بسم الله الرحمن الرحيم

1. بسم الله الرحمن الرحيم

2. 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

3. 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

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 MRI SOGC Clinical Practice Guideline No. 258, May 2011

5. Tran cranial U/S I.V. Hemorrhage MIR left lateral I.V. Hemorrhage T1 &T2 MRI T2 White Matter Injury

6. 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

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. 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.

9. Spastic CP Ataxic CP Spastic CP

10. 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

11. 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 Australia :The person cost/annum :AUD$115,000 The community / annum. : AUD$4 billion US CDC, 2003. 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 measures SOGC 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, 90-10877(9321)359;2002 Duleyet 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 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

15. 1-Observational Studies Preterm infants born to women with preeclampsia had a lower incidence of adverse CNS outcomes than those without preeclampsia. Levitonetal . ObstetGynecol 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 ObstetGynecol 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 RCT Crowther et al , JAMA. 2003;290(20):1062. Australia Rouse et al , N Engl J Med. 2008;359(9):895 USA Marett et al., GynecolObstetFertil. 2008;36(3):278 (France)

18. The 3 large, well-done RCTs (Placebo) MgSO4 significantly ↓risk of CP in early preterm birth

19. 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

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 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 ObstetGynecol . 609-200:595,200

21. 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 hadNo significant effect of on pediatric (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):CD004661.

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 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 **

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=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

25. 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

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. 2009 Costantine 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 pathology • Intraventricular hemorrhage • White matter injury • Other adverse developmental outcomes • Developmental delay& neurological impairment. • Blindness • Deafness 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.

28. 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.

29. Validations : Clinical Practice GuidelinesAnd 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

30. 1- The Australian National Clinical Practice Guidelines March 2010. In women at risk of early preterm imminent Birth(expected within 24 Hs), use MaGS4 for neuroprotection of the fetus, infant and child: • The gestational age : < 30 weeks • Dosage: 4g IV loading dose, over 30 minutes. followed by a 1g/hr , maintenance infusion until birth. Grade A Grade A Grade C 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.

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):669-71.

32. 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.

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. SOGC Guideline Recommendations What is the Imminent Preterm Birth For women with imminent preterm birth (< 32 weeks), antenatal MgSO4 administration should be considered for fetal neuroprotection. (I-A) 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

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 upper G. age ,antenatal MgSO4 should be considered from viability to < 32 weeks. (II-1B) If antenatal MgSO4has been started, tocolysis should be discontinued. (III-A) SOGC Clinical Practice Guideline No. 258, May 2011

39. 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

40. 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

41. 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

42. 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

43. 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.

44. Thank You