1) The study evaluated different loading infusion rates (60 minutes vs 20 minutes) of magnesium sulfate given to women before 30 weeks gestation for preterm fetal neuroprotection. 2) Overall, 71% of women experienced adverse effects during the first hour of infusion, with no significant difference between the 60-minute (60%) and 20-minute (81%) groups. 3) Women in the 60-minute group experienced significantly less warmth and flushing at 20 minutes into the infusion compared to the 20-minute group, but there were no other significant differences in adverse effects between the groups.

1. Maternal adverse effects with different loading
infusion rates of antenatal magnesium sulphate
for preterm fetal neuroprotection: the IRIS
randomised trial
ES Bain,a
PF Middleton,a
LN Yelland,a
PJ Ashwood,a
CA Crowthera,b
a
Australian Research Centre for Health of Women and Babies, Robinson Institute, School of Paediatrics and Reproductive Health,
The University of Adelaide, Adelaide, Australia b
The Liggins Institute, The University of Auckland, Auckland, New Zealand
Correspondence: Ms ES Bain, Australian Research Centre for Health of Women and Babies, Robinson Institute, School of Paediatrics and
Reproductive Health, The University of Adelaide, Women’s and Children’s Hospital, 72 King William Road, North Adelaide 5006, SA,
Australia. Email emily.bain@adelaide.edu.au
Accepted 14 September 2013. Published Online 6 January 2014.
Objective To evaluate a slower (compared with a standard)
infusion rate of the loading dose of magnesium sulphate for
preterm fetal neuroprotection as a strategy to reduce maternal
adverse effects.
Design Randomised controlled trial.
Setting South Australian maternity hospital.
Population Fifty-one women at <30 weeks of gestation, where
birth was planned or expected within 24 hours.
Methods Women received a loading infusion of 4 g of magnesium
sulphate over either 60 or 20 minutes (followed by maintenance of
1 g/hour until birth, or for up to 24 hours).
Main outcome measures Any maternal adverse effects associated
with the infusion.
Results Overall, 71% of women experienced adverse effects
during the first hour of their infusion; the difference between
groups was not significant [15/25 (60%) 60-minute loading;
21/26 (81%) 20-minute loading; risk ratio (RR) 0.74;
95% confidence interval (95% CI) 0.51–1.08]. Although no
serious maternal complications occurred, adverse effects led to
three women ceasing the loading treatment (1/25 in the
60-minute loading group; 2/26 in the 20-minute loading
group; RR 0.52; 95% CI 0.05–5.38). Women in the 60-minute
loading group experienced significantly less warmth and
flushing at 20 minutes into the infusion (7/25 in the 60-minute
loading group; 15/26 in the 20-minute loading group; RR 0.49;
95% CI 0.24–0.99). No other differences between groups for
maternally reported and clinical adverse effects were shown.
Conclusions A slower rate of administering the loading dose
of magnesium sulphate did not reduce the occurrence of maternal
adverse effects overall. Flushing and warmth at 20 minutes into
the infusion was reduced with a slower infusion.
Keywords Adverse effect, antenatal, clinical trial, magnesium
sulfate, magnesium sulphate, preterm.
Please cite this paper as: Bain ES, Middleton PF, Yelland LN, Ashwood PJ, Crowther CA. Maternal adverse effects with different loading infusion rates of
antenatal magnesium sulphate for preterm fetal neuroprotection: the IRIS randomised trial. BJOG 2014;121:595–603.
