- Email: [email protected]
Magnesium sulfate for neuroprotection: now or not yet
SMFM Debates
www. AJOG.org
The editors of the Journal and the SMFM Publication Committee are pleased to provide this summary of a debate conducted at the 31st annual meeting of the Society for Maternal–Fetal Medicine (The Pregnancy Meeting), San Francisco, CA, Feb. 7-12, 2011. One entry in this series will run every month from May through October 2011.
Magnesium sulfate for neuroprotection: now or not yet THE ISSUE: Cerebral palsy is infrequent, but causes devastating neurologic consequences in preterm infants. Three recent randomized trials
and several metaanalyses have evaluated the role of antenatal magnesium sulfate for neuroprotection in patients at risk for early preterm delivery. Despite the recommendations from the metaanalyses, there is uncertainty about whether to treat or who to treat, if any, with magnesium sulfate.
Magnesium sulfate for fetal neuroprotection Dwight J. Rouse, MD
I
n the 3 large, well-done randomized placebo-controlled trials, antenatal magnesium sulfate (MgSO4) reduced the risk of cerebral palsy among children who survived early preterm birth. Crowther and colleagues1 studied 1062 women. Moderate or severe cerebral palsy (inability to walk unaided) was significantly less frequent among children in the MgSO4 group, 3.4% vs 6.6%. In the National Institutes of Health Maternal-Fetal Medicine Units Network trial (the BEAM trial) 2241 women were enrolled.2 As in the trial of Crowther et al,1 MgSO4 significantly reduced the risk of moderate to severe cerebral palsy, 1.9% vs 3.5%. Among the offspring of women randomized ⬍28 weeks, the respective risks were 2.7% and 6.1%. Marret et al3 studied 573 mothers: MgSO4 lowered the risk of cerebral palsy, 7.0% vs 10.2%. These 3 trials and 2 more (6145 children) are included in a Cochrane Systematic Review that concluded that MgSO4 reduced the risk of cerebral palsy by 32% but had no effect on fetal or infant mortality.4 Should we wait for more data or an even more definitive trial? The BEAM trial cost $25 million and took 10 years to complete. It is doubtful that a comparable trial will ever be mounted. Thus for the foreseeable future (and perhaps forever), the debate will center on the data from the completed trials. Basic research may elucidate mechanisms, and individual level patient metaanalysis may help to more precisely quantify the benefits to various candidate subgroups, but the necessary clinical research has been done. Importantly, the confidence that we can place in the consistent results of the randomized trials is heightened, not diminished, by their different inclusion and exclusion criteria, and their administration of MgSO4 according to different protocols. (continued) 0002-9378/$36.00 • © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.02.006
296
American Journal of Obstetrics & Gynecology OCTOBER 2011
...........................................................................................................................................................................................
Professor of Obstetrics and Gynecology, Alpert Medical School of Brown University and Maternal-Fetal Medicine Specialist, Women & Infants Hospital of Rhode Island, Providence, RI
Magnesium sulfate for neuroprotection in patients at risk for early preterm delivery: not yet Baha M. Sibai, MD Department of Obstetrics and Gynecology, University of Cincinnati, College of Medicine, Cincinnati, OH
nfants born at ⬍34 weeks are at increased risk for cerebral palsy (CP). This risk increases inversely according to gestational age at delivery: approximately 10% at ⬍28 weeks, 6% at 28-29 weeks, and 1.4% at 30-33 weeks. Several retrospective studies evaluated the association between magnesium sulfate (Mag) exposure and the risks of neonatal germinal matrix hemorrhage and CP; some found a beneficial effect whereas others did not. Recently, 4 randomized placebo-controlled trials investigated the benefits of Mag for neuroprotection in women at risk for early preterm delivery.1 The results of these trials found no differences in the rate of the primary outcome (death/CP) with the use of Mag,2 but secondary analysis of outcomes in 3 trials found a significant reduction in the rate of neonatal CP among those exposed to Mag.3-5 These trials were the subject of several recent metaanalyses and expert opinions with recommendations that have created some uncertainty about whether to offer Mag for neuroprotection and, if offered, about the dose to be used, and the proper gestational age.6 When we consider the design of these trials, they were variable in regard to gestational age at randomization (23-32 weeks) and latency period (median of 1.5 hours in 10 days). Two trials used only a loading dose of 4 g of Mag, 1 used 4 g loading and 1 g/h for 24 hours (median 6.5 g), and the other used 6 g loading followed by 2 g/h and allowed retreatment (median dose 31.5 g).3-5 Because the rate of CP increases as gestational age at birth declines, a large number of pregnant women must be exposed to Mag to prevent 1 case of CP at 30-33 weeks compared to those at ⬍28 weeks. If Mag is to be offered to those eligible at ⬍34 weeks, the annual number exposed will be 105,000, whereas it will be 30,000 if offered to ⬍30 weeks, and 12,000
I
(continued)
SMFM Debates
www.AJOG.org
MgSO4 is inexpensive and its safety profile is excellent: there were no life-threatening events or deaths in any of the ⬎3000 women in the Cochrane Review who received the drug. In the United States, 2% of women deliver ⬍32 weeks’ gestation. If these women received MgSO4 prior to delivery, ⬎1000 cases of handicapping cerebral palsy would be prevented safely and inexpensively every year in this country alone. To forgo this opportunity is irrationally nihilistic–it is time to use MgSO4 for fetal neuroprotection. f REFERENCES 1. 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. 2. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895-905. 3. Marret S, Maroeau L, Follet-Bouhamed C, et al. Effect of magnesium sulphate on mortality and neurologic morbidity of the very preterm newborn with two-year neurological outcome: results of the prospective PREAMAG trial. Gynecol Obstet Fertil 2008;36:278-88. 4. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;1:CD004661.
