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Magnesium Sulfate for Neuroprotection in

Preterm InfantsJin Chang, D.O.Clinical Fellow, Maternal Fetal MedicineUniversity of California, San FranciscoOctober 28, 2010

+Objectives

�Define Cerebral Palsy

� Review mechanisms of brain injury at the neuronal

level

�Discuss potential mechanisms of MgSO4 as a

neuroprotective agent

� Review the current literature on the use of antenatal

MgSO4

� Review UCSF MgSO4 protocol

+Cerebral Palsy

�Definition: Global term for a hetergeneous group of

chronic, nonprogressive disabilities of the central

nervous system affecting movement and muscle

coordination.

� Incidence: 2-3 children per 1,000 live births

�Higher incidence in preterm infants, risk

indirectly proportional to gestational age

� Incidence in VLBW (<1500gm) ranges from 4-8%

� Slightly higher incidence in males and in multiple

gestation

� Increasing incidence in the US- increased survival

of premature infants

+Cerebral Palsy

�Risk Factors:

�Preterm Birth

�Damage to a developing brain

�PVL, IVH

�Birth Asphyxia

�Hypoxia ischemic encephalopathy (HIE)

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+Early Observational Data

� 1980’s, studies showed decreased rates of IVH and CP in

VLBW infants born to women with preeclampsia.

� Van de Bor, Leviton

� Early 1990’s, it was shown that VLBW infants exposed to

MgSO4 for tocolysis also had decreased rates of IVH.

� Kuban

� 1996 – Lower rate of CP in VLBW infants exposed

MgSO4

� Grether et al.

� Could this be explained by exposure to MgSO4?

+Magnesium: Functions

� 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

� Anticonvulsant

� Block Voltage Dependent

Ca++ Channel

� NMDA receptor antagonist

+Background: Biochemistry

� Glutamate is an excitatory amino acid known to play an important

role in brain injury by increasing intracellular Ca++

� Increase in intracellular Ca++

� 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

+Mechanism of Action: MgSO4

Not clearly understood, but current theories:

� Magnesium is a non-competitive antagonist of the

glutamate NMDA receptor

� ↑ Extracellular magnesium => blocks NMDA receptor

=> inhibits intracellular calcium => block neuronal

injury

� Vasodilitation of cerebral blood vessels, increasing

cerebral blood flow

� Reduction of oxygen free radicals

� Reduction of inflammatory cytokines

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+Current Evidence

� Mittendorf (AJOG 2002)

� aka MagNET

� Crowther (JAMA 2003)

� aka ACTOMgSO4

� Magpie Trial Follow-Up Study Collaborative Group

(BJOG 2007)

� Marret (BJOG 2007)

� aka PREMAG

� Rouse (NEJM 2008)

� aka BEAM

� Constantine (Obstet Gynecol 2009)

� Meta-analysis

+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/PVL/CP/Death)

� 149 women

� Singleton or twin 24-34 weeks with PPROM or PTL

� 2 protocols; one which examined use for CP prevention,

the other evaluated MgSO 4 as a tocolytic

� Prevention group - >4cm, received 4 gm load

+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

MgSO4 and adverse outcomes.

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+ACTOMgSO4

� Crowther, et al. 2003. Australian Collaborative Trial of

Magnesium Sulfate Collaborative Group

� “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

� Singleton/twin/triplet/quadruplet pregnancies

� PPROM- 8% of patients enrolled

� Birth expected within 24 hours.

� 4 gram load followed by 1 gram/hr x 24hrs

+ACTOMgSO4

�Primary outcome:

�Rates of total pediatric mortality, CP, and the

combined outcome of death and CP at

corrected age of 2 years

Copyright restrictions may apply.

Crowther, C. A. et al. JAMA 2003;290:2669-2676.

Randomization, Treatment, and Follow-up of Participants in the Australasian Collaborative Trial of Magnesium Sulphate Study

Table 1. Characteristics of Women in the Magnesium Sulfate and Placebo Groups at Trial Entry*

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Table 2. Total Mortality and Cerebral Palsy at a Corrected Age of 2 Years Among Infants*

Table 5. Secondary Neurosensory Outcomes for Children Assessed at a Corrected Age of 2 Years*

+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 not

statistically significant.

� Substantial gross motor dysfunction was significantly less

frequent among surviving children of women randomized to

MgSO4 group

� RR 0.51, 95% CI 0.29-0.91, p<0.02

� Combined death rate or substantial motor dysfunction at

corrected age of 2

� RR 0.75, 95% CI 0.59-0.96, p<0.02

+Magpie

� Magpie Trial Follow-up Study Collaborative Group, 2007

� “The Magpie trial: a randomised trial comparing magnesium

sulfate with placebo for pre-eclampsia. Outcome for children

at 18 months”

� 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: to assess long-term effects of in-

utero exposure to MgSO4 for children whose mothers had pre-

eclampsia

� 2895 of 4483 children assessed at 18 months of age for the

primary outcome of death or neurosensory disability.