Introduction
Infants born preterm (before 37 weeks of gestation) are at an
increased risk of mortality.1,2
Although the survival rate of
these infants has improved substantially over time, survival
can be associated with complex, lifelong neurosensory dis-
abilities,3,4
including cerebral palsy, blindness, deafness, and
developmental delay.1,5
The social and economic costs asso-
ciated with preterm birth and its sequelae are considerable.4
Following observational data in the 1990s suggesting associa-
tions between exposure to magnesium sulphate in utero and
reductions in intraventricular haemorrhage, cerebral palsy,
and neonatal mortality,6,7
five randomised controlled trials
were conducted assessing magnesium sulphate for preterm
fetal neuroprotection.8–12
Meta-analysis of these trials sup-
ported a neuroprotective role for magnesium sulphate,
showing a 32% relative reduction in the risk of cerebral palsy
(RR 0.68; 95% CI 0.54–0.87; 6145 infants).13
595ª 2014 Royal College of Obstetricians and Gynaecologists
DOI: 10.1111/1471-0528.12535
www.bjog.org
General obstetrics

2. Given the widespread use of magnesium sulphate in
obstetrics to prevent and treat eclampsia,14,15
for acute toc-
olysis,16
and for maintenance tocolysis,17
the associated
maternal adverse effects are widely recognised. Whereas
life-threatening adverse effects are considered to be extre-
mely rare in obstetrics,18
severe consequences of magne-
sium toxicity are known: respiratory arrest may occur,
along with altered cardiac function, cardiac arrest, and
death.19,20
The ‘well recognised’, more commonly reported
maternal adverse effects include flushing, warmth and
sweating, nausea, vomiting, headaches, blurred vision, and
intravenous or intramuscular site pain/discomfort.18
No
substantial differences between treatment groups in major
maternal complications were reported in the Cochrane
review assessing magnesium sulphate for fetal neuroprotec-
tion.13
As expected, however, higher rates of minor adverse
effects were observed among women exposed to magne-
sium sulphate, including increased risks of hypotension,
tachycardia, flushing, nausea/vomiting, sweating, and
problems at the injection site.13
Importantly, significantly
more women receiving magnesium sulphate ceased therapy
because of these adverse effects (RR 3.26; 95% CI
2.46–4.31; three trials; 4847 women).13
The importance of assessing strategies to reduce mater-
nal adverse effects during administration, and in turn to
reduce the cessation rate of this beneficial therapy, has
been highlighted in the relevant Cochrane review,21
and in
the Australian and New Zealand Clinical Practice Guide-
lines recommending antenatal magnesium sulphate for
fetal neuroprotection.22
To date, there have been no
randomised controlled trials comparing the different infu-
sion rates of the loading dose of antenatal magnesium sul-
phate. The IRIS Trial (Different Infusion Rates of
Magnesium Sulphate Prior to Preterm Birth) aimed to
compare the effects of two different rates of administering
the loading dose of magnesium sulphate, given to women
at risk of preterm birth before 30 weeks of gestation for
fetal neuroprotection, on maternal adverse effects during
the infusion.
Methods
Participants
Women with a single or twin pregnancy at <30 weeks of
gestation at the Women’s and Children’s Hospital, Adela-
ide, South Australia, who gave informed consent, were eli-
gible for the IRIS Trial if birth was planned or expected
within 24 hours, as per the current Australian and New
Zealand,22
and South Australian Clinical Practice Guide-
lines.23
A best estimate of gestational age was made at trial
entry derived from the menstrual history and early ultra-
sound. Women were not eligible if they were in the second
stage of labour, had already received magnesium sulphate
therapy in this pregnancy, or had any of the following con-
traindications to magnesium sulphate: absent patellar
reflexes; hypocalcaemia; respiratory rate of <16 breaths/
minute; renal failure; or urine output of <100 ml during
the last 4 hours.
Randomisation
The IRIS Trial protocol was approved by the Children,
Youth and Women’s Health Services Human Research
Ethics Committee (REC1651/2/2013). All participants were
given written information on the study, and gave informed,
signed consent before random assignment to either the
60-minute loading group, or the 20-minute loading group.
The randomisation sequence was computer generated, with
stratification by plurality, and treatment allocated by the
telephone randomisation service at the University of Adela-
ide.
Interventions
Women randomised to the 60-minute loading group were
administered a loading infusion of 4 g of magnesium sul-
phate intravenously over 60 minutes, whereas women
randomised to the 20-minute loading group were adminis-
tered a loading infusion of 4 g over 20 minutes. Both
groups were administered a maintenance infusion of 1 g
per hour intravenously until birth (if occurring within
24 hours), or for up to 24 hours, as per the clinical prac-
tice guidelines.22,23
In the event that birth did not occur
within 24 hours, the infusion was ceased. The midwives,
who could not be blinded to the treatment group alloca-
tion, reduced the rate of the infusion at 20 minutes for
women in the 20-minute loading group, and after 1 hour
for women in the 60-minute loading group. Midwives and
obstetricians were asked not to discuss treatment group
allocation with the women.
