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Antenatal magnesium sulphate

#Background

The use of magnesium sulphate for the treatment and prevention of eclampsia or for tocolysis in preterm pregnancies in the 1970s and 1980s led to the observation of reduced neonatal intraventricular haemorrhage and a lower prevalence of cerebral palsy in low birthweight pēpi.1-3 These findings, alongside biological plausibility of effect, led to randomised placebo-controlled trials of magnesium sulphate specifically to explore its neuroprotective effect prior to preterm birth.

The 2009 Cochrane Review included four high-quality trials specific to neuroprotection after preterm birth.4 These same four trials were included with one further trial in the AMICABLE Study: a systematic review and individual participant data meta-analysis in 2017.5 Similar effects were demonstrated in both analyses. Using the 2017 data, antenatal magnesium sulphate use for neuroprotection prior to early preterm birth is associated with a reduction in the risk of death or cerebral palsy (RR 0.86, 95% CI 0.75-0.99). The effect is non-significant for infant death alone but highly protective against cerebral palsy (RR 0.68, 95% CI 0.53-0.87) with no evidence of significant maternal harm (all trials considered to be at an overall low risk of bias).5

The Cochrane Review has been updated (2024) to include the Magnesium sulphate at 30 to 34 weeks gestational age: neuroprotection trial (MAGENTA),6 and now has a total of six studies and 5917 wāhine/people and 6759 pēpi included.7 Findings up to two years of age remain consistent with antenatal magnesium sulphate use being associated with a reduction in cerebral palsy (RR 0.71, 95% CI 0.57-0.89) and death or cerebral palsy (RR 0.87, 95% CI 0.77-0.98) but no significant effect on death alone.7 Magnesium sulphate also probably reduces severe intraventricular haemorrhage (RR 0.76, 95% CI 0.60-0.98). Only two trials included assessment at early school age and hence evidence was considered to be low and very-low certainty in demonstrating no difference. However, magnesium sulphate use may be associated with non-significant trends towards reduced death or cerebral palsy and death or major neurodevelopmental disability.7

There are no national data available to report on magnesium sulphate use for neuroprotection in Aotearoa. Data from the Australian and New Zealand Newborn Network includes births in both countries across Level 2 and Level 3 units and reports only for pēpi admitted to a neonatal unit. In 2020, of the pēpi born <30+0 weeks, 79.4% had received magnesium sulphate prior to birth, of which 29.7% are reported to have received a ‘complete course’ given within 24 hours of birth (‘complete course’ is not defined).8

Magnesium sulphate plays an essential role in key cellular processes within the human body. There are several proposed mechanisms for magnesium’s neuroprotective effect after preterm birth, including its role in several pathways involved in preterm brain injury, and its anti-inflammatory properties.9 Magnesium sulphate has been shown in preclinical studies to reduce post-hypoxic brain injury through its role as a non-competitive N-methyl-d-aspartate receptor antagonist, reducing calcium-induced brain injury from glutamate release.9,10 Magnesium also has anti-inflammatory properties and can reduce oxidative stress and production of pro-inflammatory cytokines.9

#Recommendations and Practice

Assessment, indications and timing for use of magnesium sulphate for fetal neuroprotection

Optimal use and timing of magnesium sulphate administration is essential to maximise benefit and minimise harm. This includes avoidance of unnecessary or prolonged use due to potential risks of toxicity for wāhine/people.

It is recommended that preterm birth should be planned or definitely expected/anticipated within 24 hours before commencing magnesium sulphate therapy.11 However, much shorter durations of treatment are still likely to be of benefit, hence this guideline also recommends commencing magnesium sulphate as close to four hours as possible before planned birth.11 A study has shown magnesium sulphate is transferred across the placenta to the pēpi within 30 minutes of infusion commencement, with neonatal magnesium sulphate concentrations remaining elevated for 24 hours.18 Furthermore, median times from randomisation to birth of 3.7 hours (IQR 1.3-12.9 hours)19 and 1 hour 38 minutes (range 5 minutes to 25 hours 5 minutes)20 in the two trials where birth was planned or anticipated within 24 hours supports this shorter timeframe of use.

