Barbara V. Parilla, MDBarbara V. Parilla, MD

Clinical Professor of Obstetrics and Clinical Professor of Obstetrics and GynecologyGynecology

University of Illinois at ChicagoUniversity of Illinois at Chicago

Director, Maternal Fetal MedicineDirector, Maternal Fetal Medicine

Advocate Lutheran General HospitalAdvocate Lutheran General Hospital

Background cerebral palsyBackground cerebral palsy Initial retrospective studiesInitial retrospective studies Prospective-randomized trials in detailProspective-randomized trials in detail Meta-analysis Meta-analysis Hill’s CriteriaHill’s Criteria Molecular mechanismMolecular mechanism Cost-effectivenessCost-effectiveness Simultaneous tocolysisSimultaneous tocolysis Summary & general recommendationsSummary & general recommendations

InexpensiveInexpensive Easy to AdministerEasy to Administer Safe Safe Used regularly by OB’s comfortable Used regularly by OB’s comfortable

with it’s use in pre-eclampsia to prevent with it’s use in pre-eclampsia to prevent seizuresseizures

In utero exposure before preterm birth In utero exposure before preterm birth appears to decrease the incidence and appears to decrease the incidence and severity of cerebral palsyseverity of cerebral palsy

Heterogeneous group of disorders of Heterogeneous group of disorders of movement and/or posturemovement and/or posture

Most common cause of severe motor Most common cause of severe motor disability in childhooddisability in childhood

Prevalence 2-3/1,000 live birthsPrevalence 2-3/1,000 live births Prematurity is a powerful risk factorPrematurity is a powerful risk factor 80x higher among infants 23-27 weeks80x higher among infants 23-27 weeks Number of children at risk is increasingNumber 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; 359:262.

Murphy DJ. BMJ 8 February 1997

Murphy DJ. BMJ 8 February 1997

Case-control study of children with & Case-control study of children with & without CP that were VLBWwithout CP that were VLBW

Children with CP significantly less likely to Children with CP significantly less likely to have been exposed to MgSOhave been exposed to MgSO44

OR 0.14, 95% CI 0.05-0.51OR 0.14, 95% CI 0.05-0.51 Subsequent observational studies Subsequent observational studies

confirmed and refuted findingsconfirmed and refuted findings MgSOMgSO44 administered as tocolytic or administered as tocolytic or

prevention of eclamptic seizure prevention of eclamptic seizure

Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95:263.

RR = incidence in exposed individuals RR = incidence in exposed individuals ÷ ÷ incidence in incidence in unexposed individuals. unexposed individuals.

RR can be calculated from studies in which the RR can be calculated from studies in which the proportion of patients exposed and unexposed to a risk proportion of patients exposed and unexposed to a risk is known, such as a cohort study. is known, such as a cohort study.

OR = the odds that an individual with a specific condition OR = the odds that an individual with a specific condition has been exposed to a risk factor has been exposed to a risk factor ÷÷ the odds that a the odds that a control has been exposed. control has been exposed.

OR is used in case-control studies and is often generated OR is used in case-control studies and is often generated in multivariate analyses as well. in multivariate analyses as well.

OR provides a reasonable estimate of the RR for OR provides a reasonable estimate of the RR for uncommon conditions uncommon conditions

Confidence interval (CI): A point estimate from a Confidence interval (CI): A point estimate from a sample population may not reflect the "true" sample population may not reflect the "true" value from the entire population. value from the entire population.

Often helpful to provide a range that is likely to Often helpful to provide a range that is likely to include the true value. A CI is a commonly used include the true value. A CI is a commonly used estimate. The boundaries of a confidence estimate. The boundaries of a confidence interval give values within which there is a high interval give values within which there is a high probability (95 percent by convention) that the probability (95 percent by convention) that the true population value can be found. true population value can be found.

The calculation of a CI considers the standard The calculation of a CI considers the standard deviation of the data and the number of deviation of the data and the number of observations. observations.

A CI narrows as the number of observations A CI narrows as the number of observations increases, or its variance (dispersion) decreases. increases, or its variance (dispersion) decreases.

StatisticsStatistics

The RR and OR are interpreted relative to the The RR and OR are interpreted relative to the number one. number one.

