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Magnesium sulphate for women at term for neuroprotection of the fetus

  1. Thuy-My N Nguyen1,
  2. Caroline A Crowther1,*,
  3. Dominic Wilkinson2,
  4. Emily Bain3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 10 DEC 2012

DOI: 10.1002/14651858.CD009395.pub2


How to Cite

Nguyen TMN, Crowther CA, Wilkinson D, Bain E. Magnesium sulphate for women at term for neuroprotection of the fetus. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD009395. DOI: 10.1002/14651858.CD009395.pub2.

Author Information

  1. 1

    The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, Discipline of Obstetrics and Gynaecology, Adelaide, South Australia, Australia

  2. 2

    Women's and Children's Hospital, University of Adelaide, Discipline of Obstetrics and Gynecology, North Adelaide, SA, Australia

  3. 3

    Discipline of Obstetrics and Gynaecology, The University of Adelaide, ARCH: Australian Research Centre for Health of Women and Babies, Adelaide, Australia

*Caroline A Crowther, ARCH: Australian Research Centre for Health of Women and Babies, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women's and Children's Hospital, 72 King William Road, Adelaide, South Australia, 5006, Australia. caroline.crowther@adelaide.edu.au.

Publication History

  1. Publication Status: New
  2. Published Online: 28 FEB 2013

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Characteristics of included studies [ordered by study ID]
Witlin 1997

MethodsRandomised controlled trial.


Participants135 women were randomised.

Setting: Memphis, US.

Recruitment: March 1995 to June 1996.

Inclusion criteria: women at at least 37 weeks' gestation with blood pressure ≥ 140 mmHg systolic, ≥ 90 mmHg diastolic and/or proteinuria (≥ 300 mg per 24 hours).

Exclusion criteria: severe pre-eclampsia, fetal malpresentation, congenital anomalies, non reassuring fetal testing, contraindications to the use of magnesium sulphate,contraindications to a trial of labour.


InterventionsMagnesium sulphate (n = 67)

Women were given a loading infusion of 6 g magnesium sulphate over 15-20 minutes followed by a maintenance infusion of 2 g per hour continued until 12 hours postpartum.

Placebo (n = 68)

Women were given an equal volume of a saline solution by infusion.


OutcomesMaternal: length of labour, postpartum haemorrhage, caesarean delivery, maternal infection, maternal side effects, maternal side effects requiring treatment cessation.

Infant: Apgar score ≤ 6 at 1 and 5 minutes, gestational age at birth.


NotesParticipant enrolment ceased at 68% of planned enrolment following a single interim analysis.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk“Randomisation was performed by use of computer-generated tables of random numbers.”

Allocation concealment (selection bias)Low risk“The women and their care givers were blinded to the randomisation assignment through the use of sealed, sequentially numbered, opaque envelopes.”

Magnesium sulphate and placebo infusions were "... dispensed by the hospital pharmacy".

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll women and their caregivers were blind to group allocation; an identically appearing placebo infusion was used.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAs above.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up were reported. No drop outs or withdrawals were reported.

Selective reporting (reporting bias)Unclear riskWith no access to a trial protocol, it was not possible to determine if outcome data for all pre-specified outcomes were reported.

Other biasUnclear riskReason for early termination of study: enrolment of women into study was terminated at 68% of planned enrolment – following a single interim analysis determining that only 37 women in each group were needed to rule out a 33% increase in the length of labour resulting from magnesium sulphate.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Magann 1995Study compared magnesium sulphate with terbutaline.

Participants: 46 women.

Intervention: 4 g IV magnesium sulphate.

Comparison: 0.25 mg subcutaneous terbutaline.

Outcomes: mean arterial pressure, arterial pressure before and after the induction of anaesthesia, maternal heart rate, maternal oxygen saturation, estimated blood loss, pre- and postoperative haematocrits. No fetal outcomes were reported.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Blackwell 2001

MethodsRandomised, placebo-controlled, double-blinded trial.

