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Review Article
Antenatal Magnesium Sulfate for Neuroprotective Effects In Preterm Infants
Young lim Oh
Kosin Medical Journal 2014;29(2):99-106.
DOI: https://doi.org/10.7180/kmj.2014.29.2.99
Published online: December 18, 2014

1Department of Obstetrics and Gynecology, College of Medicine, Kosin University, Busan, Korea

Corresponding Author : Young Lim Oh, Department of Obstetrics and Gynecology, College of Medicine, Kosin University, 262, Kamcheon-ro, Seo-gu, Busan, 602-702, Korea TEL: +82-51-990-6359 FAX: +82-51-244-6939 E-mail: marianna1113@naver.com
• Received: October 10, 2014   • Accepted: October 15, 2014

Copyright © 2014 Kosin University School of Medicine Proceedings

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Fetal or neonatal brain injury can result in lifelong neurologic disability. Although survival rates for preterm infants have increased dramatically with the advent of modern perinatal and neonatal intensive care, but the rates of neurologic abnormalities in survivors, particularly motor disorders such as cerebral palsy, have not diminished. Antenatal magnesium sulfate may reduce the rates of cerebral palsy in survivors of preterm birth. There are five randomized controlled trials of magnesium sulfate administered to women at risk of preterm delivery before 34 weeks of gestation which have reported neurological outcomes for the child. From meta-analysis of these randomized trials, the rate of cerebral palsy was reduced by magnesium sulfate (RR, ᄋ·69; 95% CI, ᄋ·54-ᄋ·87; five trials; 6,145 infants) as did the moderate/severe cerebral palsy incidence (RR, 0.64; 95% CI, ᄋ·44-ᄋ·92; three trials; 4387 infants). There was no statistically significant difference between the rates of neonatal adverse outcomes of the magnesium administration group and the control group. In most prospective randomized studies, no significant difference in the severe mother-side side effects between the magnesium sul- fate administration group and the control group.
    Antenataᅵ magnesium sulfate therapy is neuroprotective against motor dysfunction in offspring for the preterm infant; however the possibility of an increase in the fetal or neonatal death rate was not completely excluded.
  • Keywords: Cerebral Palsy; Magnesium Sulfate; Mortality; Neroprotection; preterm birth
Table 1.
Characteristics of Included Studies
Study Centers NumbeT of participants Gestational age Magnesium regimen Neuroprotective outcomes
MagNET 1 149 mothers 25-33 weeks 4 gm bolus Antenatal MgSO4 was associated with worse perinatal
Mittendorff et al (United States) 165 fetus   (neuroprotective arm) outcome
ACTOMgSO4 16 1,062 mothers <30 weeks 4 gm bolus, 1 gm/h CP RR:0.83; 95% CI: 0,54-1.27
Crowther et al (Austrailia and New Zealand) 1,255 fetuses   maintenance  
PreMAG trial + folllow up trial 18
(France)		 573 mothers
6S8 fetuses		 <33 weeks 4 gm bolus, no maintenance Original trial: Nonsignificant decrease in risk of short-term severe white matter injury, mortality before hospital discharge
Marret et al   (original trial)      
    472 children     Follow-up trial (2 years): Combined death or cerebral palsy
    (follow-up trial)     OR, 0.65; 95% CI: 0.42-1.03
         
          Combined death or gross motor dysfunction OR: 0.62; 95%
          CI: 0.41-0,95 (siatisiicatly significant)
BEAM. Rouse et al 20
(United States)		 2.241 mothers
2,444 fetuses		 24-31 weeks 6 gm bolus. 2gm/h maintenance Significant dcciease in the risk of moderate or severe CP (RR: 0,55; 95% CI: 0,32-0.92) among survival children in the MgSO4 group
          Death and CP RR: 0.97; 95% CI:
Magpie trial 125 3.283 children <37 weeks c 4 gm bolus, 1 gm/h IV Combined death or neuroseasory disability RR: 1.06; 95% CI:
Duley et al (International)   preeclampsia matnieaance or, 4 gm 0.40-1.29
        bolus combined wilh 10  
        gm IM, then 5 gm/4 hrs  
        IM maintenance  

