An updated Cochrane Systematic Review of magnesium sulfate administered before preterm birth for neuroprotection has reaffirmed that the compound significantly reduces the risk of cerebral palsy and has added the finding that it also may reduce the risk of severe neonatal intraventricular hemorrhage.
Still unknown, however, is whether the effects of magnesium sulfate vary according to patient characteristics such as gestational age, or by treatment characteristics such as timing and dose. “We need further research to determine exactly who to treat, and when and how, to ideally standardize clinical practice recommendations across the world,” said Emily S. Shepherd, PhD, lead author of the review.
Magnesium sulfate is widely used for preterm cerebral palsy prevention but variance in national and local recommendations for its use may impede its optimal uptake in some places, she and her co-investigators wrote in the review.
In the United States, the American College of Obstetricians and Gynecologists advises institutions to develop their own guidelines regarding inclusion criteria and treatment regimens “in accordance with one of the larger trials.” (ACOG’s Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection was originally published in 2010 and was reaffirmed in 2023.)
In a Master Class column on magnesium sulfate for neuroprotection published earlier this year in Ob.Gyn. News, Irina Burd, MD, PhD, wrote that most hospitals in the United States have chosen a higher dose of magnesium sulfate administered up to 31 weeks’ gestation (6-g bolus, followed by 2 g/hour), in keeping with the protocols used in the BEAM trial published by the National Institute of Child Health and Human Development (NICHD). Dr. Burd is the Sylvan Frieman, MD, Endowed Professor and chair of the department of obstetrics, gynecology and reproductive sciences at the University of Maryland School of Medicine, Baltimore, Maryland.
The new Cochrane review included six randomized controlled trials (including the NICHD trial) covering 5917 pregnant participants and 6759 fetuses. Eligibility criteria varied, but all the RCTs included patients in preterm labor or with expected or planned imminent preterm birth at less than 34 weeks’ gestation.
Treatment regimens varied: three trials administered a 4-g loading dose only, and three included a maintenance dose (a 4-6-g loading dose and a 1-2 g/hour maintenance dose). “Although we attempted to explore variation through subgroup analyses, the ability to do this was limited,” the researchers wrote.
Up to 2 years of corrected age, magnesium sulfate reduced the risk of cerebral palsy compared with placebo (relative risk, 0.71; 95% confidence interval (CI), 0.57-0.89) and death or cerebral palsy (RR, 0.87; 95% CI, 0.77-0.98), with a high-certainty grade of evidence. The number needed to treat to prevent one case of cerebral palsy was 60 and the number needed to treat death or cerebral palsy was 56. The impact on severe intracranial hemorrhage (RR, 0.76; 95% CI, 0.60-0.98), a secondary outcome, was backed by moderate-certainty evidence.
Compared with the 2009 Cochrane review, the new study includes two new randomized controlled trials. One of which, the MAGENTA trial, administered magnesium sulfate at 30-34 weeks gestation and included new school-age follow-up data from two previously included trials. While the available data suggest little to no difference in outcomes at school age, more follow-up data are needed to assess this with greater certainty, the reviewers wrote.
While severe adverse outcomes (death, cardiac or respiratory arrest) for pregnant individuals appear not to have increased in pregnant patients who received magnesium sulfate (low-certainty evidence), the compound “probably increased maternal adverse effects severe enough to stop treatment,” the reviewers report (average RR, 3.21; 95% CI, 1.88-5.48; moderate-certainty evidence).
Side effects that were more frequent among women receiving magnesium sulfate include hypotension, tachycardia, warmth over body/flushing, nausea or vomiting, sweating, and dizziness.
“Treatment cessation due to such side effects was in the context of trials being conducted to establish benefit,” noted Dr. Shepherd, of the University of Adelaide in Australia. “With benefit now shown, these side effects may be viewed as comparatively minor/generally tolerable considering the potential benefits for children.”
Proving the neuroprotective value of magnesium sulfate took many years, Dr. Burd explained in the Master Class, as none of the randomized controlled trials analyzed in eventual meta-analyses and systematic reviews had reached their primary endpoints. It wasn’t until researchers obtained unpublished data and conducted these analyses and reviews that a significant effect of magnesium sulfate on cerebral palsy could be seen. Dr. Burd and other researchers are now working to better understand its biologic plausibility and precise mechanisms of action.
Dr. Shepherd disclosed that she is a former editor for Cochrane Pregnancy and Childbirth and current sign-off editor for Cochrane Central Editorial Service but reported having no involvement in the editorial processing of the review. Other authors disclosed that they were investigators for included trials and/or have published opinions in medical journals related to magnesium sulfate to reduce cerebral palsy. Dr. Burd reported no disclosures.