Magnesium sulphate at 30 to 34 weeks’ gestational age: neuroprotection trial (MAGENTA) - study protocol

BMC Pregnancy and Childbirth

Ross Haslam¹  Pat Ashwood²  Dominic Wilkinson²  Philippa F Middleton²  Caroline A Crowther³ 

[1] Department of Neonatal Medicine, The Women’s and Children’s Hospital, Adelaide, South Australia, Australia;Australian Research Centre for Health of Women and Babies (ARCH), The Robinson Institute, The University of Adelaide, Adelaide, Australia;Liggins Institute, The University of Auckland, Auckland, New Zealand

关键词: Cerebral palsy;    Randomised controlled trial;    Preterm birth;    Neuroprotection;    Magnesium sulphate;   

Others  :  1138089
DOI  :  10.1186/1471-2393-13-91

 received in 2013-03-27, accepted in 2013-03-28,  发布年份 2013

【 摘 要 】

Background

Magnesium sulphate is currently recommended for neuroprotection of preterm infants for women at risk of preterm birth at less than 30 weeks’ gestation, based on high quality evidence of benefit. However there remains uncertainty as to whether these benefits apply at higher gestational ages.

The aim of this randomised controlled trial is to assess whether giving magnesium sulphate compared with placebo to women immediately prior to preterm birth between 30 and 34 weeks’ gestation reduces the risk of death or cerebral palsy in their children at two years’ corrected age.

Methods/design

Design: Randomised, multicentre, placebo controlled trial.

Inclusion criteria: Women, giving informed consent, at risk of preterm birth between 30 to 34 weeks’ gestation, where birth is planned or definitely expected within 24 hours, with a singleton or twin pregnancy and no contraindications to the use of magnesium sulphate.

Trial entry & randomisation: Eligible women will be randomly allocated to receive either magnesium sulphate or placebo.

Treatment groups: Women in the magnesium sulphate group will be administered 50 ml of a 100 ml infusion bag containing 8 g magnesium sulphate heptahydrate [16 mmol magnesium ions]. Women in the placebo group will be administered 50 ml of a 100 ml infusion bag containing isotonic sodium chloride solution (0.9%). Both treatments will be administered through a dedicated IV infusion line over 30 minutes.

Primary study outcome: Death or cerebral palsy measured in children at two years’ corrected age.

Sample size: 1676 children are required to detect a decrease in the combined outcome of death or cerebral palsy, from 9.6% with placebo to 5.4% with magnesium sulphate (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2).

Discussion

Given the magnitude of the protective effect in the systematic review, the ongoing uncertainty about benefits at later gestational ages, the serious health and cost consequences of cerebral palsy for the child, family and society, a trial of magnesium sulphate for women at risk of preterm birth between 30 to 34 weeks’ gestation is both important and relevant for clinical practice globally.