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+Magpie: Outcomes

� Original study – MgSO4 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 MgSO4 while in-utero was not associated with

a clear difference in the risk of death or disability for

children at 18 months.

� 245/1635 (15%) in MgSo4 group vs 233/1648 (14.1%) in

placebo group

� RR 1.06, 95% CI 0.9-1.25

+PREMAG

� Marret, et al. 2007

� “Benefit of magnesium sulfate given before very preterm

birth to protect infant brain”

� Objective: evaluate whether MgSO4 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

� Studied 573 mothers randomized to receive 4gm MgSO4

bolus or placebo

� Gestational age < 33 weeks whose birth was planned or

expected within 24 hours

+PREMAG: Outcomes

�Primary outcomes: 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 not statistically

significant

� Total mortality (9.4% vs. 10.4%; OR 0.79, 95% CI 0.44-1.44)

� Severe WMI (10.0% vs. 11.7%; OR 0.78, 95% CI 0.47-1.31)

� Combined (16.5% vs. 17.9%; OR 0.86, 95% CI 0.55-1.34)

+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 CP in their children.

� 20 participating centers of NICHD MFMU

� 2241 women, singleton or twin gestations 24-31 wks.

� MgSO4 administered as 6gm loading dose followed by

infusion of 2g/hr for up to 12 hours

� if no delivery within 12 hours, MgSO4 was stopped, then

restarted if delivery was imminent

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+BEAM

�Primary outcomes measured:

�Composite of stillbirth or infant death by

1 year or moderate to severe CP at or

beyond 2 years

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+BEAM: Outcomes

� The rate of the primary outcome was not significantly

different in the MgSO4 group and the placebo group (11.3%

and 11.7%, respectively )

� RR 0.97 95% CI 0.77-1.2

� Prespecified secondary analysis: when mortality and CP

were looked at separately, CP occurred significantly less

frequently in the MgSO4 group than the placebo group

among surviving children (1.9% vs 3.5%, respectively )

� RR 0.55, 95% CI 0.32-0.95

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+Interpreting BEAM

� Although the RR is not that different among the 2 groups,

because of higher overall risk in infants <28 weeks,

absolute risk reduction is greater (2.7% in MgSO4

group vs. 6.0% in placebo group)

� Compared to a no difference in absolute risk if ≥28

weeks

� NNT: 63 women to prevent one case of moderate to

severe CP, but 29 women to prevent one case among

infants 28 weeks or below

+Interpreting BEAM: Criticisms

� 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?

� Only 2 additional infants from the group who died in

those who received MgSO4 would have had to have

survived and been diagnosed with CP to lose statistical

significance

+Meta-Analysis

� Constantine M. and Weiner S., 2009

� “Effects of Antenatal Exposure to Magnesium Sulfate on

Neuroprotection and Mortality in Preterm Infants: A

Meta-analysis”

� Objective: To review the evidence regarding

neuroprotective effects of antenatal exposure to

MgSO4 and specifically explore the findings at

different gestational ages .

� Two thresholds for analysis

� Less than 32-34 wks

� Less than 30 weeks

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+Meta-Analysis

� Primary outcome:

� Composite of perinatal/infant death or CP among

survivors

� Secondary outcomes:

� Death

� CP

� Moderate-severe CP

� Combined death or moderate-severe CP

+Meta-Analysis: Outcomes

� 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.

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+Meta-Analysis

� Strengths:

� RCTs 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

+The Cochrane Collaboration

�Crowther, et al. 2009

�“Magnesium sulphate for women at risk of

preterm birth for neuroprotection of the fetus

(Review)”

�5 trials, 6145 babies were eligible for review

+The Cochrane Collaboration:

Outcomes

� MgSO4 therapy given to women at risk for preterm birth

substantially reduced:

� risk of CP in their child (RR 0.68; 95% CI 0.54-0.87)

� rate of substantial gross motor dysfunction (RR 0.61;

95% CI 0.44-0.85)

� No statistically significant effect of antenatal MgSO4 therapy

on pediatric mortality

� Plain language summary:

� “Magnesium sulfate given to women at risk of preterm birth

helps to protect the baby’s brain and improve long-term

outcomes.”

+ACOG Committee Opinion:

Number 455, March 2010

� “The Committee on Obstetric Practice and the Society for

Maternal-Fetal Medicine 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.”

� “Physicians electing to use MgSO4 for fetal neuroprotection

should develop specific guidelines regarding inclusion

criteria, treatment regimens, concurrent tocolysis and

monitoring in accordance with one of the larger trials.”