Good Practice
— Risk assessment for use of magnesium sulphate for fetal neuroprotection

  • Regardless of the indication, risk assessment for magnesium sulphate use should usually be undertaken in a hospital setting by an experienced clinician.
  • Assessment should be made in consultation with an obstetrician or obstetric registrar and with consideration of availability of Level 3 neonatal services (as indication for use is <30 weeks gestation).
  • An initial assessment of preterm birth risk may be required to be undertaken by a LMC midwife or a general practitioner in the community or within a primary birthing unit if birth is imminent. However, access to magnesium sulphate and availability of staff and equipment to provide appropriate monitoring mean that administration is likely to need to be deferred until transfer has been arranged and completed.
  • For wāhine/people at risk of spontaneous preterm birth, assessment should confirm that preterm labour is established.
  • For wāhine/people at risk of provider-initiated preterm birth, magnesium sulphate should only be commenced once decision for planned early birth has been made (and is within 24 hours and as close to four hours as possible).

 

Guideline Recommendations
— Indications and timing for use of magnesium sulphate for fetal neuroprotection

Magnesium sulphate should be given for fetal neuroprotection:

  • When gestational age is <30+0 weeks.*
  • When preterm birth is anticipated within 24 hours.
  • When preterm birth is planned in next four hours.
  • Regardless of the reason the wahine/person is at risk of preterm birth.
  • Regardless of the planned mode of birth.
  • Regardless of whether antenatal corticosteroids have been given.
  • Regardless of the number of pēpi in utero.

* for lower gestational age limit, see use at extreme preterm gestation (23+0 to 24+6 weeks).

Good Practice
— Indications and timing for use of magnesium sulphate for fetal neuroprotection

  • There is likely to be benefit even if birth occurs within four hours and so magnesium sulphate should still be given even if birth is planned or anticipated within this time.
  • Birth should not be delayed to allow time for magnesium sulphate administration if the delay would be detrimental to the immediate health of the wāhine/person or pēpi.
  • Wāhine/people with preeclampsia and considered to be at risk of seizures, should receive magnesium sulphate therapy regardless of gestational age.
  • Wāhine/people and whānau should be provided with verbal and written information about antenatal magnesium sulphate use.
  • Interpreter services and cultural support should be available and offered to all wāhine/people and whānau to support the provision of information.

The Carosika Whānau Information on Magnesium Sulphate may be used to support conversations with wāhine/people and whānau.

Published: October 2024 | PDF

Download - The Carosika Whānau Information on Magnesium Sulphate may be used to support conversations with wāhine/people and whānau.

The Carosika Magnesium Sulphate Standard Operating Procedure may be used to support institutional practice change and provides aide memoire for clinicians.

PDF








Download - The Carosika Magnesium Sulphate Standard Operating Procedure may be used to support institutional practice change and provides aide memoire for clinicians.

 

Magnesium sulphate dosing

The AMICABLE Study subgroup analyses by time interval of treatment within 24 hours (and beyond 24 hours), by total dose of magnesium sulphate received and by use of maintenance therapy or not, did not find any consistent differences in treatment effect5 and therefore do not provide any evidence to direct a change in recommendations. Recommendations of the National Clinical Practice Guidelines 2010 are consistent with the dosing regimen recommended for use in Aotearoa in the treatment and prevention of seizures for wāhine/people with pre-eclampsia.21 There are likely to be safety advantages in using similar dosing regimes for both indications.

Guideline Recommendations
— Magnesium sulphate dosing

  • Use a loading dose of 4 grams over 20-30 minutes intravenously.
  • Use a maintenance dose of 1 gram per hour intravenously.
  • Maintenance therapy should be continued until birth or for 24 hours, whichever comes first.

