Dr. Azadeh Pravin Patel Second Year P. G Student V. S. Hospital Guided By : Dr. Sushma Shah | Dr. Megha Patel | D

2. Dr. AzadehPravin PatelSecond Year P. G Student V. S. HospitalGuided By :Dr. Sushma Shah | Dr. Megha Patel | Dr. ShashwatJani Is MgSO4 a Neuroprotectorin Preterm delivery?

3. Defination of Preterm Labor • 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.

4. 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

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

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

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

8. CEREBRAL PALSY • 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

9. 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%

10. 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.

11. Spastic CP Ataxic CP Spastic CP

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

13. Use of MgSO4 in Obstetrics : • Eclampsia:Prophylaxis& management • Tocolysis :No longer recommended • Fetal neuroprotection in preterm delivery : A new evidence &validation

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. Observational Studies 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.

16. 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

17. Mechanism : • 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

18. The Cochrane Review :Result  1) MgSO4significantly reduced the risk of : • Cerebral palsy • Substantial gross motor dysfunction (inability to walk without assistance ) at 2 years of age 2) MgSO4had No significant effect of on pediatric (fetal, neonatal and later) mortality. Doyle et al., Cochrane Database Syst Rev. 2009

19. Cochrane review 2009 MgSO4 Vs no MgSO4 , Outcome 6 Substantial gross motor dysfunction.

20. 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 63women. These compare favorably with the 70 women with preeclampsia to prevent one eclamptic fit. Doyle et al Cochrane Database Syst Rev. 2009 *

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

22. 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

23. Doyle et al Cochrane Database Syst Rev. 2009 3- MgSO4 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

24. 4 :There is no information on the effect of MgSO4 on outcomes beyond 2 years of age : • Age on learning disabilities • School difficulties & disabilities Doyle et al Cochrane Database Syst Rev. 2009

25. 1- The Australian National Clinical Practice Guidelines March 2010. In women at risk of early preterm imminent Birth(expected within 24 Hs), use MgSO4 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.

26. 2- The ACOG Committee Opinion on MgSO4 for March 2010. The available evidence suggests that MgSO4given 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:

27. SOGC Guideline Recommendations 1)For women with imminent preterm birth (< 32 weeks), antenatal MgSO4 administration should be considered for fetal neuroprotection. (I-A) 2) Antenatal MgSO4should be considered from viability to < 32 weeks. (II-1B) (still controversial) 3) If antenatal MgSO4has been started, tocolysis should be discontinued. (III-A) SOGC Clinical Practice Guideline No. 258, May 2011

28. 4) MgSO4 should be discontinued if delivery is no longer imminent or maximum of 24 hours therapy has been administered (II-2B) 5)RECOMMENDED DOSE :4g MgSO4IV 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 SO4should be started, ideally within 4 hours before birth .(II-2B)

29. 7) No sufficient evidence is available for repeat administration of antenatal MgSO4. (III-L) 8) Delivery should not be delayed if there are maternal and/or fetal indications for emergency delivery. (III-E) 9)When MgSO4 is given for fetal neuroprotection, maternal care providers should use existing protocols to monitor women who are receiving MgSO4 for preeclampsia/eclampsia. (III –A) 10) Fetal Heart Rate should be monitored.

30. 11) MgSO4 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)

31. 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

32. Criteria for administration : SOGC Clinical Practice Guideline No. 258, May 2011

33. Close monitoring of maternal urine output is not required if MgSO4 is used for neuroprotection. Monitoring of Serum Mg level is not required. SOGC Clinical Practice Guideline No. 258, May 2011

34. Conclusion • Magnesium sulphate has proven role to reduce the rate of cerebral palsy in case of imminent preterm delivered babies. • Dose being : 4gm MgSO4i.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.