OR of 0.6, for example, suggests that patients OR of 0.6, for example, suggests that patients exposed to a variable of interest were 40 exposed to a variable of interest were 40 percent less likely to develop a specific percent less likely to develop a specific outcome compared to the control group. outcome compared to the control group.

Similarly, OR of 1.5 suggests that the risk was Similarly, OR of 1.5 suggests that the risk was increased by 50 percent. increased by 50 percent.

If the 95% CI crosses 1, it is NOT statistically If the 95% CI crosses 1, it is NOT statistically significantsignificant

StatisticsStatistics

Mittendorf R. Lancet; 11/22/97, Vol. 350 Issue 9090, p1517.

149 maternal randomizations149 maternal randomizations Randomized 4 arms Randomized 4 arms

– Tocolytic PTL <34 wks <4cm (MgSOTocolytic PTL <34 wks <4cm (MgSO44 v v “other”-unblinded, switchover to different “other”-unblinded, switchover to different tocolytic allowed if MgSOtocolytic allowed if MgSO44 failed) 4g load, 2-3 failed) 4g load, 2-3 g/h g/h n=46, 47n=46, 47

– Preventive arm- double-blinded PTL>4cm Preventive arm- double-blinded PTL>4cm received MgSOreceived MgSO4 4 or saline or saline n=28n=28

– Primary outcome total paediatric mortality Primary outcome total paediatric mortality (fetal, neonatal, and post neonatal) and (fetal, neonatal, and post neonatal) and cerebral palsycerebral palsy

Interim safety monitoring showed 9 Interim safety monitoring showed 9 paediatric deaths paediatric deaths

10 total deaths: 5 singletons, 3 twin 10 total deaths: 5 singletons, 3 twin pairs where 1 sibling died, 1 twin pair pairs where 1 sibling died, 1 twin pair where both diedwhere both died

Non-twin deaths ? sequelae Non-twin deaths ? sequelae infections ? additional tocolysisinfections ? additional tocolysis

Mittendorf R. Lancet; 11/22/97, Vol. 350 Issue 9090, p1517.

The Australian Collaborative Trial of The Australian Collaborative Trial of Magnesium Sulphate - ACTOMgSOMagnesium Sulphate - ACTOMgSO44

1062 women <30 wks 1062 women <30 wks expected to deliver <24 hrsexpected to deliver <24 hrs

Randomly assigned 4 g load then 1g/hr Randomly assigned 4 g load then 1g/hr or placebo for 24 hr maxor placebo for 24 hr max

Primary outcomes: rates of total pediatric Primary outcomes: rates of total pediatric mortality, cerebral palsy, and combined mortality, cerebral palsy, and combined outcome at 2 yrs (available for 99%)outcome at 2 yrs (available for 99%)

Crowther CA, Hiller JE, Doyle LW, Haslam RR. JAMA 2003;290:2669

MgSOMgSO44 v placebo v placebo Pediatric mortality 13.8 v 17.1 Pediatric mortality 13.8 v 17.1

(RR 0.83, 95% CI 0.64-1.09)(RR 0.83, 95% CI 0.64-1.09) Cerebral Palsy 6.8 v 8.2 Cerebral Palsy 6.8 v 8.2

(RR 0.83, 95% CI 0.54-1.27)(RR 0.83, 95% CI 0.54-1.27) Combined outcome 19.8 v 24 Combined outcome 19.8 v 24

(RR 0.83. 95% CI 0.66-1.03)(RR 0.83. 95% CI 0.66-1.03) Despite lack of statistical significance, Despite lack of statistical significance,

potentially clinically importantpotentially clinically important

Crowther CA, Hiller JE, Doyle LW, Haslam RR. JAMA 2003;290:2669

When only gross motor function When only gross motor function considered MgSOconsidered MgSO44 exposed had exposed had significantly lower rates significantly lower rates 3.4 v 6.6% 3.4 v 6.6%

(RR 0.51, 95% CI (RR 0.51, 95% CI 0.29-0.91)0.29-0.91)

Combined outcome gross motor and death Combined outcome gross motor and death 17 v 22.7% 17 v 22.7%

(RR 0.75, 95% CI 0.59-0.96)(RR 0.75, 95% CI 0.59-0.96)

Magnesium sulfate Magnesium sulfate tocolysis: time to quittocolysis: time to quit