Participants22 women were randomised.

Inclusion criteria: women with singleton gestations at at least 32 weeks with no clinical indications for magnesium sulphate therapy (pre-eclampsia or tocolysis) and either clinical chorioamnionitis or prolonged rupture of membranes.

Exclusion criteria: any indication for magnesium sulphate therapy (seizure prophylaxis or tocolysis), known maternal hypersensitivity to magnesium sulphate, fetal structural defects, fetal growth restriction (birth weight < 10th percentile for gestational age), systemic maternal infection (e.g., pneumonia or pyelonephritis), advanced cervical dilation (8 cm), or imminent delivery and disorders such as any renal, cardiac, or pulmonary disease, pulmonary hypertension, or myasthenia gravis.

InterventionsMagnesium sulphate (n = 11)

Women were given a 6 g magnesium sulphate loading dose followed by 2 g per hour until birth.

Placebo (n = 11)

Women were given a matched volume of lactated Ringer's solution until birth.

OutcomesMaternal: mode of delivery, histological chorioamnionitis.

Infants: fetal blood for total magnesium, ionised magnesium, IL-1beta, IL-6, and TNF-alpha; birth weight; 5-minute Apgar score; fetal death; major intraventricular haemorrhage; necrotising enterocolitis, bronchopulmonary dysphasia.

Notes3 publications (including 2 abstracts) were identified likely relating to the same trial. Women included were at "at least 32 weeks gestation". Author has been contacted regarding the availability of relevant data.

Chen 1995

MethodsRandomised trial - no further information provided.

Participants64 women were randomised.

Inclusion criteria: women with blood pressure ≥ 150/100 fulfilling at least 1 of 11 features of severe pre-eclampsia that were listed.

Exclusion criteria: intrauterine death, chronic hypertension, eclampsia.

InterventionsMagnesium sulphate (n = 34)

Women were given a 4 g IV loading dose of magnesium sulphate over 10 minutes followed by a maintenance dose of 1 g per hour until 1 day after birth.

Comparison (n = 30)

No treatment.

OutcomesMaternal: mode of delivery (caesarean section, spontaneous), convulsions, abruption.

Infant: Apgar score ≤ 6 at 1 minute.

Notes

Coetzee 1998

MethodsRandomised, placebo-controlled trial.

Women were allocated using consecutively numbered cards placed inside sealed opaque envelopes instructing the use of solution A or B. Envelopes were distributed in mixed batches of 20 and always had equal numbers of A and B. The solutions were prepared by the pharmacy and the identity of the solutions marked A or B were changed periodically.

Participants822 women were randomised (data presented for 645 women).

Setting: South Africa.

Inclusion criteria: women with severe pre-eclampsia (at least 2 of: of diastolic blood pressure ≥ 110 mmHg, significant proteinuria, symptoms of imminent eclampsia) requiring termination of pregnancy by induction of labour or caesarean section.

Exclusion criteria: women less than 16 years old; women already receiving anticonvulsant therapy.

InterventionsMangesium sulphate (n = 345)

Women were given a 4 g IV magnesium sulphate loading dose in 200 mL saline over 20 minutes, followed by 1 g per hour (200 mL over 4 hours) until 24 hours after birth.
Placebo (n = 340)

Women were given 200 mL of a placebo solution over 20 minutes, followed by 200 mL over 4 hours until 24 hours after birth.
Treatment was stopped if urine output was less than 30 mL per hour.

OutcomesMaternal: convulsions, maternal death, adverse reaction, antihypertensive therapy, caesarean section.

Infant: live births, stillbirths.

Notes

Livingston 2003

MethodsRandomised, placebo-controlled trial. Allocation was by sealed, consecutively numbered opaque envelopes. All medication was mixed in the pharmacy and labelled 'study drug'.

Participants222 women were randomised.

Setting: Memphis, US.