Trial registration

Australian New Zealand Clinical Trials Registry - ACTRN12611000491965

【 授权许可】

   
2013 Crowther et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]ANZNN (Australian and New Zealand Neonatal Network): Report of the Australian and New Zealand Neonatal Network 2008 and 2009. Sydney: ANZNN; 2012.
• [2]Saigal S, Doyle LW: An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008, 371(9608):261-269.
• [3]Doyle LW, Victorian Infant Collaborative Study Group: Evaluation of neonatal intensive care for extremely low birth weight infants in Victoria over two decades: II. Efficiency. Pediatrics 2004, 113(3 Pt 1):510-514.
• [4]Petrini JR, Dias T, McCormick MC, Massolo ML, Green NS, Escobar GJ: Increased risk of adverse neurological development for late preterm infants. J Pediatr 2009, 154(2):169-176.
• [5]Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N: The cost of preterm birth throughout childhood in England and Wales. Pediatrics 2009, 123(2):e312-317.
• [6]Oxford Register of Early Childhood Impairment: National Perinatal Epidemiology Unit, Annual Report. Oxford: Institue of Health Sciences; 2001: .
• [7]Hutton JL, Cooke T, Pharoah POD: Life expectancy in children with cerebral palsy. Brit Med J 1994, 309(6952):431-435.
• [8]Drummond PM, Colver AF: Analysis by gestational age of cerebral palsy in singleton births in north-east England 1970–94. Paediatr Perinat Epidemiol 2002, 16(2):172-180.
• [9]Winter S, Autry A, Boyle C, Yeargin-Allsopp M: Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 2002, 110(6):1220-1225.
• [10]ACPR Group: Report of the Australian Cerebral Palsy Register, Birth Years 1993–2003. Sydney: ACPR; Dec 2009.
• [11]Marret S, Ancel PY, Marpeau L, Marchand L, Pierrat V, Larroque B, Foix-L'Helias L, Thiriez G, Fresson J, Alberge C: Neonatal and 5-year outcomes after birth at 30–34 weeks of gestation. Obstet Gynecol 2007, 110(1):72-80.
• [12]McIntyre S, Novak I, Cusick A: Consensus research priorities for cerebral palsy: a Delphi survey of consumers, researchers, and clinicians. Dev Med Child Neurol 2010, 52(3):270-275.
• [13]Nelson KB, Grether JK: Can magnesium sulphate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics 1995, 95:1-1.
• [14]Hauth JC, Goldenberg RL, Nelson KG, Dubard MB, Peralta MA, Gaudier FL: Reduction of cerebral palsy with maternal MgSO4 treatment in newborns weighing 500-1000 g. Am J Obstet Gynecol 1995, 172(1 Pt 2):419.
• [15]Schendel DE, Berg CJ, YearginAllsopp M, Boyle CA, Decoufle P: Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years. JAMA 1996, 276(22):1805-1810.
• [16]Wiswell TE, Graziani LJ, Caddell JL, Vecchione N, Stanley C, Spitzer AR: Maternally-administered magnesium sulfate (MgSO4) protects against early brain injury and long-term adverse neurodevelopmental outcomes in preterm infants: A prospective study. Pediatr Res 1996, 39(4):1502.
• [17]FineSmith RB, Roche K, Yellin PB, Walsh KK, Shen C, Zeglis M, Kahn A, Fish I: Effect of magnesium sulfate on the development of cystic periventricular leukomalacia in preterm infants. Am J Perinat 1997, 14(5):303-307.
• [18]Grether JK, Hoogstrate J, Selvin S, Nelson KB: Magnesium sulfate tocolysis and risk of neonatal death. Am J Obstet Gynecol 1998, 178(1):1-6.
• [19]Kimberlin DF, Hauth JC, Goldenberg RL, Bottoms SF, Iams JD, Mercer B, MacPherson C, Thurnau GR: The effect of maternal magnesium sulfate treatment on neonatal morbidity in <= 1000-gram infants. Am J Perinat 1998, 15(11):635-641.
• [20]Paneth N, Jetton J, PintoMartin J, Susser M, Clark C, Gardiner J, Holzman C, Lorenz JM, Reuss ML: Magnesium sulfate in labor and risk of neonatal brain lesions and cerebral palsy in low birth weight infants. Pediatrics 1997, 99(5):E1.
• [21]Weintraub Z, Solovechick M, Reichman B, Rotschild A, Waisman D, Davkin O, Lusky A, Bental Y, Israel Neonatal Network: Effect of maternal tocolysis on the incidence of severe periventricular/intraventricular haemorrhage in very low birthweight infants. Arch Dis Child 2001, 85(1):F13-F17.
• [22]Grether JK, Hoogstrate J, Walsh-Greene E, Nelson KB: Magnesium sulfate for tocolysis and risk of spastic cerebral palsy in premature children born to women without preeclampsia. Am J Obstet Gynecol 2000, 183(3):717-725.
• [23]O'Shea TM, Klinepeter KL, Meis PJ, Dillard RG: Intrauterine infection and the risk of cerebral palsy in very low-birthweight infants. Paediatr Perinat Epidemiol 1998, 12(1):72-83.
• [24]Mildvan AS: Role of magnesium and other divalent cations in ATP-utilizing enzymes. Magnesium 1987, 6(1):28-33.
• [25]McIntosh TK, Vink R, Yamakami I, Faden AI: Magnesium protects against neurological deficit after brain injury. Brain Res 1989, 482(2):252-260.
• [26]Hoffman DJ, Marro PJ, McGowan JE, Mishra OP, Delivoriapapadopoulos M: Protective effect of MgSO4 infusion on nmda receptor binding characteristics during cerebral cortical hypoxia in the newborn piglet. Brain Res 1994, 644(1):144-149.
• [27]Shogi T, Miyamoto A, Ishiguro S, Nishio A: Enhanced release of IL-1 beta and TNF-alpha following endotoxin challenge from rat alveolar macrophages cultured in low-Mg2+ medium. Magnesium Res 2003, 16(2):111-119.
