Crowther CA, Hiller JE, Doyle LW, Haslam RR, for the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4)
Collaborative Group . Effect of Magnesium Sulfate Given for Neuroprotection Before Preterm BirthA Randomized Controlled Trial. JAMA. 2003;290(20):2669-2676. doi:10.1001/jama.290.20.2669
Author Affiliations: Departments of Obstetrics and Gynaecology (Dr Crowther) and Public Health (Dr Hiller), The University of Adelaide, and Department of Neonatal Medicine, Women's and Children's Hospital (Dr Haslam), Adelaide, South Australia; and Departments of Obstetrics and Gynaecology and Paediatrics, The University of Melbourne, The Royal Women's Hospital, Melbourne, Victoria, Australia (Dr Doyle).
Context Prenatal magnesium sulfate may reduce the risk of cerebral palsy or
death in very preterm infants.
Objective To determine the effectiveness of magnesium sulfate given for neuroprotection
to women at risk of preterm birth before 30 weeks' gestation in preventing
pediatric mortality and cerebral palsy.
Design, Setting, and Patients Randomized controlled trial at 16 tertiary hospitals in Australia and
New Zealand with stratification by center and multiple pregnancy. A total
of 1062 women with fetuses younger than 30 weeks' gestation for whom birth
was planned or expected within 24 hours were enrolled from February 1996 to
September 2000 with follow-up of surviving children at a corrected age of
Interventions Women were randomly assigned to receive a loading infusion of 8 mL (4
g [16 mmol] of 0.5 g/mL of magnesium sulfate solution or isotonic sodium chloride
solution [0.9%]) for 20 minutes followed by a maintenance infusion of 2 mL/h
for up to 24 hours.
Main Outcome Measures Rates of total pediatric mortality, cerebral palsy, and the combined
outcome of death or cerebral palsy at a corrected age of 2 years.
Results Data were analyzed for 1047 (99%) 2-year survivors. Total pediatric
mortality (13.8% vs 17.1%; relative risk [RR], 0.83; 95% confidence interval
[CI], 0.64-1.09), cerebral palsy in survivors (6.8% vs 8.2%; RR, 0.83; 95%
CI, 0.54-1.27), and combined death or cerebral palsy (19.8% vs 24.0%; RR,
0.83; 95% CI, 0.66-1.03) were less frequent for infants exposed to magnesium
sulfate, but none of the differences were statistically significant. Substantial
gross motor dysfunction (3.4% vs 6.6%; RR, 0.51; 95% CI, 0.29-0.91) and combined
death or substantial gross motor dysfunction (17.0% vs 22.7%; RR, 0.75; 95%
CI, 0.59-0.96) were significantly reduced in the magnesium group.
Conclusions Magnesium sulfate given to women immediately before very preterm birth
may improve important pediatric outcomes. No serious harmful effects were
Infants born very preterm have increased risks of mortality or of surviving
with cerebral palsy or other neurosensory impairments and disabilities. Very
preterm birth and very low birth weight are principal risk factors for cerebral
palsy.1- 5 Intraventricular
hemorrhage (IVH) is a known risk factor for cerebral palsy,6,7 with
the risk of IVH increasing the lower the gestational age at birth.8
In observational studies, maternal administration of magnesium sulfate
has been associated with a subsequent reduction in the risk of IVH,9- 12 cerebral
palsy,11,13- 15 and
pediatric mortality.16 However, not all observational
studies that examined risk factors for IVH,17- 20 cerebral
palsy,17,21- 23 or
pediatric mortality19 have shown protective
effects for magnesium sulfate, and neither has a small randomized controlled
Although observational studies suggest a role for prenatal magnesium
sulfate as a neuroprotective agent, there have been no large randomized controlled
trials in which magnesium sulfate was given solely for neuroprotection. The
Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4) was designed
to determine the efficacy of magnesium sulfate given solely for neuroprotection
to women at risk of preterm birth before 30 weeks' gestation in preventing
pediatric mortality and/or cerebral palsy.
Women pregnant with single, twin, triplet, or quadruplet fetuses younger
than 30 weeks' gestational age were eligible for the trial if birth was planned
or expected within 24 hours. There was no lower limit on gestational age at
enrollment; such limits were determined by individual hospital policies about
viability. A best estimate of gestational age was made at trial entry derived
from the menstrual history and early ultrasound. Women were excluded if they
were in the second stage of labor, if they had received magnesium sulfate
therapy in this pregnancy, or if there were contraindications to magnesium
sulfate (respiratory rate <16/min, absent patellar reflexes, urine output
<100 mL during the previous 4 hours, renal failure, or hypocalcemia). Recruitment
started in February 1996 and stopped in September 2000.
