By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Magnesium sulfate did not improve neurological function and child survival at 2 years of age in women at risk of imminent preterm birth treated between 30 and 34 weeks of gestation.
SOURCE: Crowther CA, Ashwood P, Middleton PF, et al. Prenatal intravenous magnesium at 30-34 weeks’ gestation and neurodevelopmental outcomes in offspring: The MAGENTA randomized clinical trial. JAMA 2023;330:603-614.
Preterm birth remains the most common cause of neonatal morbidity and mortality. Improving the neurological outcomes of children born premature, a known complication of preterm birth, remains a crucial issue in obstetrics and neonatology.1 Among the many potential neurological complications associated with preterm birth, cerebral palsy is one of the most severe. Cerebral palsy comprises a spectrum of movement and cognitive deficits, generally marked by persistent difficulties throughout the lives of those with the disorder and their families.2,3 Cerebral palsy is on the rise, making it a major public health issue that has prompted new methods of prevention and treatment.
Antenatal magnesium sulfate administration has been the only preventive medical therapy used for neuroprotection in preterm infants at risk of neurological complications, including cerebral palsy. Although the exact mechanisms behind this neuroprotective effect are unknown, a number of studies have suggested several theories, including the possibility that magnesium can reduce excitotoxicity by acting as an antagonist on the N-methyl-D-aspartic acid receptor and lower the amount of glutamate that is released extracellularly. In several landmark randomized clinical trials, including the ACTOMgSO4, PREMAG, and BEAM trials, the rate of motor dysfunction was demonstrated to be lower in the magnesium sulfate group compared to controls.4-6 For example, in the BEAM trial, the rate of moderate or severe cerebral palsy was reduced significantly in the magnesium sulfate group compared to controls (1.9% vs. 3.5%; relative risk [RR], 0.55; 95% confidence interval [CI], 0.32, 0.95).6 Despite the convincing evidence on the efficacy of magnesium sulfate, there is no globally universal agreement regarding the optimal gestational age for the antenatal use of magnesium sulfate for neuroprotection. Although certain obstetrics and gynecology societies recommend using magnesium sulfate for neuroprotection before 30 weeks of pregnancy, other societal guidelines suggest using magnesium before 32 weeks, 34 weeks, or between 30 and 34 weeks of pregnancy. To determine an optimal gestational age for administering magnesium sulfate for neuroprotection, Crowther and colleagues designed the Magnesium Sulphate at 30 to 34 Weeks’ Gestational Age (MAGENTA) trial to assess the effects of magnesium sulfate compared with placebo administered to pregnant women at risk of imminent preterm birth between 30 and 34 weeks of gestation.7
This was a Phase IV, multicenter, randomized clinical trial conducted at 24 Australian and New Zealand hospitals.7 Pregnant women met inclusion criteria if they were at risk of imminent preterm birth between 30 and 34 weeks of gestation, carrying a singleton or twin gestation, gave written informed consent, had a birth planned or expected within 24 hours, and had no contraindications (myasthenia gravis, respiratory depression, kidney failure, absent patellar reflexes, or hypotension) to the use of magnesium. Pregnant women were excluded from the trial if they were < 30 weeks or > 34 weeks of gestation, and if magnesium sulfate therapy was indicated for seizure prophylaxis in the setting of preeclampsia.7
Eligible pregnant women were randomly assigned to the magnesium sulfate or the placebo groups in a 1:1 ratio. Stratification occurred by hospital site, gestational age (30 to 31 weeks of gestation and 32 to 33 weeks of gestation), and number of fetuses (singleton or twin gestation). In addition to other standard obstetric practices at each hospital, 4 g of magnesium sulfate (or placebo) was administered intravenously for 30 minutes in participants who met inclusion criteria. Children were assessed by a pediatrician and an assessor trained to administer the third edition of the Bayley Scales of Infant Development (BSID-III) at 2 years of age.
The primary outcome was death (defined as stillbirth, death of a live-born infant before hospital discharge, or death after hospital discharge before 2 years of age) or cerebral palsy (defined by the authors as loss of motor function and abnormalities of muscle tone and power, as assessed by a pediatrician) at 2 years of age. There were 36 secondary outcomes that evaluated several aspects of maternal, neonatal, infant, and child health. Based on an expected incidence of 9.6% for the primary outcome of mortality or cerebral palsy at 2 years of age in this cohort (born between 30 and 34 weeks of gestation), the trial’s target sample size was determined. At a two-tailed type-1 error rate of 0.05, a sample size of 1,676 children (838 per group) would have 80% power to detect a clinically important absolute risk difference of 4.2% (from 9.6% to 5.4%) for the primary outcome.7 Binary outcomes were analyzed using log-binomial regression and the treatment effects are expressed as RRs and 95% CIs. Generalized linear regression with a binary distribution as an identity function was used to estimate the risk differences and 95% CIs.
A total of 1,433 pregnant women were randomized and enrolled between January 2012 and February 2018 (1,679 infants alive at enrollment). Of these, 729 pregnant women (51%) received magnesium sulfate (858 infants) and 704 pregnant women (49%) received placebo (821 infants). Baseline characteristics were comparable between both groups. For the primary endpoint of mortality or cerebral palsy at 2 years of age, the trial included 691/858 (80.5%) children in the magnesium sulfate group and 674/821 (82.1%) children in the placebo group. At 2 years of age, 2.7% (18/674) of children in the placebo group and 3.3% (23/691) of children in the magnesium sulfate group had cerebral palsy or death (risk difference, 0.61% [95% CI, -1.27% to 2.50%]; adjusted RR [aRR], 1.19 [95% CI, 0.65 to 2.18]; P = 0.57).
