Advertisement
JOGC
SOGC Clinical Practice Guideline| Volume 41, ISSUE 4, P505-522, April 2019

Download started.

Ok

No. 376-Magnesium Sulphate for Fetal Neuroprotection

      Abstract

      Objective

      The objective is to provide guidelines for the use of antenatal magnesium sulphate for fetal neuroprotection of the preterm infant.

      Options

      Antenatal magnesium sulphate administration should be considered for fetal neuroprotection when women present at ≤33 + 6 weeks with imminent preterm birth, defined as a high likelihood of birth because of active labour with cervical dilatation ≥4cm, with or without preterm pre-labour rupture of membranes, and/or planned preterm birth for fetal or maternal indications. There are no other known fetal neuroprotective agents.

      Outcomes

      The outcomes measured are the incidence of cerebral palsy (CP) and neonatal death.

      Evidence

      Published literature was retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library in December 2017, using appropriate controlled vocabulary and key words (magnesium sulphate, cerebral palsy, preterm birth). Results were restricted to systematic reviews, randomized controlled trials, and relevant observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment–related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

      Values

      The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table1).

      Benefits, harms, and costs

      Antenatal magnesium sulphate for fetal neuroprotection reduces the risk of “death or CP” (relative risk [RR] 0.85; 95% confidence interval [CI] 0.74–0.98; 4 trials, 4446 infants), “death or moderate-severe CP” (RR 0.85; 95% CI 0.73–0.99; 3 trials, 4250 infants), “any CP” (RR 0.71; 95% CI 0.55–0.91; 4, trials, 4446 infants), “moderate-to-severe CP” (RR 0.60; 95% CI 0.43–0.84; 3 trials, 4250 infants), and “substantial gross motor dysfunction” (inability to walk without assistance) (RR 0.60; 95% CI 0.43–0.83; 3 trials, 4287 women) at 2years of age. Results were consistent between trials and across the meta-analyses. There is no anticipated significant increase in health care–related costs because women eligible to receive antenatal magnesium sulphate will be judged to have imminent preterm birth.

      Validation

      Australian National Clinical Practice Guidelines were published in March 2010 by the Antenatal Magnesium Sulphate for Neuroprotection Guideline Development Panel. Antenatal magnesium sulphate was recommended for fetal neuroprotection in the same dosage as recommended in these guidelines. However, magnesium sulphate was recommended only at <30 weeks gestation, based on 2 considerations. First, no single gestational age subgroup was considered to show a clear benefit. Second, in the face of uncertainty, the committee felt it was prudent to limit the impact of their clinical practice guidelines on resource allocation. In March 2010, the American College of Obstetricians and Gynecologists issued a Committee Opinion on magnesium sulphate for fetal neuroprotection. It stated that “the available evidence suggests that magnesium sulfate given before anticipated early preterm birth reduces the risk of cerebral palsy in surviving infants.” No official opinion was given on a gestational age cut-off, but it was recommended that physicians develop specific guidelines around the issues of inclusion criteria, dosage, concurrent tocolysis, and monitoring in accordance with 1 of the larger trials. Similarly, the World Health Organization also strongly recommends use of magnesium sulphate for fetal neuroprotection in its 2015 recommendations on interventions to improve preterm birth outcomes but cites further researching on dosing regimen and re-treatment.

      Sponsors

      Canadian Institutes of Health Research (CIHR).

      Summary Statement

      • 1
        “Imminent preterm birth” is defined as a high likelihood of birth due to 1 or both of the following conditions (II-2):
        • Active labour with ≥4cm of cervical dilation, with or without preterm pre-labour rupture of membranes.
        • Planned preterm birth for fetal or maternal indications.

