Magnesium sulfate is being studied for its potential neuroprotective effects in preventing cerebral palsy. Several studies have investigated administering magnesium sulfate either postnatally to newborns with hypoxic-ischemic encephalopathy or antenatally to mothers at risk of preterm birth. While some individual studies found magnesium sulfate improved short-term outcomes like reducing brain lesions or improving outcomes at hospital discharge, the larger trials found no clear statistically significant benefits. Overall the evidence remains unclear whether magnesium sulfate administration prevents long-term disabilities like cerebral palsy, though some studies found signals of potential benefit worth further investigation. Larger multicenter trials are still needed to provide more definitive evidence.

1. MAGNESIUM SULFATE FOR
CEREBRAL PALSY PREVENTION
A. Goodwin-Samson, MD B. Brocato, DO
1

2. Objectives
 Define Cerebral Palsy
 Review hypoxia-ischemia injury at neuronal
level
 Discuss magnesium sulfate as a potential
neuroprotective agent
 Review the current literature of postnatal
magnesium sulfate (MgSO4)
 Review the current literature of antenatal
MgSO4
2

3. Cerebral Palsy: History
 1861 Dr. William John Little described a disorder that
was crippling and made children’s muscle weak, stiff
and prone to twitching.
 Little’s Disease
 Followed complicated delivery  lack of O2 brain
damage
 1897 Dr. Sigmund Freud disputed Dr. Little's claim
disorder began before birth
 Research by National Institute of Neurological Disorders and Stroke
(NINDS) in 1980’s No single etiology of CP

4. Cerebral Palsy
 Definition: Global term for a group of disorder which
effect movement and muscle coordination which is
nonprogressive in nature.
 Incidence: 2-3 children per 1,000
 Increasing in the US increased survival of premature infants
 Etiology: Multifactorial
 Damage to a developing brain
 Risk Factors:
 Preterm Birth
 Birth Asphyxia 6-20%
 Hypoxia Ischemic encephalopathy(HIE)
4

5. Hypoxia-Ischemia Background
 Hypoxia-Ischemic encephalopathy: clinical and lab
evidence of acute or subacute brain injury
secondary to asphyxia
 Hypoxia-Ischemia Encephalopathy can result in CP
 2 to 4/1000 full-term infants suffer asphyxia
 Incidence of asphyxia leading to CP 0.2 to
0.4/1000 infants
5

6. Ischemic Brain Injury (IBI)
6

7. Hypoxia-Ischemia at Neuronal Level7

8. Background: Sodium and Potassium
Regulation
 Presynaptic membrane Na+/K+ pump
 Maintains ion gradient across cell membrane
 Adenosine TriPhosphate (ATP) driven
↑↑Na+
↑↑K+
2K+
3Na+
2K+
8
2K+
K+
K+
Na+
3Na+
+++++++ ++
Na+

9. Background: Calcium Regulation
 Ca2+ is 10,000X extracellular>> cytoplasm
 ATP-driven pump
 Voltage-gated ion channel
 Ion-Exchangers
9

10. Cellular Energy
 ATP in manufactured in
the mitochondria
 Na+/K+ pump require
ATP to continue to
work
 ATP in mitochondria
requires O2
10

11. Hypoxia: Cellular Level
 Generate ATP
 Glycolysis
 Glucose 2 ATP + Lactate
 Regenerate ATP
 Phosphocreatine (PCr)
 ADP ATP
Hypoxic Environment
Phosphocreatine (PCr)/ATP vs.
Time
11

12. Hypoxia-Ischemia: Cellular Level
 Net breakdown of glycolysis
 ADP, AMP, phosphate, lactate and acid accumulation
 ↑ CO2 carbonic acid (H2CO3)
 Within mins w/o 02 ↓↓ ATP  Na+/K+
pump stops working  depolarization
 K+ exits cell
 Na+ influx
Acidosis
12

13. Depolarization of Presynaptic Neuron
13
Postsynaptic
Neuron
Presynaptic Neuron

14. IBI: Cellular Level
 Voltage-Dependent Calcium Channels
 Glutamate receptors
 N-Methyl-D-Aspartate (NMDA)
 AMPA
 Glutamate receptors  ↑↑ Ca 2+ entry into intracellular
space
NMDA RECEPTOR
14
Glutamate Recognition Site
Ca 2+

15. Biochemical Cascade: Increased
Calcium
 Excitotoxic
 Interference with enzymatic
reactions
 Phospholipase
 Membrane phospholipid
hydrolysis
 Arachidonic acid cycle
 Prostaglandin synthesis
 Gene expression
 Protein synthesis
 Production of free radical
 Release of Cytochrome C
15