Good Practice
— Magnesium sulphate dosing

  • If birth does not occur within 24 hours of completion of magnesium sulphate therapy, and preterm birth <30+0 weeks appears likely (planned or anticipated within 24 hours), a repeat dose of magnesium sulphate may be given, following consideration of gestational age and likely neonatal benefit, potential maternal risks, and certainty whether birth will occur.
  • Premixed bags of magnesium sulphate infusion are available within Aotearoa and should be used, they allow ease of use and have potential to reduce drug errors and potential toxicity risks.

 

Precautions and monitoring with magnesium sulphate use

Common side effects of magnesium sulphate for wāhine/people include flushing, sweating, and tachycardia. Less commonly, wāhine/people may experience nausea and vomiting, headaches, palpitations, and rarely, pulmonary oedema. Hypotension and respiratory depression may also occur. Administration of magnesium sulphate at doses above the recommended therapeutic range can lead to toxicity, which if unrecognised and untreated can result in respiratory or cardiac arrest and death.

Specific safety considerations must be made for wāhine/people who require in utero transfer when magnesium sulphate is indicated, wāhine/people with renal impairment (as magnesium sulphate is renally excreted and hence the risk of toxicity is higher), and in some rare neurological and cardiac conditions.

Guideline Recommendations
— Precautions and monitoring with magnesium sulphate use

  • Magnesium sulphate should be avoided for wāhine/people with myasthenia gravis and other rare neuromuscular disorders involving the acetylcholine receptor.

Good Practice
— Precautions and monitoring with magnesium sulphate use

  • Magnesium should be administered in a hospital setting with availability of trained staff and appropriate monitoring equipment.
  • Magnesium sulphate should only be continued during in utero transfer if suitable equipment and expertise is available for monitoring and for resuscitation and ventilatory support. Otherwise, it should be temporarily stopped during transfer and restarted on arrival at the Level 3 unit.
  • Wāhine/people should be provided with specific advice on potential side effects including flushing, sweating, and tachycardia.
  • Wāhine/people should be closely monitored including pulse, blood pressure, respiratory rate and deep tendon reflexes.
  • Wāhine/people should be cared for in an area where equipment and expertise for resuscitation and ventilatory support are immediately available.
  • Continuous CTG monitoring should occur unless at an extreme preterm gestation and CTG monitoring has not be planned.
  • Serum magnesium concentrations should not be routinely measured in wāhine/people.
  • Serum magnesium concentrations are recommended in wāhine/people with renal impairment (serum creatinine >90 mmol/l and/or urine output <25ml/hour for >4 hours). Dose adjustment may be required, and should be undertaken in consultation with an obstetric physician if available.
  • The magnesium sulphate infusion should be stopped if there are signs of toxicity (including reduced level of consciousness, loss of tendon reflexes and respiratory depression) and serum magnesium concentrations should be measured.
  • Calcium gluconate should be given for magnesium toxicity with respiratory depression. Dose 1 gram (10 mls of 10% solution), given intravenously over 10 minutes.

 

Additional considerations for use of magnesium sulphate

 

Extreme preterm gestation (23+0 to 24+6 weeks)

Rates of cerebral palsy are inversely proportional to gestational age at birth, so pēpi born at extreme preterm gestations may be expected to have a higher chance of benefit from magnesium sulphate than those born at later preterm gestations. Randomised trial evidence is limited for pregnancies <24 weeks gestation and the National Clinical Practice Guidelines 2010 provide no recommendations for use below 24 weeks.11 More recent international guidelines22 (published since our guideline search) and our own national consensus statement23 recommend magnesium sulphate use in preparation for preterm birth at extreme preterm gestations, once a decision for active intervention has been made.

Good Practice
— Magnesium sulphate use at extreme preterm gestation (23+0 to 24+6 weeks)

  • In Aotearoa, active intervention for pēpi may be considered from 23+0 weeks gestation, following appropriate counselling and shared decision-making with wāhine/people and whānau. Magnesium sulphate should be part of the package of care when active intervention is planned and should be given as recommended for general use.