CI: Confidence Interval; CP: Cerebral Palsy; OR: Odds ratio; RR: Relative risk

Table 2.
Meta-Analysis of Mortality, Cerebral Palsy, Substantial Gross Motor Dysfonction an Combined Outcome by Subcategory of Intent23
Outcome and Subcategory No. of Studies Magnesium n/N (%) Control n/N (%) RR∗ 95% CI∗ Statistical Significance Heterogeneity [I2(%)]
Mortality              
  Neuroprotective intent 4 226/2,199(10.3) 242/2,247 (10.8) 0.94 0.77-1.15 Z=0.58,P=.56 19.6
  Other intent 2 217/853 (25.4) 188/846 (22.2) 2.86 0.23-35.8 Z=0.81,P=.42 71.2
Total 5† 443/3,052 (145) 430/3,093 (13.9) 1.01 0.82-1.23 Z=0.08,P=.94 44.9
  Cerebral palsy              
  Neuroprotective intent 4 102/2,199(4.6) 146/2,247 (6.5) 0.71 0.55-0.91 Z=2.74,P=006 25.2
Other intent 1 2/853 (0.2) 8/846 (0.9) 0.29 0.07-1.16 Z=I.75,P=.08 0
  Total 5† 104/3,052 (3.4) 154/3,093(5.0) 0.69 0.54-0,87 Z=3.07,P=.002 11.7
Mortality or cerebral palsy              
  Neuroprotective intent 4 528/2,199(14.9) 387/2,247 (172) 0.85 0.74-0.98 Z=2.21,P=.03 5.3
  Other intent 2 219/853 (25.7) 196/846 (23.2) 1.28 0,68-1.12 Z=0.75,P=.45 36.5
  Total 5† 547/3,052(17.9) 583/3,095 (18.8) 0.94 0.78-1.12 z=0.70,p=.48 51.3
Substantial gross motordysfunction              
  Neuroprotective intent 3 56/2,169 (2.6) 94/2.218(4.2) 0.60 0.43-0.83 z=3.08,p=.002 0
  Other intent 1 1/798(0.1) 0/795 (0) 199 0.12-73.3 z=0.67,p=.50 NA
  Total 4 57/2,967(1,9) 94/3,013(3.1) 0.61 0.44-0.85 z=2.98,p=.003 0
Mortality or substantial gross motor dysfunction              
  Netiroprotective intent 3 280/2,169 (12.9) 335/2,218 (15.1) 0,84 0,71-1.00 z=1.95p=.05 25.2
  Other intent 1 210/798 (26.3) 188/795 (23.6) 1.11 0,94-1.32 z=1.23,p=.22 NA
  Total 4 490/2,967 (16.5) 523/3,013(17.4) 0.92 0.75-1.12 z=0.87, p=.39 65.0

RR, relative risk; CI, confidence interval; NA, not applicable.

∗Values obtained from meta-analysis, which is not obtained simply by comparing pooled rates of events.

†One study4 represented in both subgroups; hence, there are only five studies overall.

Table 3.
Effect of magnesium sulfate on cerebral palsy and pediatric mortality24
Outcome No. of trials No. of events/total number Relative risk (95% O) I2(°/o)
Mngnesium No magnesium
Cerebral palsy 6 104/2658 152/2699 0.69 (0.55-0,88) 4.4
Moderate/severe cerebral palsy 3 45/2169 72/2218 0.64 (0.44-0,92) 0,0
Mild cerebral palsy 3 54/2169 74/2218 0.74 (0.52-1.04) 0.0
Tolal pediatric mortality 6 401/2658 400/2699 1.01 (0.89-1 J4) 38.9
Fetal mortality 5 17/2254 22/2298 0,78 (0,42-1.46) 0,0
Under 2 y of corrected age mortality 5 217/2254 220/2298 1.00 (0.84-1.19) 47.3
Death or cerebral palsy 6 505/2658 551/2699 0.92 (0.83-1.02) 43.3

CI, confidence interval.

