Magnesium Sulfate for Neuroprotection Friend or Foe?

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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

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MgSO4 for neuroprotection

• Background cerebral palsy
• Initial retrospective studies
• Prospective-randomized trials in detail
• Meta-analysis
• Hills Criteria
• Molecular mechanism
• Cost-effectiveness
• Simultaneous tocolysis
• Summary general recommendations

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Magnesium Sulfate

• Inexpensive
• Easy to Administer
• Safe
• Used regularly by OBs comfortable with its use
  in pre-eclampsia to prevent seizures
• In utero exposure before preterm birth appears to
  decrease the incidence and severity of cerebral
  palsy

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Cerebral Palsy

• 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

Moster D, Lie RT, Markestad T. Long-term medical
and social consequences of preterm birth. N Engl
J Med 2008 359262.
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Murphy DJ. BMJ 8 February 1997
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Murphy DJ. BMJ 8 February 1997
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Initial Studies

• 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

Nelson KB, Grether JK. Can magnesium sulfate
reduce the risk of cerebral palsy in very low
birthweight infants? Pediatrics 199595263.
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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

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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.

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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

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Is tocolytic MgSO4 associated with increased
total paediatric mortality?

• 149 maternal randomizations
• Randomized 4 arms
• Tocolytic PTL lt34 wks lt4cm (MgSO4 v
  other-unblinded, switchover to different
  tocolytic allowed if MgSO4 failed) 4g load, 2-3
  g/h n46, 47
• Preventive arm- double-blinded PTLgt4cm received
  MgSO4 or saline n28
• Primary outcome total paediatric mortality
  (fetal, neonatal, and post neonatal) and cerebral
  palsy

Mittendorf R. Lancet 11/22/97, Vol. 350 Issue
9090, p1517.
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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.
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MgSO4 for NeuroprotectionRandomized controlled
trials

• The Australian Collaborative Trial of Magnesium
  Sulphate - ACTOMgSO4
• 1062 women lt30 wks expected to deliver lt24 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 20032902669
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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 20032902669
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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)

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Magnesium sulfate tocolysis time to quit

• Intravenous magnesium sulfate tocolysis 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
  magnesium sulfate 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 magnesium sulfate
  (relative risk 2.8 95 confidence interval
  1.2-6.6). Given its lack of benefit, possible
  harms, and expense, magnesium sulfate should not
  be used for tocolysis. Any further use of
  magnesium sulfate 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
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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 359895.
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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 lt28 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

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PREMAG

• Enrolled 573 women lt 33 wks expected to deliver
  lt24 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

Marret S, Marpeau L, Follet-Bouhamed C, et al.
Gynecol Obstet Fertil 2008 36278
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PREMAG

• 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

Marret S, Marpeau L, Follet-Bouhamed C, et al.
Gynecol Obstet Fertil 2008 36278
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Magnesium Sulfate for Neuroprotection
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Magnesium Sulfate for Neuroprotection
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Hills Criteria Assessing Cause Effect

• Consistency of the association
• Strength of the association
• Dose-response relationship
• Temporal relationship
• Biologic plausibility
• Experiment
• Coherence

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Molecular MechanismsMgSO4

• Most prevalent pathologic lesion in CP is peri
  ventricular white matter (PVWM) injury resulting
  from vulnerability of immature preoligodendrocytes
  (POD) lt32 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

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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

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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

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Reduction of Cerebral Palsy with Antenatal MgSO4

• Strong argument for use in women at risk of PTD
  lt32
• Limitations include variations in inclusion
  exclusion criteria GA at administration load
  ing and maintenance doses duration of
  intervention and use of retreatment

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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 gt8000 women lt32
  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

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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 lt32
  weeks will prevent 1 case of mod to severe CP
• If threshold limited to lt28 weeks, NICHD MFMU
  network suggests that only 29 women would need to
  be treated to prevent 1 case

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Simultaneous Tocolysis MgSO4 for
neuroprotection

• Services in which calcium channel blockers are
  primary tocolytic pose a dilemma
• Choices include MgSO4 primary tocolytic
  (not efficacious) Indomethacin Continu
  e to use calcium channel blockers and MgSO4
  simultaneously and risk hypotension (not
  recommended)

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Ductal constriction

• 144 echos
• 44 pregnancies
• 17/60 fetus 28

• KJ Moise AJOG 19931681350-3

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Ductal constriction

• llAll reversible!

• KJ Moise AJOG 19931681350-3

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

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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

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MgSO4 for neuroprotection

• In the United States, 2 of women deliver lt32
  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
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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

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Inclusion criteria, treatment regimens, large
trials
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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

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Rescue Steroids

• GA lt 33 weeks
• Single course given lt 30 weeks
• gt 2 weeks ago
• Delivery considered likely

Garite TJ. AJOG March 2009
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Thank You

• Barbara.Parilla_at_advocatehealth.com