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Review

Antenatal Magnesium Sulfate and Neurologic


Outcome in Preterm Infants
A Systematic Review
Lex W. Doyle, MD, FRACP, Caroline A. Crowther, MD, FRANZCOG, Philippa Middleton, MPH,
and Stphane Marret, MD, PhD
OBJECTIVE: To systematically review rates of neurologic
outcomes reported in childhood for the preterm fetus
exposed to antenatal magnesium sulfate.
DATA SOURCES: We searched the Cochrane Pregnancy
and Childbirth Groups Trials Register, CENTRAL (The Co-
chrane Library 2008, Issue 3), relevant references from re-
trieved articles, and abstracts submitted to major congresses.
METHODS OF STUDY SELECTION: We sought all ran-
domized controlled trials (RCTs) of antenatal magnesium
sulfate with neurologic outcomes reported for the fetus.
TABULATION, INTEGRATION, AND RESULTS: Five eli-
gible RCTs with 6,145 fetuses were identified; in four
studies (4,446 fetuses) the primary intent was neuropro-
tection of the fetus. Methods of the Cochrane Collabo-
ration were used to analyze the data. Antenatal magne-
sium sulfate therapy given to women at risk of preterm
birth substantially reduced the risk of cerebral palsy in
their children (relative risk [RR] 0.69; 95% confidence
interval [CI] 0.540.87; five trials; 6,145 infants). The
number needed to treat to prevent one case of cerebral
palsy was 63 (95% CI 43155). Moreover, there was a
significant reduction in the rate of substantial gross motor
dysfunction (RR 0.61; 95% CI 0.440.85; four trials; 5,980
infants). No statistically significant effect of antenatal
magnesium sulfate therapy was detected on pediatric
mortality (RR 1.01; 95% CI 0.821.23; five trials; 6,145
infants), or on other neurologic impairments or disabili-
ties in the first few years of life. There were no significant
effects of antenatal magnesium sulfate on combined rates
of mortality with neurologic outcomes, except in the
studies where the primary intent was neuroprotection,
where there was a reduction in death or cerebral palsy
(RR 0.85; 95% CI 0.740.98; four trials; 4,446 infants).
CONCLUSION: Antenatal magnesium sulfate therapy
given to women at risk of preterm birth is neuroprotective
against motor disorders in childhood for the preterm fetus.
(Obstet Gynecol 2009;113:132733)
S
urvival rates for extremely low birth weight in-
fants (birth weight less than 1,000 g) have in-
creased dramatically with the advent of modern peri-
natal and neonatal intensive care.
1
However, rates of
major neurologic abnormalities, particularly motor
disorders such as cerebral palsy, in such survivors in
early childhood have not diminished over several
decades and are five times more common than in
survivors at term.
1
Not only children born extremely
low birth weight but also children born preterm may
experience cerebral palsy and other neurodevelop-
mental impairments, including those with gestational
ages less than 26 weeks,
2
less than 33 weeks,
3
and
3034 weeks.
4
Animal data suggesting a neuroprotective role for
antenatal magnesium sulfate therapy in preterm preg-
nancy have recently been reviewed.
5
Theoretically,
magnesium might be neuroprotective because of ef-
fects on cellular metabolism, cell death or injury, or
blood flow to the brain. Some
6,7
but not all
811
obser-
See related editorial on page 1202.
From the Royal Womens Hospital, the University of Melbourne, and Murdoch
Childrens Research Institute, Melbourne, Victoria, Australia; the Discipline of
Obstetrics and Gynaecology, the University of Adelaide, Adelaide, South
Australia, Australia, and the Department of Neonatal Medicine, University
Hospital, Rouen, France.
Supported in part by grants from the National Health and Medical Research
Council (Project Grants 34295 and 350326), Department of Health and
Ageing, Australia.