• [28]Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A: Magnesium Gates Glutamate-Activated Channels in Mouse Central Neurons. Nature 1984, 307(5950):462-465.
• [29]Ovbiagele B, Kidwell CS, Starkman S, Saver JL: Potential Role of Neuroprotective Agents in the Treatment of Patients with Acute Ischemic Stroke. Curr Treat Options Cardiovasc Med 2003, 5(6):441-449.
• [30]Rantonen TH, Gronlund JU, Jalonen JO, Ekblad UU, Kaapa PO, Kero PO, Valimaki IAT: Comparison of the effects of antenatal magnesium sulphate and ritodrine exposure on circulatory adaptation in preterm infants. Clin Physiol Funct Imaging 2002, 22(1):13-17.
• [31]Macdonald RL, Curry DJ, Aihara Y, Zhang ZD, Jahromi BS, Yassari R: Magnesium and experimental vasospasm. J Neurosurg 2004, 100(1):106-110.
• [32]Hallak M, Cotton DB: Transfer of maternally administered magnesium sulfate into the fetal compartment of the rat. Am J Obstet Gynecol 1993, 169(2):427-431.
• [33]Doyle L, Crowther C, Middleton P, Marret S, Rouse D: Antenatal magnesium sulphate and neuroprotection for very preterm infants – The updated Cochrane review. J Paediatr Child H 2009, 45(suppl 1):A47.
• [34]Crowther C, Hiller J, Doyle L, Lumley J, Carlin J: Tocolytic magnesium sulphate and paediatric mortality. Lancet 1998, 351(9098):291-291.
• [35]Crowther CA, Hiller JE, Doyle LW: Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Db Syst Rev 2002., (Issue 4) Art. No.: CD001060. doi:
• [36]Duley L, Gulmezoglu A, Henderson-Smart D: Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Db Syst Rev 2003., (Issue 2) Art. No.: CD000025. doi:
• [37]Baraka A, Yazigi A: Neuromuscular interaction of magnesium with succinylcholine-vecuronium sequence in the eclamptic parturient. Anesthesiology 1987, 67(5):806-808.
• [38]Snyder SW, Cardwell MS: Neuromuscular blockade with magnesium sulfate and nifedipine. Am J Obstet Gynecol 1989, 161(1):35-36.
• [39]Ben-Ami M, Giladi Y, Shalev E: The combination of magnesium sulphate and nifedipine: a cause of neuromuscular blockade. Br J Obstet Gynaecol 1994, 101(3):262-263.
• [40]McDonnell NJ: Cardiopulmonary arrest in pregnancy: two case reports of successful outcomes in association with perimortem Caesarean delivery. Br J Anaesth 2009, 103(3):406-409.
• [41]Levene M, Blennow M, Whitelaw A, Hanko E, Fellman V, Hartley R: Acute effects of two different doses of magnesium sulphate in infants with birth asphyxia. Arch Dis Child-Fetal 1995, 73(3):F174-177.
• [42]Lipsitz PJ: The clinical effects of excess magnesium in the newborn. Pediatrics 1971, 47(3):501-509.
• [43]Mittendorf R, Dambrosia J, Pryde PG, Lee KS, Gianopoulos JG, Besinger RE, Tomich PG: Association between the use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants. Am J Obstet Gynecol 2002, 186(6):1111-1118.
• [44]Rouse DJ, Hirtz DG, Thom E, Varner MW, Spong CY, Mercer BM, Iams JD, Wapner RJ, Sorokin Y, Alexander JM: A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy. New Engl J Med 2008, 359(9):895-905.
• [45]Crowther CA, Hiller JE, Doyle LW, Haslam RR, 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 J Am Med Assoc 2003, 290(20):2669-2676.
• [46]Marret S, Marpeau L, Benichou J: Benefit of magnesium sulfate given before very preterm birth to protect infant brain. Pediatrics 2008, 121(1):225-226.
• [47]The Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel: Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant and child: National clinical practice guidelines. Adelaide: The University of Adelaide; 2010.
• [48]Crowther CA, Doyle LW, Haslam RR, Hiller JE, Harding JE, Robinson JS, ACTORDS Study Group: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. New Engl J Med 2007, 357(12):1179-1189.
• [49]Stanley FJ, Watson L: Trends in Perinatal-Mortality and Cerebral-Palsy in Western-Australia, 1967 to 1985. BMJ 1992, 304(6843):1658-1663.
• [50]Paneth N: Establishing the Diagnosis of Cerebral Palsy. Clin Obstet Gynecol 2008, 51(4):742-748.
• [51]Doyle LW, Victorian Infant Collaborative Study Group: Changing availability of neonatal intensive care for extremely low birthweight infants in Victoria over two decades. Med J Aust 2004, 181(3):136-139.
• [52]Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B: Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997, 39(4):214-223.
• [53]Bayley N: Bayley Scales of Infant and Toddler Development (Third Edition). San Antonio: Harcourt Assessment (PsychCorp); 2006.
• [54]Achenbach T: Manual for the Child Behaviour Checklist/2-3 and1992 Profile. Burlington, VT: University of Vermont Department of Psychiatry; 1992.
• [55]Rosner B, Prineas RJ, Loggie JM, Daniels SR: Blood pressure nomograms for children and adolescents, by height, sex, and age, in the United States. J Pediatr 1993, 123(6):871-886.
• [56]Freeman JV, Cole TJ, Chinn S, Jones PRM, White EM, Preece MA: Cross-sectional stature and weight reference curves for the UK 1990. Arch Dis Child 1995, 73(1):17-24.
• [57]Laws P, Li Z, Sullivan EA: Australia's mothers and babies 2008. Perinatal statistics series no. 24. Cat. no. PER 50. AIHW: Canberra; 2010.