The women’s pulse rate, blood pressure, and respiratory
rate were measured manually and recorded before initiating
the infusion, at the end of 20 minutes of the infusion, and
after the first hour of the infusion. Maternally reported
adverse effects and any serious clinically observed effects
were recorded by the attending midwives 20 and 60 min-
utes after commencement. The midwives asked the women
an open-ended question regarding side effects experienced
after 20 minutes and after 1 hour. If the loading infusion
was stopped before treatment was complete, the time and
date of cessation were recorded along with the reason for
cessation. The total dose of magnesium sulphate adminis-
tered prior to birth was recorded.
Data were recorded using trial-specific forms, and addi-
tional demographic and clinical outcome information was
collected from the medical records. The care that women
and infants received was otherwise according to standard
practice at the hospital.
596 ª 2014 Royal College of Obstetricians and Gynaecologists
Bain et al.

3. Outcomes
The primary outcome was the occurrence of any maternal
adverse effects attributed to the magnesium sulphate infu-
sion (maternally reported and clinically observed), includ-
ing: arm discomfort; blurred vision; dizziness; headache;
mild nausea; mouth dryness; muscle weakness; palpitations;
sleepiness; sweating; warmth over body; respiratory depres-
sion (a decrease in respiratory rate of >4 breaths/minute
from baseline); tachycardia (pulse rate of >160 beats/min-
ute or pulse rate increase of >20 beats/minute from base-
line); or other.
Secondary outcomes included any serious adverse cardio-
respiratory effects of the infusion (defined as respiratory
arrest, cardiac arrest, or death), cessation of treatment for
maternal adverse effects attributed to the infusion, other
adverse cardiorespiratory effects of the infusion (defined as
a respiratory rate of <16 breaths/minute, or a decrease in
diastolic blood pressure of >15 mmHg), maternal self-
reported and clinical adverse effects of the infusion, and the
total dose (g) of magnesium sulphate given prior to birth.
Sample size
A sample size of 48 women (24 in each group) would
detect an absolute percentage reduction in the occurrence
of any maternal adverse effects of 36%, from 89% in the
20-minute loading group [as found by the Australasian
Collaborative Trial of Magnesium Sulphate (ACTOMgSO4),
Crowther and colleagues 2003]8
to 53% in the 60-minute
loading group, with 80% power and a two-tailed a = 0.05.
Allowing for a 5% loss, we aimed to recruit 51 women in
total.
Statistical analysis
Analyses were performed using intention-to-treat princi-
ples, blind to the allocated treatment, with the use of SAS
9.3 (SAS Institute Inc., Cary, NC, USA). Analysis of all
available data was performed for each outcome. Binary
outcomes were analysed using log-binomial regression, to
give risk ratios (RRs) and 95% confidence intervals
(95% CIs). The Fisher’s exact test was used to calculate
P-values where it was not possible to calculate RRs because
of zero events in one treatment group. Continuous out-
comes, if approximately normally distributed, were analy-
sed using linear regression, to give differences in means
and 95% CIs, and the Wilcoxon rank-sum test was used
for skewed outcomes. All reported P-values were two-sided,
and the level of statistical significance was 5%. For adverse
effects measured over time, two analysis approaches were
taken. First, a new outcome indicating whether the out-
come of interest occurred at either time point was defined
for the analysis. Second, where the outcome was sufficiently
common, the repeated measurements were analysed using
generalised estimating equations with an exchangeable
working correlation structure. Models initially included
treatment, time, and their interaction. If the interaction
was significant, and for the primary outcome, separate esti-
mates of treatment effect were calculated for the two time
points (20 minutes and 60 minutes). Where no evidence of
an interaction was identified, the interaction was removed
from the model and the overall treatment effect, assumed
to apply at each time point, was calculated.
Results
Of the 51 women enrolled in the IRIS Trial, 25 were allo-
cated to the 60-minute loading group and 26 women were
allocated to the 20-minute loading group (Figure 1).