      Recommendations

      • 1
        For women with imminent preterm birth (≤33 + 6 weeks), antenatal magnesium sulphate administration should be considered for fetal neuroprotection (I-A).
      • 2
        Although there is controversy about upper gestational age, antenatal magnesium sulphate for fetal neuroprotection should be considered from viability to ≤33 + 6 weeks (II-1B).
      • 3
        If antenatal magnesium sulphate has been started for fetal neuroprotection based on a clinical diagnosis of imminent preterm birth, tocolysis is no longer indicated and should be discontinued (III-A).
      • 4
        Magnesium sulphate should be discontinued if delivery is no longer imminent or a maximum of 24hours of therapy has been administered (II-2B).
      • 5
        For women with imminent preterm birth, antenatal magnesium sulphate for fetal neuroprotection should be administered as a 4-g intravenous loading dose, over 30 minutes, with or without a 1g per hour maintenance infusion until birth (II-2B).
      • 6
        For planned preterm birth for fetal or maternal indications, magnesium sulphate should be started, ideally within 4hours before birth, as a 4-g intravenous loading dose, over 30 minutes (II-2B).
      • 7
        There is insufficient evidence that a repeat course of antenatal magnesium sulphate for fetal neuroprotection should be administered (III-L).
      • 8
        Delivery should not be delayed in order to administer antenatal magnesium sulphate for fetal neuroprotection if there are maternal and/or fetal indications for emergency delivery (III-E).
      • 9
        When magnesium sulphate is given for fetal neuroprotection, maternity care providers should use existing protocols to monitor women who are receiving magnesium sulphate for preeclampsia/eclampsia (III-A).
      • 10
        Indications for fetal heart rate monitoring in women receiving antenatal magnesium sulphate for neuroprotection should follow the fetal surveillance recommendations of the Society of Obstetricians and Gynaecologists of Canada 2007 Fetal Health Surveillance: Antepartum and Intrapartum Consensus Guideline (III-A).
      • 11
        Decisions about neonatal resuscitation should not be influenced by whether or not the other received magnesium sulphate for fetal neuroprotection (II-I B).

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Obstetrics and Gynaecology Canada
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Public Health Agency of Canada
        Canadian perinatal health report.
        Minister of Public Works and Government Services Canada, Ottawa2008
        • Rogers EE
        • Hintz SR
        Early neurodevelopmental outcomes of extremely preterm infants.
        Semin Perinatol. 2016; 40: 497-509
        • Allotey J
        • Zamora J
        • Cheong-See F
        • et al.
        Cognitive, motor, behavioural andacademic performances of children born preterm: a meta- analysis andsystematic review involving 64 061 children.
        BJOG. 2018; 125: 16-25
        • Petrini JR
        • Dias T
        • McCormick MC
        • et al.
        Increased risk of adverse neurological development for late preterm infants.
        J Pediatr. 2009; 154: 169-176
        • Rosenbaum P
        • Paneth N
        • Leviton A
        A report: the definition and classification of cerebral palsy April 2006.
        Dev Med Child Neurol Suppl. 2007; 109: 8-14
        • Novak I
        • Morgan C
        • Adde L
        • et al.
        Early, accurate diagnosis and early intervention in cerebral palsy. Advances in diagnosis and treatment.
        JAMA Pediatr. 2017; 171: 897-907
      1. Centers for Disease Control and Prevention. Cerebral Palsy. Available at: http://www.cdc.gov/ncbddd/dd/ddcp.htm. Accessed on October 19, 2018.