The authors thank the Chief Investigators and Steering Committees of the
MAGPIE Trial Collaborative Group and the MAGPIE Trial Follow-up Study
Collaborative Group for providing unpublished data from the MAGPIE trial.
Corresponding author: Lex W. Doyle, Department of Obstetrics and Gynaecology,
7th floor Womens Research Precinct, The Royal Womens Hospital, 20 Flemington
Road, Parkville Victoria 3052, Australia; e-mail: lwd@unimelb.edu.au.
Financial Disclosure
The authors did not report any potential conflicts of interest.
2009 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/09
VOL. 113, NO. 6, JUNE 2009 OBSTETRICS & GYNECOLOGY 1327
vational studies in humans are also suggestive of a
neuroprotective effect for magnesium sulfate. When
reviewed in the Cochrane Library in 2007,
12
it was
concluded that randomized controlled trials (RCTs) of
antenatal magnesium sulfate as a neuroprotectant in
humans have been inconclusive thus far, but only one of
four RCTs was designed to address long-term neuro-
logic outcomes, and there were limitations in how
long-term outcomes had been assessed in some studies.
The recent report
13
of the largest RCT to date designed
specifically to assess the neuroprotective role of antena-
tal magnesium sulfate in very preterm delivery requires
a reconsideration of antenatal magnesium sulfate as a
neuroprotectant. The aim of this study was to review
systematically the current evidence from RCTs in hu-
mans on the neuroprotective role of antenatal magne-
sium sulfate in the preterm fetus.
SOURCES
We searched the Cochrane Pregnancy and Child
birth Groups Trials Register by contacting the Trials
Search Coordinator (August 2008) and CENTRAL
(The Cochrane Library 2008, Issue 3), which covers a
number of health databases. We manually searched
relevant references from retrieved articles. We also
searched abstracts submitted to major international
congresses, such as the Society for Pediatric Research
(1996 to 2008). We did not apply language or publi-
cation status restrictions.
STUDY SELECTION
We sought all RCTs of magnesium sulfate where cere-
bral palsy or other neurologic outcome data for the fetus
were reported, among other outcomes, including sur-
vival. We followed the guidelines for systematic reviews
of interventions in the Cochrane Handbook for System-
atic Reviews of Interventions,
14
including criteria for
considering articles for inclusion, the methodologic
quality of trials, and the processing of included trials.
Whenever possible, we sought from the investigators
unpublished data and information about quality issues
that were unclear from the published reports.
We performed statistical analyses using the Re-
view Manager software (RevMan 5.0.16; The Nordic
Cochrane Centre, Copenhagen, Denmark) and com-
pared categorical data using relative risks and risk differ-
ences, with 95%confidence intervals. Data were analyzed
on an intention-to-treat basis where possible. We tested
for statistical heterogeneity between trials using the I
2
statistic.
15
If substantial heterogeneity was found (I
2
greater than 50%), we used a random-effects model.
The major outcomes were pediatric mortality,
cerebral palsy, and the combination of mortality or
cerebral palsy. We planned other analyses for sub-
stantial gross motor dysfunction (Gross Motor Func-
tion Classification System
16
worse than grade 1 or
equivalent), with and without mortality. Other acute
neurologic outcomes compared included some in the
newborn period (Apgar scores less than 7 at 5 min-
utes, need for ongoing respiratory support, any intra-
ventricular hemorrhage, periventricular leukomala-
cia, or neonatal convulsions), and at follow-up
(blindness, deafness, developmental delay [develop-
mental quotient more than 2 standard deviations
below the mean], and any major neurologic disability
[any of blindness, deafness, developmental delay, or
moderate or severe cerebral palsy (Gross Motor Func-
tion Classification System worse than grade 1)]). We
also planned subgroup analyses for the major pediat-
ric outcomes according to whether the primary inten-
tion of administering magnesium sulfate was for neu-
roprotection of the fetus, as distinct from other
indications.
