Use of Magnesium Sulfate as a Neuroprotector

Abstract & Commentary

By John C. Hobbins, MD, Professor and Chief of Obstetrics, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.

Dr. Hobbins reports no financial relationship to this field of study.

Synopsis: Although still controversial, pooling of data from randomized trials suggests the neuroprotective benefit of magnesium sulfate in patients in preterm labor prior to 34 weeks of gestation.

June seems to have been magnesium sulfate month in both the Obstetrics & Gynecology and American Journal of Obstetrics & Gynecology journals. There were two reviews of the literature (with meta-analyses), one clinical opinion, and one editorial in the American Journal of Obstetrics & Gynecology, all on its neuroprotective effect. In addition, there was another review on the same subject and a current commentary on magnesium sulfate as a tocolytic in the June issue of Obstetrics & Gynecology. For the most part, magnesium sulfate came off reasonably well as the protector against cerebral palsy (CP).1-5

I will summarize the five studies that provided the bulk of the data that were analyzed in the meta-analyses and discussed in the commentaries.

1. Magnesium and Neurological Endpoints Trial (MAGNET).6 This study had two arms, which were applied to patients who entered the hospital with singletons or twins at less than 34 weeks in preterm labor (PTL) or with premature rupture of membranes (pPROM). Ninety-two were randomized to magnesium sulfate or placebo to stop labor, and 52 were randomized to having magnesium sulfate or placebo for neuroprophylaxis. In the tocolysis arm, 29% (16/55) had adverse outcomes (intraventricular hemorrhage, neonatal morbidity, periventricular leukomalacia, or CP), compared with 18% (9/51) who had placebo. In the neuroprophylaxis arm, 27% (11/30) of those having magnesium sulfate had adverse outcomes, compared with 21% (6/29) in the placebo arm. Although the differences were not statistically significant, the trend in this study was worrisome for increased risk with magnesium sulfate.

2. Australasian Collaborative Trial of Magnesium Sulfate (ACTOMgSO4).7 This was a multicenter study designed to test the neuroprotective capacity of 24 hours worth of magnesium sulfate in patients in labor with advanced cervical dilatation at less than 34 weeks. Only 70 of the 535 patients in the placebo group and 70 of 527 patients in the magnesium sulfate group were undelivered after 24 hours. In this select cohort, 24% of neonates in the placebo group and 19.8% of the neonates in the magnesium sulfate group died or had CP. Also, gross motor function was impaired in children by 2 years of age in 17% of the magnesium sulfate group vs 22.7% in the placebo group. This study suggested a beneficial effect of magnesium sulfate, although not a dramatic one.

3. Magnesium Sulfate for Prevention of Pre-eclampsia (Magpie) trial.8 One hundred seventy-five hospitals in 33 countries participated in this study to see if magnesium sulfate prevented seizures (which it did in 58% fewer patients). In a subset of 2895 infants studied later, there were no significant differences in death rates or neurosensory disabilities between children exposed in utero to magnesium sulfate compared with placebo.

4. PREMAG Study.9 Follow-up data were presented in a letter to the editor of the journal Pediatrics, involving a multicenter study in France in which 508 patients about to deliver prior to 34 weeks were randomized to a loading dose of magnesium sulfate or placebo. The perinatal mortality rate in the magnesium sulfate group was similar to the placebo group (9.4% vs 10.4%), but the incidence of moderate-to-severe CP was significantly lower in the magnesium sulfate group (1.9% vs 3.5%; relative risk [RR], 0.55; confidence interval [CI], 0.32-0.95). This represented a check in the good column for magnesium sulfate.

5. Beneficial Effects of Antenatal Magnesium (BEAM) trial.10 This was a large study conducted by the NICHD perinatal network in 2241 patients at risk for delivering prior to 32 weeks of gestation. The perinatal mortality was roughly the same between magnesium sulfate and placebo groups (9.4% magnesium sulfate vs 8.5% in the control group), but the rate of moderate-to-severe CP was significantly higher in the control group (1.9% vs 3.5%; RR, 0.55; CI, 0.32-0.95). This represented a strong check in the good column for magnesium sulfate, but, as we will see, not two checks.