        • Moster D
        • Lie RT
        • Markestad T
        Long-term medical and social consequences of preterm birth.
        N Engl J Med. 2008; 359: 262-273
        • Stanley FJ.
        Survival and cerebral palsy in low birthweight infants: implications for perinatal care.
        Paediatr Perinat Epidemiol. 1992; 6: 298-310
        • 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: 172-180
        • Pharoah PO
        • Cooke T
        • Johnson MA
        • et al.
        Epidemiology of cerebral palsy in England and Scotland, 1984-9.
        Arch Dis Child Fetal Neonatal Ed. 1998; 79: F21-F25
        • Winter S
        • Autry A
        • Boyle C
        • et al.
        Trends in the prevalence of cerebral palsy in a population-based study.
        Pediatrics. 2002; 110: 1220-1225
        • Petterson B
        • Nelson KB
        • Watson L
        • et al.
        Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s.
        BMJ. 1993; 307: 1239-1243
        • Hack M
        • Costello DW
        Trends in the rates of cerebral palsy associated with neonatal intensive care of preterm children.
        Clin Obstet Gynecol. 2008; 51: 763-774
        • Robertson CM
        • Watt MJ
        • Yasui Y
        Changes in the prevalence of cerebral palsy for children born very prematurely within a population-based program over 30 years.
        JAMA. 2007; 297: 2733-2740
        • Hagberg B
        • Hagberg G
        • Beckung E
        • et al.
        Changing panorama of cerebral palsy in Sweden. VIII. Prevalence and origin in the birth year period 1991-94.
        Acta Paediatr. 2001; 90: 271-277
        • Centers for Disease Control and Prevention
        Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment–United States, 2003.
        MMWR Morb Mortal Wkly Rep. 2004; 53: 57-59
        • Sotiriadis A
        • Tsiami A
        • Papatheodorou S
        • et al.
        Neurodevelopmental outcome after a single course of antenatal steroids in children born preterm: a systematic review and meta-analysis.
        Obstet Gynecol. 2015; 125: 1385-1396
        • O'Shea TM
        • Doyle LW
        Perinatal glucocorticoid therapy and neurodevelopmental outcome: an epidemiologic perspective.
        Semin Neonatol. 2001; 6: 293-307
        • Leviton A
        • Kuban KC
        • Pagano M
        • et al.
        Maternal toxemia and neonatal germinal matrix hemorrhage in intubated infants less than 1751 g.
        Obstet Gynecol. 1988; 72: 571-576
        • van de Bor M
        • Verloove-Vanhorick SP
        • Brand R
        • et al.
        Incidence and prediction of periventricular-intraventricular hemorrhage in very preterm infants.
        J Perinat Med. 1987; 15: 333-339
        • Nelson KB
        • Grether JK
        Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants?.
        Pediatrics. 1995; 95: 263-269
        • Grether JK
        • Cummins SK
        • Nelson KB
        The California Cerebral Palsy Project.
        Paediatr Perinat Epidemiol. 1992; 6: 339-351
        • Kuban KC
        • Leviton A
        • Pagano M
        • et al.
        Maternal toxemia is associated with reduced incidence of germinal matrix hemorrhage in premature babies.
        J Child Neurol. 1992; 7: 70-76
        • Grether JK
        • Hoogstrate J
        • Walsh-Greene E
        • et al.
        Magnesium sulfate fortocolysis and risk of spastic cerebral palsy in premature children borntowomen without preeclampsia.
        Am J Obstet Gynecol. 2000; 183: 717-725
        • O'Shea TM
        • Klinepeter KL
        • Dillard RG
        Prenatal events and the risk of cerebralpalsy in very low birth weight infants.
        Am J Epidemiol. 1998; 147: 362-369
        • Schendel DE
        • Berg CJ
        • Yeargin-Allsopp M
        • et al.
        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: 1805-1810
        • Altman D
        • Carroli G
        • Duley L
        • et al.
        Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial.
        Lancet. 2002; 359: 1877-1890
      2. Which anticonvulsant for women with eclampsia—evidence from the Collaborative Eclampsia Trial.