The study protocol was approved by the research and ethics committee
at each of the 16 collaborating tertiary hospitals, all with a neonatal intensive
care unit (13 in Australia and 3 in New Zealand). Stratification was by center
and multiple pregnancy (3 groups—singleton, twin, and higher-order multiple).
The study randomization numbers were generated by computer with variable block
sizes of 4, 6, or 8 and managed by nonclinical staff at the University of
Adelaide's Maternal Perinatal Clinical Trials Unit. Each study number was
placed on a masked treatment pack. Packs were sent to participating centers
ready for use.
Eligible women who gave written informed consent were enrolled by taking
the next treatment pack, corresponding to the number of fetuses, from the
drug supplies held at the center. If eligible, the treatment pack was opened,
which was the point of randomization, regardless of whether the infusion was
commenced or completed.
Each treatment pack looked identical and contained an infusion bag of
60 mL of either a 0.5-g/mL solution of magnesium sulfate or isotonic sodium
chloride solution (0.9%). Women were given a loading infusion of 8 mL (4 g
[16 mmol] of magnesium sulfate or isotonic sodium chloride solution) for 20
minutes followed by a maintenance infusion of 2 mL/h until birth (if occurred
within 24 hours) or up to 24 hours. Magnesium sulfate was given as a neuroprotective
agent only and not for tocolysis.
Women's pulse rate, blood pressure, and respiratory rate were monitored
throughout the infusion and any maternal adverse effects recorded. The loading
or maintenance infusions were stopped if the respiratory rate decreased more
than 4/min or the diastolic blood pressure decreased more than 15 mm Hg below
the baseline level. The infusion could be resumed when the respiratory rate
or blood pressure returned to baseline levels. Clinicians were asked not to
measure magnesium levels to maintain blinding.
The care women and infants received was otherwise according to standard
practice at each collaborating center. All perinatal staff were blinded to
treatment group allocation. All surviving infants had a cranial ultrasound
performed within the first 7 days of life to detect IVH and a later ultrasound
(beyond 4 weeks of age and as close to discharge as possible) to identify
periventricular leukomalacia. Women and their children were followed up until
the child was 2 years of age, corrected for prematurity. All pediatric deaths
were reviewed by an independent committee, blinded to therapy, to determine
the principal cause of death.
Surviving children were assessed at a corrected age of 2 years by developmental
pediatricians and psychologists blinded to treatment group allocation. The
criteria for cerebral palsy included abnormalities of tone and loss of motor
function as previously reported.27 Apart from
providing criteria for the diagnosis of cerebral palsy, we did not attempt
to train assessors at all 16 centers in its diagnosis. Instead we relied on
the judgment of individual developmental pediatricians. In addition, gross
motor function in all children was assessed by criteria derived from Palisano
et al28; children were classified as walking
normally, walking with minimal limitations such as toe walking or asymmetrical
gait, or not walking independently, the last group being considered to have
substantial gross motor dysfunction. Vision was assessed and children were
considered blind if vision in both eyes was worse than 6/60. Hearing was assessed
and children were considered deaf if they required hearing aids. The psychological
assessment included the Psychomotor Developmental Index (PDI) and Mental Developmental
Index (MDI) of the Bayley Scales of Infant Development.29 Children
unable to complete the PDI or MDI because of severe psychomotor or developmental
delay were assigned scores of 49, a score that automatically implies severe
The primary outcomes were total pediatric mortality up to a corrected
age of 2 years (including stillbirths, neonatal deaths, and mortality after
hospital discharge), cerebral palsy at a corrected age of 2 years, and the
combined adverse outcome of death or cerebral palsy at 2-year follow-up.
For infants, secondary outcomes were rates of major IVH (grade III or
IV), cystic periventricular leukomalacia, and neurosensory disability. Severe
neurosensory disability comprised any of severe cerebral palsy (considered
permanently nonambulant), severe developmental delay (MDI, <3 SDs), or
blindness. Moderate disability comprised any of moderate cerebral palsy (nonambulant
at 2 years but likely to walk), moderate developmental delay (MDI, −3
SDs to <−2 SDs), or deafness. Mild disability comprised either mild
cerebral palsy (walking at 2 years) or mild developmental delay (MDI, −2
SDs to <−1 SD). Children without any neurosensory impairment were
considered to have no disability.