 

Fetal neuroprotection >30 weeks

It is possible that the benefits of magnesium sulphate may extend to gestational ages >30 weeks. Evidence supporting the recommendations made in the National Clinical Practice Guidelines 2010 included wāhine/people and their pēpi at later preterm gestations, however, as differences in death and cerebral palsy were less clear at these gestations11 and due to concerns about resource allocations with a new practice in Aotearoa and Australia24 the 30 week upper gestational limit for use was set. The AMICABLE Study included subgroup analysis by gestational age at first treatment and did not find any consistent differences in treatment effect.5

The only trial specific to later gestational ages is the Magnesium sulphate at 30 to 34 weeks gestational age: neuroprotection trial (MAGENTA) which has been recently published (2023).6 This Australasian multi-centre, randomised placebo-controlled trial of a loading dose of magnesium sulphate (4 g over 30 minutes) included wāhine/people at risk of preterm birth within the next 24 hours at 30 to 34 weeks gestation.25 The trial reported some interesting secondary outcome results that warrant further consideration (differences in respiratory distress syndrome, chronic lung disease and caesarean section birth), but found that magnesium sulphate given to wāhine/people prior to expected birth at 30-34 weeks did not improve the chance of child survival free of cerebral palsy at two years of age or of any other neurodevelopmental outcome.6

Guideline Recommendation
— Magnesium sulphate use for fetal neuroprotection >30 weeks

  • Magnesium sulphate should not be given for fetal neuroprotection >30 weeks.

Good Practice
— Magnesium sulphate use for fetal neuroprotection >30 weeks

  • Evidence specific to magnesium sulphate use at 30 to 34 weeks gestation does not demonstrate improved childhood survival free of cerebral palsy or any impact on neurodevelopmental outcomes.

#Auditable Standards

To be added

Standards should be considered across your population and by ethnic group to allow objective assessment of equity in practice.

The Carosika Magnesium Sulphate Audit Tool document may be used to be support hospitals and healthcare professionals to undertake local practice audit on magnesium sulphate use in preparation for preterm birth.

PDF








Download - The Carosika Magnesium Sulphate Audit Tool document may be used to be support hospitals and healthcare professionals to undertake local practice audit on magnesium sulphate use in preparation for preterm birth.


 

#Included guidelines

The search identified seven clinical practice guidelines relevant to magnesium sulphate use for neuroprotection after preterm birth that met criteria for high-quality and/or were recommended for use.11-17 Two of these were assessed to be high-quality in Rigour of Development (score >60%) and in Overall Assessment (score >60%)11,17 and were recommended for use in clinical practice by the Review Panel. The ‘Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant and child: National Clinical Practice Guidelines 2010’ (National Clinical Practice Guidelines 2010) were developed by a multidisciplinary guideline development panel with systematic review of all relevant evidence to provide evidence-based recommendations to guide clinical decision-making on antenatal magnesium sulphate use for neuroprotection after preterm birth.11 The guideline was developed in Australia and was identified as a ‘national’ guideline to enable endorsement by the National Health and Medical Research Council of Australia. However, the Executive Panel members included representatives from Aotearoa (in obstetrics, midwifery, neonatology and a consumer), statements on impact refer to data from both Australia and Aotearoa and the requirements of the New Zealand Guidelines Group were followed during development. It is hence regarded as a bi-national document that has been widely adopted in practice in Aotearoa. The second guideline scored as high-quality was the ‘World Health Organization (WHO) recommendations on interventions to improve preterm birth outcomes’ which includes a section on magnesium sulphate use for neuroprotection after preterm birth.

The remaining five guidelines did not meet high-quality criteria but were recommended for use with modifications by the Review Panel.12-16

Recommendations in this section have been based on National Clinical Practice Guidelines 2010.11 However, as both this and the WHO guideline17 are >5 years old and have not been updated, additional evidence from more recent high-quality clinical trials and systematic reviews published since 2015 has been considered and included where appropriate.