RESULTS
Five trials (6,145 fetuses) qualified for inclusion in
this review, two from the United States (Magnesium
and Neurologic Endpoints Trial [MagNET]; Mittendorf
et al
17
; Beneficial Effects of Antenatal Magnesium Sul-
fate [BEAM]; Rouse et al
13
), one from Australia and
New Zealand (Australasian Collaborative Trial of Mag-
nesiumSulphate [ACTOMgSO
4
]; Crowther et al
18
), one
from France (PREMAG; Marret et al
1921
), and one
that was worldwide, but predominantly from devel-
oping countries (Magnesium Sulphate for Prevention
of Eclampis [MAGPIE]; Duley at al
22,23
). The first four
trials specifically targeted women who were likely to
give birth early and magnesium was being used for
neuroprotection, although one study (MagNET
17
) also
had a tocolytic arm. The fifth study, the MAGPIE
trial,
22,23
was designed to prevent eclampsia in women
with preeclampsia and included women at all gesta-
tional ages. Data from the MAGPIE
22,23
study relevant
to undelivered women less than 37 weeks when ran-
domly assigned were provided by the authors for inclu-
sion in this review. Details of the five studies are shown
in Table 1.
In the MagNET study by Mittendorf et al,
17
a
total of 149 women in preterm labor 25 to 33 weeks of
gestation were enrolled from October 1995 to January
1997 at a single U.S. center. Women were excluded if
there was nonreassuring fetal assessment or clinical
features of infection or preeclampsia or more than
twin pregnancy. Stratification was by race (black
compared with other), gestational age (25 to 28 weeks
and 29 to 33 weeks), and several months into the trial,
1328 Doyle et al Magnesium Sulfate and Cerebral Palsy OBSTETRICS & GYNECOLOGY
plurality (singleton compared with twin). There were
two treatment strategies dependent upon cervical
dilatation at entry: those with active labor and cervi-
cal dilatation 4 cm or less were considered candidates
for tocolysis with magnesium sulfate (the tocolytic
arm); they were randomly allocated to receive mag-
nesium sulfate as a 4-g bolus followed by 2- to 3-g/h
maintenance (n46 women, 55 neonates), or an
alternative tocolytic (nonblinded) (n46 women, 51
neonates). The remainder (with cervical dilatation
more than 4 cm) were considered for the neuropro-
tective arm of the study and were randomly allo-
cated to either a 4-g magnesium sulfate bolus (n29
women, 30 neonates) or saline placebo (n28
women, 29 neonates). The study was stopped prema-
turely because of concerns with higher pediatric
mortality in the magnesium group.
24
Cerebral palsy
was verified by a developmental pediatrician, who
was blinded to treatment allocation, after survivors
had been assessed at 18 months corrected age.
17
The
follow-up rate of survivors was not reported.
In the most recent multicenter study (BEAM) by
Rouse et al,
13
2,241 women with singletons or twins at
2431 weeks of gestation and at high risk of delivery
were randomly assigned to either magnesium sulfate,
6-g loading dose and 2 g/h maintenance infusion, or
identical placebo. Stratification was by center (n20),
twin pregnancy, and gestation less than 28 weeks or
2831 weeks. The majority of women (87%) were
eligible because of premature rupture of the mem-
branes, rather than because of spontaneous prema-
ture labor, because magnesium sulfate within the
previous 12 hours was an exclusion criterion, and
magnesium sulfate is a common tocolytic in the
United States. The major endpoint was survival free
of moderate or severe cerebral palsy at 2 years of age.
Cerebral palsy was diagnosed by certified pediatri-
cians or pediatric neurologists, and severity was based
on the Gross Motor Classification System (GMFCS)
16
;
moderate or severe cerebral palsy comprised children
with a level of 2 or worse on this system, which was
also used to define substantial gross motor dysfunc-
tion for this review. Children were also assessed with
the Bayley Scales of Infant Development II
25
; a
Mental Developmental Index less than 85 comprised
developmental delay. The primary outcome was as-
sessed for 96% of fetuses.
