Magnesium Sulphate (MgSO4)
For Fetal Neuroprotection In
Preterm Delivery
"An Evidence Based View"
ERC RCOG Second Annual International Meeting
March, 3rd -4th , 2012
Dr. Mohamed El Sherbiny
MD Ob.& Gyn. Senior Consultant
Damietta, Egypt
Sources of Evidence
• PubMed (RCT , Meta analysis & Reviews) 3-2012
• Cochrane Library till 3-2012.
• Australian National Clinical P. Guidelines 2010
• ACOG , Committee Opinion 2010
• SOGC Clinical Practice Guideline 2011
• UpToDate 19.3 , January 2012
Preterm Birth And CNS Injuries
Pathologically :2 CNS injuries :
(1) Intraventricular Hemorrhage (IVH)
Usually diagnosed by ultrasound (U/S)
(2) White Matter Injury.
Usually diagnosed by MRI
SOGC Clinical Practice Guideline No. 258, May 2011
Tran cranial U/S
I.V. Hemorrhage
MIR left lateral I.V. Hemorrhage T1 &T2
MRI T2 White Matter Injury
Preterm Birth And CNS Injuries
Clinically: The most frequent adverse
CNS outcomes are
1-Cerebral palsy (CP)
2-Cognitive impairment
3-Blindness,deafness & developmental
delay.
SOGC Clinical Practice Guideline No. 258, May 2011
The Etiology Of CP
It is multi factorial
Prematurity :42*-78 %
Intrauterine growth restriction:34%
Intrauterine infection :28%
Antepartum hemorrhage : 27%
Severe placental pathology : 21%
Multiple pregnancy : 20%
Strijbis et al. ,Obstet Gynecol. 2006;107(6):1357.
*(Australian Cerebral Palsy Register Group
2009)
Clinical Types of CP
There are 4 main types of CP:
1. Spastic (increased muscle tone)
2. Dyskinetic (slow, uncontrolled movements)
3. Ataxic (problems with balance and depth
perception)
4. Mixed
The most common pattern is spasticity plus
dyskinetic movements.
CP can be reliably diagnosed by the age of 2 years.
Center for Disease Control and Prevention (CDC).. Accessed March 3,2011.
Spastic CP
Spastic CP
Ataxic CP
Cerebral Palsy (CP)
The Magnitude Of The Problem
CP is the most common cause of severe motor
disability in childhood
CP increases inversely according to G. age:
All live births : 0.25 %
Compared with infants at term the CP risk is:
 At 34-36 weeks : 3 fold
 At 30-33 weeks : 8- 14 fold
 At 28-30 weeks : 46 fold
 At < 28 weeks : 80 Fold
SOGC Clinical Practice Guideline No. 258, May 2011
Cerebral Palsy (CP)
The Magnitude Of The Problem
The Economic Burden: Health care,
productivity, and social costs
USA: Lifetime for a person :US$ 1 billion
The community cost (year2000) : $11.5billion
US CDC, 2003. MMWR Morb Mortal Wkly Rep 2004;53:57–9.
Australia : The person cost/annum :AUD$115,000
The community / annum. : AUD$4 billion
(Access Economics 2008).
Australian National Clinical Practice Guidelines. Adelaide 2010
Cerebral Palsy (CP)
The Magnitude Of The Problem
To date, there is no known :
Cure for CP.
Effective antenatal preventive
measures
SOGC Clinical Practice Guideline No. 258, May 2011
MgSO4 Use in Obstetrics
 Eclampsia: Prophylaxis & management*
 Tocolysis :No longer recommended **
 Fetal neuroprotection in preterm delivery
: A new evidence &validation
*Altman et al,Lancet, 90-10877(9321)359;2002 Duley et al ,. Lancet 1995;345(8963):1455–63.
*Magee et al.,SOGC Clinical Practice Guideline no. 206, March 2008
** Doyle
et al Cochrane Database Syst Rev 2009;(1):CD004661
Evidence Of The Neuroprotective
Effects Of MgSO4
Observational studies
Randomized controlled trials
Meta-analyses.
