1. MAGNESIUM SULPHATE IN OBSTETRICS MS CHARLEEN LIA SENIOR REGISTRAR IN OBSTETRICS AND GYNAECOLOGY

2. WHAT DO WE KNOW ABOUT MAGNESIUM SULPHATE? Oral MgSO4 is Epsom Salts!

3. SEVERE PRE-ECLAMPSIA/ECLAMPSIA Hypertensive disorders of pregnancy are a leading cause of maternal mortality and morbidity in the UK Death rate from eclampsia in the UK is now < 1% - about 5 - 6 women die each year in the UK from PET and Eclampsia Severe pre-eclampsia is responsible for approximately 40% of severe obstetric morbidity (including severe prematurity)

4. MAGNESIUM SULPHATE IN PRE-ECLAMPSIA Women on the severe pre-eclampsia protocol should receive magnesium sulphate. Magnesium sulphate is used to prevent and treat eclamptic seizures Specific mechanisms of action remain unclear: likely multi-factorial.  May act as a vasodilator, with actions in the peripheral vasculature or the cerebrovasculature, to decrease peripheral vascular resistance or relieve vasoconstriction  May protect the blood-brain barrier and limit cerebral edema formation  May act through a central anticonvulsant action.

5. DOSING REGIME Loading dose: Give 4g magnesium sulphate IV as a bolus over 5-10 minutes (ie: 8ml of 50% magnesium sulphate, which should be given into an IV line through which an infusion is running) Maintenance therapy: Give 1g magnesium sulphate per hour IV by syringe pump (make 10ml of 50% magnesium sulphate up to 50ml with normal saline. Infuse at 10ml per hour).

6. MAGNESIUM SULPHATE IN ECLAMPSIA In eclamptic seizures with no IV access, Magnesium Sulphate can be given intramuscularly as two 4ml doses in separate sites

7. MAGNESIUM SULPHATE (MGSO4) FOR FETAL NEUROPROTECTION IN PRETERM DELIVERY

8. PRETERM BIRTH Prevalence of preterm birth is increasing! Possible reasons include:  increases in maternal age  underlying maternal health problems eg. diabetes, hypertension  infertility treatments leading to more multiple pregnancies  Increased identification of fetal problems antenatally such as severe growth restriction Survival of prem babies has improved due to improved interventions including antenatal steroids and surfactant.

9. PRETERM BIRTH While the survival of infants born preterm has improved, the prevalence of cerebral palsy has risen. Rates of cerebral palsy inversely proportional to gestational age at delivery – 22-27 wks: 14.6% – 28-31 wks: 6.2% – 32-36 wks: 0.7% – Term: 0.1% Very preterm birth (less than 34 weeks) and very low birth-weight (less than 1500 g) are principal risk factors for cerebral palsy (17-32% of all CP cases) (Drummond 2002; Lorenz 1998; Pharoah 1998; Winter 2002)

10. 2 IDENTIFIED PATTERNS OF INJURY APPEAR TO UNDERLIE THE CNS COMPLICATIONS OF PREM BABIES: (1)Intraventricular Hemorrhage (IVH) Usually diagnosed by ultrasound (U/S) Occurs primarily in babies born at or < 28/40 (2)White Matter Injury. Usually diagnosed by MRI Peak prevalence at 28/40

11. INTRAVENTRICULAR HAEMORRHAGE

12. WHITE MATTER INJURY

13. BACKGROUND Case control studies suggested link between in utero exposure to MgSO4 and reduced rates of CP Noted in patients given MgSO4 as tocolytic or for eclampsia prophylaxis (Kuban et al, 1992, Nelson et al, 1995 ) Conflicting results from subsequent studies Several RCTs commenced to evaluate potential utility of MgSO4 as a neuroprotective agent

14. META-ANALYSES 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

15. COCHRANE META-ANALYSIS PRENATAL MGSO4 EXPOSURE AND CP D oyle et al. (2008) Antenatal magnesium sulphate therapy given to women at risk of preterm birth substantially reduced the risk of cerebral palsy in their child (relative risk (RR) 0.68; 95% Confidence interval (CI) 0.54 to 0.87; five trials; 6145 infants). Significant reduction in the rate of substantial gross motor dysfunction (RR 0.61; 95% CI 0.44 to 0.85; four trials; 5980 infants). No statistically significant effect on paediatric mortality (RR 1.04; 95% CI 0.92 to 1.17; five trials; 6145 infants), or on other neurological impairments or disabilities in the first few years of life. Number needed to treat to prevent one case cerebral palsy: 63 (95% CI: 43 – 87)

16. CONSTANTINE ET AL META-ANALYSIS (2009) Babies born at < 30 weeks gestation, number needed to treat to prevent one case of cerebral palsy is 46 (95% CI 26–187) Babies born between 32 and 34 weeks of gestation, number needed to treat to prevent one case of cerebral palsy is 56 (95% CI 34–164).