In the ACTOMgSO4 study by Crowther et al,
18
a
total of 1,062 women less than 30 weeks of gestation
and in whom birth was anticipated within 24 hours
were enrolled from February 1996 to September
2000. Women were excluded if birth was imminent
(they were in the second stage of labor), if they had
already received magnesium sulfate during the preg-
nancy, or if there were contraindications to magne-
sium sulfate therapy. There were 16 collaborating
centers within Australia and New Zealand. Stratifica-
tion was by center and multiple pregnancy (three
groupssingleton, twins or higher order multiples).
Women were randomly allocated to either intrave-
nous magnesium sulfate (n535 women, 629 live
neonates) or an identical volume of saline placebo
(n527 women, 626 live neonates). The magnesium
sulfate dose was 4 g over 20 minutes, followed by 1
g/h for up to 24 hours or until birth, whichever came
first. There were no repeat courses of treatment. The
major endpoint was survival free of cerebral palsy at
2 years of age corrected for prematurity, which was
diagnosed by pediatricians blinded to treatment allo-
cation. Motor function was assessed by the GMFCS
16
for all children, with and without cerebral palsy;
substantial gross motor dysfunction comprised chil-
Table 1. Characteristics of Included Studies
Study (First Author) Inclusions Women (n) Fetuses (n) Magnesium Dose
MagNET
(Mittendorf et al
17
)
2533 wk in preterm labor 149 165 Tocolytic arm; 4 g loading, 23 g/h
maintenance. Neuroprotective
arm; 4 g loading only
ACTOMgSO
4
(Crowther et al
18
)
30 wk, likely to deliver within
24 h
1,062 1,255 4 g loading, 1 g/h maintenance
MAGPIE
(Duley et al
22,23
)
All gestations* with severe
preeclampsia
1,544* 1,593* 4 g loading, 1 g/h IV maintenance,
or 5 g every 4 h IM
PREMAG
(Marret et al
19
)
33 wk of gestation in labor 573 688 4 g loading only
BEAM
(Rouse et al
13
)
2431 wk at high risk of
spontaneous birth
2,241 2,444 6 g loading, 2 g/h maintenance
MagNET, Magnesium and Neurologic Endpoints Trial; ACTOMgSO
4
, Australasian Collaborative Trial of Magnesium Sulphate
;
MAGPIE,
Magnesium Sulphate for Prevention of Eclampis; IV, intravenously; IM, intramuscularly; BEAM, Beneficial Effects of Antenatal
Magnesium Sulfate.
* Only less than 37 weeks and undelivered at enrolment included in this analysis.
VOL. 113, NO. 6, JUNE 2009 Doyle et al Magnesium Sulfate and Cerebral Palsy 1329
dren with a level of 2 or worse on the GMFCS.
Children were also assessed with the Bayley Scales of
Infant Development II
25
; a Mental Developmental
Index less than 85 comprised developmental delay.
The follow-up rate of survivors was 99%.
In the PREMAG trial by Marret et al,
19
a total of
573 women whose birth was planned or expected within
24 hours with singletons, twins, or triplets less than 33
weeks of gestation were enrolled at 18 collaborating
centers in France, but data from only 13 centers (564
women) were included in the final report; two of the 18
centers recruited no women, and three centers enrolled
fewer than five women and were excluded on the basis
of a prespecified criterion for exclusion of centers.
Women were randomly allocated to either intravenous
magnesium sulfate 4 g or an equal volume of isotonic
saline placebo over 30 minutes. The major endpoint of
the study was white matter injury to the infant diagnosed
by cranial ultrasonography. However, follow-up data for
surviving children to 2 years of age have also been
reported.
20,21
Physicians caring for the children or the
study investigators, who were blinded to treatment
allocation, obtained data either by clinical examination
or telephone with a standardized questionnaire with
cognitive and motor developmental scales scored, rang-
ing from one (normal) to four (severely impaired).