Table 4.
Meta-Analysis of Other Neurologic Outcomes23
Outcome No. of studies Magnesium [n/N(%)] Control [n/N(%)] RR(95% CI)∗ Statistical 11 Significance Heterogeneity [I2(%)]
Newborn period
  Apgar less than 7 at 5 minutes 3 351/2469(16.2) 351/2,218(15.8) 1.03 (0.90-1.18) Z=0.42,P=.68 7
  Ongoing respiratory support 3 980/2,169(45,2) 1,069/2,218(48.2) 0,94 (0.89 L00) Z=1.91, P=.06 24
  Any imraventricular heinontiage 4 467/2,254(20,7) 493/2,298 (21,5) 0,96(0.86 1.08) Z=0.65,P=.51 20
  Periventricular Icukomalacia 4 71/2,254(3.1) 76/2,298 (3.3) 0.93 (0.68 1.28) Z=0.43,P=.67 0
  Neonatal convulsions 3 55/2,169(2.5) 70/2,218(3.2) 0.80(0.56-1.13) Z=1.28,P=.20 0
Follow-up
  Blindness 3 3/1,779 (0,2) 4/1,757(0.2) 0.74(0.17 3.30) 2=0.40, p=m 0
  Deafness 3 9/1,779 (0.5) 12/1,757(0.7) 0.79 (0.24-2.56) z=0.40, p=.69 17
  Devctopmcnlal delay 4 647/2,967(21.8) 670/3,013 (22.2) 0.99(0.91 1.09) z=0.11, p=.91 0

RR, relative risk; CI, confidence interval.

∗Values obtained from meta-analysis, which is not obtained simply by comparing pooled rates of events.

Table 5.
Effect of magnesium sulfate on neonatal outcomes24
Outcome No. of trials No, of events/total number Relative risk (95% CI) I2/(%)
Magnesium No magnesium
Intraventricular hemorrhage (ala grades) 5 467/2254 493/2298 0,96 (0.86-1.08) 20.1
Grade III/IV intraventricular hemorrhage 4 74/1902 91/1962 0.83(0.61-1.11) 0.0
Periventricular leukomalacia 5 71/2254 76/2298 0.93 (0.68-1,28) 0.0
Apgar score < 7 at 5 min 3 351/2169 351/2218 1.03 (0.90-1.18) 7.3
Neonatal seizures 3 55/2169 70/2218 0.80(0.56-1.13) 0
Respiratory distress syndrome 2 730/1540 779/1592 1.01 (0.85-1,19) 65.8
Need for supplemental oxygen at 36wk 2 220/981 195/962 1.12(0.95-132) 23.1
Bronchopulmonary dysplasia 1 213/188 218/1256 1.03(0.87-1.23) NA
Mechanical ventilation 3 1381/2169 1446/2218 0,99 (0.89-1.09) 82.1
Necrotizing enterocolitis 3 155/2169 131/2218 1.23 (0.98-1.54) 0.0

CI, confidence interval; NA, not applicable.

Table 6.
Effect of magnesium sulfate on maternal outcomes24
Outcome No. of trials No. of events/total number Relative risk (95% CI) I2 (%)
Magnesium No magnesium
Death 3 0/1917 1/1950 0.32 (0.01-7.92) 0.0
Cardiac or respiratory arrest 3 0/1917 35 0/1950 Not estimable NA
Fulmonary edema 1 8/1096 3/1145 2.79(0.74-10.47) NA
Respiratory depression 2 41/1631 31/1672 1.31 (0.83-2.07) 0.0
Hypotension 2 80/821 52/S05 1.51 (1,09-2.09) 3.6
Tachycardia 1 56/535 36/527 1.53 (1.03-2.29) NA
Severe postpartum hemorrhage 2 28/821 26/805 1.06(0,63-1.79) 0.0
Cesarean section 3 822/1917 BM/1950 1.00 (0.93-1.07) 21.6
Clinical and self-assessed maternal side effects of the infusion          
  Flushing 3 1119/1917 162/1950 7.56(339-16.88) 93,8
  Nausea or vomiting 3 312/1917 76/1950 4.60(1.54-13,75) 91.5
  Sweating 2 411/1631 57/1672 6.37(1.96-20.68) 94,6
  Problems at injection site 2 614/1631 68/1672 9.12 (7J9-11.57) 0.0
  Stopping of infusion because of adverse effects 2 125/J631 44/1672 2.81 (2.01-3.93) 0.0
  Any side effect 3 1356/1917 343/1950 105 (2.06-12.39) 983

CI, confidence interval; NA, not applicable.