.......................................................................................................................................................................................
Dr Rouse (continued)
Dr Sibai (continued) if offered at ⬍28 weeks. Despite the fact that Mag is inexpensive and easy to give, it is associated with high rates of minor side effects, and rare but serious side effects such as cardiorespiratory arrest and death. In addition, its use requires close nursing observation and need for enormous resources in labor and delivery. Finally, the use of trial sequential analysis to assess the data from the included randomized trials for the effect of antenatal Mag on CP revealed that the apparently conclusive beneficial effect resulting from the recent Cochrane metaanalyses may, in fact, be a false-positive result because of a risk of random error. Thus, it seems that the apparent beneficial effects of Mag on CP remain uncertain. f REFERENCES 1. Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;3:1-93. 2. American College of Obstetricians and Gynecologists. ACOG Committee on Obstetric Practice; Society for Maternal-Fetal Medicine. Committee opinion no. 455: magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol 2010;115:669-71. 3. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial; Australasian collaborative trial of magnesium sulphate (ACTOMg SO4) collaborative group. JAMA 2008;290:2669-76. 4. Marret S, Marpeau I, Zupan-Simunek V, et al. Magnesium sulphate given before very very-preterm birth to protect infant brain: the randomized controlled PREMAG trial. BJOG 2007;114:310-8. 5. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy; Eunice Kennedy Shriver NICHD Maternal-Fetal Units Network. N Engl J Med 2008;359: 895-905. 6. Huusom LD, Secher NJ, Pryds O, et al. Antenatal magnesium sulfate may prevent cerebral palsy in preterm infants– but are we convinced? Evaluation of an apparently conclusive meta-analysis with trial sequential analysis. BJOG 2011;118:1-5.
OCTOBER 2011 American Journal of Obstetrics & Gynecology
297
www. AJOG.org
The editors of the Journal and the SMFM Publication Committee are pleased to provide this summary of a debate conducted at the 31st annual meeting of the Society for Maternal–Fetal Medicine (The Pregnancy Meeting), San Francisco, CA, Feb. 7-12, 2011. One entry in this series will run every month from May through October 2011.
Magnesium sulfate for neuroprotection: now or not yet THE ISSUE: Cerebral palsy is infrequent, but causes devastating neurologic consequences in preterm infants. Three recent randomized trials
and several metaanalyses have evaluated the role of antenatal magnesium sulfate for neuroprotection in patients at risk for early preterm delivery. Despite the recommendations from the metaanalyses, there is uncertainty about whether to treat or who to treat, if any, with magnesium sulfate.
Magnesium sulfate for fetal neuroprotection Dwight J. Rouse, MD
I
n the 3 large, well-done randomized placebo-controlled trials, antenatal magnesium sulfate (MgSO4) reduced the risk of cerebral palsy among children who survived early preterm birth. Crowther and colleagues1 studied 1062 women. Moderate or severe cerebral palsy (inability to walk unaided) was significantly less frequent among children in the MgSO4 group, 3.4% vs 6.6%. In the National Institutes of Health Maternal-Fetal Medicine Units Network trial (the BEAM trial) 2241 women were enrolled.2 As in the trial of Crowther et al,1 MgSO4 significantly reduced the risk of moderate to severe cerebral palsy, 1.9% vs 3.5%. Among the offspring of women randomized ⬍28 weeks, the respective risks were 2.7% and 6.1%. Marret et al3 studied 573 mothers: MgSO4 lowered the risk of cerebral palsy, 7.0% vs 10.2%. These 3 trials and 2 more (6145 children) are included in a Cochrane Systematic Review that concluded that MgSO4 reduced the risk of cerebral palsy by 32% but had no effect on fetal or infant mortality.4 Should we wait for more data or an even more definitive trial? The BEAM trial cost $25 million and took 10 years to complete. It is doubtful that a comparable trial will ever be mounted. Thus for the foreseeable future (and perhaps forever), the debate will center on the data from the completed trials. Basic research may elucidate mechanisms, and individual level patient metaanalysis may help to more precisely quantify the benefits to various candidate subgroups, but the necessary clinical research has been done. Importantly, the confidence that we can place in the consistent results of the randomized trials is heightened, not diminished, by their different inclusion and exclusion criteria, and their administration of MgSO4 according to different protocols. (continued) 0002-9378/$36.00 • © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.02.006
296
American Journal of Obstetrics & Gynecology OCTOBER 2011
...........................................................................................................................................................................................
