MANUSCRIPT CITATION

Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CtY, Mercer BM, Iams JD, Wapner RJ, Sorokin Y, Alexander JM, Harper M, Thorp JM Jr, Ramin SM, Malone FD, Carpenter M, Miodovnik M, Moawad A, O’Sullivan MJ, Peaceman AM, Hankins GD, Langer O, Caritis SN, Roberts JM. Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Networks. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008; 359(9):895-905. PMID 18753646.

REVIEWED BY

Megan E. Paulsen, MD
Assistant Professor
Department of Pediatrics, Division of Neonatology
University of Minnesota Medical School

Robert M. Dietz, MD, PhD
Assistant Professor
Department of Pediatrics, Section of Neonatology
University of Colorado Anschutz Medical Campus

TYPE OF INVESTIGATION

Treatment

QUESTION

Did fetal exposure to magnesium sulfate in preterm delivery between 24-31 weeks of gestation reduce the incidence of death by 1 year of age or the incidence of moderate/severe cerebral palsy at 2 years of age?
P: 24-31week gestational age neonates born secondary to preterm labor and delivery
I: Maternal magnesium sulfate treatment, fetal exposure to magnesium sulfate
C: No maternal magnesium sulfate treatment, no fetal exposure to magnesium sulfate
O: Decreased incidence of infant death at 1 year of age or moderate/severe cerebral palsy at 2 years of age
T: Neonatal follow-up at 1 and 2 years of age

METHODS

• Design: Multicenter, placebo-controlled, double-blind randomized controlled trial
• Allocation: Computer generated random sequence
  Blinding: Treatment team (physician, nurses, etc.) were blinded
• Follow-up period: Delivery and at 6, 12, and 24 months of age (corrected for prematurity)
• Setting: 20 participating Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network sites in the United States from December 1997 to May 2004
• Patients: Women who delivered singletons or twins at 24 through 31 weeks of gestation and were considered high risk for spontaneous delivery because of premature rupture of membranes occurring at 22 through 31 weeks of gestation or because of advanced preterm labor with cervical dilation of 4 to 8 cm and intact membranes. Additionally, women were eligible if they had an indicated preterm delivery anticipated in 2-24 hours for other causes such as fetal growth restriction. Women were not eligible if delivery was anticipated within less than 2 hours, cervical dilation exceeded 8 cm, PPROM prior to 22 weeks, unwillingness of obstetrician to intervene for the benefit of the fetus, major fetal anomalies or death, maternal hypertension or preeclampsia, maternal contraindications to magnesium sulfate (e.g. severe pulmonary disorders), and receipt of intravenous magnesium sulfate within the previous 12 hours.
• Intervention: 6-gram bolus of magnesium sulfate over 20-30 minutes followed by a maintenance infusion of 2 grams of magnesium sulfate per hour.  The infusion was discontinued if delivery had not occurred within 12 hours and no longer was considered imminent. The magnesium sulfate infusion was restarted once delivery was thought to occur; if there was a window of greater than 6 hours since stopping the infusion an additional 6-gram bolus of magnesium sulfate was given prior to restarting the maintenance infusion. Retreatment was held if the patient developed preeclampsia or eclampsia, was thought to be detrimental to mother or fetus, or mother reached 34 weeks gestational age prior to delivery.
• Outcomes:
  • Primary outcome: Composite of stillbirth or infant death by 1 year of age or moderate/severe cerebral palsy at 2 years of age (ages corrected for prematurity)
  • Secondary outcomes: Various maternal outcomes and complications, adverse events potentially attributable to the study intervention, neonatal complications, cerebral palsy at 2 years of age (classified as mild, moderate, or severe), stillbirth, infant death, scores on the Bayley Scales of Infant Development II, and cranial ultrasound evidence of IVH/PVL
• Analysis and Sample Size: Estimating that the primary outcome would occur in 14% of the placebo group, a rate of death at 6% and a rate of moderate or severe cerebral palsy among survivors at 8%, a sample of 2200 was targeted assuming a 30% reduction in the primary outcome, 10% rate of loss to follow-up, a type I error (two-sided) of 0.05, and a power of 80%.
• Patient follow-up: 2241 eligible women were enrolled; the primary outcome was assessed in 95.6% of the fetuses and 95% of examinations of cerebral palsy were completed by 32 months of corrected age.