For the mother, secondary outcomes were adverse cardiovascular and respiratory
effects of the infusion (defined as a respiratory rate of <16/min, decrease
in diastolic blood pressure of >15 mm Hg, cardiac arrest, respiratory arrest),
primary postpartum hemorrhage (defined as estimated blood loss of >600 mL),
and major postpartum hemorrhage (defined as blood loss of >1000 mL). Subsidiary
outcomes included other adverse effects of the infusion, pregnancy outcome,
and other neonatal outcomes.
All statistical analyses were undertaken on an intention-to-treat basis,
including outcome data from women who did not give birth preterm. Baseline
variables were included as confounders if there was imbalance between the
treatment groups and an association with the primary outcome under analysis.
The variables with imbalance—race, hospital, public patient status,
and either antepartum hemorrhage or preterm prelabor rupture of the membranes
as reasons for preterm birth—were only associated with mortality, not
with cerebral palsy, so an adjusted analysis was only performed for mortality.
Analysis of all available data was performed for each outcome. Binary outcomes
are presented as relative risks (RRs) with 95% confidence intervals (CIs).
The RRs were calculated using log binomial regression,30 since
the resulting metric is an RR that is more easily interpreted by clinicians
than an odds ratio.31 Robust variance estimation
was used to account for clustering of infants within mothers. The statistical
software used was SAS version 8.2 (SAS Institute Inc, Cary, NC), and the significance
level was .05.
Sample size was calculated to detect a 50% reduction in the risk of
cerebral palsy at 2 years in survivors from 10% to 5%, with 80% probability
at an α level of .05. This was considered a conservative estimation
given the 86% reduction in the odds of cerebral palsy in a case-control study.13 This sample size of 848 children was adjusted upward
to 1250 infants to account for a predicted mortality rate of 20% and a small
design effect due to nonindependence of observations from multiple births.
Data were reviewed twice by an independent data monitoring committee.
These reviews were undertaken in June 1997 for safety reasons following the
recruitment of 219 women and in November 1999 to look at the overall cerebral
palsy rates in the 230 infants with assessments at a corrected age of 2 years.
A total of 1062 women entered the study; 535 were allocated to the magnesium
sulfate group and 527 to placebo (Figure 1). Approximately 65% of all women who gave birth before 30 weeks'
gestation in participating centers were enrolled. A similar number of women
in each group with a multiple pregnancy had infants who were dead at the time
of randomization (4 in the magnesium sulfate group and 3 in the placebo group).
Outcome data were obtained, up to the time of hospital discharge, on all 1062
women and their 1255 infants alive at the time of randomization, and 2-year
corrected age outcomes were available for 1047 children (99% of 2-year survivors).
Fourteen children (9 in the magnesium sulfate group and 5 in the placebo group)
without 2-year corrected age cerebral palsy assessments were treated as missing
data and excluded from the cerebral palsy analysis.
Baseline maternal characteristics and reasons for preterm birth were
similar in both groups (Table 1)
and reflect the eligible high-risk population. The median gestational age
at entry was 27 weeks. Almost half the women were in their first pregnancy,
17% had a multiple pregnancy, 27% had experienced a previous very preterm
birth (<32 weeks) and 19% had experienced a perinatal death. The primary
reason for preterm birth was preterm labor (63%), followed by preeclampsia
(15%), antepartum hemorrhage (14%), chorioamnionitis (14%), severe intrauterine
growth restriction (9%), preterm prelabor rupture of the membranes (9%), and
fetal distress (3%). Of the infants who were alive at randomization, there
were 343 male infants (55%) in the magnesium sulfate group and 357 male infants
(57%) in the placebo group.
Most women (522 [98%] in the magnesium sulfate group and 509 [97%] in
the placebo group) received some of the loading infusion, with the full loading
dose given to 484 women (90%) who were allocated magnesium sulfate and 495
(94%) who were allocated placebo. Somewhat fewer women (451 [84%] in the magnesium
sulfate group and 459 [87%] in the placebo group) received some of the maintenance
infusion (Figure 1). The total dose
of infusion administered was similar in both groups, with median volumes of
medication received of 13 mL (interquartile range [IQR], 9-28 mL) in the magnesium
sulfate group and 13 mL (IQR, 10-29 mL) in the placebo group. Few women received
magnesium for clinical reasons after enrollment (4 [0.7%] in the magnesium
sulfate group and 11 [2.1%] in the placebo group).