16. Glutamate
 In Neuron culture
Glutamate toxic
 Glutamate or glutamate
agonist injected into
regions of the brain
neuronal injury = after
hypoxia-ischemia
 Deafferentation of
glutaminergic excitatory
input in hippocampus ↓
damage from hypoxia-
ischemia
In Vitro In Vivo
16

17. Potential Neuroprotective Strategies
17

18. Magnesium
 Intracellular cation, Mg ++
 Essential for cellular functions
 DNA transcription
 Hormone receptor binding, mitochondrial oxidative phosphorylation
 Gating calcium channels
 Transmembrane ion flux
 Adenylate cyclase regulation
 Muscle contraction
 Control of vasomotor tone
 Cardiac excitability
 Neuronal transmitter release
 Block Voltage Dependent Ca2+ Channel
 NMDA receptor antagonist
18

19. Why Would Magnesium Sulfate Work??
 Magnesium is a non-competitive antagonist of
the glutamate NMDA receptor
 ↑ Extracellular magnesium  block calcium
influx into the cell block neuronal injury
19

20. Post Magnesium: NDMA Receptor
20
Ca2+

21. Animal Studies
 In Vitro
 Neuron culture and hippocampal slices die in anoxic environment
 In presence of Mg 2+ death is prevented
 Hamsters
 Mg2+ def ↑ susceptibility of hamster hearts to free radical damage
 Immature Rats
 ↓ Brain lesions after Magnesium sulfate
 Piglets
 Does not protect against cerebral damage
 Near-Term (Late Preterm?) Lamb
 No improvement neuro outcome after umbilical cord occlusion
21

22. Postnatal Magnesium Sulfate
 ICHIBA et al. (2002). Randomized controlled trial of
magnesium sulfate infusion for severe birth asphyxia.
 Randomized controlled trial
 Objective: To determine whether postnatal MgSO4 infusion
(250 mg/kg per day) for 3 days is both safe and able to
improve outcome in infants with severe birth asphyxia
 Magnesium Sulfate 250mg/kg q 24h X 3 days
 Conclusion:
 Postnatal magnesium safe
 Improved short-term outcomes
22

23. Postnatal Magnesium Sulfate
• Ichiba H, et al (2006). Neurodevelopmental outcome
of infants with birth asphyxia treated with magnesium
sulfate.
• 30 Term Newborns, nonrandomized
• 250mg/kg of Magnesium Sulfate within 6 hours of birth q
12hr x two additional doses
• No sign adverse effects
• Follow up at 18months of age
• 6 infants with cerebral palsy
• 73% with nL development
23

24. Postnatal Magnesium Sulfate
 Bhat MA, et al 2009 Magnesium Sulfate in Severe
Perinatal Asphyxia: A Randomized, Placebo-Controlled
Trial
 Randomized, Placebo-Controlled Trial
 Objective: To study whether postnatal magnesium sulfate infusion could
improve neurologic outcomes at discharge for term neonates with severe
perinatal asphyxia.
 Eligibility:
 ≥ 37 weeks
 < 6 hours of age
 Severe asphyxia
 Moderate or severe HIE
 Treatment Group vs. Placebo
 Magnesium sulfate 250mg/kg per dose q 24hrs
 Normal Saline same volume
24

25. Postnatal Magnesium: Status at Discharge
25

26. Postnatal Magnesium: Study
Conclusion
 Primary Outcome: neurologic outcomes at discharge
 Neuro exam
 CT scan
 EEG
 Oral feedings
 Seizures
 Composite good short term outcome
 Study Conclusion: Postnatal magnesium sulfate treatment
improves neurologic outcomes at discharge for term
neonates with severe perinatal asphyxia.
26

27. Conclusion
 Magnesium has potential neuroprotective use in
hypoxic-ischemic insults to the newborn brain.
 Pros
 Cheap
 No equipment to buy
 Easy to administer
 Literature:
 Studies results variable
 Some reports promising
 Multicenter randomized placebo controlled trial
27

28. Antepartum Magnesium Sulfate28

29. Antenatal MgSO4 - Opinions vary. . .
 “MgSO4 for CP prevention: too good to be true? . . . helped me put the confusing
data into context”. -Macones, MD
 “. . .the answer to the question of whether evidence-based medicine supports the
use of magnesium for neuroprophylaxis in preterm infants remains unclear.” – Cahill,
MD , Caughey, MD
 “. . . results suggest that antenatal magnesium sulfate could be used for the primary
prevention of cerebral palsy in preterm infants. . .”
-Conde-Agudelo, MD, Romero, MD
 “. . .trials provide strong support for the utilization of MgSO4 to lower the risk of
cerebral palsy among survivors of early preterm birth. . . Has the potential to
prevent 1000 cases of handicapping cerebral palsy annually.” – Rouse, MD

