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Use of Magnesium Sulfate in Preterm Deliveries For Neuroprotection of The Neonate
Use of Magnesium Sulfate in Preterm Deliveries For Neuroprotection of The Neonate
12328 2017;19:21–8
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Key content To become familiar with the main studies assessing the use of
The prevalence of preterm birth is increasing and owing to MgSO4 for neuroprotection in preterm deliveries.
advances in neonatal care, more infants are surviving. However, in To become aware of the relevant international guidelines.
parallel with this, the incidence of cerebral palsy (CP) is also rising.
Ethical issues
Magnesium sulfate (MgSO4) is currently recommended for use in
Concerns have been raised regarding the higher number of
women who are at risk of giving birth at less than 30–32 weeks of
perinatal deaths reported with the use of MgSO4 in the MagNET
gestation for neuroprotection of their infants. The exact
study. This was not substantiated in the Cochrane review.
mechanism of action remains unclear. Given that MgSO4 is a safe, readily available and inexpensive drug,
Meta-analyses report encouraging results that are consistent with a
even if there were only to be modest benefits from its use, the risk–
modest but tangible benefit for the use of MgSO4, and suggest a
benefit ratio is in favour of its use.
number needed to treat (NNT) to prevent one in 46 cases of CP in
infants born preterm before 30 weeks of gestation and one in 63 Keywords: cerebral palsy / intrapartum / magnesium sulfate
cases of CP in infants born preterm before 34 weeks of gestation. (MgSO4) / neuroprotection / preterm deliveries
Learning objectives Linked resource: Single best answer questions are available for this
To gain an understanding of the risk of neurodisability in infants article at https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
delivered preterm.
Please cite this paper as: Usman S, Foo L, Tay J, Bennett PR, Lees C. Use of magnesium sulfate in preterm deliveries for neuroprotection of the neonate. The
Obstetrician & Gynaecologist 2017;19:21–8.
2 years of age in children born between 23 and 26 weeks of administration and reduction in the prevalence of cerebral
gestation and found that 40% had a developmental quotient palsy in infants born weighing less than 1500 g.
(DQ) less than one standard deviation (SD) below the mean,
6% had a DQ between 1 SD and 2 SD (mild delay) below the Randomised controlled trials
mean, 35% had a DQ between 2 SD and 3 SD (moderate From 1997 to 2008, results from five randomised controlled
delay) below the mean and 19% had a DQ less than 3 SD trials (RCTs) were published that included data from
(severe delay) below the mean.22 6145 babies.
In 1997, the MagNET trial, the first RCT, published
interim safety data because an unexpectedly high number of
Proposed mechanism of action of
adverse outcomes were found in fetuses exposed to MgSO4.36
magnesium sulfate (MgSO4) for
This was a four-arm study of 149 women in preterm labour
neuroprotection
between 24 and 34 weeks of gestation. In the two unblinded
There remains a lack of understanding of how MgSO4 may tocolytic arms, women in preterm labour were randomised to
act as a neuroprotective agent. MgSO4 freely crosses the receive MgSO4 or an alternative tocolytic. In the other two
placenta and takes part in many intracellular processes, double-blinded arms MgSO4 was given to mothers in one
resulting in effects including cerebral vasodilation, reduction group purely as a neuroprotective agent (and compared with
in inflammatory cytokines and inhibition of calcium influx normal saline). The study found ten intrauterine deaths in
into cells.23,24 those receiving MgSO4, compared with one death in those
One widely cited theory for the possible neuroprotective given saline; a significant difference. On further analysis,
effect of MgSO4 is that, by blocking calcium processes and other causes of death such as congenital abnormality in one
thus acting as a vasodilator, it may inhibit or delay ischaemic case and twin-to-twin transfusion in two cases were found in
cell death during and after cerebral ischaemic events.25 There fetuses exposed to MgSO4, leaving seven unexplained.
is also evidence that MgSO4 decreases the production of The Magpie trial was originally designed to assess maternal
proinflammatory cytokines and free radicals during hypoxic- eclamptic outcomes in 33 countries.37 Analysis of a secondary
ischaemic reperfusion.26,27 This theory is supported by measure (neonatal outcome of mothers that received MgSO4
several recent papers that demonstrate a suppression of in labour) reported a lower risk of death or CP in children at
cord blood cytokine production with MgSO4 use.28–30 In 18 months of age, however this was not statistically
2014, a randomised controlled trial in 72 women showed significant (RR 0.83, 95% CI 0.66–1.03).38 The main
increased levels of brain-derived neurotrophic factor (BDNF) criticism of this study was the inconsistency of the
in cord blood of preterm babies (born before 34 weeks of paediatric follow-up.