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

Grimes D. Obstet Gynecol (Oct 2006) 108(4):986-9

NICHD/MFMU multicenter placebo NICHD/MFMU multicenter placebo controlled trial “beneficial effects of controlled trial “beneficial effects of antenatal magnesium sulfate”antenatal magnesium sulfate”

2241 women 24-31 wks at risk for 2241 women 24-31 wks at risk for imminent deliveryimminent delivery

6 gm load, 2 g/hr6 gm load, 2 g/hr Infusion stopped after 12 hrs if delivery Infusion stopped after 12 hrs if delivery

no longer considered imminentno longer considered imminent F/U available 95.6% childrenF/U available 95.6% children

Rouse DJ, Hirtz DG, Thom E, et al. N Engl J Med. 2008; 359:895.

Primary study outcome “stillbirth or infant Primary study outcome “stillbirth or infant death by one year corrected age or moderate to death by one year corrected age or moderate to severe CP ≥ 2 yrs corrected age”severe CP ≥ 2 yrs corrected age”

MgSOMgSO4 4 v placebo 11.3 v 11.7%v placebo 11.3 v 11.7% Rate of moderate to severe CP 1.9 v 3.5% Rate of moderate to severe CP 1.9 v 3.5%

(RR 0.55, 95% CI 0.32-0.95)(RR 0.55, 95% CI 0.32-0.95) Only infants randomized at <28 wks showed a Only infants randomized at <28 wks showed a

significant reduction in moderate or severe CPsignificant reduction in moderate or severe CP Risk of death similar in the 2 groups 9.5 v 8.5Risk of death similar in the 2 groups 9.5 v 8.5

(RR 1.12 95% CI 0.85-1.47)(RR 1.12 95% CI 0.85-1.47) Suggests that lower rate of CP not simply due Suggests that lower rate of CP not simply due

to increased death rate in MgSOto increased death rate in MgSO44 group group

Enrolled 573 women < 33 wks expected to Enrolled 573 women < 33 wks expected to deliver <24 hrsdeliver <24 hrs

Single 4 gm loading dose or placebo, no Single 4 gm loading dose or placebo, no maintenancemaintenance

Infants followed for 2 years after hospital D/CInfants followed for 2 years after hospital D/C Primary outcome was white matter injury on Primary outcome was white matter injury on

neonatal cranial USneonatal cranial US Composite outcomes of “CP or death” and Composite outcomes of “CP or death” and

“severe motor dysfunction or death” were “severe motor dysfunction or death” were secondarysecondary

Marret S, Marpeau L, Follet-Bouhamed C, et al. Gynecol Obstet Fertil 2008; 36:278

Protective effect of MgSOProtective effect of MgSO44 against against “cerebral palsy or death” OR 0.65, 95% CI “cerebral palsy or death” OR 0.65, 95% CI 0.42-1.030.42-1.03

Exposure to MgSOExposure to MgSO44 was protective against was protective against “severe motor dysfunction or death” “severe motor dysfunction or death”

OR 0.62, 95% CI 0.41-0.93OR 0.62, 95% CI 0.41-0.93 Despite lack of statistical significance, the Despite lack of statistical significance, the

average size of the reduction is potentially average size of the reduction is potentially clinically importantclinically important

Marret S, Marpeau L, Follet-Bouhamed C, et al. Gynecol Obstet Fertil 2008; 36:278

Consistency of the associationConsistency of the association Strength of the associationStrength of the association Dose-response relationshipDose-response relationship Temporal relationshipTemporal relationship Biologic plausibilityBiologic plausibility ExperimentExperiment CoherenceCoherence

Most prevalent pathologic lesion in CP is peri Most prevalent pathologic lesion in CP is peri ventricular white matter (PVWM) injury ventricular white matter (PVWM) injury resulting from vulnerability of immature resulting from vulnerability of immature preoligodendrocytes (POD) <32 weekspreoligodendrocytes (POD) <32 weeks

POD are precursors of myelinating POD are precursors of myelinating oligidendrocytes which constitute a major oligidendrocytes which constitute a major glial population in white matterglial population in white matter

Oxidative stress & excitotoxicity from Oxidative stress & excitotoxicity from excessive stimulation of ionotropic glutamate excessive stimulation of ionotropic glutamate receptors on POD are the most prominent receptors on POD are the most prominent molecular mechanism for PVWM injurymolecular mechanism for PVWM injury