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  • 17.Crowther CA, Hiller JE, Doyle LW, Haslam RR. Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgS04) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669–76.ArticlePubMed
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        Antenatal Magnesium Sulfate for Neuroprotective Effects In Preterm Infants
        Kosin Med J. 2014;29(2):99-106.   Published online December 18, 2014
        DOI: https://doi.org/10.7180/kmj.2014.29.2.99
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      Antenatal Magnesium Sulfate for Neuroprotective Effects In Preterm Infants
      Antenatal Magnesium Sulfate for Neuroprotective Effects In Preterm Infants

      Characteristics of Included Studies

      Study Centers NumbeT of participants Gestational age Magnesium regimen Neuroprotective outcomes
      MagNET 1 149 mothers 25-33 weeks 4 gm bolus Antenatal MgSO4 was associated with worse perinatal
      Mittendorff et al (United States) 165 fetus   (neuroprotective arm) outcome
      ACTOMgSO4 16 1,062 mothers <30 weeks 4 gm bolus, 1 gm/h CP RR:0.83; 95% CI: 0,54-1.27
      Crowther et al (Austrailia and New Zealand) 1,255 fetuses   maintenance  
      PreMAG trial + folllow up trial 18
      (France)      		 573 mothers
      6S8 fetuses      		 <33 weeks 4 gm bolus, no maintenance Original trial: Nonsignificant decrease in risk of short-term severe white matter injury, mortality before hospital discharge
      Marret et al   (original trial)      
          472 children     Follow-up trial (2 years): Combined death or cerebral palsy
          (follow-up trial)     OR, 0.65; 95% CI: 0.42-1.03
               
                Combined death or gross motor dysfunction OR: 0.62; 95%
                CI: 0.41-0,95 (siatisiicatly significant)
      BEAM. Rouse et al 20
      (United States)      		 2.241 mothers
      2,444 fetuses      		 24-31 weeks 6 gm bolus. 2gm/h maintenance Significant dcciease in the risk of moderate or severe CP (RR: 0,55; 95% CI: 0,32-0.92) among survival children in the MgSO4 group
                Death and CP RR: 0.97; 95% CI:
      Magpie trial 125 3.283 children <37 weeks c 4 gm bolus, 1 gm/h IV Combined death or neuroseasory disability RR: 1.06; 95% CI:
      Duley et al (International)   preeclampsia matnieaance or, 4 gm 0.40-1.29
              bolus combined wilh 10  
              gm IM, then 5 gm/4 hrs  
              IM maintenance  

      Meta-Analysis of Mortality, Cerebral Palsy, Substantial Gross Motor Dysfonction an Combined Outcome by Subcategory of Intent23

