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Magnesium Sulfate for Neuroprotection Friend or Foe?

Magnesium Sulfate for Neuroprotection Friend or Foe?. Barbara V. Parilla, MD Clinical Professor of Obstetrics and Gynecology University of Illinois at Chicago Director, Maternal Fetal Medicine Advocate Lutheran General Hospital. MgSO 4 for neuroprotection. Background cerebral palsy

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Magnesium Sulfate for Neuroprotection Friend or Foe?

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  1. Magnesium Sulfate for NeuroprotectionFriend or Foe? Barbara V. Parilla, MD Clinical Professor of Obstetrics and Gynecology University of Illinois at Chicago Director, Maternal Fetal Medicine Advocate Lutheran General Hospital

  2. MgSO4for neuroprotection Background cerebral palsy Initial retrospective studies Prospective-randomized trials in detail Meta-analysis Hill’s Criteria Molecular mechanism Cost-effectiveness Simultaneous tocolysis Summary & general recommendations

  3. Magnesium Sulfate Inexpensive Easy to Administer Safe Used regularly by OB’s comfortable with it’s use in pre-eclampsia to prevent seizures In utero exposure before preterm birth appears to decrease the incidence and severity of cerebral palsy

  4. Cerebral Palsy Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med 2008; 359:262. Heterogeneous group of disorders of movement and/or posture Most common cause of severe motor disability in childhood Prevalence 2-3/1,000 live births Prematurity is a powerful risk factor 80x higher among infants 23-27 weeks Number of children at risk is increasing

  5. Murphy DJ. BMJ 8 February 1997

  6. Murphy DJ. BMJ 8 February 1997

  7. Initial Studies Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95:263. Case-control study of children with & without CP that were VLBW Children with CP significantly less likely to have been exposed to MgSO4 OR 0.14, 95% CI 0.05-0.51 Subsequent observational studies confirmed and refuted findings MgSO4 administered as tocolytic or prevention of eclamptic seizure

  8. Statistics RR = incidence in exposed individuals ÷ incidence in unexposed individuals. RR can be calculated from studies in which the proportion of patients exposed and unexposed to a risk is known, such as a cohort study. OR = the odds that an individual with a specific condition has been exposed to a risk factor ÷ the odds that a control has been exposed. OR is used in case-control studies and is often generated in multivariate analyses as well. OR provides a reasonable estimate of the RR for uncommon conditions

  9. Statistics • Confidence interval (CI): A point estimate from a sample population may not reflect the "true" value from the entire population. • Often helpful to provide a range that is likely to include the true value. A CI is a commonly used estimate. The boundaries of a confidence interval give values within which there is a high probability (95 percent by convention) that the true population value can be found. • The calculation of a CI considers the standard deviation of the data and the number of observations. • A CI narrows as the number of observations increases, or its variance (dispersion) decreases.

  10. Statistics • The RR and OR are interpreted relative to the number one. • OR of 0.6, for example, suggests that patients exposed to a variable of interest were 40 percent less likely to develop a specific outcome compared to the control group. • Similarly, OR of 1.5 suggests that the risk was increased by 50 percent. • If the 95% CI crosses 1, it is NOT statistically significant

  11. Is tocolytic MgSO4 associated with increased total paediatric mortality? • 149 maternal randomizations • Randomized 4 arms • Tocolytic PTL <34 wks <4cm (MgSO4 v “other”-unblinded, switchover to different tocolytic allowed if MgSO4 failed) 4g load, 2-3 g/h n=46, 47 • Preventive arm- double-blinded PTL>4cm received MgSO4 or saline n=28 • Primary outcome total paediatric mortality (fetal, neonatal, and post neonatal) and cerebral palsy Mittendorf R. Lancet; 11/22/97, Vol. 350 Issue 9090, p1517.

  12. Is tocolytic MgSO4 associated with increased total paediatric mortality? Interim safety monitoring showed 9 paediatric deaths 10 total deaths: 5 singletons, 3 twin pairs where 1 sibling died, 1 twin pair where both died Non-twin deaths ? sequelae infections ? additional tocolysis Mittendorf R. Lancet; 11/22/97, Vol. 350 Issue 9090, p1517.