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+UCSF Protocol: Inclusion Criteria

� Patients at Risk for Preterm Birth (PTB)

� Preterm Premature Rupture of Membranes (PPROM) patients with

clinical evidence of labor/imminent delivery: 24 0/7 to 32 0/7

weeks

� Preterm Labor with Advanced Cervical Dilation (ACD): patients

admitted at 24 0/7 to 32 0/7 weeks,

� admitted with preterm labor and ACD (typically ≥ 4cm

dilation), or

� admitted with preterm labor and progress to ACD (typically ≥

4cm dilation)

� Anticipated, Indicated Preterm Delivery: patients 24 0/7

to 32 0/7 weeks, with maternal/fetal indication(s) for

preterm delivery within 2-12 hours

+UCSF Protocol: Treatment Regimen

� Magnesium Sulfate Administration

� Initial Dose:

� 4 gram (gm) bolus given over 30 minutes, followed by

� 1 gm/hour (hr) continuous infusion x 12 hrs

� Appropriate obstetric care, including delivery, should not be

delayed in order to complete 12 hrs of magnesium therapy

+UCSF Protocol: Treatment Regimen

� Re-dose: (For patients who remain pregnant after the 12

hour initial infusion)

� If > 6 hrs since last magnesium exposure, re-bolus with 4gm over

20-30 minutes, followed by 1gm/hr x 12 hours

� If < 6hrs since last magnesium exposure, restart infusion at

1gm/hr x 12 hrs without a bolus

� Typical reasons for re-dosing in the setting of PPROM

will be:

� Induction

� Non-reassuring fetal parameters with need for delivery

suspected

� Clinical suspicion for chorioamnionitis, leading to delivery

� Threatened preterm labor/imminent delivery

+UCSF Protocol: Concurrent

Tocolysis

� Nifedipine’s half-life is 2 hours so patients previously exposed to a

calcium channel blocker, for any indication, should be 4 hours out

from their last dose before magnesium sulfate, at any dose, is

initiated

� Magnesium sulfate may be used as the first-line tocolytic therapy in

patients with high clinical suspicion for imminent delivery. This

approach is aimed to avoid any delay in initiating magnesium

sulfate and to prevent concomitant exposure with calcium channel

blockers.

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+UCSF Protocol: Consent and

Monitoring� Please include the following elements in your verbal consent and

record in the patient chart that “the risks and benefits of

magnesium neuroprophylaxis were reviewed – patient accepts or

declines treatment”.

� The risks for disabilities, and even death, are significant for infants

born at this early gestational age.

� Recent data suggest that magnesium decreases, but does not

eliminate, the risk of cerebral palsy in children who survive. Given

this, we would like to offer you magnesium therapy.

� We monitor women who receive magnesium closely to minimize

side effects of magnesium, which are commonly mild.

� NICU will be informed of the use of magnesium sulfate prior to

delivery of preterm infant.

+Summary

� Although none of the primary outcomes of the studies proved

to be statistically significant, there is compelling data

suggesting MgSO4 reduces risk of CP in preterm infants.

� Greatest risk reduction in <28 week group

� Physicians and institutions implementing a new protocol for

use of MgSO4 for neuroprotection should develop specific

guidelines.

+References

� Cahill A, Caughey A. Magnesium for neuroprophylaxis: fact or fiction? Am J Obstet

Gynecol 2009;200:590-4

� Constantine M, Weiner J. Effects of Antenatal Exposure to Magnesium Sulfate on

Neuroprotection and Mortality in Preterm Infants, A Meta-analysis. Obstetrics and

Gynecology 2009;114:354-64

� Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for

neuroprotection before preterm birth: a randomized controlled trial. JAMA

2003;290:2669-76.

� Grether JK, Nelson KB, Emery SE, Cummins SK. Prenatal and perinatal factors and

cerebral palsy in very low birth weight infants. J Pediatr 1996; 128:407-14.

� Leviton A, Kuban KC, Pagano M, et al. Maternal toxemia and neonatal germinal

matrix hemorrhage in intubated infants less than 1751 grams. Obstet Gynecol 1988;

72:571-76

� Magpie Trial Follow-Up Study Collaborative Group. The Magpie Trial: a randomised

trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for

children at 18 months. BJOG 2007;114:289-99.

+References

� Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Lévêque Hellot MF, et al. Magnesium

sulphate given before very-preterm birth to protect infant brain: the randomised

controlled PREMAG trial. BJOG 2007;114:310-8.

� Marret S, Marpeau L, Follet-Bouhamed C, Cambonie G, Astruc D, Delaporte B, et al.

Effect ofmagnesium sulphate on mortality and neurologic morbidity of the very-

preterm new-born with two-year neurologic outcome: results of the prospective

PREMAG trial. Gynecol Obstet Fertil 2008;36:278-88.

� Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, et al.

Association between the use of antenatal magnesium sulfate in preterm labor and

adverse health outcomes in infants. Am J Obstet Gynecol 2002;186:1111-8.

� Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized,

controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J

Med 2008;359:895-905

� Van de Bor M, Verloove-Vanhorick SP, Brand R, et al. Incidence and prediction of

periventricular-intraventricular hemorrhage in very preterm infants. J Perinat Med

1987; 15:333-39.

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+ Thank You!