Validation: Guidelines& Committee Opinion
 Australian National Clinical P. Guidelines 2010
 ACOG , Committee Opinion 2010
 SOGC Clinical Practice Guideline May 2011
1-Observational Studies
Preterm infants born to women with preeclampsia
had a lower incidence of adverse CNS outcomes
than those without preeclampsia.
Levitonetal . Obstet Gynecol 1988;72:571–6. Van de B et al . J Perinat Med 1987;15:333–9.
There was an association between antenatal
MgSO4 administration and reduction of of CP
among infants born < 1500 g.
Nelson & Grether ,Pediatrics 1995; 95:263–9. (California Cerebral Palsy project)
Randomized Controlled Trials (RCT)
From 2002 to 2008: 5 RCTs (6145 babies)
1- Mittendorf et al., Am J Obstet Gynecol
2002;186:1111–8. (+ tocolytic arm)
2-Altman , et al, Lancet 2002;359 (9321)
:1877–90. (+ preeclampsia arm)
1&2 have a neuroprotective and other arm
Randomized Controlled Trials (RCT)
From 2002 to 2008: 5 RCTs (6145 babies):
3,4,&5 were specifically for neuroprotective effect
3-ACTOMgSO4: The Australasian Collaborative
Trial of MgSO4 Group:1062 women
Crowther et al , JAMA. 2003;290(20):1062. Australia
4-BEAM : Beneficial Effects of Antenatal MgSO4 :
Multicenter 2241 women
Rouse et al , N Engl J Med. 2008;359(9):895 USA
5- PREMAG : 573 women Multicenter(15)
Reregistered as International RCT
Marett et al., Gynecol Obstet Fertil. 2008;36(3):278 (France)
The 3 large, well-done RCTs (Placebo)
Trial & No.
Inclusion Dose of
ACTOMgSO4
< 30 Ws
Crowther et al (2003)
n.:1062 Australia
BEAM
24-31 Ws
Rouse et al , N Engl J
Med. 2008;359(9):895
cost $25
million and
took 10 years
n.2241
USA
PREMAG
Marett et al., Gy. Ob.
Fertil. 2008;36(3):278
n.573 France.
<33 Ws
Significant
MgSO4
reduction of CP
4 g Loading Moderate to
then1 g/h severe CP
(3.4% Vs 6.6 % )
6 g loading Moderate to
then 2 g/h severe CP
(1.9% Vs 3.5 %)
Single 4 g
loading
Death & gross
motor dysfunction
(0.6% Vs 0.4%)
MgSO4 significantly ↓risk of CP in early preterm birth
The Mechanism Of Neuroprotective Effect






The mechanism is not well understood
potential neuroprotective actions include:
Antioxidant effects
Reduction in pro-inflammatory cytokines
Inhibition of calcium influx into cells
Stabilization of membranes
Increased cerebral blood flow
Prevention of large blood pressure fluctuations
Gathwala ,. Neuronal protection with magnesium. Indian J Pediatr 2001;68:417–9
Marret et al ., Semin Fetal Neonatal Med. 2007;12(4):311.
Hyagriv & Katherine .,UpToDate 19.3: January 2012
Meta-analyses
In 2009, a milestone was reached with
the publication of 3 meta- analyses, all
of which included the same 5 RCTs and
concluded that :
MgSO4 for fetal neuroprotection
decreases the risk of childhood CP
Doyle et al. Cochrane Database Syst Rev. 2009
Costantine et al. Obstet Gynecol. 2009;114(2 Pt 1):354.
Conde-Agudelo et al. Am J Obstet Gynecol . 609-200:595,200
The Cochrane Review :Result
I-MgSO4 significantly reduced the risk of :
 Cerebral palsy
 Substantial gross motor dysfunction
(inability to walk without assistance ) at 2
years of age
II- MgSO4 had No significant effect of on
pediatric (fetal, neonatal and later) mortality.