      Outcome and Subcategory No. of Studies Magnesium n/N (%) Control n/N (%) RR∗ 95% CI∗ Statistical Significance Heterogeneity [I2(%)]
      Mortality              
        Neuroprotective intent 4 226/2,199(10.3) 242/2,247 (10.8) 0.94 0.77-1.15 Z=0.58,P=.56 19.6
        Other intent 2 217/853 (25.4) 188/846 (22.2) 2.86 0.23-35.8 Z=0.81,P=.42 71.2
      Total 5† 443/3,052 (145) 430/3,093 (13.9) 1.01 0.82-1.23 Z=0.08,P=.94 44.9
        Cerebral palsy              
        Neuroprotective intent 4 102/2,199(4.6) 146/2,247 (6.5) 0.71 0.55-0.91 Z=2.74,P=006 25.2
      Other intent 1 2/853 (0.2) 8/846 (0.9) 0.29 0.07-1.16 Z=I.75,P=.08 0
        Total 5† 104/3,052 (3.4) 154/3,093(5.0) 0.69 0.54-0,87 Z=3.07,P=.002 11.7
      Mortality or cerebral palsy              
        Neuroprotective intent 4 528/2,199(14.9) 387/2,247 (172) 0.85 0.74-0.98 Z=2.21,P=.03 5.3
        Other intent 2 219/853 (25.7) 196/846 (23.2) 1.28 0,68-1.12 Z=0.75,P=.45 36.5
        Total 5† 547/3,052(17.9) 583/3,095 (18.8) 0.94 0.78-1.12 z=0.70,p=.48 51.3
      Substantial gross motordysfunction              
        Neuroprotective intent 3 56/2,169 (2.6) 94/2.218(4.2) 0.60 0.43-0.83 z=3.08,p=.002 0
        Other intent 1 1/798(0.1) 0/795 (0) 199 0.12-73.3 z=0.67,p=.50 NA
        Total 4 57/2,967(1,9) 94/3,013(3.1) 0.61 0.44-0.85 z=2.98,p=.003 0
      Mortality or substantial gross motor dysfunction              
        Netiroprotective intent 3 280/2,169 (12.9) 335/2,218 (15.1) 0,84 0,71-1.00 z=1.95p=.05 25.2
        Other intent 1 210/798 (26.3) 188/795 (23.6) 1.11 0,94-1.32 z=1.23,p=.22 NA
        Total 4 490/2,967 (16.5) 523/3,013(17.4) 0.92 0.75-1.12 z=0.87, p=.39 65.0

      Effect of magnesium sulfate on cerebral palsy and pediatric mortality24

      Outcome No. of trials No. of events/total number Relative risk (95% O) I2(°/o)
      Mngnesium No magnesium
      Cerebral palsy 6 104/2658 152/2699 0.69 (0.55-0,88) 4.4
      Moderate/severe cerebral palsy 3 45/2169 72/2218 0.64 (0.44-0,92) 0,0
      Mild cerebral palsy 3 54/2169 74/2218 0.74 (0.52-1.04) 0.0
      Tolal pediatric mortality 6 401/2658 400/2699 1.01 (0.89-1 J4) 38.9
      Fetal mortality 5 17/2254 22/2298 0,78 (0,42-1.46) 0,0
      Under 2 y of corrected age mortality 5 217/2254 220/2298 1.00 (0.84-1.19) 47.3
      Death or cerebral palsy 6 505/2658 551/2699 0.92 (0.83-1.02) 43.3

      Meta-Analysis of Other Neurologic Outcomes23

      Outcome No. of studies Magnesium [n/N(%)] Control [n/N(%)] RR(95% CI)∗ Statistical 11 Significance Heterogeneity [I2(%)]
      Newborn period
        Apgar less than 7 at 5 minutes 3 351/2469(16.2) 351/2,218(15.8) 1.03 (0.90-1.18) Z=0.42,P=.68 7
        Ongoing respiratory support 3 980/2,169(45,2) 1,069/2,218(48.2) 0,94 (0.89 L00) Z=1.91, P=.06 24
        Any imraventricular heinontiage 4 467/2,254(20,7) 493/2,298 (21,5) 0,96(0.86 1.08) Z=0.65,P=.51 20
        Periventricular Icukomalacia 4 71/2,254(3.1) 76/2,298 (3.3) 0.93 (0.68 1.28) Z=0.43,P=.67 0
        Neonatal convulsions 3 55/2,169(2.5) 70/2,218(3.2) 0.80(0.56-1.13) Z=1.28,P=.20 0
      Follow-up
        Blindness 3 3/1,779 (0,2) 4/1,757(0.2) 0.74(0.17 3.30) 2=0.40, p=m 0
        Deafness 3 9/1,779 (0.5) 12/1,757(0.7) 0.79 (0.24-2.56) z=0.40, p=.69 17
        Devctopmcnlal delay 4 647/2,967(21.8) 670/3,013 (22.2) 0.99(0.91 1.09) z=0.11, p=.91 0

