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2. Is MgSO 4 a Neuroprotector in Preterm delivery? 2

3.  Labor is preterm when it occurs in a patient whose gestation is less than 37 completed weeks (less than 259 days) from the first day of last menstrual period. 3

4.  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

5. A) Pathologically :2 CNS injuries : (1) Intraventricular Hemorrhage Usually diagnosed by ultrasound (2) White Matter Injury. Usually diagnosed by MRI SOGC Clinical Practice Guideline No. 258, May 2011 5

6. MRI left lateral I.V. Hemorrhage T1 &T2 Tran cranial U/S I.V. Hemorrhage MRI T2 White Matter Injury 6

7. B ) Clinically: 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

8. CP is the most common cause of severe motor disability in childhood. PREVELENCE : 2 TO 2.5 per 1000 live births. For ALL Live birth,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 8

9. It is multi factorial Prematurity :42-78 % Intrauterine growth restriction:34% Intrauterine infection :28% Antepartum hemorrhage : 27% Severe placental pathology : 21% Multiple pregnancy : 20% 9

10. 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. 10

11. Ataxic CP Spastic CP 11

12. To date, there is no known : Cure for CP. Effective antenatal preventive measures SOGC Clinical Practice Guideline No. 258, May 2011 12

13.  Eclampsia:Prophylaxis & management  Tocolysis :No longer recommended  Fetal neuroprotection in preterm delivery : A new evidence &validation 13

14. 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 14

15. Preterm infants born to women with preeclampsia had a lower incidence of adverse CNS outcomes than those without preeclampsia. There was an association between antenatal MgSO4 administration and reduction of of CP among infants born < 1500 g. 15

16. 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 16

17. 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 17

18. 1) MgSO 4 significantly reduced the risk of :  Cerebral palsy  Substantial gross motor dysfunction (inability to walk without assistance ) at 2 years of age 2) MgSO 4 had No significant effect of on pediatric (fetal, neonatal and later) mortality. Doyle et al., Cochrane Database Syst Rev. 2009 18

19. Cochrane review 2009 MgSO 4 Vs no MgSO 4, Outcome 6 Substantial gross motor dysfunction. 19

20. The Cochrane Systematic Review concluded that : MgSO 4 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 favorably with the 70 women with preeclampsia to prevent one eclamptic fit. Doyle et al Cochrane Database Syst Rev. 2009 * 20

21. The Cochrane Systematic Review Maternal side effects : Nausea Flushing Hypotension Tachycardia,Palpitation There were no differences seen in rates of :  Maternal respiratory depression  Postpartum haemorrhage  Caesarean delivery Doyle et al Cochrane Database Syst Rev. 2009 21

22. 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 The 3 Meta-analyses Conclusion : 22

23. 3- MgSO 4 has not been associated with ↓ in : CNS pathology  Intraventricular hemorrhage  White matter injury(Cystic periventricular leucomalacia) Other adverse developmental outcomes  Developmental delay& neurological impairment.  Blindness  Deafness Doyle et al Cochrane Database Syst Rev. 2009 23

24. 4 :There is no information on the effect of MgSO 4 on outcomes beyond 2 years of age :  Age on learning disabilities  School difficulties & disabilities Doyle et al Cochrane Database Syst Rev. 2009 24

25. In women at risk of early preterm imminent Birth(expected within 24 Hs), use MgSO 4 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. 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. 25

26. The available evidence suggests that MgSO 4 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: 26

27. 1)For women with imminent preterm birth (< 32 weeks), antenatal MgSO 4 administration should be considered for fetal neuroprotection. (I-A) 2) Antenatal MgSO 4 should be considered from viability to < 32 weeks. (II-1B) (still controversial) 3) If antenatal MgSO 4 has been started, tocolysis should be discontinued. (III-A) SOGC Clinical Practice Guideline No. 258, May 2011 SOGC Guideline Recommendations 27

28. 4) MgSO 4 should be discontinued if delivery is no longer imminent or maximum of 24 hours therapy has been administered (II-2B) 5) RECOMMENDED DOSE :4g MgSO 4 IV loading dose, over 30 minutes, followed by a maintenance infusion of 1g/ hours until birth or for 24hours, whichever comes first..(II-2B) 6) Mg SO 4 should be started, ideally within 4 hours before birth.(II-2B) 28

29. 7) No sufficient evidence is available for repeat administration of antenatal MgSO 4. (III-L) 8) Delivery should not be delayed if there are maternal and/or fetal indications for emergency delivery. (III-E) 9)When MgSO 4 is given for fetal neuroprotection, maternal care providers should use existing protocols to monitor women who are receiving MgSO 4 for preeclampsia/eclampsia. (III –A) 10) Fetal Heart Rate should be monitored. 29

30. 11) MgSO 4 has potential to alter neonate’s neurological evaluation, causing hypotonia or apnea, so health care providers caring for neonate should have increased awareness of this effect. (III-C) 30

31. 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 31

32. INCLUSION CRITERIAEXCLUSION CRITERIA Singleton and multiple pregnancies Nulliparous and parous Anticipated vaginal or caesarean delivery Any reason for preterm birth Magnesium sulphate already administered for preeclampsia/eclampsia <12 hours of discontinuation of previously MgSO4 infusion Magnesium sulphate contraindicated Fetus unlikely to benefit. SOGC Clinical Practice Guideline No. 258, May 2011 32

33. Close monitoring of maternal urine output is not required if MgSO 4 is used for neuroprotection. Monitoring of Serum Mg level is not required. SOGC Clinical Practice Guideline No. 258, May 2011 33

34.  Magnesium sulphate has proven role to reduce the rate of cerebral palsy in case of imminent preterm delivered babies.  Dose being : 4gm MgSO 4 i.v. slowly over 30mins, and 1gm/hour infusion until birth or 24 hours which ever is earliest.  There is no increase risk to the mother as compared to its use in pre eclampsia/ eclampsia.  Maternal urine output and serum magnesium level need not to be monitored. 34

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