There were no important differences between the treatment groups for
outcomes related to pregnancy, labor and delivery, or measures of neonatal
morbidity. The time from randomization to birth was similar in the magnesium
sulfate group (median, 3.7 hours; IQR, 1.4-13.8 hours) and the placebo group
(median, 3.1 hours; IQR, 1.3-12.9 hours). Gestational age at birth was also
similar in the magnesium sulfate group (median, 27 weeks 5 days; IQR, 26 to
29 weeks) and the placebo group (median, 27 weeks 3 days; IQR, 25 weeks 6
days to 29 weeks). Just more than half of all women gave birth by cesarean
delivery (magnesium sulfate group, 289 [54%]; placebo group, 290 [55%]). There
were no substantial differences between the groups in the mean (SD) birth
weight of the infants (magnesium sulfate group, 1027  g; placebo group,
1026  g) or in the proportion with Apgar scores less than 7 at 5 minutes
of age (magnesium sulfate group, 94 [15%] of 620; placebo group, 91 [15%]
The primary outcomes of total pediatric mortality, cerebral palsy in
survivors, and combined death or cerebral palsy were all lower in the magnesium
sulfate group, but no differences were statistically significant (Table 2). Among infants alive at randomization,
there were 194 deaths (15.5%), 87 (13.8%) in the magnesium sulfate group and
107 (17.1%) in the placebo group, although this was not a statistically significant
difference (adjusted RR, 0.83; 95% CI, 0.64-1.09). The mortality rate difference
between the groups was similar for singleton (RR, 0.82; 95% CI, 0.60-1.12)
and multiple pregnancies (RR, 0.80; 95% CI, 0.46-1.39). The principal causes
of death were similar between the 2 groups. The cerebral palsy rate at a corrected
age of 2 years was lower for children in the magnesium sulfate group (36 [6.8%]
vs 42 [8.2%]), although this was not a statistically significant difference
(RR, 0.83; 95% CI, 0.54-1.27) (Table 2).
The combined outcome of death or cerebral palsy was also lower for children
in the magnesium sulfate group (123 [19.8%] vs 149 [24.0%]), although this
was not a statistically significant difference (RR, 0.83; 95% CI, 0.66-1.03)
(Table 2). A sensitivity analysis
that included participants who had received a complete loading dose gave similar
results for each of these primary analyses.
There were no major maternal adverse effects (death, cardiac arrest,
respiratory arrest) seen in either treatment group. There were no differences
in the rate of respiratory depression of less than 16/min, but significantly
more women in the magnesium sulfate group had a decrease in diastolic blood
pressure of more than 15 mm Hg from baseline (77 [14.4%] vs 52 [9.9%]; RR,
1.46; 95% CI, 1.05-2.03). There were no substantial differences between treatment
groups in the rates of postpartum hemorrhage (Table 3).
Minor maternal adverse effects were more common in the magnesium sulfate
group compared with the placebo group (89.0% vs 37.8%; RR, 2.36; 95% CI, 2.10-2.64),
including tachycardia (>160/min or pulse >20/min from baseline), respiratory
depression (decrease of >4/min from baseline), a feeling of warmth over the
body, discomfort in the arm receiving the infusion, dryness of the mouth,
nausea, sleepiness, sweating, dizziness, and blurred vision (Table 3). The adverse effects led to the infusion being stopped
only in a small percentage of women but more often in the magnesium sulfate
group (78 [14.6%] vs 28 [5.3%]; RR, 2.74; 95% CI, 1.81-4.15).
For the infant secondary outcomes of major IVH and cystic periventricular
leukomalacia, no substantial differences were seen between the treatment groups
(Table 4). There were also no
major differences in the rates of chronic lung disease, necrotizing enterocolitis,
or mechanical ventilation or in the duration of hospitalization between the
treatment groups (Table 4).
There was no significant difference between the groups in the distribution
of neurosensory disability (Table 5),
although a significant reduction was seen in the proportion of children at
the corrected age of 2 years with substantial motor dysfunction in the magnesium
group compared with the placebo group (3.4% vs 6.6%; RR, 0.51; 95% CI, 0.29-0.91)
(Table 5). Of the 52 children
with substantial gross motor dysfunction, 39 had cerebral palsy (3 mild, 27
moderate, and 9 severe). The combined rate of death or substantial motor dysfunction
at a corrected age of 2 years was significantly lower in the magnesium group
compared with the placebo group (105 [17.0%] vs 141 [22.7%]; RR, 0.75; 95%
CI, 0.59-0.96) (Table 5). There
were no major differences in the rates of blindness, deafness, or delayed
development or in the mean scores for the PDI or MDI between the treatment
groups (Table 5).