Professor of Obstetrics and Gynecology, Alpert Medical School of Brown University and Maternal-Fetal Medicine Specialist, Women & Infants Hospital of Rhode Island, Providence, RI
Magnesium sulfate for neuroprotection in patients at risk for early preterm delivery: not yet Baha M. Sibai, MD Department of Obstetrics and Gynecology, University of Cincinnati, College of Medicine, Cincinnati, OH
nfants born at ⬍34 weeks are at increased risk for cerebral palsy (CP). This risk increases inversely according to gestational age at delivery: approximately 10% at ⬍28 weeks, 6% at 28-29 weeks, and 1.4% at 30-33 weeks. Several retrospective studies evaluated the association between magnesium sulfate (Mag) exposure and the risks of neonatal germinal matrix hemorrhage and CP; some found a beneficial effect whereas others did not. Recently, 4 randomized placebo-controlled trials investigated the benefits of Mag for neuroprotection in women at risk for early preterm delivery.1 The results of these trials found no differences in the rate of the primary outcome (death/CP) with the use of Mag,2 but secondary analysis of outcomes in 3 trials found a significant reduction in the rate of neonatal CP among those exposed to Mag.3-5 These trials were the subject of several recent metaanalyses and expert opinions with recommendations that have created some uncertainty about whether to offer Mag for neuroprotection and, if offered, about the dose to be used, and the proper gestational age.6 When we consider the design of these trials, they were variable in regard to gestational age at randomization (23-32 weeks) and latency period (median of 1.5 hours in 10 days). Two trials used only a loading dose of 4 g of Mag, 1 used 4 g loading and 1 g/h for 24 hours (median 6.5 g), and the other used 6 g loading followed by 2 g/h and allowed retreatment (median dose 31.5 g).3-5 Because the rate of CP increases as gestational age at birth declines, a large number of pregnant women must be exposed to Mag to prevent 1 case of CP at 30-33 weeks compared to those at ⬍28 weeks. If Mag is to be offered to those eligible at ⬍34 weeks, the annual number exposed will be 105,000, whereas it will be 30,000 if offered to ⬍30 weeks, and 12,000
I
(continued)
SMFM Debates
www.AJOG.org
MgSO4 is inexpensive and its safety profile is excellent: there were no life-threatening events or deaths in any of the ⬎3000 women in the Cochrane Review who received the drug. In the United States, 2% of women deliver ⬍32 weeks’ gestation. If these women received MgSO4 prior to delivery, ⬎1000 cases of handicapping cerebral palsy would be prevented safely and inexpensively every year in this country alone. To forgo this opportunity is irrationally nihilistic–it is time to use MgSO4 for fetal neuroprotection. f REFERENCES 1. 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. 2. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895-905. 3. Marret S, Maroeau L, Follet-Bouhamed C, et al. Effect of magnesium sulphate on mortality and neurologic morbidity of the very preterm newborn with two-year neurological outcome: results of the prospective PREAMAG trial. Gynecol Obstet Fertil 2008;36:278-88. 4. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;1:CD004661.
.......................................................................................................................................................................................
Dr Rouse (continued)
Dr Sibai (continued) if offered at ⬍28 weeks. Despite the fact that Mag is inexpensive and easy to give, it is associated with high rates of minor side effects, and rare but serious side effects such as cardiorespiratory arrest and death. In addition, its use requires close nursing observation and need for enormous resources in labor and delivery. Finally, the use of trial sequential analysis to assess the data from the included randomized trials for the effect of antenatal Mag on CP revealed that the apparently conclusive beneficial effect resulting from the recent Cochrane metaanalyses may, in fact, be a false-positive result because of a risk of random error. Thus, it seems that the apparent beneficial effects of Mag on CP remain uncertain. f REFERENCES 1. Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulfate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009;3:1-93. 2. American College of Obstetricians and Gynecologists. ACOG Committee on Obstetric Practice; Society for Maternal-Fetal Medicine. Committee opinion no. 455: magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol 2010;115:669-71. 3. Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial; Australasian collaborative trial of magnesium sulphate (ACTOMg SO4) collaborative group. JAMA 2008;290:2669-76. 4. Marret S, Marpeau I, Zupan-Simunek V, et al. Magnesium sulphate given before very very-preterm birth to protect infant brain: the randomized controlled PREMAG trial. BJOG 2007;114:310-8. 5. Rouse DJ, Hirtz DG, Thom E, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy; Eunice Kennedy Shriver NICHD Maternal-Fetal Units Network. N Engl J Med 2008;359: 895-905. 6. Huusom LD, Secher NJ, Pryds O, et al. Antenatal magnesium sulfate may prevent cerebral palsy in preterm infants– but are we convinced? Evaluation of an apparently conclusive meta-analysis with trial sequential analysis. BJOG 2011;118:1-5.
OCTOBER 2011 American Journal of Obstetrics & Gynecology
297