        Lancet. 1995; 345: 1455-1463
        • Gathwala G
        Neuronal protection with magnesium.
        Indian J Pediatr. 2001; 68: 417-419
        • Nelson KB
        • Grether JK
        Causes of cerebral palsy.
        Curr Opin Pediatr. 1999; 11: 487-491
        • Burd I
        • Breen K
        • Friedman A
        • Chai J
        • Elovitz MA
        Magnesium sulfate reduces inflammation-associated brain injury in fetal mice.
        Am J Obstet Gynecol. 2010; 202 (e1–9): 292
        • McDonald JW
        • Silverstein FS
        • Johnston MV
        Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats.
        Neurosci Lett. 1990; 109: 234-238
        • Crowther CA
        • Hiller JE
        • Doyle LW
        • et al.
        Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial.
        JAMA. 2003; 290: 2669-2676
        • 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
        • Mittendorf R
        • Dambrosia J
        • Pryde PG
        • 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
        • 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
        • 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
        • Conde-Agudelo A
        • Romero R
        Antenatal magnesium sulfate for the prevention of cerebral palsy in preterm infants less than 34 weeks' gestation: a systematic review and metaanalysis.
        Am J Obstet Gynecol. 2009; 200: 595-609
        • Costantine MM
        • Weiner SJ
        • Eunice Kennedy Shriver National Institute of Child Health and Human Development
        Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis.
        Obstet Gynecol. 2009; 114: 354-364
        • Doyle LW
        • Crowther CA
        • Middleton P
        • et al.
        Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.
        Cochrane Database Syst Rev. 2009; CD004661
        • Huusom LD
        • Brok J
        • Hegaard HK
        • et al.
        Does antenatal magnesium sulfate prevent ceberal palsy in preterm infants? The final trial?.
        Acta Obstet Gynecol Scand. 2012; 91: 1346-1347
        • Huusom LD
        • Secher NJ
        • Pryds O
        • et al.
        Antenatal magnesium sulphate may prevent cerebral palsy in preterm infants–but are we convinced? Evaluation of an apparently conclusive meta-analysis with trial sequential analysis.
        BJOG. 2011; 118: 1-5
        • Crowther CA
        • Middleton PF
        • Wilkinson D
        • for the MAGENTA Study Group
        Magnesium sulphate to 30 to 34 weeks' gestational age: neuroprotection trial(MAGENTA)–study protocol.
        BMC Pregnancy Childbirth. 2013; 13: 91
        • Crowther CA
        • Middleton PF
        • Voysey M
        • et al.
        Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: an individual participant data meta-analyisis.
        PLoS Med. 2017; 14e1002398
        • Bickford CD
        • MAgee LA
        • Mitton C
        • et al.
        Magnesium sulphate for fetal neuroprotection: a cost-effectiveness analysis.
        BMC Health Serv Res. 2013; 13: 527
        • Cahill AG
        • Odibo AO
        • Stout MJ
        • et al.
        Magnesium sulfate therapy for the prevention of cerebral palsy in preterm infants: a decision-analytic and economic analysis.
        Am J Obstet Gynecol. 2011; 205 (e1–7): 542
        • Magee LA
        • Helewa M
        • Moutquin JM
        • et al.
        Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy.
        J Obstet Gynaecol Can. 2008; 30: S1-48
        • Mittendorf R
        • Covert R
        • Boman J
        • et al.
        Is tocolytic magnesium sulphate associated with increased total paediatric mortality?.
        Lancet. 1997; 350: 1517-1518
        • Magpie Trial Follow-Up Study Collaborative Group
        The Magpie trial: arandomised trial comparing magnesium sulphate with placebo for pre-eclampsia.Outcome for women at 2 years.
        BJOG. 2007; 114: 300-309
        • Hirtz DG
        • Weiner SJ
        • Bulas D
        • et al.
        Antenatal magnesium and cerebral palsy in preterm infants.
        J Pediatr. 2015; 167: 834-839
        • Doyle LW
        • Anderson PJ
        • Haslam R