Two meta-analyses were published in June, one by Doyle et al4 and another by Conde-Agudelo and Romero.2 After breaking down and combining the best available data, the authors of both studies concluded that magnesium sulfate had a protective effect against moderate-to-severe CP (RR = 0.61 and 0.64, respectively) and one meta-analysis showed a lessening of gross motor dysfunction (RR = 0.60). Neither showed any significant difference in pediatric mortality.

Commentary

The authors of the meta-analyses came down rather strongly for the benefit of magnesium sulfate and Rouse,3 the lead author of the BEAM study, in an opinion piece in the same issue of the American Journal of Obstetrics & Gynecology, calculated that by treating 63 women threatening to deliver prior to 32 weeks, one case of moderate-to-severe CP would be prevented. Despite this tilt toward the virtues of magnesium sulfate, the above study should not represent a slam dunk endorsement for its ability to protect against CP. Actually, of the five studies, only two showed a benefit and it was the meta-analysis that made the major difference.

The benefit of meta-analysis is to pool data when the individual studies do not have the statistical clout to show a difference between groups. However, as is often the case, the above study designs were not identical, as well as the criteria for inclusion and the heterogeneity of patients. For example, 8% of the ACTOMgSO4 patients had pPROM, while 86% in the BEAM study had this complication of pregnancy. Also, perhaps the most important factor, as pointed out by Cahill and Caughey in a companion review,1 was that the study that tipped the scale with regard to CP was the BEAM trial.4 In this study, the death rate was higher (but not statistically significantly so) in the magnesium sulfate group. Since many of the neonatal deaths represented CP cases waiting to happen, the authors calculated that of the 99 deaths in the magnesium sulfate arm, just two more cases of CP in infants that might have survived would have rendered the results statistically insignificant.

Last, magnesium sulfate is certainly not devoid of side effects — just ask any women who has had it. For example, Elliott et al in the same issue of Obstetrics & Gynecology, made a pitch for resurrecting magnesium sulfate as a tocolytic.5 In their commentary, the authors enumerate the well-known side effects that clinicians observed in patients who have had magnesium sulfate: loss of reflexes, blurred vision, lethargy, muscles weakness, as well as the more dangerous complication of fluid overload and pulmonary edema (occurring in one study in 4 of 455 patients). Also, there is always the risk of inadvertent drug overdose.

The point is that, despite the suggestion of its worth in two meta-analyses above, some feel that there still is not enough evidence from randomized trials with uniform protocols to endorse giving every patient at risk for preterm delivery prior to 32 weeks a drug that is expensive (by being labor intensive to administer) and has many side effects. In fact, as calculated above, it may be ineffective or unnecessary in 62 of the 63 patients being treated in a best case scenario. I do wish we were better at predicting true preterm labor so that only a small proportion of those with preterm contractions would need to be treated.

In the meantime, every clinician will have to make his/her decision based on the total clinical picture.

References

  1. Cahill AG, Caughey AB. Magnesium for neuroprophylaxis: Fact or fiction? Am J Obstet Gynecol 2009;200:590-594.
  2. Conde-Agudelo MD, Romero R. Antenatal magnesium sulfate for prevention of cerebral palsy in preterm infants in less than 34 weeks' gestation: A systematic review and meta-analysis. Am J Obstet Gynecol 2009;200:595-609.
  3. Rouse DJ. Magnesium sulfate for prevention of cerebral palsy. Am J Obstet Gynecol 2009;200:610-612.
  4. Doyle LW, et al. Antenatal magnesium sulfate and neurological outcome in preterm infants: A systematic review. Obstet Gynecol 2009;113:1327-1333.
  5. Elliott JP, et al. In defense of magnesium sulfate. Obstet Gynecol 2009;113:1341-1348.
  6. Mittendorf R, et al. Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol 2002;186:1111-1118.
  7. Crowther CA, et al; for the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: A randomized controlled trial. JAMA 2003;290:2669-2676.
  8. Magpie Trial Follow-up Study Collaborative Group. The Magpie Trial: A randomised trial comparing magnesium sulphate with placebo for pre-eclampsia. Outcome for children at 18 months. BJOG 2007;114:289-299.
  9. Marret S, et al. Benefit of magnesium sulfate given before very preterm birth to protect infant brain. Pediatrics 2008;121:225-226.
  10. Rouse DJ, et al. A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. N Engl J Med 2008;359:895-905.