#Impact on equity

National data on magnesium sulphate use for neuroprotection by ethnic group, region of residence, socioeconomic status and other equity factors are not routinely reported. It is likely that differences in use by these factors may occur and contribute to differences seen in perinatal outcomes.

Review Panel assessments identified that the recommendations in all seven clinical practice guidelines relevant to magnesium sulphate use for neuroprotection prior to preterm birth had potential to reduce differences by ethnicity and other equity factors in preterm birth outcomes. However, it was noted that consistent availability of these recommendations in all main centres with appropriate staff resourcing and training is required. In particular, several reviewers noted the critical midwifery shortages across Aotearoa, including midwives trained in high-risk care, and that this may compromise safe and equitable delivery of magnesium sulphate. The cost and availability of premixed magnesium sulphate infusions was also noted as an issue of equity for this resource.

#Research in progress that may inform future practice recommendations

None currently identified.

#Statement on rationale for any differing recommendations from the high-quality guidelines

The ‘World Health Organization (WHO) recommendations on interventions to improve preterm birth outcomes’ includes one recommendation on magnesium sulphate use.15 It recommends use of magnesium sulphate before 32 weeks gestation. The evidence included in their subanalysis was for trials <30 weeks versus <34 weeks gestation at randomisation and it is unclear how a cut-off of 32 weeks was selected. The rationale for guidance limited to <30 weeks made in the National Clinical Practice Guidelines 2010 above. The WHO recommendation included three different potential dosing regimes, we have included only one dosing recommendation (consistent with Aotearoa national recommendation for dosing in seizure prevention and treatment for wāhine/people with preeclampsia).

#References

1. Kuban KC, Leviton A, Pagano M, Fenton T, Strassfeld R, Wolff M. Maternal toxemia is associated with reduced incidence of germinal matrix hemorrhage in premature babies. J Child Neurol. 1992;7(1):70-6. DOI: 10.1177/088307389200700113.

2. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Pediatrics. 1995;95(2):263-9.

3. Hauth J, Goldenberg R, Nelson K, DuBard M, Peralta M, Gaudier F. Reduction of cerebral palsy with maternal MgSO4 treatment in newborns weighing 500-1000 g. Am J Obstet Gynecol. 1995;172(1):419.

4. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev. 2009(1). DOI: 10.1002/14651858.CD004661.pub3.

5. Crowther CA, Middleton PF, Voysey M, Askie L, Duley L, Pryde PG, et al. Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis. PLoS Med. 2017;14(10):e1002398. DOI: 10.1371/journal.pmed.1002398.

6. Crowther CA, Ashwood P, Middleton PF, McPhee A, Tran T, Harding JE. Prenatal Intravenous Magnesium at 30-34 Weeks' Gestation and Neurodevelopmental Outcomes in Offspring: The MAGENTA Randomized Clinical Trial. JAMA. 2023;330(7):603-14. DOI: 10.1001/jama.2023.12357.

7. Shepherd ES, Goldsmith S, Doyle LW, Middleton P, Marret S, Rouse DJ, et al. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database of Systematic Reviews. 2024(5). DOI: 10.1002/14651858.CD004661.pub4.

8. Chow S, Creighton P, Chambers G, Lui K. Report of the Australian and New Zealand Neonatal Network 2020. Sydney: Australian and New Zealand Neonatal Network; 2022. Available from: https://anznn.net/Portals/0/AnnualReports/Report of the Australian and New Zealand Neonatal Network 2020.pdf.

9. Chollat C, Sentilhes L, Marret S. Fetal Neuroprotection by Magnesium Sulfate: From Translational Research to Clinical Application. Front Neurol. 2018;9:247. DOI: 10.3389/fneur.2018.00247.