Doyle et al., Cochrane Database Syst Rev. 2009
Cochrane review 2009 MgSO4 Vs no MgSO4 ,
Outcome 6 Substantial gross motor dysfunction.
Doyle et al . Cochrane Database Syst Rev 2009;(1):CD004661.
The Cochrane Systematic Review concluded
that :
MgSO4 reduced the risk of cerebral palsy by 32 %
(from 5.4% to 3.7% with absolute risk reduction
of 1.7 %.)*
The number needed to treat(NNT) to benefit one
baby was 63 women. These compare favourably
with the 70 women with preeclampsia to prevent
one eclamptic fit.**
Doyle et al Cochrane Database Syst Rev. 2009 *
Sibai , Obstet Gynecol. 2005;105(2):402 **
The Cochrane Systematic Review concluded
that :
There were no significant differences observed for
the major maternal outcomes of:
 Death (RR=1.25; 95%ci=0.51-3.07)
 Cardiac arrest (RR=0.34; 95%ci=0.04-3.26)
Respiratory arrest (rr=1.02; 95%ci=0.06-16.25).
Doyle et al Cochrane Database Syst Rev. 2009
The Cochrane Systematic Review concluded
that :
Regarding secondary maternal outcomes,MgSO4
therapy was associated with significantly more:
 Hypotension (RR=1.51; 95%ci=1.09-2.09)
 Tachycardia (rr=1.53, 95%ci=1.03-2.29).
There were no differences seen in rates of :
Maternal respiratory depression
Postpartum haemorrhage
Caesarean delivery
Doyle et al Cochrane Database Syst Rev. 2009
The 3 Meta-analyses Conclusion :
Despite these favourable results, strong
Evidence is lacking with respect to 4 clinical
issues:.
1-The gestational age below which this
therapy should be offered.
2. The optimal loading and maintenance
doses.
Doyle et al Cochrane Database Syst Rev. 2009
Costantine et al Obstet Gynecol. 2009;114(2 Pt 1):354.
Doyle Obstet Gynecol. 2009;113(6):1327.
The 3 Meta-analyses Conclusion :
Strong Evidence is lacking with (cont).
3- MgSO4 has not been associated with ↓ in :
CNS pathology
Intraventricular hemorrhage
 White matter injury
Other adverse developmental outcomes
Developmental delay& neurological impairment.
Blindness
et al Cochrane Database Syst Rev. 2009
Deafness Doyle
Costantine et al Obstet Gynecol. 2009;114(2 Pt 1):354.
Doyle Obstet Gynecol. 2009;113(6):1327.
The 3 Meta-analyses Conclusion :
Strong Evidence is lacking with(cont.)
4 :There is no information on the effect of
MgSO4 on outcomes beyond 2 years :
Age on learning disabilities
 School difficulties & disabilities
Doyle et al Cochrane Database Syst Rev. 2009
Costantine et al Obstet Gynecol. 2009;114(2 Pt 1):354.
Doyle Obstet Gynecol. 2009;113(6):1327.
Validations : Clinical Practice Guidelines
And Committee Opinion
1- The Australian National Clinical Practice
Guidelines March 2010 by the Antenatal
MgSO4 for Neuroprotection Guideline
Development Panel.
2- The ACOG Committee Opinion on MgSO4 for
Fetal Neuroprotection March 2010.
3- SOGC Clinical Practice Guideline No. 258 , May
2011
1- The Australian National Clinical
Practice Guidelines March 2010.
In women at risk of early preterm imminent
Grade A
Birth(expected within 24 Hs), use MaGS4 for
neuroprotection of the fetus, infant and child:
Grade A
The gestational age : < 30 weeks
Dosage: 4g IV loading dose, over 30 minutes.
followed by a 1g/hr , maintenance infusion until
Grade C
birth.
The Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. :
National Clinical Practice Guidelines. The Australian Research Centre for Health of Women
and Babies, The University of Adelaide; 2010.
2- The ACOG Committee Opinion on
MgSO4 for March 2010.
