2 Magnesium Sulphate (MgSO4) For Fetal Neuroprotection In Preterm Delivery "An Evidence Based View" ERC RCOG Second Annual International MeetingMarch, 3rd -4th , 2012Dr. Mohamed El SherbinyMD Ob.& Gyn. Senior ConsultantDamietta, Egypt
3 Sources of Evidence PubMed (RCT , Meta analysis & Reviews) 3-2012 Cochrane Library tillAustralian National Clinical P. Guidelines 2010ACOG , Committee Opinion 2010SOGC Clinical Practice Guideline 2011UpToDate , January 2012
4 Preterm Birth And CNS Injuries Pathologically :2 CNS injuries :Intraventricular Hemorrhage (IVH)Usually diagnosed by ultrasound (U/S)White Matter Injury.Usually diagnosed by MRISOGC Clinical Practice Guideline No. 258, May 2011
5 Tran cranial U/SI.V. HemorrhageMIR left lateral I.V. Hemorrhage T1 &T2MRI T2 White Matter Injury
6 Preterm Birth And CNS Injuries Clinically: The most frequent adverseCNS outcomes are1-Cerebral palsy (CP)2-Cognitive impairment3-Blindness,deafness & developmental delay.SOGC Clinical Practice Guideline No. 258, May 2011
7 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)
8 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. MixedThe most common pattern is spasticity plusdyskinetic movements.CP can be reliably diagnosed by the age of 2 years.Center for Disease Control and Prevention (CDC).. Accessed March 3,2011.
10 Cerebral Palsy (CP) The Magnitude Of The Problem CP is the most common cause of severe motordisability in childhoodCP increases inversely according to G. age:All live births : 0.25 %Compared with infants at term the CP risk is:At weeks : 3 foldAt weeks : foldAt weeks : 46 foldAt < 28 weeks : 80 FoldSOGC Clinical Practice Guideline No. 258, May 2011
11 Cerebral Palsy (CP) The Magnitude Of The Problem The Economic Burden: Health care, productivity, and social costsUSA: Lifetime for a person :US$ 1 billionThe community cost (year2000) : $11.5billionAustralia : The person cost/annum :AUD$115,000The community / annum. : AUD$4 billionUS CDC, MMWR Morb Mortal Wkly Rep 2004;53:57–9.(Access Economics 2008).Australian National Clinical Practice Guidelines. Adelaide 2010
12 Cerebral Palsy (CP) The Magnitude Of The Problem To date, there is no known :Cure for CP.Effective antenatal preventive measuresSOGC Clinical Practice Guideline No. 258, May 2011
13 MgSO4 Use in Obstetrics Eclampsia: Prophylaxis & management* Tocolysis :No longer recommended **Fetal neuroprotection in preterm delivery : A new evidence &validation*Altman et al,Lancet, (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
14 Evidence Of The Neuroprotective Effects Of MgSO4 Observational studiesRandomized controlled trialsMeta-analyses.Validation: Guidelines& Committee OpinionAustralian National Clinical P. Guidelines 2010ACOG , Committee Opinion 2010SOGC Clinical Practice Guideline May 2011
15 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)
16 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
17 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 4-BEAM : Beneficial Effects of Antenatal MgSO4 : Multicenter 2241 women 5- PREMAG : 573 women Multicenter(15) Reregistered as International RCTCrowther et al , JAMA. 2003;290(20):1062. AustraliaRouse et al , N Engl J Med. 2008;359(9):895 USAMarett et al., Gynecol Obstet Fertil. 2008;36(3):278 (France)
18 The 3 large, well-done RCTs (Placebo) Significant reduction of CPDose of MgSO4InclusionTrial & No.Moderate to severe CP(3.4% Vs 6.6 % )4 g Loadingthen1 g/h< 30 WsACTOMgSO4Crowther et al (2003)n.:1062 Australia(1.9% Vs 3.5 %)6 g loading then 2 g/h24-31 Wscost $25 million and took 10 yearsBEAMRouse et al , N Engl J Med. 2008;359(9):895n USADeath & gross motor dysfunction (0.6% Vs 0.4%)Single 4 g loading<33 WsPREMAGMarett et al., Gy. Ob. Fertil. 2008;36(3):278n.573 France.MgSO4 significantly ↓risk of CP in early preterm birth
19 The Mechanism Of Neuroprotective Effect The mechanism is not well understoodpotential neuroprotective actions include:Antioxidant effectsReduction in pro-inflammatory cytokinesInhibition of calcium influx into cellsStabilization of membranesIncreased cerebral blood flowPrevention of large blood pressure fluctuationsGathwala ,. Neuronal protection with magnesium. Indian J Pediatr 2001;68:417–9Marret et al ., Semin Fetal Neonatal Med. 2007;12(4):311.Hyagriv & Katherine .,UpToDate 19.3: January 2012
20 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 CPDoyle et al. Cochrane Database Syst Rev. 2009Costantine et al. Obstet Gynecol. 2009;114(2 Pt 1):354.Conde-Agudelo et al. Am J Obstet Gynecol :595,200
21 The Cochrane Review :Result I-MgSO4 significantly reduced the risk of :Cerebral palsySubstantial gross motor dysfunction(inability to walk without assistance ) at 2years of ageII- MgSO4 had No significant effect of onpediatric (fetal, neonatal and later) mortality.Doyle et al., Cochrane Database Syst Rev. 2009
22 Cochrane review 2009 MgSO4 Vs no MgSO4 , Outcome 6 Substantial gross motor dysfunction. Doyle et al . Cochrane Database Syst Rev 2009;(1):CD
23 The Cochrane Systematic Review concluded that : MgSO4 reduced the risk of cerebral palsy by 32 %(from 5.4% to 3.7% with absolute risk reductionof 1.7 %.)*The number needed to treat(NNT) to benefit onebaby was 63 women. These compare favourablywith the 70 women with preeclampsia to preventone eclamptic fit.**Doyle et al Cochrane Database Syst Rev *Sibai , Obstet Gynecol. 2005;105(2):402 **
24 The Cochrane Systematic Review concluded that : There were no significant differences observed for the major maternal outcomes of:Death (RR=1.25; 95%ci= )Cardiac arrest (RR=0.34; 95%ci= )Respiratory arrest (rr=1.02; 95%ci= ).Doyle et al Cochrane Database Syst Rev. 2009
25 The Cochrane Systematic Review concluded that : Regarding secondary maternal outcomes,MgSO4 therapy was associated with significantly more:Hypotension (RR=1.51; 95%ci= )Tachycardia (rr=1.53, 95%ci= ).There were no differences seen in rates of :Maternal respiratory depressionPostpartum haemorrhageCaesarean deliveryDoyle et al Cochrane Database Syst Rev. 2009
26 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. 2009Costantine et al Obstet Gynecol. 2009;114(2 Pt 1):354.Doyle Obstet Gynecol. 2009;113(6):1327.