gestation) where MgSO4 (4 g loading dose and 1 g/h until Between 2003 and 2008, three large RCTs specific for
delivery) had been given antenatally, compared with neuroprotection in the preterm infant followed the Magpie
placebo.31 BDNF is a neurotrophin shown to be protective trial (see Table 1 for comparison of the trials).
against neonatal hypoxic-ischaemic brain injury in vivo.32 In In ACTOMgSO4, Crowther et al.39 recruited 1062 women
a recent study in which MgSO4 was given prior to preterm from Australia and New Zealand. The study reported a non-
delivery (less than 32 weeks of gestation), there was significant reduction in CP and death; however, a significant
subsequently an associated reduction in risk of developing reduction in the prevalence of gross motor dysfunction was noted.
echodensities and echolucencies associated with cystic PVL, BEAM, a study involving 2241 women in the USA used a
on neonatal cranial ultrasound.33 different prescribing regimen (6 g loading dose and then 2 g/
h for up to a further 12 h). It found a significant difference in
outcome between placebo and MgSO4 for the occurrence of
Key studies on MgSO4 use for
severe CP but not for milder forms of CP.40
neuroprotection in preterm deliveries
PREMAG, a French study of 688 infants where the mothers
Observational studies had been given a 4g bolus dose of MgSO4 perinatally, reported
The first observational study in 1988 by Leviton et al.34 on data from 200641 with further 2-year follow-up data
discovered that infants born preterm to women with pre- published in 2008.42 Initially, the primary outcome of neonatal
eclampsia toxaemia had a lower incidence of adverse central mortality before discharge was assessed and it was reported that
nervous system outcomes. Very low birthweight babies total mortality, severe white matter injury, and the
(weighing less than 1751 g) who had been exposed to combination of these outcomes, were less frequent in babies
MgSO4 in utero were found to have fewer germinal matrix exposed to MgSO4, but these differences were not statistically
haemorrhages. Six years later, in a case–control study derived significant. The complete 2-year follow-up data did not show a
from the California Cerebral Palsy project, Nelson and significant difference in rates of CP, gross motor dysfunction or
Grether35 reported an association between antenatal MgSO4 combined death and CP between the control and treatment
ACTOMgSO439 <30 weeks 2 years 4 g loading dose Total paediatric mortality up to a corrected Composite outcome (combined death or CP):
Magnesium sulfate neuroprotection
n = 1062 then 1 g/h age of 2 years 19.8% versus 24.0%; RR 0.83, 95% CI 0.66–1.03
Australia CP at corrected age of 2 years Death: 13.8% versus 17.1%; RR 0.83, 95% CI 0.64–1.09
Combined adverse outcome of death or CP at CP: 6.8% versus 8.2%; RR 0.83, 95% CI 0.54–1.27
2 years of age Gross motor dysfunction*: 17.0% versus 22.7%; RR
Minimum sample size: 848 (50% reduction in 0.75, 95% CI 0.59–0.96
CP at 2 years in survivors from 10% to 5%,
80% power, alpha level 0.05)
BEAM40 <32 weeks 2 years 6 g loading dose Composite of stillbirth or infant death by 1 Composite outcome (combined death or CP):
n = 2241 then 2 g/h for 12 h year of age or moderate or severe CP, as 11.3% versus 11.7%; RR 0.97, 95% CI 0.77–1.23
USA assessed at or beyond 2 years of age (with CP*: moderate to severe 1.9% versus 3.5%; RR 0.55,
ages corrected for prematurity). 95% CI 0.85–1.47
Minimum sample size: 2200 (30% reduction Gross motor dysfunction: Not considered.
in primary outcome, 80% power and alpha
level 0.05, 10% rate of loss to follow-up)
PREMAG41 <33 weeks 6 years Single loading Overall neonatal mortality before hospital Severe white matter injury and/or death: 16.5%
n = 573 mothers; dose 4 g discharge. versus 17.9%; OR 0.86, 95% CI 0.55–1.34
688 infants Detection of neonatal cranial ultrasound Death: 9.4% versus 10.4%; OR 0.79, 95% CI 0.44–1.44
France abnormalities evocative of severe white Severe white matter injury: 10.0% versus 11.7%; OR:
matter injury (WMI) 0.78, 95% CI 0.47–1.31
Combination of severe WMI, and/or neonatal
mortality.
Minimum sample size: 1106 (50% reduction
of the risk of severe WMI from 8 to 4%, 80%
power and 0.05 alpha level)
PREMAG follow-up42 Death and CP: OR 0.65, 95% CI 0.42–1.03
CP alone: OR 0.63, 95% CI 0.35–1.15
Gross motor dysfunction: OR 0.65, 95% CI 0.41–1.02
Death and/or gross
motor dysfunction: OR 0.62, 95% CI 0.41–0.93*
*P<0.05; CI = confidence interval; CP = cerebral palsy; MgSO4 = magnesium sulfate; OR = odds ratio; RR = relative risk.
