcome 2 Cerebral palsy.
Comparison: 2 Studies with lowest risk of bias only
Outcome: 2 Cerebral palsy
Study or subgroup Magnesium No magnesium Risk Ratio Weight Risk Ratio

Crowther 2003 36/629 42/626 36.9 % 0.85 [ 0.55, 1.31 ]
Rouse 2008 41/1188 74/1256 63.1 % 0.59 [ 0.40, 0.85 ]
Total (95% CI ) 1817 1882 100.0 % 0.68 [ 0.52, 0.91 ]

Total events: 77 (Magnesium), 116 (No magnesium)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Favours magnesium Favours no magnesium
Analysis 2.3. Comparison 2 Studies with lowest risk of bias only, Outcome 3 Neurological impairment.
Published in final edited form as:
Am J Obstet Gynecol. 2009 June ; 200(6): 595609. doi:10.1016/j.ajog.2009.04.005.
ANTENATAL MAGNESIUM SULFATE FOR THE PREVENTION OF CEREBRAL PALSY IN PRETERM INFANTS <34 WEEKS GESTATION: A
SYSTEMATIC REVIEW AND META-ANALYSIS
Agustin Conde-Agudelo, MD, MPHa and Roberto Romero, MDa,b

aPerinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and
Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD and Detroit, MI.
bCenter for Molecular Medicine and Genetics, Wayne State University, Detroit, MI.
Abstract
We conducted a systematic review and meta-analysis of randomized controlled trials to determine whether magnesium sulfate administered
to women at risk of preterm delivery before 34 weeks of gestation may reduce the risk of cerebral palsy in their children. Six trials involving
4796 women and 5357 infants were included. Antenatal magnesium sulfate was associated with a significant reduction in the risk of cerebral
palsy (relative risk [RR], 0.69; 95% confidence interval [CI], 0.550.88]), moderate or severe cerebral palsy (RR, 0.64; 95% CI, 0.440.92), and
substantial gross motor dysfunction (RR, 0.60; 95% CI, 0.430.83). There was no overall difference in the risk of total pediatric mortality
(RR, 1.01; 95% CI, 0.891.14). Minor side effects were more frequent among women receiving magnesium sulfate. In conclusion, magnesium
sulfate administered to women at risk of delivery before 34 weeks of gestation reduces the risk of cerebral palsy.
Keywords
Magnesium sulfate; cerebral palsy; pediatric mortality; meta-analysis; systematic review; prematurity; preterm birth; neurologic handicap;
infant development; preterm birth
Cochrane Dat abase of Syst emat ic Reviews
Magnesium sulphate for women at term for neuroprotection

of the fetus (Review)
Nguyen TMN, Crowther CA, Wilkinson D, Bain E
Nguyen TMN, Crowt her CA, Wilkinson D, Bain E.

Magnesium sulphat e for women at t erm for neuroprot ect ion of t he fet us.
Cochrane Database of Systemat ic Reviews 2013, Issue 2. Art . No.: CD009395.
DOI: 10.1002/ 14651858.CD009395.pub2.
www.cochranelibrary.com
Magnesium sul phat e for women at t erm for neuroprot ect ion of t he fet us (Review)
Copyright 2013 The Cochrane Collaborat ion. Published by John Wiley & Sons, Ltd.
Magnesium sulphate for women at term for neuroprotection

of the fetus
Thuy-M y N N guyen1 , Caroline A Crowther1 , Dominic Wilkinson2 , Emily Bain3
1
ARCH : Australian Research Centre for H ealth of Women and Babies, Disci pline of Obstetrics and Gynaecology, The University of
Adelaide, Adelaide, Australia. 2Disci plineof Obstetricsand Gynecology, Womensand ChildrensH ospital, University of Adelaide, North
Adelaide, Australia. 3 ARCH : Australian Research Centre for H ealth of Women and Babies, D isci pline of Obstetrics and Gynaecology,
The University of Adelaide, Adelaide, Australia
Contact address: Caroline A Crowther, ARCH : Australian Research Centre for H ealth of Women and Babies, D isci pline of Obstetrics
and Gynaecology, T he University of Adelaide, Womens and Childrens H ospital, 72 King William Road, Adelaide, South Australia,
5006, Australia. caroline.crowther@adelaide.edu.au.