27 The 3 Meta-analyses Conclusion : Strong Evidence is lacking with (cont).3- MgSO4 has not been associated with ↓ in :CNS pathologyIntraventricular hemorrhageWhite matter injuryOther adverse developmental outcomesDevelopmental delay& neurological impairment.BlindnessDeafnessDoyle et al Cochrane Database Syst Rev. 2009Costantine et al Obstet Gynecol. 2009;114(2 Pt 1):354.Doyle Obstet Gynecol. 2009;113(6):1327.
28 The 3 Meta-analyses Conclusion : Strong Evidence is lacking with(cont.)4 :There is no information on the effect ofMgSO4 on outcomes beyond 2 years :Age on learning disabilitiesSchool difficulties & disabilitiesDoyle et al Cochrane Database Syst Rev. 2009Costantine et al Obstet Gynecol. 2009;114(2 Pt 1):354.Doyle Obstet Gynecol. 2009;113(6):1327.
29 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 SOGC Clinical Practice Guideline No. 258 , May 2011
30 1- The Australian National Clinical Practice Guidelines March 2010. In women at risk of early preterm imminentBirth(expected within 24 Hs), use MaGS4 forneuroprotection of the fetus, infant and child:The gestational age : < 30 weeksDosage: 4g IV loading dose, over 30 minutes.followed by a 1g/hr , maintenance infusion untilbirth.Grade AGrade AGrade CThe 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.
31 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 . larger trials.American College of Obstetricians and Gynecologists ACOG Committee on Obstetric Practice; Society for Maternal-Fetal Medicine. Committee Opinion 19. No. 455:Obstet Gynecol. 2010;115(3):
32 3- SOGC Clinical Practice Guideline No 3- SOGC Clinical Practice Guideline No. 258 , May Mgso4for Fetal NeuroprotectionMagee et al . SOGC Clinical Practice Guideline. Magnesium sulphate for fetal neuroprotection. J Obstet 14. Gynaecol Can. 2011;33(5):
33 Canadian Task Force on Preventive Health Care Recommendations SOGC Clinical Practice Guideline
34 Canadian Task Force on Preventive Health Care Recommendations SOGC Clinical Practice Guideline
35 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
36 What is the Imminent Preterm Birth SOGC Guideline RecommendationsFor women with imminent preterm birth (< 32 weeks), antenatal MgSO4 administration should be considered for fetal neuroprotection. (I-A)What is the Imminent Preterm BirthOne 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 maternalindications.SOGC Clinical Practice Guideline No. 258, May 2011
37 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
38 What Is The Cut-off Gestational Age For MgSO4 ? Although there is controversy about upperG. age ,antenatal MgSO4 should be considered from viability to < 32 weeks. (II-1B)If antenatal MgSO4 has been started, tocolysisshould be discontinued. (III-A)SOGC Clinical Practice Guideline No. 258, May 2011
39 Should MgSO4 Course Be Repeated ? There is insufficient evidence that a repeatcourse 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
40 What Is The Recommended Dose ? 4g Mg SO4 IV loading dose, over 30minutes, followed by a maintenanceinfusion of 1g/ hours until birth or for 24hours, 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
41 What Is The Recommended Dose ? Although strong evidence supports theuse 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 Feb 15;2:CD009302
42 What Is The Recommended Dose ? Research should be directed towardscomparisons of different dosages andother variations in regimens, evaluating both maternal and infant outcomes.Bain et al. Cochrane Database SystRev Feb 15;2:CD009302
43 ConclusionsMgSO4 should be considered from viability to ≤ 31+6 weeks with imminent preterm birth.The best available evidence recommendeddose is 4g IV loading dose, over 30 minutes,followed by a maintenance infusion of 1g/ hoursuntil birth or for 24 hours, whichever comes first.