MAIN RESULTS

CONCLUSION

Fetal exposure to magnesium sulfate in preterm delivery between 24-31 weeks of gestation did not reduce the combined incidence of death by 1 year of age or moderate/severe cerebral palsy at 2 years of age, however among survivors the rate of cerebral palsy was significantly reduced.

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COMMENTARY

The current American College of Obstetricians and Gynecologists (ACOG) Committee Opinion supports the use of magnesium sulfate for fetal neuroprotection before 32 weeks of gestation (1). The clinical trial reviewed here is the largest and most recent to inform these guidelines (2). This randomized control trial (RCT), aimed to determine if the administration of magnesium sulfate to women at high risk of preterm delivery would reduce the risk of cerebral palsy (CP), found a reduction in moderate/severe CP at 2 years of age following antenatal magnesium sulfate exposure (RR 0.55, 95% CI 0.32-0.95) (2).  These results were consistent with previous RCTs primarily evaluating the neuroprotective benefits of magnesium sulfate on the incidence of CP in preterm infants (3-5). Additionally, a Cochrane review concluded that 63 women were needed to prevent one diagnosis of CP (6).

Further investigation is warranted to provide updated and unified guidelines regarding the use of magnesium sulfate for fetal neuroprotection. There was significant heterogeneity in treatment regimens between RCTs with no trial sharing the same loading dose, treatment dose, duration of dosing, or retreatment regimen of magnesium sulfate (2-6). Additionally, although no serious maternal complications of antenatal magnesium exposure have been reported, there were several minor complications, including a 50% increase in maternal hypotension, leading to a 3.2-fold increase in cessation of therapy (6). Optimal treatment regimens would likely lead to a refined understanding of treatment effect size, better protocol adherence, and ultimately improved neurodevelopmental outcomes.

The results of this trial should be considered in light of advances in neonatal medicine affecting neurodevelopmental outcomes. For example, during the time of this study’s enrollment, the American Academy of Pediatrics (AAP) recommended against routine use of postnatal corticosteroids in preterm infants because of its negative effect on neurodevelopmental outcomes (7). This recommendation significantly curtailed the use of early postnatal steroids, potentially altering neurodevelopmental outcomes if differed between treatment groups (7). Second, there has been increased survival of infants 22-23 weeks of gestation (8). Currently, there are no RCTs that investigate the neuroprotective benefit of magnesium sulfate in <24 weeks of gestation.

It has been 20 years since recruitment started and nearly 10 years since the publication of this landmark trial has influenced the practice of obstetricians in the United States (2). In that same time, there continue to be advances in the care of the extremely low birth weight infants allowing for changes in survival and neurodevelopmental outcomes. Although many institutions follow ACOG recommendations of administering antenatal magnesium sulfate in preterm delivery, there are no recommendations for magnesium sulfate treatment regimens or gestational age thresholds presumably leading to a variety of clinical practices (1). Perhaps it is time to repeat this clinical trial in a new era to help elucidate both the optimal treatment regimen as well as the effect of antenatal magnesium exposure in the setting of preterm labor and delivery on neurodevelopmental outcomes. In the meantime, this trial remains consistent with available evidence supporting antenatal magnesium sulfate exposure in preterm infants to reduce cerebral palsy.

REFERENCES

• Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455. American College of Obstetricians and Gynecologists. Obstet Gynecol 2010; 115: 669–71.
• Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, et al. A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. Eunice Kennedy Shriver NICHD Maternal-Fetal Medicine Units Network. N Engl J Med 2008; 359: 895–905.
• 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: 1111–18.
• Crowther CA, Hiller JE, Doyle LW, Haslam RR, Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003; 290: 2669–76.
• Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Leveque C, Hellot MF, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial. PREMAG trial group. BJOG 2007; 114: 310-18.
• Doyle LW, Crowther CA, Middleton P, et al. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009; 1:CD004661.
• Postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Committee on Fetus and Newborn. Pediatrics 2010; 126: 800-808.
• Younge N, Goldstein RF, Bann CM, Hintz SR, Patel RM, Smith PB, et al. Survival and neurodevelopmental outcomes among periviable infants. N Engl J Med 2017; 376: 617-28.