Recent studies have identified Recent studies have identified functional N-methyl-D-aspartate functional N-methyl-D-aspartate (NMDA) glutamatergic receptors in (NMDA) glutamatergic receptors in oligodendroglial injury processesoligodendroglial injury processes

Antagonists of the NMDA receptors for Antagonists of the NMDA receptors for glutamate are potent neuroprotective glutamate are potent neuroprotective agents in several animal models of agents in several animal models of perinatal brain lesionsperinatal brain lesions

In addition, MgSOIn addition, MgSO4 4 could also reverse could also reverse the destructive action of oxygen the destructive action of oxygen radicals and excitatory amino acidsradicals and excitatory amino acids

Growing evidence suggests MgSOGrowing evidence suggests MgSO44 may reverse the harmful effects of may reverse the harmful effects of hypoxic/ischemic brain damage by hypoxic/ischemic brain damage by blocking the NMDA receptors and, as a blocking the NMDA receptors and, as a calcium antagonist, hindering calcium calcium antagonist, hindering calcium influx into the cells influx into the cells

Strong argument for use in women at Strong argument for use in women at risk of PTD <32risk of PTD <32

Limitations include variations in Limitations include variations in inclusion & exclusion criteriainclusion & exclusion criteria

GA at administrationGA at administrationloading and loading and

maintenance doses maintenance doses duration of duration of intervention intervention and use and use of retreatmentof retreatment

In the placebo arm of the NICHD/MFMU In the placebo arm of the NICHD/MFMU trial, rate of mod-severe CP was 3.5%trial, rate of mod-severe CP was 3.5%

Assuming a MgSOAssuming a MgSO44 effect size of 30%, with effect size of 30%, with 80% power and a 2-tailed alpha of 0.0580% power and a 2-tailed alpha of 0.05

Confirmatory trial would require >8000 Confirmatory trial would require >8000 women <32 weeks and 100% F/U of women <32 weeks and 100% F/U of childrenchildren

Enrollment of 2241 mothers in the 20 Enrollment of 2241 mothers in the 20 center NICHD/MFMU Network trial took 10 center NICHD/MFMU Network trial took 10 years and cost $25 millionyears and cost $25 million

The number needed to treat with MgSOThe number needed to treat with MgSO44 is is in line with current use of MgSOin line with current use of MgSO44 for other for other indicationsindications

Treating 63 women threatening to deliver Treating 63 women threatening to deliver <32 weeks will prevent 1 case of mod to <32 weeks will prevent 1 case of mod to severe CPsevere CP

If threshold limited to <28 weeks, NICHD If threshold limited to <28 weeks, NICHD MFMU network suggests that only 29 MFMU network suggests that only 29 women would need to be treated to women would need to be treated to prevent 1 caseprevent 1 case

Services in which calcium channel Services in which calcium channel blockers are primary tocolytic pose a blockers are primary tocolytic pose a dilemmadilemma

Choices include Choices include MgSOMgSO44 primary tocolytic primary tocolytic (not (not efficacious)efficacious)IndomethacinIndomethacinContinue to use calcium channel Continue to use calcium channel blockers and MgSOblockers and MgSO44 simultaneously and simultaneously and risk hypotension (not recommended)risk hypotension (not recommended)

144 echos 44 pregnancies17/60 fetus =28%

KJ Moise AJOG 1993;168:1350-3

KJ Moise AJOG 1993;168:1350-3

llAll reversible!

Systematic Review of TocolyticsEffect on Delay of Delivery

Gyetvai et al. Obstet Gynecol 1999;94:869-77

Beta-mimetics MgSO4 Indomethacin

Delivery < 24 h

Delivery < 48 h

Delivery < 7 d

Del ivery < 37 wks __________________ ____________________ ___________________

1 1 10.1 10 0.1 10 0.1 10

·

·

·

·

·

·

··

·

·

·

0.12

0.07

0.09

1.07

0.53

1.54

0.67

0.34

0.56

0.65

0.29

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

For women at risk of PTB we suggest For women at risk of PTB we suggest antenatal administration of MgSOantenatal administration of MgSO44