Approximately 40% of all women who gave birth before
30 weeks of gestation in the participating hospital during
the study period were enrolled. Study outcome data were
obtained up to birth for all 51 women. There was one still-
birth after randomisation in the 20-minute loading group,
with cause of death classified as fetal growth restriction
associated with evidence of reduced vascular perfusion on
Doppler studies (Perinatal Society of Australia and New
Zealand Perinatal Death Classification 8.1).24
Baseline maternal and pregnancy characteristics
Most baseline maternal characteristics were similar between
groups (see Table S1), and reflect the eligible high-risk
population. The median gestational age at entry was
28 weeks. Over 50% of women were in their first preg-
nancy, 25% had experienced a previous preterm birth, and
10% had experienced a perinatal death. The reasons
women were at risk of very preterm birth included preterm
prelabour rupture of membranes (37%), preterm labour
(35%), pre-eclampsia (31%), intrauterine growth restriction
(22%), chorioamnionitis (16%), and antepartum haemor-
rhage (16%). Women in the 60-minute loading group were
more likely to be at risk of preterm birth as a result of pre-
term prelabour rupture of membranes and preterm labour
(48% versus 27% and 52% versus 19%, respectively).
Treatment
The majority of women (49/51) received some of the load-
ing infusion [25 women (100%) in the 60-minute loading
group and 24 women (92%) in the 20-minute loading
group], with the full loading dose given to 23 women
(92%) in the 60-minute loading group and 22 women
(85%) in the 20-minute loading group (Figure 1). The
median time from randomisation to birth was 5.6 hours
(interquartile range, IQR = 1.9–20.1 hours) in the 60-min-
ute loading group and 8.7 hours (IQR = 3.1–18.6 hours)
in the 20-minute loading group (P = 0.52).
597ª 2014 Royal College of Obstetricians and Gynaecologists
Magnesium sulphate infusion adverse effects

4. Primary outcome
Maternal adverse effects associated with the magnesium
sulphate infusion occurred in 60% of women in the
60-minute loading group (15/25), and in 81% of the
women in the 20-minute loading group (21/26); this differ-
ence was not statistically significant (RR 0.74; 95% CI
0.51–1.08; Table 1). Considering the two time points when
maternal adverse effects were assessed (after 20 minutes
and after 60 minutes), there was evidence of a significant
treatment by time interaction (P = 0.01). When separate
estimates of treatment effect were calculated for each of the
two time points, however, no statistically significant differ-
ences between groups were observed (Table 1).
Secondary outcomes
There were no serious maternal adverse effects (death, car-
diac arrest, or respiratory arrest) in either treatment group
(Table 2). From the clinical observations, only one (4%)
woman in the 60-minute loading group experienced a
decrease in diastolic blood pressure of >15 mmHg from
Table 1. Any maternal adverse effects of the magnesium sulphate infusion (primary outcome)
Outcome 60-minute
loading n = 25
20-minute
loading n = 26
RR (95% CI) P Interaction P*
Any adverse effects 15 (60.0) 21 (80.8) 0.74 (0.51–1.08) 0.12
Adverse effects over time 0.01
20 minutes 14 (56.0) 20 (76.9) 0.73 (0.48–1.09) 0.13
60 minutes 14 (56.0) 11 (42.3) 1.32 (0.75–2.34) 0.33
Values are n and %.
*Treatment by time interaction P-value.
Eligible women (n = 130)
Women not randomised (n = 79)
Consented but not randomised (n = 10)
Declined to participate (n = 9)
Not approached to participate
(emergency/rapid birth; language
barriers; other) (n = 60)
Women included in analyses (n = 25)
Live births (n = 28); including three sets of twins
Stillbirths after randomisation (n = 0)
Allocated to 60-minute loading group (n = 25)
25 received treatment
Loading dose started (n = 25)
Loading dose completed (n = 23)
Maintenance dose started (n = 19)
Maintenance dose completed (n = 14)
Live births (n = 29); including four sets of twins
Stillbirths after randomisation (n = 1)
Allocated to 20-minute loading group (n = 26)
24 received treatment
Loading dose started (n = 24)
Loading dose completed (n = 22)
Maintenance dose started (n = 21)
Maintenance dose completed (n = 16)
Women included in analyses (n = 26)
Allocation
Analysis
Randomised (n = 51)
Enrolment
Figure 1. Randomisation, treatment, and participants.
598 ª 2014 Royal College of Obstetricians and Gynaecologists
Bain et al.

5. baseline. In the 20-minute loading group, two (8%)
women experienced a decrease in diastolic blood pressure
of >15 mmHg from baseline, and three (14%) women
experienced a respiratory rate of <16 breaths/minute
(Table 2).