10. Espinoza MI, Parer JT. Mechanisms of asphyxial brain damage, and possible pharmacologic interventions, in the fetus. Am J Obstet Gynecol. 1991;164(6 ):1582-9. DOI: 10.1016/0002-9378(91)91440-8.

11. 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: Australian Research Centre for Health of Women and Babies, The University of Adelaide; 2010. Available from: https://cdn.auckland.ac.nz/assets/liggins/docs/Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant & child, National clinical practice guidelines.pdf.

12. Lakes District Health Board. Magnesium Sulfate for Pre-eclampsia and for Neuroprotection in Pre- Term Births < 30 Weeks. Rotorua: Lakes District Health Board; 2021.

13. Waikato District Health Board. Magnesium sulphate (MgSO4) for neuroprotection in pre-term births <30 weeks. Hamilton: Waikato District Health Board; 2020.

14. Capital and Coast District Health Board. Magnesium Sulphate Administration for Pre-Eclampsia, Eclampsia and Neuroprotection for Preterm Birth. Wellington: Capital and Coast District Health Board; 2021.

15. MidCentral District Health Board. Antenatal magnesium sulphate prior to preterm birth for neuroprotection of the fetus, infant and child. Palmerston North: MidCentral District Health Board; 2018.

16. Northland District Health Board. Magnesium sulphate for pre-eclampsia, eclampsia and neuroprotection in the pre-term fetus. Whangarei: Northland District Health Board; 2019.

17. World Health Organisation. WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Geneva: World Health Organisation; 2015. Available from: https://apps.who.int/iris/bitstream/handle/10665/183037/9789241508988\_eng.pdf.

18. Smith CA, Crowther CA, Willson K, Hiller JE, LW. Placental transfer of magnesium sulphate: a randomised placebo controlled trial. Perinatal Society of Australia and New Zealand 7th Annual Congress 2003; Tasmania, Australia.

19. 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(20):2669-76. DOI: 10.1001/jama.290.20.2669.

20. Marret S, Marpeau L, Zupan-Simunek V, Eurin D, Lévêque C, Hellot MF, et al. Magnesium sulphate given before very-preterm birth to protect infant brain: the randomised controlled PREMAG trial. BJOG. 2007;114(3):310-8. DOI: 10.1111/j.1471-0528.2006.01162.x.

21. Ministry of Health. Diagnosis and Treatment of Hypertension and Pre-eclampsia in Pregnancy in New Zealand: A clinical practice guideline. Wellington: Ministry of Health; 2018. Available from: https://www.health.govt.nz/system/files/documents/publications/diagnosis-and-treatment-of-hypertension-and-pre-eclampsia-in-pregnancy-in-new-zealand-v3.pdf.

22. Shennan A, Suff N, Jacobsson B. FIGO good practice recommendations on magnesium sulfate administration for preterm fetal neuroprotection. Obstet Gynecol Int J. 2021;155(1):31-3. DOI: 10.1002/ijgo.13856.

23. Newborn Clinical Network. New Zealand Consensus Statement on the Care of Mother and Baby(ies) at Periviable Gestations: Newborn Clinical Network; 2019. Available from: https://www.starship.org.nz/guidelines/new-zealand-consensus-statement-on-the-care-of-mother-and-baby-ies-at/.

24. Bain E, Bubner T, Ashwood P, Van Ryswyk E, Simmonds L, Reid S, et al. Barriers and enablers to implementing antenatal magnesium sulphate for fetal neuroprotection guidelines: a study using the theoretical domains framework. BMC Pregnancy Childbirth. 2015;15(1):176. DOI: 10.1186/s12884-015-0618-9.

25. Crowther CA, Middleton PF, Wilkinson D, Ashwood P, Haslam R. Magnesium sulphate at 30 to 34 weeks' gestational age: neuroprotection trial (MAGENTA) - study protocol. BMC Pregnancy Childbirth. 2013;13:91. DOI: 10.1186/1471-2393-13-91.

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