For the secondary outcomes, the magnesium group’s neonates had lower rates of respiratory distress syndrome compared to placebo (34% [294/858] vs. 41% [334/821], respectively; aRR, 0.85 [95% CI, 0.76, 0.95]) and chronic lung disease (5.6% [48/858] vs. 8.2% [67/821]; aRR, 0.69 [95% CI, 0.48, 0.99]). Although no major side effects were reported, pregnant women who received magnesium sulfate were more likely to experience adverse effects than those who were randomized to placebo (77% [531/690] vs. 20% [136/667], respectively; aRR, 3.76 [95% CI, 3.22, 4.39]). Although more pregnant women in the magnesium sulfate group experienced a major postpartum hemorrhage (3.4% [25/729] vs. 1.7% [12/704]; aRR, 1.98 [95% CI, 1.01, 3.91]) than in the placebo group, fewer women in the magnesium sulfate group had a cesarean delivery (56% [406/729] vs. 61% [427/704], respectively; aRR, 0.91 [95% CI, 0.84, 0.99]).
COMMENTARY
The results of this trial are at variance with those of other magnesium sulfate neuroprotection trials that demonstrated that children born at earlier gestational ages benefited from intravenous magnesium. Some possible explanations for these differences include the use of a single 4-g magnesium bolus without a maintenance infusion in this trial vs. 4-g to 6-g bolus doses in other trials, the combination of cerebral palsy and death as an outcome in this trial rather than just cerebral palsy, and potential variations in the brain injury mechanism responsible for cerebral palsy at earlier gestational ages compared to later gestational ages, including the role of magnesium sulfate in mediating such mechanisms.7
The dosing of magnesium for neuroprotection varies widely across countries.8 Most labor and delivery units administer magnesium sulfate for neuroprotection to patients with preterm labor with advanced cervical dilation (> 4 cm cervical dilation), patients with preterm labor anticipated to be delivered within two to 24 hours, or women with preterm premature rupture of fetal membranes between 23-31 weeks 6 days gestational age.9 The loading dose typically is a 4-g to 6-g bolus administered over 30 minutes, followed by a 2 g/hour continuous infusion for maintenance for up to 12 hours. If the patient has not yet been delivered, the infusion may be stopped at that point. If the patient remains pregnant after receiving magnesium sulfate for neuroprotection for a duration of 12 hours and delivery becomes imminent, it is advised to administer a 6 g re-bolus over a 20- to 30-minute period if the last magnesium exposure was more than six hours ago. If the last magnesium exposure was less than six hours ago, the infusion should be restarted at a rate of 2 g/hour for 12 hours without a bolus.9 Magnesium sulfate therapy has been demonstrated to be highly cost-effective and cost-saving when used for prevention of moderate to severe cerebral palsy.10
Assessing developmental milestones of infants exposed to the neuroprotective effects of magnesium is pertinent. The BSID-III is among the most widely recognized tools for assessing neurological development in children of mothers exposed to magnesium sulfate.11 The BSID-III is standardized and assesses multiple domains of development, including cognition, language, motor, social-emotional, and adaptive behavior, allowing for a holistic understanding of a child’s developmental trajectory and the need for early intervention services. Despite these advantages, administration of the BSID-III can be time-consuming, expensive, require lots of expertise and training, may not be equally applied across all cultural and linguistic groups, and has not been validated for children > 3.5 years of age. In addition, the BSID-III’s cognitive, language, and motor composites overestimate development, causing children with developmental delay to be under-identified.12
In summary, although magnesium sulfate did not improve neurological function and child survival at 2 years of age in women at risk of imminent preterm birth treated between 30 and 34 weeks of gestation, the authors admitted that the sample size lacked adequate power to detect subtle but possibly significant differences in the risk of death or cerebral palsy (the occurrence rates for both conditions were lower than anticipated).
REFERENCES
- Cao G, Liu J, Liu M. Global, regional, and national incidence and mortality of neonatal preterm birth, 1990-2019. JAMA Pediatr 2022;176:787-796.
- Patel DR, Neelakantan M, Pandher K, Merrick J. Cerebral palsy in children: A clinical overview. Transl Pediatr 2020;9(Suppl 1):S125-S135.
- Sadowska M, Sarecka-Hujar B, Kopyta I. Cerebral palsy: Current opinions on definition, epidemiology, risk factors, classification and treatment options. Neuropsychiatr Dis Treat 2020;16:1505-1518.
- Crowther CA, Hiller JE, Doyle LW, Haslam RR. Effect of magnesium sulfate given for neuroprotection before preterm birth: A randomized controlled trial. JAMA 2003;290:2669-2676.
- Marret S, Marpeau L, Zupan-Simunek V, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: The randomised controlled PREMAG trial*. BJOG 2007;114:310-318.
- 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.
- Crowther CA, Ashwood P, Middleton PF, et al. Prenatal intravenous magnesium at 30-34 weeks’ gestation and neurodevelopmental outcomes in offspring: The MAGENTA randomized clinical trial. JAMA 2023;330:603-614.
- Chollat C, Marret S. Magnesium sulfate and fetal neuroprotection: Overview of clinical evidence. Neural Regen Res 2018;13:2044-2049.
- [No authors listed]. Committee Opinion No. 455: Magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol 2010;115:669-671.
- Cahill AG, Odibo AO, Stout MJ, et al. Magnesium sulfate therapy for the prevention of cerebral palsy in preterm infants: A decision-analytic and economic analysis. Am J Obstet Gynecol 2011;205:542.e1-7.
- Ayed M, Ahmed J, More K, et al. Antenatal magnesium sulfate for preterm neuroprotection: A single-center experience from Kuwait tertiary NICU. Biomed Hub 2022;7:80-87.
- Anderson PJ, Burnett A. Assessing developmental delay in early childhood – concerns with the Bayley-III scales. Clin Neuropsychol 2017;31:371-381.