Adverse effects led to the loading infusion being stopped
in three women: one woman (4%) in the 60-minute load-
ing group and two women (8%) in the 20-minute loading
group (P = 0.58; Table 2). The reasons for the infusion
being ceased were arm discomfort and/or problems at the
intravenous site (one woman in each group), and other
maternal discomfort, including warmth (one woman in the
20-minute loading group).
The most commonly reported adverse effects included
arm discomfort (52% in the 60-minute loading group ver-
sus 65% in the 20-minute loading group), warmth over
body (36% versus 62%), mouth dryness (12% versus 31%),
mild nausea (12% versus 27%), and sleepiness (8% versus
19%). No significant differences between groups were
observed for any maternally reported adverse effects or
clinical observations (Table 2). There was evidence of a
treatment by time interaction for only two of the adverse
effects: warmth or flushing and arm discomfort (Table 3).
When warmth or flushing was assessed at the two time
points separately, it was observed that at 20 minutes,
significantly fewer women in the 60-minute loading group
(seven, 28%) experienced warmth and flushing as com-
pared with women in the 20-minute loading group (15,
58%; RR 0.49; 95% CI 0.24–0.99; P = 0.046); however, the
groups were similar at 60 minutes. Although a significant
treatment by time interaction was identified for arm dis-
comfort (P = 0.02), when separate estimates of treatment
effect were calculated for each of the two time points, no
statistically significant difference between groups was
observed at either time point.
The median total magnesium sulphate dose administered
prior to birth was 7.00 g (IQR 4.50–9.00 g) in the 60-min-
ute loading group and 7.75 g (IQR 5.00–13.00 g) in the
20-minute loading group (P = 0.31).
Birth outcomes
There were no important differences seen between the
treatment groups for outcomes relating to birth.
Gestational age at birth was similar in the 60-minute load-
ing group (median 26.9 weeks, IQR 25.7–29.3 weeks)
and 20-minute loading group (median 28.3 weeks, IQR
27.1–29.1 weeks). More than half of all women gave birth
by caesarean section [60-minute loading group, 14 (56%);
20-minute loading group, 19 (73%)]. There was no sub-
stantial difference between the groups in the mean (SD)
Table 2. Secondary maternal outcomes assessed during treatment
Outcome 60-minute
loading n = 25
20-minute
loading n = 26
RR (95% CI) P
Cardiac arrest 0 (0.0) 0 (0.0) Not Estimable
Respiratory arrest 0 (0.0) 0 (0.0) Not Estimable
Death 0 (0.0) 0 (0.0) Not Estimable
Any respiratory rate of <16 breaths/minute** 0 (0.0) 3 (13.6) Not Estimable* 0.11
Any diastolic blood pressure decrease of >15 mmHg 1 (4.0) 2 (7.7) 0.52 (0.05–5.38) 0.58
Loading infusion ceased for adverse effects 1 (4.0) 2 (7.7) 0.52 (0.05–5.38) 0.58
Any warmth over body 9 (36.0) 16 (61.5) 0.59 (0.32–1.07) 0.08
Any arm discomfort 13 (52.0) 17 (65.4) 0.80 (0.50–1.27) 0.34
Any mouth dryness 3 (12.0) 8 (30.8) 0.39 (0.12–1.31) 0.13
Any mild nausea 3 (12.0) 7 (26.9) 0.45 (0.13–1.53) 0.20
Any sleepiness 2 (8.0) 5 (19.2) 0.42 (0.09–1.95) 0.27
Any sweating 2 (8.0) 4 (15.4) 0.52 (0.10–2.59) 0.42
Any blurred vision 0 (0.0) 2 (7.7) Not Estimable* 0.49
Any palpitations 0 (0.0) 2 (7.7) Not Estimable* 0.49
Any headache 2 (8.0) 1 (3.8) 2.08 (0.20–21.52) 0.54
Any dizziness 1 (4.0) 1 (3.8) 1.04 (0.07–15.74) 0.98
Any muscle weakness 1 (4.0) 1 (3.8) 1.04 (0.07–15.74) 0.98
Any respiratory depression*** 1 (4.3) 0 (0.0) Not Estimable* 1.00
Any maternal tachycardia*** 1 (4.3) 2 (9.5) 0.46 (0.04–4.68) 0.51
Values are n and %, unless stated otherwise.
