Antenatal magnesium sulfate for neuroprotection before preterm birth?

Preterm infants are at increased risk for serious, lifelong neurologic abnormalities such as cerebral palsy.1,2 As the survival of preterm infants has improved with advances in perinatal care,2 the occurrence of cerebral palsy has increased further, since infants who would previously have died now survive with their cerebral pathology. Currently, more than 30% of children with cerebral palsy are born preterm.1 Compounding these concerns are the trends, particularly in the United States, to increases in preterm birth.3 An emphasis on improving the survival of very preterm infants without associated strategies to prevent preterm birth or the neurologic disorders associated with it results in substantial costs to society and anguish for parents. Limited data have suggested that magnesium sulfate may have neuroprotective effects on babies born preterm.4 Magnesium sulfate has been widely used for tocolysis in the United States,5 although studies show that it is ineffective for this indication6 but is effective for the treatment and prevention of eclampsia.7 In several observational studies, preterm infants whose mothers received magnesium sulfate were reported to have marked reductions in cerebral palsy, as compared with infants of untreated mothers.8 Although biologically plausible mechanisms by which magnesium sulfate might be neuroprotective, such as the blocking of glutamate receptors,9 have been proposed, not all observational studies have shown an association between the use of magnesium sulfate and a reduced risk of cerebral palsy.10 Moreover, because they were not randomized, controlled trials, such observational studies cannot show whether any association reflects cause and effect or is a result of unmeasured or unknown confounding factors. The Cochrane review4 on the use of magnesium sulfate for neuroprotection of the fetus in women at risk for preterm birth included four randomized, placebo-controlled trials11-14 involving 3701 babies and concluded that the role of magnesium sulfate “is not yet established.” The meta-analysis overall did not show any significant effect of magnesium sulfate on either death (relative risk, 0.97; 95% confidence interval [CI], 0.74 to 1.28) or cerebral palsy (relative risk, 0.77; 95% CI, 0.56 to 1.06), but there was a significant reduction in the rate of substantial gross motor dysfunction (relative risk, 0.56; 95% CI, 0.33 to 0.97). There was significant statistical heterogeneity for mortality among the trials, with one12 but not the other three11,13,14 showing an increased risk of perinatal death. The different main reasons for preterm birth (preeclampsia in one13 and preterm labor in the others11,12,14), gestational ages at the time of treatment (range, <30 to <37 weeks), and treatment regimens among the trials (all of which could influence risks for both death and cerebral palsy) make it difficult to interpret pooled treatment effects. In this issue of the Journal, Rouse et al.15 report the results of a multicenter, placebo-controlled, randomized trial in which 2241 women at imminent risk for preterm birth between 24 and 31 weeks of gestation were randomly assigned to receive either intravenous magnesium sulfate (a 6-g bolus infused for 20 to 30 minutes, followed by a maintenance infusion of 2 g per hour) or placebo. Participants were at high risk for spontaneous preterm birth because of preterm prelabor rupture