30. Early Studies and Theories of Mechanism
 Early hypothesis was that intracranial hemorrhage lead to CP
 1980’s, studies showed decreased rates of IVH in VLBW infants
born to women with preeclampsia.
 Could this be explained by exposure to MgSO4?
 Early 1990’s, it was shown that VLBW infants exposed to
MgSO4 for tocolysis also had decreased rates of IVH.
 1995 – Nelson and Grether found a lower rate of CP in VLBW
infants exposed MgSO4

31. Review of recent studies
 MagNET
 ACTOMgSO4
 MAGPIE
 PREMAG
 BEAM
 Metaanalysis of these 5 studies
31

32. MagNET
 Mittendorf, et al 2002. Association between the use of
antenatal magnesium sulfate in preterm labor and
adverse health outcomes in infants.( Magnesium and
Neurologic Endpoints Trial)
• Objective: determine whether antenatal MgSO4 prevents
adverse outcomes ( IVH/Periventricular
leukomalacia/CP/Death)
• 149 women
• Singleton or twin 24-34 weeks c PPROM or PTL
• 2 protocols; one which examined use for CP prevention, the
other evaluated MgSO4 as a tocolytic
• Prevention group - >4cm, received 4 gm load

33. MagNET - Outcomes
• In neuroprophylaxis arm – 37% (11/30) had an adverse
event compared to 21% (6/29) of those that received
placebo.
• When the 2 arms were combined, 32% of infants that
received MgSO4 had an adverse event compared to 19% of
the infants of mothers that received placebo.
• The findings were not statistically significant (p=.07) yet
raised concern that MgSO4 might be harmful to neonates.
There appeared to be a dose response relationship between
magnesium sulfate and adverse outcomes.

34. ACTOMgSO4
 Crowther, et al 2003. Effect of Magnesium Sulfate
Given for Neuroprotection Before Preterm Birth.
• Objective: determine effectiveness of MgSO4 given for
neuroprotection to women @ risk for preterm delivery before
30 wks
• RCT at 16 tertiary hospitals in Australia and New Zealand
• 1062 women, less than 30 wks gestation.
Single/twin/triplet/quadruplet pregnancies
• Birth expected within 24 hours.
• 4 gram load followed by 2 grams/hr.

35. ACTOMgSO4 - Inclusion criteria

36. ACTOMgSO4 - Outcomes
 The primary outcomes of total pediatric mortality,
cerebral palsy in survivors, and combined death or
cerebral palsy were all lower in the magnesium sulfate
group, but no differences were statistically significant.
 There was a reduction in substantial gross motor
dysfuction in the group treated with MgSO4

37. MAGPIE – Trial follow-Up Study
 MAGPIE – Prospective RCT conducted at 175 hospitals in
33 countries. Originally included 8804 women with pre-
eclampsia randomized to MgSO4 or placebo. Concluded
that risk of seizure was 58% lower in pre-eclamptic
women given MgSO4.
• Objective of the follow-Up study – assess long-term effects of
in utero exposure to magnesium sulfate for children whose
mothers had pre-eclampsia. (Is MgSO4 safe?)
• 2895 of 4483 children assessed at 18 months of age for the
primary outcome of death or neurosensory disability.

38. MAGPIE - Conclusion
 Original study – Magnesium sulfate for women with pre-
eclampsia more than halves the risk of eclampsia and
probably reduces the risk of maternal death before
discharge from the hospital
 No substantive harmful effects were apparent in the short
term, for either mother or baby. Exposure to magnesium
sulfate while in utero was not associated with a clear
difference in the risk of death or disability for children at
18 months.
38

39. PREMAG
 Marret, et al 2008. Benefit of Magnesium Sulfate Given
before Very Preterm Birth to Protect Infant Brain.
• Objective: To evaluate whether magnesium sulfate given to
women at risk of very-preterm birth would be
neuroprotective in preterm newborns and would prevent
neonatal mortality and severe white-matter injury.
• Carried out in 18 French tertiary hospitals
• Gestational age < 33 weeks whose birth was planned or
expected within 24 hours
• Women received a single 4 gram infusion of MgSO4 or
placebo

40. PREMAG – Maternal Characteristics
• Preterm labor – 84%
• PPROM – 53%
• Chorioamnionitis – 9.5%
• Antepartum hemorrhage – 19%
• Other – 9.8%
• Tocolysis – 67%
• Antibiotics – 77%
• Corticosteriods – 95%
40

