Antenatal Magnesium Sulfate for Neuroprotective Effects In Preterm Infants

Article information

Kosin Med J. 2014;29(2):99-106
Publication date (electronic) : 2014 December 18
doi : https://doi.org/10.7180/kmj.2014.29.2.99
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 2014 October 10; 2014 October 10; Accepted 2014 October 15.

Abstract

Abstract

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.

Characteristics of Included Studies

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

Effect of magnesium sulfate on cerebral palsy and pediatric mortality24

Meta-Analysis of Other Neurologic Outcomes23

Effect of magnesium sulfate on neonatal outcomes24

Effect of magnesium sulfate on maternal outcomes24

References

1. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists'Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122.
2. Kuban K, Leviton A, Pagano M, Fenton T, Strasfeld R, Wolff M. Maternal toxemia is associated with reduced incidence of germinal matrix hemorrhage in premature babies. Journal of Child Neurology 1992;7:70–6.
3. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995;95:263–9.
4. Mittendorf RS, 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.
5. Scudiero R: Khoshnood B, Pryde PG, Lee KS, Wall S, Mittendorf R. Perinatal death and tocolytic magnesium sulfate. Obstet Gynecol 2000;96:178–82.
6. Kimberlin DF, Hauth JC, Goldenberg RL, Bottoms SF, lams JD, Mercer B, et al. The effect of maternal magnesium sulfate treatment on neonatal morbidity in < or = 1000-gram infants. Am J Perinatol 1998;15:635–41.
7. Farkouh LJ, Thorp JA, Jones PG, Clark RH, Knox GE. Antenatal magnesium exposure and neonatal demise. Am J Obstet Gynecol 2001;185:869–72.
8. Marret S: Gres sens P, Gadisseux JF, Evrard P. Prevention by magnesium of excitotoxic neuronal death in the developing brain: an animal model for clinical intervention studies. Dev Med Child Neurol 1995;37:473–84.
9. Marret S: Doyle LW, Crowther CA: Middleton P. Antenatal magnesium sulphate neuroprotection in the preterm infant. Semin Fetal Neonatal Med. 2007;2:311–7.
10. Turkyilmaz C, Turkyilmaz Z, Atalay Y5, Soylemezoglu F, Celasun B. Magnesium pretreatment reduces neuronal apoptosis in newborn rats in hypoxiaeischemia. Brain Res 2002;955:133–7.
11. Choi DW, Maulucci-Gedde M: Kriegstein AR. Glutamate neurotoxicity in cortical cell culture. J Neurosci 1967;7:357–68.
12. Marinov MB, Harbaugh KS, Hoopers PJ, et al. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia. J Neurosurg 1996;85:117–24.
13. Shogi T: Miyamoto A, Ishiguro S: Nishio A. Enhanced release of IL-lbeta and TNF-alpha following endotoxin challenge from rat alveolar macrophages cultured in low-Mg (2J)) medium. Magnes Res 2003;16:111–9.
14. Ovbiagele B: Kidwell CS, Starkman S: Saver JL. Neuroprotective agents for the treatment of acute ischemic stroke. Curr Neurol Neurosci Rep 2003;3:9–20.
15. MacDonald RL, Curry DJ, Aihara Y, Zhang ZD, Jahromi BS, Yassari R. Magnesium and experimental vasospasm. J Neurosurg 2004;100:106–10.
16. 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.
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.
18. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Leeue C, Hellot MF, et al. PREMAG Trial Group. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomized controlled PREMAG trial. BJOG 2007;114:310–8.
19. Marret S, Marpeau L, Follet-Bouhamed C, Cambonie G, Astruc D, Delaporte B, et al. PREMAG Trial Group. Effect of magnesium sulphate on mortality and neurologic morbidity of the very-preterm newborn with two-year neurologic outcome: results of the prospective PREMAG trial. Gynecol Obstet Fertil 2008;36:278–88.
20. Rouse DJ, Hirtz DG, Thom E, Vamer MW, Spong CY, Mercer BM, et al. Eunice Kennedy Shriver NICHD Matemal-Fetal Medicine Units Network. A randomized trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895–905.
21. Magpie Trial Follow-Up Study Collaborative Group. The Magpie Trial: a randomized trial comparing magnesium sulphate with placebo for preeclampsia. Outcome for children at 18 months. BJOG 2007;114:289–99.
22. 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.
23. Doyle LW. Antenatal magnesium sulfate and neuroprotection. Curr Opin Pediatr 2012;24:154–9.
24. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks'gestation: a systematic review and metaanalysis. Am J Obstet Gynecol 2009;200:595–609.
25. Food and Drug Administration. FDA recommends against prolonged use of magnesium sulfate to stop preterm labor due to bone changes in exposed babies. FDA Drug Safety Communication Silver Spring (MD): FDA; 2013. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM3533.pdf.
26. Amerian College of Obstetricians and Gynecologists Committee on Obstetric Practice Society for Matemal-Fetal Medicine. Committee opinion no. 573: Magnesium sulfate use in obstetrics. Obstet Gynecol 2013;122:727–8.

Article information Continued

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.