In our randomized controlled trial of magnesium sulfate as a neuroprotective
agent before very preterm birth, total mortality, cerebral palsy, and the
combined outcome of mortality or cerebral palsy were all lower in the magnesium
sulfate group, but differences were not statistically significant. Despite
the lack of statistical significance, the average sizes of the reductions
in these adverse outcomes are potentially clinically important. There was
a statistically significant reduction in substantial motor dysfunction among
survivors in the magnesium sulfate group and in the combined outcome of death
or substantial motor dysfunction, both of which are considered to be clinically
Since most preterm children with cerebral palsy are not severely disabled,25 we considered it essential to find out if the overall
rates of neurosensory disability or motor dysfunction were lowered with maternal
magnesium therapy rather than solely determining the presence or absence of
cerebral palsy at a corrected age of 2 years. Moreover, the diagnosis of cerebral
palsy is not 100% accurate in early childhood,32 especially
in preterm children, even when only a few well-trained experts are involved
in the diagnosis.33 A limitation of our study
is that we did not have the resources to train individual assessors or to
ensure that every child suspected of having cerebral palsy was evaluated by
several well-trained independent experts, which would have improved the diagnostic
accuracy. However, the way that cerebral palsy was diagnosed in this study
was reflective of usual clinical practice. We did not find any substantial
differences between the groups when neurosensory disability was determined
solely by the presence and severity of specific neurosensory impairments (cerebral
palsy, blindness, deafness, and developmental delay). However, when we used
the Gross Motor Classification System developed by Palisano et al,28 we found a reduction in substantial gross motor dysfunction
in the group treated with magnesium sulfate. Follow-up into school age will
be important to determine if magnesium sulfate has any long-term beneficial
cognitive or other neurological effects.
The only other trial of which we are aware that has reported on the
use of magnesium sulfate for prophylactic neuroprotection, in the preventive
groups of the trial, randomly allocated 57 women in active labor who were
more than 4 cm dilated to either a 4-g loading dose of magnesium sulfate or
isotonic sodium chloride solution.24 The trial
was stopped early because of concerns of a higher total pediatric mortality
rate in the magnesium sulfate group. Pediatric mortality was lower in our
trial. Childhood neurological outcome from the trial by Mittendorf et al25,26 showed that of the 43 survivors assessed
at 18 months of age, 3 (15%) of 20 exposed to magnesium sulfate had cerebral
palsy compared with 0 of 23 exposed to saline. The small size of the study,
the follow-up rate of survivors to 18 months of age (77%; 43/56), and lack
of reported methodological details make it difficult to compare the results
with our findings.
Our study is the largest randomized trial of magnesium sulfate used
solely as a neuroprotective agent before very preterm birth, but the benefit
observed was smaller than anticipated from the nonrandomized human studies,
and the event rates for total mortality and cerebral palsy were lower than
originally predicted. Hence, our study was relatively underpowered to detect
smaller but still clinically important differences than we originally hypothesized.
Although the results of our trial suggest that prenatal magnesium sulfate
given specifically for neuroprotection has beneficial effects for the fetus
expected to be born before 30 weeks' gestation, we do not consider the evidence
currently strong enough to recommend widespread use of magnesium sulfate unless
confirmed by other randomized controlled trials in humans. We are aware of
2 such studies currently in progress in the United States and France.
Maternal adverse effects from magnesium sulfate therapy in obstetrics
are well known. It was no surprise to find higher rates of minor adverse effects
in women receiving magnesium sulfate infusion in our study, although in only
a few women were they severe enough for the infusion to be stopped. We did
not detect any obvious harmful effects of magnesium sulfate for either the
fetus or infant.
Although there have been several reports that maternal administration
of magnesium sulfate was associated with a reduced risk of IVH in infants,9- 12 there
was little evidence in our study of any effect of magnesium sulfate on the
rate of IVH, including the more severe grades, or on the rate of cystic periventricular
leukomalacia. Any neuroprotective effect of magnesium sulfate on motor dysfunction
might work through other mechanisms, such as stabilization of blood flow or
ameliorating the effects of hypoxic ischemic episodes, free radicals, and
infection, rather than by reducing IVH or cystic periventricular leukomalacia.
In conclusion, the potential clinically important improvement in pediatric
outcomes from magnesium sulfate given to women immediately before very preterm
birth for neuroprotection urgently needs confirmation in further trials. Widespread
use of prenatal magnesium sulfate as a neuroprotective agent cannot be recommended
solely on the basis of the current study. Although minor adverse effects are
common in women receiving magnesium sulfate, there do not appear to be any
serious harmful effects for the women or their children.