  13. MgSO4 for NeuroprotectionRandomized controlled trials The Australian Collaborative Trial of Magnesium Sulphate - ACTOMgSO4 1062 women <30 wks expected to deliver <24 hrs Randomly assigned 4 g load then 1g/hr or placebo for 24 hr max Primary outcomes: rates of total pediatric mortality, cerebral palsy, and combined outcome at 2 yrs (available for 99%) Crowther CA, Hiller JE, Doyle LW, Haslam RR. JAMA 2003;290:2669

  14. ACTOMgSO4 MgSO4 v placebo Pediatric mortality 13.8 v 17.1 (RR 0.83, 95% CI 0.64-1.09) Cerebral Palsy 6.8 v 8.2 (RR 0.83, 95% CI 0.54-1.27) Combined outcome 19.8 v 24 (RR 0.83. 95% CI 0.66-1.03) Despite lack of statistical significance, potentially clinically important Crowther CA, Hiller JE, Doyle LW, Haslam RR. JAMA 2003;290:2669

  15. ACTOMgSO4 When only gross motor function considered MgSO4 exposed had significantly lower rates 3.4 v 6.6% (RR 0.51, 95% CI 0.29-0.91) Combined outcome gross motor and death 17 v 22.7% (RR 0.75, 95% CI 0.59-0.96)

  16. Magnesium sulfate tocolysis: time to quit • “Intravenous magnesiumsulfatetocolysis remains a North American anomaly. This therapy rose to prominence based on poor science and the recommendations of authorities. However, a Cochrane systematic review concluded that magnesiumsulfate is ineffective as a tocolytic. The review found no benefit in preventing preterm or very preterm birth. Moreover, the risk of total pediatric mortality was significantly higher for infants exposed to magnesiumsulfate (relative risk 2.8; 95% confidence interval 1.2-6.6). Given its lack of benefit, possible harms, and expense, magnesiumsulfate should not be used for tocolysis. Any further use of magnesiumsulfate for tocolysis should be restricted to formal clinical trials with approval by an institutional review board and signed informed consent for participants. Should tocolysis be desired, calcium channel blockers, such as nifedipine, seem preferable.” Grimes D. Obstet Gynecol (Oct 2006) 108(4):986-9

  17. BEAM NICHD/MFMU multicenter placebo controlled trial “beneficial effects of antenatal magnesium sulfate” 2241 women 24-31 wks at risk for imminent delivery 6 gm load, 2 g/hr Infusion stopped after 12 hrs if delivery no longer considered imminent F/U available 95.6% children Rouse DJ, Hirtz DG, Thom E, et al. N Engl J Med. 2008; 359:895.

  18. BEAM Primary study outcome “stillbirth or infant death by one year corrected age or moderate to severe CP ≥ 2 yrs corrected age” MgSO4 v placebo 11.3 v 11.7% Rate of moderate to severe CP 1.9 v 3.5% (RR 0.55, 95% CI 0.32-0.95) Only infants randomized at <28 wks showed a significant reduction in moderate or severe CP Risk of death similar in the 2 groups 9.5 v 8.5 (RR 1.12 95% CI 0.85-1.47) Suggests that lower rate of CP not simply due to increased death rate in MgSO4 group

  19. PREMAG Marret S, Marpeau L, Follet-Bouhamed C, et al. Gynecol Obstet Fertil 2008; 36:278 Enrolled 573 women < 33 wks expected to deliver <24 hrs Single 4 gm loading dose or placebo, no maintenance Infants followed for 2 years after hospital D/C Primary outcome was white matter injury on neonatal cranial US Composite outcomes of “CP or death” and “severe motor dysfunction or death” were secondary

  20. PREMAG Marret S, Marpeau L, Follet-Bouhamed C, et al. Gynecol Obstet Fertil 2008; 36:278 Protective effect of MgSO4 against “cerebral palsy or death” OR 0.65, 95% CI 0.42-1.03 Exposure to MgSO4 was protective against “severe motor dysfunction or death” OR 0.62, 95% CI 0.41-0.93 Despite lack of statistical significance, the average size of the reduction is potentially clinically important

  21. Magnesium Sulfate for Neuroprotection

  22. Magnesium Sulfate for Neuroprotection

  23. Hill’s Criteria Assessing Cause & Effect Consistency of the association Strength of the association Dose-response relationship Temporal relationship Biologic plausibility Experiment Coherence

