Published online December 31, 2007
PEDIATRICS Vol. 121 No. 1 January 2008, pp. 225-226 (doi:10.1542/10.1542/peds.2007-2971)

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LETTER TO THE EDITOR

Benefit of Magnesium Sulfate Given Before Very Preterm Birth to Protect Infant Brain

Stéphane Marret, MD, PhD
Department of Neonatal Medicine
Rouen University Hospital and INSERM Avenir Research Group (IFR 23)
Institute for Biomedical Research
University of Rouen
76000 Rouen, France

Loïc Marpeau, MD
Department of Obstetrics and Gynecology
Rouen University Hospital
76000 Rouen, France

Jacques Bénichou, MD, PhD
Department of Biostatistics
Rouen University Hospital and INSERM U657
Institute for Biomedical Research
University of Rouen
76000 Rouen, France
for the PREMAG Trial Group

To the Editor.—

Brain protection remains a challenge in infants who are born very preterm. Given its potential neuroprotective properties, magnesium sulfate (MgSO₄) has been one of the rare pharmacologic interventions used in randomized trials.^1,2 Our PREMAG Trial Collaborative Group found nonsignificantly decreased risks of short-term severe white matter injury, mortality before hospital discharge, and their combined outcome.² In this letter we report results from the 2-year follow-up of the PREMAG Trial.

METHODS

Overall, 573 women with fetuses of <33 weeks’ gestation whose birth was planned within 24 hours were enrolled in 13 tertiary hospitals from 1997 to 2003, with 286 and 278 women, respectively, assigned to receive a single infusion of 4 g of MgSO₄ or 0.9% saline.² Mortality and neurologic outcomes were assessed at 2 years of age alone or in combination. Pediatricians, who were blinded to treatment, evaluated motor and cognitive functions by using a questionnaire with developmental items extracted from the Amiel-Tison and Denver scales^3,4 and the European Cerebral Palsy Network definition. When direct examination was not possible, assessment was performed through parent telephone interview, an approach shown to be reliable for 2-year-olds.⁵ Statistical analysis was conducted on an intention-to-treat basis. Comparisons between groups accounted for the correlations of outcomes for twins or triplets born to the same mother through a generalized estimating equation approach within logistic regression and were further adjusted for gestational age, singleton/multiple pregnancy, and birth weight.² Stata software (Stata Corp, College Station, TX) was used. PREMAG is a registered International Standard Randomized Control Trial (identifier 00120588).

RESULTS

Of the 688 randomly assigned infants, 72 died. Of the 616 survivors, 472 (76.6%) were assessed at 2 years through clinical examination, 134 (21.7%) were assessed through parent telephone interview, and 10 (1.6%) were lost-to-follow-up. The rates of pediatric mortality and neurologic outcomes alone or in combination were all lower in the MgSO₄ group, with 0.62 to 0.82 odds ratios. Differences for gross motor dysfunction and 4 combinations approached significance or were significant (Table 1). Gender-specific results were similar.

View this table: [in this window] [in a new window]   TABLE 1 Mortality and Neurologic Outcomes at 2 Years of Age

 

DISCUSSION

Prenatal low-dose MgSO₄ does not increase pediatric mortality in very preterm infants and has beneficial neuroprotection effects. Our results are consistent with those of the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO₄)¹ (eg, 0.62 odds ratio in PREMAG and 0.71 relative risk in ACTOMgSO₄ for death or gross motor dysfunction). Given its beneficial effects and safety, prenatal low-dose MgSO₄ use for preventing neurodisabilities of very preterm infants should be discussed either as a stand-alone treatment or as part of a combination treatment, at least in the context of clinical trials.

Dr Marret had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Marret, Marpeau, and Bénichou conceived the study concept and design; Dr Marret acquired the data; Drs Marret, Marpeau, and Bénichou analyzed and interpreted the data; Drs Marret and Bénichou drafted the manuscript; Drs Marret, Marpeau, and Bénichou critically revised the manuscript for intellectual content; Dr Bénichou performed the statistical analysis; and Drs Marret and Bénichou obtained funding.

None of the funding bodies were involved in the study design or conduct; collection, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

ACKNOWLEDGMENTS

This research was funded by a 3-year grant ("Programme Hospitalier de Recherche Clinique"), obtained in 1997 from the French Department of Health, and a grant from Rouen University Hospital, obtained in 1997.

We are indebted to the women and their children who participated in the study, and we are grateful to all the members of the PREMAG Trial Collaborative Group: investigators, members of the steering committee, pharmacists, clinical research assistants, and administrative assistants.

REFERENCES

1. Crowther CA, Hiller JE, Doyle LW, Haslam RR; 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[Abstract/Free Full Text]
2. Marret S, Marpeau L, Zupan-Simunek V, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial. BJOG. 2007;114 :310 –318[CrossRef][Web of Science][Medline]
3. Amiel-Tison C, Gosselin J. Neurological Development From Birth to 6 Years: User Manual and Examination Chart. Baltimore, MD: John Hopkins University Press; 2001
4. Frankenburg WK, Dodds J, Archer P, Shapiro H, Bresnick B. The Denver II: a major revision and restandardization of the Denver Developmental Screening Test. Pediatrics. 1992;89 :91 –97[Abstract/Free Full Text]
5. Saudino KJ, Dale PS, Oliver B, et al. The validity of parent-based assessment of the cognitive abilities of 2-year-olds. Br J Dev Psychol. 1998;16 :349 –363

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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This Article Extract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Marret, S. Articles by Bénichou, J. Search for Related Content PubMed PubMed Citation Articles by Marret, S. Articles by Bénichou, J. Related Collections Developmental/Behavior Social Bookmarking                         What's this?