*P-value based on Fisher’s exact test.
**n = 23, 60-minute loading; n = 22, 20-minute loading.
***n = 23, 60-minute loading; n = 21 20-minute loading.
599ª 2014 Royal College of Obstetricians and Gynaecologists
Magnesium sulphate infusion adverse effects

6. birthweight of the infants [60-minute loading group 958 g
(352 g); 20-minute loading group 971 g (429 g)].
Discussion
Main findings
In this randomised trial of two infusion rates for adminis-
tering the loading dose of antenatal magnesium sulphate to
women at risk of preterm birth, for fetal neuroprotection
at <30 weeks of gestation, no statistically significant differ-
ence between treatment groups was observed for the pri-
mary outcome of any maternal adverse effects of treatment.
Although a significant treatment by time interaction was
identified for this outcome, indicating that the trial treat-
ments had a time-dependent effect on ‘any maternal
adverse effects’, when separate estimates of treatment effect
were calculated at 20 minutes and at 1 hour, no significant
differences between groups were observed.
Our findings indicated no clear differences in the risks of
minor maternally reported and clinically assessed adverse
effects between treatment groups, except for warmth or
flushing when assessed at 20 minutes into the infusion,
which was experienced by significantly fewer women receiv-
ing the slower loading infusion.
Strengths and limitations
The high rate of minor adverse effects for women receiving
magnesium sulphate (71% overall) observed in the IRIS
Trial is broadly consistent with the high rates reported for
women receiving magnesium sulphate for fetal neuropro-
tection in two large randomised trials: one from Australia
and New Zealand (ACTOMgSO4) that recruited 1062
women (89%)8
; and one from the USA (BEAM) that
recruited 2241 women (77%).12
Based on the ACTOMgSO4
trial,8
however, we anticipated a higher rate of any mater-
nal adverse effects than was observed, which limited our
statistical power to detect the expected 36% reduction in
the occurrence of our primary outcome. To detect the 36%
absolute reduction from the observed 81% rate of any
maternal adverse effects in the 20-minute loading group,
with an 80% power, 33 women per group would have been
required.
With utmost care taken to ensure that the randomisation
procedures were secure and to reduce selection bias, base-
line imbalances observed between treatment groups when
considering reasons women were at risk of preterm birth
were considered reflective of the trial’s sample size.
Although such differences were believed to be unlikely to
influence the maternal outcomes reported in this analysis,
any imbalances will be important to consider when assess-
ing later health outcomes for the infants.
As the methods used to monitor and detect adverse
effects are known to greatly influence the adverse effect fre-
quencies reported, for example, with active methods such
as the use of checklists yielding substantially higher fre-
quencies than more passive methods,25,26
care was taken to
ensure consistency, with all women being asked an open-
ended question at each of the time points at which adverse
effects were assessed during the infusion. A limitation of
the IRIS Trial is that we were not able to blind midwives
and obstetricians to treatment group allocation; although
all study personnel were asked not to discuss or reveal
Table 3. Secondary maternal outcomes assessed over time
Outcome 60-minute
loading n = 25
20-minute
loading n = 26
RR (95% CI) P Interaction P*
Warmth over body
At 20 minutes 7 (28.0) 15 (57.7) 0.49 (0.24–0.99) 0.046 0.01
At 60 minutes 8 (32.0) 6 (23.1) 1.39 (0.56–3.43) 0.48
Arm discomfort
At 20 minutes 12 (48.0) 17 (65.4) 0.73 (0.45–1.20) 0.22 0.02
At 60 minutes 10 (40.0) 6 (23.1) 1.73 (0.74–4.06) 0.20
Mouth dryness
At 20 minutes 3 (12.0) 7 (26.9) 0.46 (0.14–1.57) 0.22 0.10
At 60 minutes 3 (12.0) 3 (11.5)
Mild nausea
At 20 minutes 1 (4.0) 6 (23.1) 0.47 (0.12–1.76) 0.26 0.05
At 60 minutes 3 (12.0) 2 (7.7)
Sleepiness
At 20 minutes 1 (4.0) 5 (19.2) 0.34 (0.07–1.74) 0.20 0.21
At 60 minutes 2 (8.0) 4 (15.4)
*Treatment by time interaction P-value.