17. ACOG COMMITTEE OPINION The available evidence suggests that magnesium sulphate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants No official opinion on gestational age cut-off Recommended that physicians develop specific guidelines around the issues of inclusion criteria, dosage, concurrent tocolysis and monitoring

18. AUSTRALIAN NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL GUIDELINE 2010 In women at risk of early preterm imminent birth use magnesium sulphate for neuroprotection of the fetus when GA is less than 30 weeks, when birth is expected within 24 hours

19. RCOG SCIENTIFIC ADVISORY COMMITTEE OPINION PAPER 2011 Magnesium sulphate given to mothers shortly before delivery reduces the risk of cerebral palsy and protects gross motor function in those infants born preterm. The effect may be greatest at early gestations and is not associated with adverse long-term fetal or maternal outcome.

20. THE MECHANISM OF NEUROPROTECTIVE EFFECT The mechanism is not well understood Potential neuro-protective actions include:  Protection against free radical injury  Reduction in pro-inflammatory cytokines  Reversal of hypoxic/ischaemic brain injury through blockage of NMDA receptor on oligodendrocytes  Inhibition of calcium influx into cells  Stabilization of membranes  Increased cerebral blood flow  Prevention of large blood pressure fluctuations  Anti-apoptotic activity

21. PRACTICAL ISSUES  Eligible patients  Gestational Age  Dosing regimen  Optimal timing  Adverse effects – Maternal monitoring – Fetal monitoring  Contraindications

22. ELIGIBLE PATIENTS Consider administration in patients in whom preterm delivery is anticipated within subsequent 12 hours  Preterm labour with evidence of cervical dilatation  Preterm prelabour rupture of the membranes with regular uterine contractions  Severe preeclampsia/HELLP with planned delivery within the subsequent 12 hours  Severe intrauterine growth restriction with planned delivery with the subsequent 12 hours  Any other medical or obstetric condition necessitating preterm delivery

23. GESTATIONAL AGE Inclusion criteria varied between trials Recommendations by NICE guideline: Offer magnesium sulphate for babies between 24+0 and 29+6 weeks of pregnancy who are in established preterm labour or having a planned preterm birth within 24 hours (Emphasis on those delivering < 28 weeks) Consider in babies between 30+0 and 33+6 weeks of pregnancy who are in established preterm labour or having a planned preterm birth within 24 hours.

24. DOSING REGIME Give a 4 g intravenous bolus of magnesium sulfate over 15 minutes, followed by an intravenous infusion of 1 g per hour until the birth or for 24 hours

25. OPTIMAL TIMING OF ADMINISTRATION Requires adequate fetal levels of magnesium sulphate at time of delivery Animal studies:  Sustained infusion of MgSO4  Crosses fetal blood-brain barrier within 2 hours  Concentrations increased in fetal forebrain after 4 hours (Hallak et al, AJOG, 1993)

26. OPTIMAL TIMING OF ADMINISTRATION (2) A study of fetal serum concentrations of MgSO4 in patients undergoing FBS was carried out Elevated levels of MgSO4 in fetal serum at 1 hour and 3 hours post administration Levels increased between 1 and 3 hours Fetal serum magnesium concentrations correlated with maternal magnesium concentrations

27. OPTIMAL TIMING OF ADMINISTRATION (3) Further research necessary to define optimal timing Aim to commence magnesium sulphate approximately 4 hours prior to delivery If not possible to achieve a 4 hour window prior to delivery, magnesium sulphate should still be administered, as it is likely that benefit will be seen when administered within this time Insufficient evidence that repeat course of antenatal magnesium sulphate for fetal neuroprotection should be administered

28. ADVERSE MATERNAL EFFECTS Maternal Side Effects Common: Flushing, sweating Vomiting Headaches Palpitations Serious adverse effects: Respiratory depression Respiratory or cardiac arrest Death

29. MONITORING OF THE MOTHER AND BABY DURING MAGNESIUM SULPHATE LOADING DOSE AND INFUSION IN PRETERM LABOUR Continuous  oxygen saturation (maintain >95%)  urine output (must be >100ml/4 hours) – measured at least 4 hrly Intermittent  respiratory rate (must be >12/min)  patellar reflex (must be present)  BP and pulse These observations should be performed: prior to the loading dose ten minutes after the loading dose has started at the end of the loading dose hourly during the infusion. The infusion should be stopped if:  respiratory rate decreases more than 4 breaths per minute below baseline  respiratory rate is less than 12 breaths per minute  diastolic blood pressure decreases more than 15mmHg below baseline level.

30. CONCLUSIONS A local guideline with all the necessary recommendations is required The recent Australian guideline from the Adelaide group provides a well-reasoned, practical guide on which to base local clinical guidelines Every effort should be made to ensure all eligible babies are given magnesium sulphate for neuroprotection as this can have a very significant impact on their future lives

31. Any Questions?