        • for the ACTOMgSO4 Study Group
        School-age outcomes of very preterm infants after antenatal treatment with magnesium sulfate vs placebo.
        JAMA. 2014; 312: 1105-1113
        • Chollat C
        • Enser M
        • Houviet E
        • et al.
        School-age outcomes following a randomized controlled trial of magnesium sulphate for neuroprotection of preterm infants.
        J Pediatr. 2014; 165: 398-400
        • De Silva DA
        • Synnes AR
        • von Dadelszen P
        • et al.
        MAGnesium sulphate for fetal neuroprotection to prevent Cerebral Palsy (MAG-CP) - implementation of a national guideline in Canada.
        Implement Sci. 2018; 13: 8
        • McPherson JA
        • Rouse DJ
        • Grobman WA
        • et al.
        Association of duration of neuroprotective magnesium sulfate infusion with neonatal and maternal outcomes.
        Obstet Gynecol. 2014; 124: 749-755
        • Sugimoto J
        • Romani AM
        • Valentin-Torres AM
        • et al.
        Magnesium decreases inflammatory cytokine production: a novel innate immunomodulatory mechanism.
        J Immunol. 2012; 188: 6338-6346
        • De Silva DA
        • Sawchuck D
        • von Dadelszen P
        • et al.
        Magnesium sulphate for eclampsia and fetal neuroprotection: a comparative analysis of protocols across Canadian tertiary perinatal centres.
        J Obstet Gynaecol Can. 2015; 37: 975-987
        • Nensi A
        • De Silva DA
        • von Dadelszen P
        • et al.
        Effect of magnesium sulphate on fetal heart rate parameters: a systematic review.
        J Obstet Gynaecol Can. 2014; 36: 1055-1064
        • Lipsitz PJ
        The clinical and biochemical effects of excess magnesium in the newborn.
        Pediatrics. 1971; 47: 501-509
        • Johnson LH
        • Mapp DC
        • Rouse DJ
        • et al.
        Association of cord blood magnesium concentration and neonatal resuscitation.
        J Pediatr. 2012; 160: 573-577
        • Weisz DE
        • Shivananada S
        • Asztalos E
        • et al.
        Intrapartum magnesium sulfate and need for intensive delivery room resuscitation.
        Arch Dis Child Neonatal Ed. 2015; 100: F59-F65
        • Drassinower D
        • Friedman AM
        • Levin H
        • et al.
        Does magnesium exposure affect neonatal resuscitation?.
        Am J Obstet Gynecol. 2015; 213 (e1–5): 424
        • Lloreda-Garcia JM
        • Lorente-Nicolas A
        • Bermejo-Costa F
        • et al.
        [Need for resuscitation in preterm neonates less than 32 weeks treated with antenatal magnesium sulphate for neuroprotection].
        Rev Chil Pediatr. 2016; 87: 261-267
        • Paradisis M
        • Osborn DA
        • Evans N
        • et al.
        Randomized controlled trial of magnesium sulfate in women at risk of preterm delivery-neonatal cardiovascular effects.
        J Perinatol. 2012; 32: 665-670
        • Del Moral T
        • Gonzalez-Quintero VH
        • Claure N
        • et al.
        Antenatal exposure to magnesium sulfate and the incidence of patent ductus arteriosus in extermely low birth weight infants.
        J Perinatol. 2007; 27: 154-157
        • PRE-EMPT
        Magnesium Sulphate for Fetal Neuroprotection to Prevent Cerebral Palsy (MAG-CP).
        PRE-EMPT, Vancouver, BC2017 (Available at:) (Accessed on October 19, 2018)
        • Liston R
        • Sawchuck D
        • Young D
        • et al.
        Fetal health surveillance: antepartum and intrapartum consensus guideline.
        J Obstet Gynaecol Can. 2007; 29: S3-56
        • 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.
        The University of Adelaide, Adelaide, Australia2010
        • American College of Obstetricians and Gynecologists Committee on Obstetric Practice, Society for Maternal-Fetal Medicine
        Committee opinion no. 455: magnesium sulfate before anticipated preterm birth for neuroprotection.
        Obstet Gynecol. 2010; 115: 669-671
        • World Health Organization (WHO)
        WHO Recommendations on Interventions to Improve Preterm Birth Outcomes.
        WHO, Geneva2015 (Available at:) (Accessed on October 19, 2018)