  24. Molecular MechanismsMgSO4 Most prevalent pathologic lesion in CP is peri ventricular white matter (PVWM) injury resulting from vulnerability of immature preoligodendrocytes (POD) <32 weeks POD are precursors of myelinating oligidendrocytes which constitute a major glial population in white matter Oxidative stress & excitotoxicity from excessive stimulation of ionotropic glutamate receptors on POD are the most prominent molecular mechanism for PVWM injury

  25. Molecular MechanismsMgSO4 Recent studies have identified functional N-methyl-D-aspartate (NMDA) glutamatergic receptors in oligodendroglial injury processes Antagonists of the NMDA receptors for glutamate are potent neuroprotective agents in several animal models of perinatal brain lesions

  26. Neuroprotective effects of MgSO4 In addition, MgSO4 could also reverse the destructive action of oxygen radicals and excitatory amino acids Growing evidence suggests MgSO4 may reverse the harmful effects of hypoxic/ischemic brain damage by blocking the NMDA receptors and, as a calcium antagonist, hindering calcium influx into the cells

  27. Reduction of Cerebral Palsy with Antenatal MgSO4 Strong argument for use in women at risk of PTD <32 Limitations include variations in inclusion & exclusion criteria GA at administration loading and maintenance doses duration of intervention and use of retreatment

  28. MgSO4 for neuroprotectionLogistics of future trials In the placebo arm of the NICHD/MFMU trial, rate of mod-severe CP was 3.5% Assuming a MgSO4 effect size of 30%, with 80% power and a 2-tailed alpha of 0.05 Confirmatory trial would require >8000 women <32 weeks and 100% F/U of children Enrollment of 2241 mothers in the 20 center NICHD/MFMU Network trial took 10 years and cost $25 million

  29. Cost-effectiveness The number needed to treat with MgSO4 is in line with current use of MgSO4 for other indications Treating 63 women threatening to deliver <32 weeks will prevent 1 case of mod to severe CP If threshold limited to <28 weeks, NICHD MFMU network suggests that only 29 women would need to be treated to prevent 1 case

  30. Simultaneous Tocolysis & MgSO4 for neuroprotection Services in which calcium channel blockers are primary tocolytic pose a dilemma Choices include MgSO4primary tocolytic (not efficacious) Indomethacin Continue to use calcium channel blockers and MgSO4 simultaneously and risk hypotension (not recommended)

  31. Ductal constriction • 144 echos • 44 pregnancies • 17/60 fetus =28% • KJ Moise AJOG 1993;168:1350-3

  32. Ductal constriction • llAll reversible! • KJ Moise AJOG 1993;168:1350-3

  33. Indomethacin was the only drug in this review associated with a decrease in preterm birth • and birth weight < 2500 g.

  34. Summary & Recommendations For women at risk of PTB we suggest antenatal administration of MgSO4 Randomized placebo-controlled trials of maternal administration of MgSO4 in women expected to have a PTD within 24 hrs have consistently demonstrated a decrease of CP and severe motor dysfunction in offspring However, the possibility of an increased risk of death in a sub group of fetuses or infants has not conclusively been excluded

  35. MgSO4 for neuroprotection In the United States, 2% of women deliver <32 weeks. If MgSO4 was uniformly administered to the 75% of women who deliver spontaneously and it was as effective as in the NICHD/MFMU Network trial, then more than 1000 fewer children a year would suffer from handicapping CP “For their sake, we should avail ourselves of this opportunity” Dwight J Rouse. AJOG June 2009

  36. ACOG Committee OpinionNumber 455 March 2010 • “The Committee on Obstetric Practice and SMFM recognize that none of the individual studies found a benefit with regard to their primary outcome. However, the available evidence suggests that MgSO4 given before anticipated early preterm birth reduces the risk of CP in surviving infants”

  37. Inclusion criteria, treatment regimens, large trials

  38. LGH protocol for administration of MgSO4 for neuroprotection MgSO4 administered when imminent delivery from either PPROM or intact preterm seems likely, or before an indicated PTD We limit to 24-32 weeks 4-6 gram load, 2 gm/hr Therapy discontinued by 24 hours if delivery has not occurred If tocolysis indicated, we use indomethacin We retreat for women who do not deliver after an initial course of therapy

  39. Rescue Steroids • GA < 33 weeks • Single course given < 30 weeks • > 2 weeks ago • Delivery considered likely Garite TJ. AJOG March 2009

  40. Thank You Barbara.Parilla@advocatehealth.com

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