600 ª 2014 Royal College of Obstetricians and Gynaecologists
Bain et al.

7. treatment group allocation, and analyses were conducted
blind, it may have been possible for women to deduce their
group allocation.
Interpretation
We are not aware of any other trials assessing the rates of
infusion of the loading dose of antenatal magnesium sul-
phate, nor of any trials comparing two regimens for the
administration of antenatal magnesium sulphate for fetal
neuroprotection. One non-randomised comparative study
conducted in the USA recruited 144 women with
pre-eclampsia: 47 women received a 10-g intramuscular
loading dose followed by a continuous intravenous infu-
sion of 1 g per hour, and 97 women received a 10-g intra-
muscular loading dose, followed by a 2-g ‘intravenous
push’ every 1–2 hours.27
Of women receiving the ‘intrave-
nous push’, 93% experienced transient, moderate falls in
blood pressure, accompanied by heat and flushing, and
79% experienced respiratory effects, from a slowing of res-
piration, to shallow and slow breathing, to complete
apnoea. No women receiving the continuous infusion
experienced these effects.27
Although there were methodo-
logical limitations associated with this trial, including the
absence of randomisation and blinding, and the incomplete
reporting of adverse effects, the findings supported the use
of a slow intravenous infusion as compared with a ‘push’
technique.
Reassuringly, and consistent with the findings from the
relevant Cochrane systematic review,13
and from other
published literature from randomised trials,8,10,12
no serious
maternal complications (death, cardiac arrest, or respira-
tory arrest) were observed among women in the IRIS Trial.
Adverse effects did, however, lead to treatment cessation
for three women (6%) in our study, and although treat-
ment was not stopped for life-threatening adverse effects
(rather, treatment ceased for arm discomfort and/or
warmth), this finding highlights the continued need to
evaluate strategies to increase comfort for women receiving
this therapy in order to reduce early cessation of this bene-
ficial treatment for preterm infants.28
Although this study was not designed to compare the
neuroprotective benefits of the two regimens used, the
median times between randomisation and birth for both
groups in the IRIS Trial (60-minute loading group,
5.6 hours; 20-minute loading group, 8.7 hours) were simi-
lar to the times reported in two of the large randomised
controlled trials upon which the Australian and New
Zealand Clinical Practice Guideline recommendations
regarding timing were made.8,10,22
These guidelines recom-
mend magnesium sulphate be administered when early pre-
term birth is planned or definitely expected within
24 hours, and when birth is planned for treatment to be
commenced as close to 4 hours before birth as possible.22
The IRIS Trial is the first to assess strategies intended to
reduce maternal adverse effects associated with antenatal
magnesium sulphate for fetal neuroprotection, and contrib-
utes to continuing, critical research surrounding the opti-
mal regimen for administration.21,22,28
In addition to
evaluating methods to reduce maternal adverse effects and
therapy cessation, important questions remain related to
the minimum effective dose required for fetal neuroprotec-
tion, whether a single loading dose may be sufficient or if
maintenance is necessary, and the optimal duration of
treatment.21
Conclusion
This study showed that a slower rate of administering the
loading dose of magnesium sulphate prior to very preterm
birth at <30 weeks of gestation for fetal neuroprotection
did not reduce the occurrence of maternal adverse effects
overall, and did not reduce therapy cessation; however,
maternal flushing and warmth at 20 minutes into the infu-
sion was reduced with the slower infusion. Further strate-
gies to reduce maternal adverse effects and therapy
cessation require evaluation; an additional study assessing a
slower (compared with a standard) infusion rate of the
loading dose, with increased power, may be warranted.
Disclosure of interests
P.J.A. and L.N.Y. declare no conflicts of interest. E.S.B.,
P.F.M., and C.A.C. were authors of the Cochrane review
‘Different magnesium sulphate regimens for neuroprotec-
tion of the fetus for women at risk of preterm birth’.21
C.A.C. was the principal investigator for the Australasian
Collaborative Trial of Magnesium Sulphate (ACT-
OMgSO4).8
Two authors (P.F.M. and C.A.C.) were mem-
bers of the Guideline Development Panel for the Australian
National Health and Medical Research Council-approved
‘Antenatal Magnesium Sulphate Prior to Preterm Birth for
Neuroprotection of the Fetus, Infant and Child National
Clinical Practice Guidelines’.22
Contribution to authorship
C.A.C. and P.F.M. conceived, designed, and initiated the
trial. E.S.B. contributed to the study design, and coordi-
nated the trial, enrolling participants and collecting the
data, in collaboration with C.A.C., P.F.M., and P.J.A. Both
L.N.Y. and E.S.B. analysed the data, and all authors partici-
pated in the interpretation of the results. E.S.B. wrote the
first draft and all authors commented on and contributed
to subsequent drafts.