Publication status and date: New, published in Issue 2, 2013.
Review content assessed as up-to-date: 10 D ecember 2012.
Citation: N guyen T M N , Crowther CA, Wilkinson D , Bain E. M agnesium sulphate for women at term for neuroprotection of the
fetus. CochraneDatabase of Systemati c Revi ews2013, Issue 2. Art. No.: CD 009395. D OI : 10.1002/ 14651858.CD 009395.pub2.
A B S T R A C T
Background
M agnesium sulphate is extensively used in obstetrics for the treatment and prevention of ecl ampsia. A recent meta-analysis has shown
that magnesium sulphate isan effectivefetal neuroprotectiveagent when given antenatally to women at risk of very preterm birth. Term
infants account for more than half of all cases of cerebral palsy, and the inci dence has remained fairly constant. It is important to assess
if antenatal administration of magnesium sulphate to women at term protects the fetus from brain injury, and associated neurosensory
disabilities including cerebral palsy.
Objectives
To assess the effectiveness of magnesium sulphate given to women at term as a neuroprotective agent for the fetus.
Search methods
We searched the Cochrane Pregnancy and Childbirth Groups Trial Register (31 July 2012) and the reference lists of other Cochrane
reviews assessing magnesium sulphate in pregnancy.
Selection criteria
Randomised controlled trials comparing antenatally administered magnesium sulphate to women at term with placebo, no treatment
or a different fetal neuroprotective agent. We also planned to include cl uster-randomised trials, and exclude cross-over trials and quasi-
randomised trials. We planned to exclude studies reported as abstracts only.
Two review authors independently assessed trials for eligibility and for risk of bias. Two authors independently extracted data. D ata
were checked for accuracy.
Magnesi um sul phat e f or w omen at t erm for neuroprot ect ion of t he f et us (Review)
Copyright 2013 The Cochrane Collaborat ion. Published by John Wil ey & Sons, Lt d.
M ain results
Weincluded one trial (involving 135 women with mild pre-ecl ampsiaat term). An additional six studiesareawaiting further assessment.
T he included trial compared magnesium sulphate with a placebo and was at a low risk of bias. T he trial did not report any of this
reviews prespeci ed primary outcomes. T here was no signicant difference between magnesium sulphate and placebo in Apgar score
less than seven at ve minutes (risk ratio (RR) 0.51; 95% condence interval (CI ) 0.05 to 5.46; 135 infants), nor gestational age at
birth (mean difference (M D ) -0.20 weeks; 95% CI -0.62 to 0.22; 135 infants).
T here were signicantly more maternal side effect s (feeling warm and ushed) in the magnesium sulphate group than in the placebo
group (RR 3.81; 95% CI 2.22 to 6.53; 135 women). H owever, no signicant difference in adverse effects severe enough to cease
treatment was observed (RR 3.04; 95% CI 0.13 to 73.42; 135 women). T here were no signicant differences seen between groups in
the rates of postpartum haemorrhage (RR 4.06; 95% CI 0.47 to 35.38; 135 women) and caesarean sect ion (RR 0.80; 95% CI 0.39 to
1.63; 135 women).
Authors conclusions
T here is currently insufcient evidence to assess the efcacy and safety of magnesium sulphate when administered to women for
neuroprotect ion of the term fetus. As there has been recent evidence for the use of magnesium sulphate for neuroprotect ion of the
preterm fetus, high-quality randomised controlled trials are needed to determine the safety prole and neurological outcomes for the
term fetus. Strategies to reduce maternal side effect s during treatment also require evaluati on.
P L A I N L A N G U A G E S U M M A R Y
M agnesium sulphate for women at term for neuroprotection of the term fetus
Babiesborn to motherswho experiencecomplicationsduring pregnancy such aspreterm birth (early birth before37 weeksof pregnancy)
and intrauterine infect ion (infections in the uterus) have a higher risk of a movement disorder called cerebral palsy. Cerebral pal sy is a
broad term used to describe a non-progressive physical disorder of movement or posture that is acquired in early life, and that results
from complications in brain development. It may also be associ ated with intellect ual disabilities, behavioural disorders, sensory defect s
(blindness and deafness) and seizures.
Another Cochrane review found that magnesium sulphate given to mothers before preterm birth could protect the babys brain and
improve long-term outcomes into childhood. T his review aimed to assess whether magnesium sulphate given to mothers before term
birth (birth at 37 weeks of pregnancy or later) could also protect the babys brain and improve long-term outcomes.
T his review included one randomised controlled study involving 135 women with mild pre-ecl ampsia (high blood pressure and/ or
protein in the urine). T here was not enough evidence from this study to determine the effect s of magnesium sulphate on babies born
at term. Women receiving magnesium sulphate were more likely to feel warm and ushed in this study than women who received a
placebo, but they were not more likely to stop treatment due to side effects. T he rates of haemorrhage after birth and rates of caesarean
birth were similar for women who received magnesium sulphate and those who received a placebo.
M ore studies are needed to establish whether magnesium sulphate given to the mother at term is protect ive for the babys brain. T he
babies in these trials should be followed up over a long period so that we can monitor the effect s of magnesium on child development.
We are awaiting further information from another six studies so that they can be assessed.
Magnesi um sul phat e for women at t erm for neuroprot ect ion of t he fet us (Review )
Copyright 2013 The Cochrane Collaborat ion. Publ ished by John Wiley & Sons, Lt d.
WHO recommendations
on interventions to improve
preterm birth outcome
2015

