Correspondence

Magnesium Sulfate for the Prevention of Cerebral Palsy

N Engl J Med 2009; 360:189-190January 8, 2009

Article

To the Editor:

In their article on the use of magnesium sulfate before preterm birth to prevent cerebral palsy, Rouse et al. (Aug. 28 issue)1 refer to a study, the Magnesium and Neurologic Endpoints Trial (MagNET), a cerebral-palsy prevention study we helped to design and analyze in collaboration with the National Institutes of Health.2 Although complaints about MagNET (e.g., the use of twins data and low mortality among control subjects) were cited by Rouse et al. in the Discussion section, our reply was not acknowledged.3 Of importance, MagNET's finding of excess pediatric mortality after tocolytic use of magnesium sulfate was subsequently affirmed (risk ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6) in a large meta-analysis in which infants from MagNET were included but comprised a minority of the subjects.4

The study by Rouse et al. included 402 of 2136 women (18.8%) who had been exposed to tocolytic magnesium sulfate before randomization. This is problematic, since women who were exposed both before and after randomization had a higher rate of infant death (10.9%) than did women who did not receive such therapy before randomization (9.2%), although the difference between the two groups was not significant. The median prophylactic dose in the study by Rouse et al. was 31.5 g. However, the higher doses among women given magnesium sulfate for tocolysis before randomization were not reported.

With respect to the use of magnesium sulfate for neuroprophylaxis, the study by Rouse et al. is indeterminate. Likewise, the accompanying editorial by Stanley and Crowther5 does not recommend its use. With all things considered, we remain gravely concerned about potential harm from high-dose magnesium sulfate in preterm labor.

Robert Mittendorf, M.D., Dr.P.H.
Loyola University Medical Center, Maywood, IL 60153
rmitten@lumc.edu

Peter G. Pryde, M.D.
University of Wisconsin Medical School, Madison, WI 53703

5 References

1. 1

   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
   Full Text | Web of Science | Medline

2. 2

   Mittendorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocolytic magnesium sulphate associated with increased total pædiatric mortality? Lancet 1997;350:1517-1518
   CrossRef | Web of Science | Medline

3. 3

   Mittendorf R, Roizen N, Siegler M, Khoshnood B, Lee K-S. Tocolytic magnesium sulphate and paediatric mortality. Lancet 1998;351:293-293
   CrossRef | Web of Science

4. 4

   Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev 2002;4:CD001060-CD001060
   Medline

5. 5

   Stanley FJ, Crowther C. Antenatal magnesium sulfate for neuroprotection before preterm birth? N Engl J Med 2008;359:962-964
   Full Text | Web of Science | Medline

Author/Editor Response

We can allay the concerns of Mittendorf and Pryde. In our study, neither the total dose of magnesium sulfate that was administered nor the concentration of magnesium in umbilical cord blood at birth was associated with stillbirth or infant death. For example, in unpublished analyses that excluded infants with major congenital malformations and were adjusted for maternal race, gestational age at delivery, and the presence or absence of chorioamnionitis, the odds ratio for death in the quartile receiving the highest total dose (range, 44 to 201 g) was 1.01 (95% CI, 0.48 to 2.10). Similarly, the respective odds ratio for the quartile with the highest level of cord-blood magnesium at birth (3.4 to 5.4 meq per liter) relative to the lowest quartile (<0.4 to 1.7 meq per liter) was 0.82 (95% CI, 0.36 to 1.84). As to whether our results were indeterminate, although magnesium sulfate had no significant effect on the rate of infant death, it significantly lowered the rate of mild, moderate, and severe cerebral palsy, findings that are consistent with the two other large and well-done trials of magnesium sulfate for fetal neuroprotection.1,2

Dwight J. Rouse, M.D.
University of Alabama at Birmingham, Birmingham, AL 35249
drouse@uab.edu

Deborah G. Hirtz, M.D.
National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892

Elizabeth A. Thom, Ph.D.
George Washington University Biostatistics Center, Rockville, MD 20852

for the Eunice Shriver Kennedy National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network

2 References

1. 1

   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
   CrossRef | Web of Science | Medline

2. 2

   Marret S, Marpeau L, Follet-Bouhamed C, et al. Effect of magnesium sulphate on mortality and neurologic morbidity of the very-preterm newborn (of less than 33 weeks) with two-year neurological outcome: results of the prospective PREMAG trial. Gynecol Obstet Fertil 2008;36:278-288
   CrossRef | Web of Science | Medline