Details of ethics approval
This study was approved by the Children, Youth and
Women’s Health Services Human Research Ethics Committee
601ª 2014 Royal College of Obstetricians and Gynaecologists
Magnesium sulphate infusion adverse effects

8. (ref. no. 1651/2/2013). All participants gave written informed
consent. This study is registered with the Australian New
Zealand Clinical Trial Registry ACTRN12605000765628.
Funding
E.S.B. was supported by the Jeffrey Robinson Honours
Scholarship, Robinson Institute, The University of Adela-
ide. The Robinson Institute had no role in study design,
data collection and analysis, decision to publish, or prepa-
ration of the article.
Acknowledgments
We are indebted to all of the women who have taken part
in the study and to the obstetric staff involved in the care
of the women, for their cooperation. We thank Dr Thach
Son Tran for his assistance with the analyses.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table S1. Characteristics of women in the 60- and
20-minute loading groups at trial entry. &
References
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602 ª 2014 Royal College of Obstetricians and Gynaecologists
Bain et al.

9. Commentary on ‘Maternal adverse effects with different
loading infusion rates of antenatal magnesium sulphate for
preterm fetal neuroprotection: the IRIS randomised trial’
The offspring of mothers who receive magnesium sulphate prior to early preterm birth are more likely to be alive in
childhood and free of cerebral palsy than the offspring of mothers who don’t receive magnesium sulphate (Doyle LW
et al. Cochrane Database Syst Rev 2009;1:CD004661). By one estimate, the systematic use of magnesium sulphate could
prevent as many as 1000 cases of disabling cerebral palsy each year in the USA alone (Rouse DJ. Am J Obstet Gynecol
2009;200:610–12). Magnesium sulphate is inexpensive, readily available, easy to administer, and – when used properly –
safe. But to say that it is well tolerated would be to stretch the truth. The majority of women who receive it report noi-
some flushing or a general feeling of warmth, and a substantial minority experience pain at the infusion site. In the first
robust randomised trial of magnesium sulphate for neuroprotection, the infusion was discontinued for minor side effects
in 14.6% of women allocated to the active drug, compared with 5.3% in those allocated to placebo (Crowther CA et al.
JAMA 2003;290:2669–76). In the second, the respective rates were 4.2 and 1.4% (Rouse DJ et al. N Engl J Med
2008;359:895–905).
Clearly, discontinuation of any therapy will undermine its effectiveness, and magnesium sulphate for fetal neuropro-
tection is not exempt from this reality. Thus, the trial of Bain et al. is welcome, because it asks an important question:
can magnesium sulphate be made more tolerable by slowing its bolus infusion from 20 to 60 minutes? Unfortunately,
the answer provided by this trial is ‘no’. Although there were fewer adverse maternal effects observed in the 60-minute
group, the 95% confidence interval for the relative risk of adverse effects includes one. This may be because, with only
51 participants, the study was underpowered (although the authors failed to acknowledge it, but should have, the
intended sample size when they originally registered the trial was 140 women). Or it may be that there really is no
difference between the two infusion rates.
It is tempting to give the benefit of doubt to the slower infusion, and chalk the non-significant result up to a type-II
statistical error. This would be a mistake, however. The effectiveness data published come from trials in which the bolus
infusion was administered over 20–30 minutes. A slower infusion rate might compromise the effectiveness of the
treatment. So before condoning a slower rate, we should at least have convincing evidence that doing so will result in a
substantially lower rate of therapy discontinuation.
Disclosure of interests
I have no conflicts of interest to declare.
DJ Rouse
Alpert Medical School of Brown University, Women Infants Hospital, Providence, RI, USA
603ª 2014 Royal College of Obstetricians and Gynaecologists
Magnesium sulphate infusion adverse effects