Premature Brain Protection

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Neurological and developmental outcome in extremely preterm children born in England in

The study demonstrate

Extreme Very Late Term

OF EXTREME PRETERM NEONATE

Carrie K. Sem Fetal and Neonatal Medicine,2012 2012,

Infants between 34 and 35

Loftin RW Rev Obstet Gynecol. 2010

More frequent admission to NICU

Inappropriate neuro-developmental achievement

Increased medical-legal litigation

32.3% (872/2693) were iatrogenic:

Gyamfi-Bannerman C. Non spontaneous late preterm birth: etiology and

Mc Gowan JE et al. Early Childood Development of late Preterm infants : A systematic

Seminars in Fetal and Neonatal Medicine 2012

5 RCTs (in 4 neuroprevention was primary aim)

No effects on mortality or on other neurological impairments or

Doyle LW, Current Opinion in Pediatrics 2012;24:154-159

To prevent one case of moderate/severe CP:

Maternal side effects:

*Guidelines Australian & Canadian COG

( NMDA-R : N-methyl-D-aspartate-Receptor ; AMPA : alpha-3-Amino-Hydroxy-5-Methyl-4

A neuroprotectant is generally defined as an agent that

( Messick JM, Middle LM. Brain protection. Advances in anethesiology

NMDA-R blockers: nitrous oxide, ketamine, opioid analgesic

Hypotermia (target body temperature, mode of hypotermia

A Randomized Controlled Trial

JAMA 2003 ; 290: 2669-76.

30,00 / $42.00 / 23.00 GET ACCESS TO FULL TEXT

Influence of antenatal magnesium sulfate application on cord blood

30,00 / $42.00 / 23.00 GET ACCESS TO FULL TEXT

Influence of antenatal magnesium sulfate application on cord blood

D oyle LW, Crowther CA, M iddleton P, M arret S, Rouse D

Magnesium sulphate for women at risk of preterm birth for

Editorial group: Cochrane Pregnancy and Childbirth Group.

Magnesium sulphate for women at risk of preterm birth for

Editorial group: Cochrane Pregnancy and Childbirth Group.

Comparison: 1 Magnesium versus no magnesium

Outcome: 4 Cerebral palsy

Study or subgroup Magnesium N o magnesium Risk Ratio Weight Risk Ratio

1 N europrotective intent: any CP

Marret 2006 22/352 30/336 21.1 % 0.70 [ 0.41, 1.19 ]

Mittendorf 2002 3/30 0/29 0.3 % 6.77 [ 0.37, 125.65 ]

Rouse 2008 41/1188 74/1256 49.5 % 0.59 [ 0.40, 0.85 ]

Subtotal (95% CI ) 2199 2247 100.0 % 0.71 [ 0.55, 0.91 ]

Marret 2006 12/352 17/336 23.7 % 0.67 [ 0.33, 1.39 ]

Rouse 2008 21/1188 36/1256 47.7 % 0.62 [ 0.36, 1.05 ]

Subtotal (95% CI ) 2169 2218 100.0 % 0.74 [ 0.52, 1.04 ]

Marret 2006 2/352 6/336 29.0 % 0.32 [ 0.06, 1.57 ]

Subtotal (95% CI ) 981 962 100.0 % 0.66 [ 0.34, 1.28 ]

Marret 2006 10/352 13/336 18.7 % 0.73 [ 0.33, 1.65 ]

Rouse 2008 20/1188 38/1256 51.8 % 0.56 [ 0.33, 0.95 ]

Subtotal (95% CI ) 2169 2218 100.0 % 0.64 [ 0.44, 0.92 ]

0.001 0.01 0.1 1 10 100 1000

Marret 2006 8/352 7/336 54.4 % 1.09 [ 0.40, 2.98 ]

Subtotal (95% CI ) 981 962 100.0 % 0.82 [ 0.37, 1.82 ]

Subtotal (95% CI ) 798 795 100.0 % 0.40 [ 0.08, 2.05 ]

Subtotal (95% CI ) 55 51 100.0 % 0.13 [ 0.01, 2.51 ]

Magpie 2006 2/798 5/795 3.3 % 0.40 [ 0.08, 2.05 ]

Marret 2006 22/352 30/336 20.1 % 0.70 [ 0.41, 1.19 ]

Mittendorf 2002 3/85 3/80 2.0 % 0.94 [ 0.20, 4.53 ]

Rouse 2008 41/1188 74/1256 47.1 % 0.59 [ 0.40, 0.85 ]

Subtotal (95% CI ) 3052 3093 100.0 % 0.68 [ 0.54, 0.87 ]

0.001 0.01 0.1 1 10 100 1000

Comparison: 1 Magnesium versus no magnesium