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Magnesium Sulfate for

Neuroprotection of

Prematurity

C. David Adair, M.D.

Professor and Vice-Chairman

The University of Tennessee College of Medicine

Department of Obstetrics & Gynecology

Section on Maternal-Fetal Medicine

Chattanooga, TN

+ Objectives

Define Cerebral Palsy

Review mechanisms of brain injury at neuronal level

Discuss mechanisms of MgSO4 as a potential

neuroprotective agent

Review the current literature of antenatal MgSO4

Review a suggested MgSO4 protocol

Conflict Statement

I have no real or potential conflicts

regarding the presentation of the material.

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+ 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 ranges from 4-8%

Slightly higher incidence in males and in multiple

gestations

+ Cerebral Palsy

Risk Factors:

Preterm Birth

Damage to a developing brain

PVL, IVH

Birth Asphyxia

Hypoxia ischemic encephalopathy (HIE)

+ 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 excitory 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 vessles, increasing

cerebral blood flow

Reduction of oxygen free radicals

Reduction of inflammatory cytokines

+ 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.

+ ACTOMgSO4

Crowther, et al. 2003. Australian Collabortive 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*

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.

Stillbirth or death before age 2 was significantly less frequent

among infants of women randomized to MgSO4 group

RR 0.83, 95% CI 0.64-1.09

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

+ 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.

+ 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.

+ 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

+ 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

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

+ Interpreting BEAM

Infants born <28 weeks had approximately same relative

risk reduction (RR 0.45, 95% CI 0.23-0.97)

Because of higher overall risk of this group, absolute risk

reduction is greater (2.7% in MgSO4 group vs. 6.1% 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

Unknown to most historians, William Tell had an older and

less fortunate son named Warren.

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+ 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

+ 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.

+ Meta-Analysis

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

+ 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 if 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:

Hot off the Press

“... 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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+ Protocol: Inclusion Criteria

Patients at Risk for Preterm Birth (PTB): all between 24

0/7-32 0/7 wks

Preterm Premature Rupture of Membranes (PPROM) patients with

clinical evidence of labor/imminent delivery

Preterm Labor with Advanced Cervical Dilation (ACD >4cm):

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

Anticipated, Indicated Preterm Delivery: maternal/fetal

indication(s) for preterm delivery within 2-12 hours

Should we look only at <28wks infants?

+ Protocol: Treatment Regimen

Magnesium Sulfate Administration for neuroprophylaxis

only

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

Note: our group uses MgSO4 as 1st line tocolytic agent at 6g

bolus to load, then titrate from 3g/hr for maintenance level x

48hr (thus we meet the minimum amount of Mg used for

neuroprophylaxis anyway)

+ 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

+ Protocol: Concurrent Tocolysis

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

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

+ 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.

+ 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.