41. PREMAG - Outcomes
 Primary outcomes were rates of severe white-matter
injury (WMI) or total mortality before hospital discharge,
and their combined outcome.
 The rates of total mortality before hospital discharge,
severe WMI, and the combination of severe WMI and/or
death were all lower for the MgSO4 group, but no
differences were statistically significant
41

42. BEAM
 Rouse, et al 2008. A Randomized, Controlled Trial of
Magnesium Sulfate for the Prevention of Cerebral Palsy.
(Beneficial Effects of Antenatal Magnesium Sulfate Trial)
• Objective: Test the hypothesis that the administration of
MgSO4 to women at high risk for early preterm delivery
would reduce the risk of cerebral palsy in their children.
• 20 participating centers across the US
• 2241 women, singleton or twin gestations 24-31 wks.
• 6 gram loading dose of MgSO4 followed by 2 g/hr
42

43. 43

44. BEAM
 Primary outcomes measured:
• Composite of stillbirth or infant death by 1 year or
moderate to severe cerebral palsy at or beyond 2
years
44

45. BEAM
 The rate of the primary outcome was not
significantly different in the MgSO4 group and the
placebo group (11.3% and 11.7%, respectively )
 Secondary analysis: When mortality and CP looked
at separately, CP occurred significantly less
frequently in the MgSO4 group than the placebo
group (1.9% vs 3.5%, respectively )
45

46. BEAM
 Criticisms of the Study:
• The composite outcomes are competing risk for the
outcome of interest: CP. Infants who die before their
first birthday cannot be evaluated for CP.
• How many of those infants that died at their first
birthday had CP?
• How many of the 99 infants who died in the MgSO4
group would have needed to survive and be diagnosed
with CP for the results to no longer be statistically
significant? = 2
46

47. BEAM
Praise of the study: Although it is a small effect, it is
statistically significant.
• Number needed to treat (NNT) = overall 63
• NNT in high-risk group (<28wks) = 29
• Low risk (>28wks)= 265
47

48. Metaanalysis
 Constantine M 2009. Effects of Antenatal Exposure
to Magnesium Sulfate on Neuroprotection and
Mortality in Preterm Infants: A Meta-analysis.
• Objective: To review the evidence of of fetal
neuroprotection by MgSO4 and specifically explore the
findings at different gestational ages.
• Two thresholds for analysis
• Less than 32-34 wks
• Less than 30 weeks
48

49. Table 1
49

50. Metaanalysis
 Primary outcome:
• Composite of perinatal/infant death or CP among
survivors
 Secondary outcomes:
• Death
• CP
• moderate-severe CP
• Combined death or moderate-severe CP
50

51. 51

52. Metaanalysis
 Results:
• In utero fetal exposure to magnesium sulfate given to
women at risk of preterm delivery significantly reduced
the risk of cerebral palsy
• NNT = 46 ( before 30 wks gestation )
• NNT = 56 ( before 32-34 wks gestation )
• No increase in the risk of perinatal or infant death
• The benefit of using magnesium sulfate beyond 32-34
weeks for fetal neuroprotection is unproven.
52

53. Metaanalysis
 Strengths:
• RCT’s specifically designed to study neuroprotective effects of
MgSO4
• Reassurance of safety of MgSO4
• Demonstrates beneficial effect of 32-34 wks, as well as less
than 30 wks
 Limitations:
• MgSO4 regimen differed among trials
• Dose received differed as well as timing
• Differences in patient characteristics
53

54. Conclusion
 Drs Mercer and Merlino, Sept 2009 Green Journal
Clinical Expert Series. Magnesium sulfate for Preterm
Labor and Preterm Birth.
 Recommendations/comments:
• Four randomized trials have been specifically designed
to evaluate magnesium sulfate for neuroprotection
• each of these four neuroprotection trials failed to
demonstrate significant improvements in the designated
primary outcome
54

55. Conclusion
• None found increased pediatric morbidities or mortality with
magnesium sulfate treatment given for this indication
• Comparisons between the published trials are made difficult
by differences in inclusion criteria, study interventions, and
evaluated outcomes
• Although a 2009 meta-analysis was supportive of magnesium
sulfate for neuroprotection before preterm birth, the optimal
treatment indication(s), gestational age range, and therapeutic
regimen remain to be determined
• Because the potential benefits of antenatal magnesium sulfate
were identified only in secondary analyses from the recent
major prospective trials, caution is warranted in incorporating
such treatment into clinical practice
55

56. References
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57. References
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