Randomized placebo-controlled trials of Randomized placebo-controlled trials of maternal administration of MgSOmaternal administration of MgSO44 in women in women expected to have a PTD within 24 hrs have expected to have a PTD within 24 hrs have consistently demonstrated a decrease of CP consistently demonstrated a decrease of CP and severe motor dysfunction in offspring and severe motor dysfunction in offspring

However, the possibility of an increased risk However, the possibility of an increased risk of death in a sub group of fetuses or infants of death in a sub group of fetuses or infants has not conclusively been excludedhas not conclusively been excluded

In the United States, 2% of women deliver In the United States, 2% of women deliver <32 weeks. If MgSO<32 weeks. If MgSO44 was uniformly was uniformly administered to the 75% of women who administered to the 75% of women who deliver spontaneously and it was as deliver spontaneously and it was as effective as in the NICHD/MFMU Network effective as in the NICHD/MFMU Network trial, then more than 1000 fewer children trial, then more than 1000 fewer children a year would suffer from handicapping CPa year would suffer from handicapping CP

““For their sake, we should avail ourselves For their sake, we should avail ourselves of this opportunity”of this opportunity”

Dwight J Rouse. AJOG June 2009

ACOG Committee OpinionACOG Committee OpinionNumber 455 March 2010Number 455 March 2010

““The Committee on Obstetric Practice The Committee on Obstetric Practice and SMFM recognize that none of the and SMFM recognize that none of the individual studies found a benefit with individual studies found a benefit with regard to their primary outcome. regard to their primary outcome. However, the available evidence However, the available evidence suggests that MgSOsuggests that MgSO44 given before given before anticipated early preterm birth anticipated early preterm birth reduces the risk of CP in surviving reduces the risk of CP in surviving infants”infants”

Inclusion criteria, treatment Inclusion criteria, treatment regimens, large trialsregimens, large trials

StudyStudy Total Total # #

InclusioInclusionn

DoseDose DurationDuration Death & Death & CPCP

DeathDeath CPCP

CrowtherCrowther 1,2551,255 <30 wks <30 wks likely likely deliv 24hdeliv 24h

4 g 4 g load 1 load 1 g/hrg/hr

Up to 24 hrUp to 24 hr RR 0.83 RR 0.83 0.66-1.030.66-1.03

RR 0.83 RR 0.83 0.64-0.64-1.091.09

RR 0.83 RR 0.83 0.54-0.54-1.271.27

MarretMarret 688688 <33 wks<33 wks 4 g 4 g load load onlyonly

Loading Loading dose onlydose only

OR 0.80 OR 0.80 0.58-1.100.58-1.10

OR 0.85 OR 0.85 0.55-0.55-1.321.32

OR 0.70 OR 0.70 0.41-0.41-1.191.19

RouseRouse 2,2412,241 24-31 24-31 wks high wks high risk SPTBrisk SPTB

6 g 6 g load 2 load 2 g/hrg/hr

Up to 12 hrs; Up to 12 hrs; retreat when retreat when deliv deliv imminentimminent

RR 0.97 RR 0.97 0.77-1.230.77-1.23

RR 1.12 RR 1.12 0.85-0.85-1.471.47

RR 0.55 RR 0.55 0.32-0.32-0.950.95

MgSOMgSO4 4 administered when imminent delivery administered when imminent delivery from either PPROM or intact preterm seems from either PPROM or intact preterm seems likely, or before an indicated PTDlikely, or before an indicated PTD

We limit to 24-32 weeksWe limit to 24-32 weeks 4-6 gram load, 2 gm/hr4-6 gram load, 2 gm/hr Therapy discontinued by 24 hours if delivery Therapy discontinued by 24 hours if delivery

has not occurredhas not occurred If tocolysis indicated, we use indomethacinIf tocolysis indicated, we use indomethacin We retreat for women who do not deliver We retreat for women who do not deliver

after an initial course of therapyafter an initial course of therapy

Rescue SteroidsRescue Steroids

GA < 33 weeksGA < 33 weeks Single course given < 30 weeksSingle course given < 30 weeks > 2 weeks ago> 2 weeks ago Delivery considered likelyDelivery considered likely

Garite TJ. AJOG March 2009

Barbara.Parilla@advocatehealth.comBarbara.Parilla@advocatehealth.com