Inclusion criteria: women with mild pre-eclampsia (blood pressure ≥ 140/90 taken on 2 occasions in the presence of new onset proteinuria). Women who developed mild pre-eclampsia only during the postpartum period were also included.

Exclusion criteria: chronic hypertension, severe pre-eclampsia.

InterventionsMagnesium sulphate (n = 109)

Women were given a 6 g IV loading dose in 100 mL normal saline over 20 minutes, followed by a maintenance dose of 2 g per hour until 12 hours postpartum.

Placebo (n = 113)

Women were given an identical,indistinguishable IV saline solution.

OutcomesMaternal: caesarean delivery, uterine atony, blood loss, chorioamnionitis.

Infant: Apgar score at 1 and 5 minutes, meconium.

NotesOnly 51% of intended sample size enrolled. Group assignment was revealed for 33 women who developed severe pre-eclampsia and they were given magnesium sulphate.

Magpie 2002

MethodsRandomised controlled trial. Randomisation through central telephone randomisation service (computer-generated allocation sequence) based in Oxford or consecutively numbered local pack system.

Participants10141 women were randomised.

Setting: 175 centres in 33 countries.

Inclusion criteria: the woman was included if she had not given birth, or was ≤ 24 hours postpartum; blood pressure ≥ 140/90 on at least 2 occasions; proteinuria of at least 1+ (30 mg/dL); and there was clinical uncertainty about whether magnesium sulphate would be beneficial.

Exclusion criteria: hypersensitivity to magnesium, hepatic coma with a risk of renal failure, or myasthenia gravis.

Women with oliguria (urine output < 25 mL per hour) were eligible, but the volume of trial treatment was halved for each dose.

InterventionsMagnesium sulphate (n = 5071)

Women were given a 4 g IV magnesium sulphate loading dose then either a 1 g per hour IV infusion. or 10 g intramuscularly with the loading dose, followed by 5 g every 4 hours. Continued for 24 hours.
2 centres in Bangladesh used 5 g intramuscular loading dose then 2.5 g every 4 hours as maintenance.

Placebo (n = 5070)
Women received a placebo solution by an identical regimen.
Dose halved if oliguria present. Clinical monitoring alone for all women.

Outcomes

Notes

Moodley 1994

MethodsRandomised controlled trial. Consecutively numbered sealed opaque envelopes were used.

Participants228 women were randomised.

Inclusion criteria: women with severe proteinuric hypertension (diastolic blood pressure ≥ 110 mmHg for 4-6 hours, proteinuria +) or imminent eclampsia requiring delivery.

Exclusion criteria: prior anticonvulsant (except single dose of phenobarbitone 200 mg IM) or antihypertensive therapy

InterventionsMagnesium sulphate (n = 112)

Women were given the 'Pritchard regime' where a 4 g magnesium sulphate IV loading dose in 200 mL of normal saline was given over 20 minutes, followed by 5 g intramuscularly in each buttock, and 5 g intramuscularly 4 hourly as maintenance, with a maximum of 4 doses.

Comparision (n = 116)

No anticonvulsant.

OutcomesMaternal: mode of delivery, convulsions, renal failure, pulmonary oedema.

Infant: death (stillbirth, early neonatal death).

Notes

 
Comparison 1. Magnesium sulphate versus placebo or no treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Apgar scores < 7 at 5 minutes1135Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.46]

 2 Gestational age at birth (weeks)1135Mean Difference (IV, Fixed, 95% CI)-0.20 [-0.62, 0.22]

 3 Maternal adverse effects requiring treatment cessation1135Risk Ratio (M-H, Fixed, 95% CI)3.04 [0.13, 73.42]

 4 Postpartum haemorrhage1135Risk Ratio (M-H, Fixed, 95% CI)4.06 [0.47, 35.38]

 5 Caesarean section1135Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.39, 1.63]

 6 Side effects (feeling warm and flushed)1135Risk Ratio (M-H, Fixed, 95% CI)3.81 [2.22, 6.53]