Table 3. International guidelines on the use of magnesium sulfate for neuroprotection of preterm infants
Gestational
Recommendations age Dosage Comments
SOGC60 <32 weeks 4 g bolus then 1 g/h Dosing to resemble current clinical practice for seizure prophylaxis
for up to 24 h
RCOG47, NICE49 <30 weeks 4 g bolus then 1 g/h NICE have recommended offering MgSO4 and the RCOG has endorsed
for up to 24 h the Australian guide
ANCP48 <30 weeks 4 g bolus then 1 g/h Limit to <30 weeks because resources are limited and the effect is
for up to 24 h greatest then
ACOG61 Not specified Not specified Development of a neuroprotection protocol based on one of the large trials
ACOG = American College of Obstetricians and Gynecologists; ANCP = Australian National Clinical Practice; CP = cerebral palsy; RCOG = Royal
College of Obstetricians and Gynaecologists; SOGC = Society of Obstetricians and Gynecologists of Canada; NICE = National Institute for Health
and Care Excellence. Reproduced with permission.59
the rate of death and CP at 2 years of age. Once reported, this was the perinatal outcome. Subsequent meta-analyses found
will enable further evidence-based recommendations for the no increase in the risk of adverse neonatal outcome or
use of MgSO4 in preterm deliveries occurring between 30 and mortality46 (Table 4).
34 weeks.
Limiting side effects in women receiving
Long-term data
MgSO4
Recently the long-term school age data became available from
two of the original RCT cohorts; ACTOMgSO4 and MgSO4 is widely regarded as a safe drug in pregnancy and
PREMAG. The long-term data from PREMAG were is commonly used in obstetrics for the prevention and
published in 2014, reporting on 431 children with a mean treatment of eclampsia. However, because of its narrow
age at follow-up of 11 years. No detrimental effects of therapeutic range, caution is necessary when deciding on
prenatal MgSO4 were reported, there was a trend for better the dose of administration. No major maternal adverse
long-term neurological and behavioural outcomes but these effects of MgSO4 were observed in any of the RCTs.
were not statistically significant.51,52 Doyle et al.53 followed- Conde-Agedulo’s meta-analysis46 published in 2009 did not
up 867 children from the original ACTOMgSO4 study, with a an effect of MgSO4 on serious maternal complications such
mean age of 8 years. The paediatric mortality rate to school as death (RR 0.32, 95% CI 0.01–7.92) or severe postpartum
age was 14.0% in the MgSO4 group, compared with 17.6% in haemorrhage (RR 1.06, 95% CI 0.63–1.79). Women were
the placebo group; this was not statistically different. There more likely to experience minor side effects with MgSO4,
was no difference in the proportions of CP in the two groups including flushing (RR 7.56, 95% CI 3.39–16.88) and
nor its severity (8% versus 7%; OR 1.26, 95% confidence nausea or vomiting (RR 4.60, 95% CI 1.54–13.75).
interval [CI], 0.84–1.91). No long-term difference in benefit Serious, but rarer, side effects (usually associated with an
or harm was found for the perinatal use of MgSO4. The overdose) include respiratory depression, pulmonary oedema
numbers in these two studies individually might be and cardiac arrest. Women receiving MgSO4 should therefore
underpowered for CP, as was the case in the original RCTs. be closely monitored, with regular recordings of blood
It wasn’t until the original RCT data were pooled in meta- pressure and other maternal observations. Calcium gluconate
analyses that the size of the true effect became apparent. should be available to give as an antidote if MgSO4 toxicity is
suspected. There is a risk of maternal hypotension, especially
if MgSO4 is used concurrently with nifidepine as a tocolytic
Concerns for fetal safety with perinatal
drug.55 There has also been a suggested risk of
MgSO4 administration
neuromuscular blockade with concomitant use of MgSO455
Concerns were originally raised in 1997 in the MagNET trial and calcium channel blockers; however, a review did not
following an interim safety report that described an increased support an increased risk.56 A slower rate of administering
rate of paediatric mortality in association with MgSO4 use.36 the loading dose of MgSO4 (over 60 minutes versus
Composite findings of the MagNET trial published in 200254 20 minutes) significantly reduced the feeling of flushing
suggested that in women administered MgSO4, the higher the and warmth. However, 71% of women experienced mild
umbilical cord MgSO4 levels in the neonate, the more severe adverse effects (arm discomfort, flushing, warmth) from the
Table 4. Effect of magnesium sulfate on neonatal outcome in preterm infants less than 34 weeks of gestation46
CI = confidence interval.
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