      Effect of magnesium sulfate on neonatal outcomes24

      Outcome No. of trials No, of events/total number Relative risk (95% CI) I2/(%)
      Magnesium No magnesium
      Intraventricular hemorrhage (ala grades) 5 467/2254 493/2298 0,96 (0.86-1.08) 20.1
      Grade III/IV intraventricular hemorrhage 4 74/1902 91/1962 0.83(0.61-1.11) 0.0
      Periventricular leukomalacia 5 71/2254 76/2298 0.93 (0.68-1,28) 0.0
      Apgar score < 7 at 5 min 3 351/2169 351/2218 1.03 (0.90-1.18) 7.3
      Neonatal seizures 3 55/2169 70/2218 0.80(0.56-1.13) 0
      Respiratory distress syndrome 2 730/1540 779/1592 1.01 (0.85-1,19) 65.8
      Need for supplemental oxygen at 36wk 2 220/981 195/962 1.12(0.95-132) 23.1
      Bronchopulmonary dysplasia 1 213/188 218/1256 1.03(0.87-1.23) NA
      Mechanical ventilation 3 1381/2169 1446/2218 0,99 (0.89-1.09) 82.1
      Necrotizing enterocolitis 3 155/2169 131/2218 1.23 (0.98-1.54) 0.0

      Effect of magnesium sulfate on maternal outcomes24

      Outcome No. of trials No. of events/total number Relative risk (95% CI) I2 (%)
      Magnesium No magnesium
      Death 3 0/1917 1/1950 0.32 (0.01-7.92) 0.0
      Cardiac or respiratory arrest 3 0/1917 35 0/1950 Not estimable NA
      Fulmonary edema 1 8/1096 3/1145 2.79(0.74-10.47) NA
      Respiratory depression 2 41/1631 31/1672 1.31 (0.83-2.07) 0.0
      Hypotension 2 80/821 52/S05 1.51 (1,09-2.09) 3.6
      Tachycardia 1 56/535 36/527 1.53 (1.03-2.29) NA
      Severe postpartum hemorrhage 2 28/821 26/805 1.06(0,63-1.79) 0.0
      Cesarean section 3 822/1917 BM/1950 1.00 (0.93-1.07) 21.6
      Clinical and self-assessed maternal side effects of the infusion          
        Flushing 3 1119/1917 162/1950 7.56(339-16.88) 93,8
        Nausea or vomiting 3 312/1917 76/1950 4.60(1.54-13,75) 91.5
        Sweating 2 411/1631 57/1672 6.37(1.96-20.68) 94,6
        Problems at injection site 2 614/1631 68/1672 9.12 (7J9-11.57) 0.0
        Stopping of infusion because of adverse effects 2 125/J631 44/1672 2.81 (2.01-3.93) 0.0
        Any side effect 3 1356/1917 343/1950 105 (2.06-12.39) 983
      Table 1. Characteristics of Included Studies

      CI: Confidence Interval; CP: Cerebral Palsy; OR: Odds ratio; RR: Relative risk

      Table 2. Meta-Analysis of Mortality, Cerebral Palsy, Substantial Gross Motor Dysfonction an Combined Outcome by Subcategory of Intent23

      RR, relative risk; CI, confidence interval; NA, not applicable.

      Values obtained from meta-analysis, which is not obtained simply by comparing pooled rates of events.

      One study4 represented in both subgroups; hence, there are only five studies overall.

      Table 3. Effect of magnesium sulfate on cerebral palsy and pediatric mortality24

      CI, confidence interval.

      Table 4. Meta-Analysis of Other Neurologic Outcomes23

      RR, relative risk; CI, confidence interval.

      Values obtained from meta-analysis, which is not obtained simply by comparing pooled rates of events.

      Table 5. Effect of magnesium sulfate on neonatal outcomes24

      CI, confidence interval; NA, not applicable.

      Table 6. Effect of magnesium sulfate on maternal outcomes24

      CI, confidence interval; NA, not applicable.

      Table 1.

      Table 2.

      Table 3.

      Table 4.

      Table 5.

      Table 6.

      KMJ : Kosin Medical Journal
      © Kosin University College of Medicine.
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