The available evidence suggests that MgSO4 given
before anticipated early preterm birth reduces the
risk of cerebral palsy in surviving infants.
No official opinion was given on a gestational age
cut-off.
It was recommended that physicians develop
guidelines around the issues of inclusion criteria,
dosage, concurrent tocolysis, and monitoring .
American College of Obstetricians and Gynecologists ACOG Committee on Obstetric
larger
trials.
Practice; Society for Maternal-Fetal Medicine. Committee Opinion 19. No. 455:
Obstet Gynecol. 2010;115(3):669-71.
3- SOGC Clinical Practice Guideline
No. 258 , May 2011
Mgso4for Fetal Neuroprotection
Magee et al . SOGC Clinical Practice Guideline. Magnesium sulphate for fetal
neuroprotection. J Obstet 14. Gynaecol Can. 2011;33(5):516-29.
Canadian Task Force on Preventive Health Care Recommendations
SOGC Clinical Practice Guideline
Canadian Task Force on Preventive Health Care Recommendations
SOGC Clinical Practice Guideline
SOGC Guideline Recommendations
For women with imminent preterm
birth (< 32 weeks), antenatal MgSO4
administration should be considered
for fetal neuroprotection. (I-A)
SOGC Clinical Practice Guideline No. 258, May 2011
SOGC Guideline Recommendations
For women with imminent preterm birth (< 32
weeks), antenatal MgSO4 administration should
be considered for fetal neuroprotection. (I-A)
What is the Imminent Preterm Birth
One or both of the following conditions (II-2):
1-Active labour with ≥ 4 cm of cervical dilation,
with or without PPROM.
2-Planned preterm birth for fetal or maternal
indications. SOGC Clinical Practice Guideline No. 258, May 2011
What is the Imminent Preterm Birth
Imminent preterm birth” is defined as a high
likelihood of birth due to one or both of the
following conditions (II-2):
1-Active labour with ≥ 4 cm of cervical dilation,
with or without PPROM.
2-Planned preterm birth for fetal or maternal
indications.
SOGC Clinical Practice Guideline No. 258, May 2011
What Is The Cut-off Gestational Age For
MgSO4 ?
Although there is controversy about upper
G. age ,antenatal MgSO4 should be considered
from viability to < 32 weeks. (II-1B)
If antenatal MgSO4 has been started, tocolysis
should be discontinued. (III-A)
SOGC Clinical Practice Guideline No. 258, May 2011
Should MgSO4 Course Be Repeated ?
There is insufficient evidence that a repeat
course of antenatal MgSO4 should be
administered. (III-L)
Should Delivery Be Delayed To Give
MgSO4 Course?
Delivery should not be delayed if there are
maternal and/or fetal indications for
emergency delivery. (III-E)
SOGC Clinical Practice Guideline No. 258, May 2011
What Is The Recommended Dose ?
4g Mg SO4 IV loading dose, over 30
minutes, followed by a maintenance
infusion of 1g/ hours until birth or for 24
hours, whichever comes first. .(II-2B)
Mg SO4 should be started, ideally within 4
hours before birth .(II-2B)
SOGC Clinical Practice Guideline No. 258, May 2011
What Is The Recommended Dose ?
Although strong evidence supports the
use of antenatal MgSO4 for neuro-
protection prior to very preterm birth,
no trials comparing different treatment
regimens have been completed.
Bain et al. Cochrane Database SystRev. 2012 Feb 15;2:CD009302
What Is The Recommended Dose ?
Research should be directed towards
comparisons of different dosages and
other variations in regimens, evaluating
both maternal and infant outcomes.
Bain et al. Cochrane Database SystRev. 2012 Feb 15;2:CD009302
Conclusions
MgSO4 should be considered from viability to
≤ 31+6 weeks with imminent preterm birth.
The best available evidence recommended
dose is 4g IV loading dose, over 30 minutes,
followed by a maintenance infusion of 1g/ hours
until birth or for 24 hours, whichever comes first.
Thank You