Substantial gross motor function from this study com-
prised those who were moderately or severely impaired
(score 3 or 4). The follow-up rate of survivors was 98%.
The primary intent of the MAGPIE trial
22,23
was
neuroprotection of the mother. A total of 10,141
women who were either undelivered or within 24
hours of birth with preeclampsia and uncertainty
about whether to use magnesium sulfate to prevent
eclampsia were enrolled from July 1998 to November
2001 in a randomized controlled trial of either mag-
nesium sulfate or saline placebo. The magnesium
sulfate dose was 4 g intravenously over 10 to 15
minutes, followed by either 1 g/h intravenously for 24
hours, or by 5 g every 4 hours intramuscularly for 24
hours. Pediatric outcome data were reported for
survivors who reached at least 18 months of age from
centers where follow-up was feasible, which was not
possible for many surviving children in this multina-
tional trial.
23
Children were assessed by a develop-
mental screening questionnaire at 18 or more months
of age, corrected for prematurity where appropriate,
and those who failed were invited for a more formal
developmental testusually the Bayley Scales of In-
fant Development. Children also were not routinely
examined by a pediatrician or neurologist. It is prob-
able that diagnoses such as developmental delay or
cerebral palsy were underestimated. For this review,
unpublished outcome data were provided from the
trial investigators for 1,593 infants whose mothers
were undelivered when treated with magnesium sul-
fate and who were less than 37 weeks gestational age
at randomization. Table 2 provides the numbers of
subjects with main individual outcomes from each of
the included trials that formed the basis of the meta-
analyses on these outcomes.
Antenatal magnesium sulfate treatment had no
overall significant effect on total pediatric mortality
(Table 3). Statistical conclusions were unaltered within
the subgroups by intention of therapy (Table 3). There
was substantial heterogeneity in the other intent sub-
Table 2. Numbers of Subjects Enrolled and With Various Outcomes, by Intent of Study
Number
Randomized Mortality Cerebral Palsy
Study (First Author) Mg Pl Mg Pl Mg Pl
Primary neuroprotective intent
MagNET (Mittendorf et al
17
) 30 29 2 (6.7) 1 (3.4) 3 (10) 0 (0)
ACTOMgSO
4
(Crowther et al
18
) 629 626 87 (13.8) 107 (17.1) 36 (5.7) 42 (6.7)
PREMAG (Marret et al
1921
) 352 336 34 (9.7) 38 (11.3) 22 (6.2) 30* (8.9)
BEAM (Rouse et al
13
) 1,188 1,256 103 (8.7) 96 (7.6) 41 (3.5) 74 (5.9)
Subtotal 2,199 2,247 226 (10.3) 242 (10.8) 102 (4.6) 146* (6.5)
Other intent
MagNET (Mittendorf et al
17
) 55 51 8 (14.5) 0 (0) 0 (0) 3 (5.9)
MAGPIE (Duley et al
22,23
) 798 795 209 (26.2) 188 (23.6) 2 (0.3) 5 (0.6)
Subtotal 853 846 217 (25.4) 188 (22.2) 2 (0.2) 8 (0.9)
Total 3,052 3,093 443 (14.5) 430 (13.9) 104 (3.4) 154* (5.0)
Mg, magnesium group; Pl, placebo group; MagNET, Magnesium and Neurologic Endpoints Trial; NA, not applicable; ACTOMgSO
4
,
Australasian Collaborative Trial of Magnesium Sulphate; BEAM, Beneficial Effects of Antenatal Magnesium Sulfate; MAGPIE,
Magnesium Sulphate for Prevention of Eclampis.
Data are n (%).
* One infant died before 2 years of age but had definite cerebral palsy before death.
1330 Doyle et al Magnesium Sulfate and Cerebral Palsy OBSTETRICS & GYNECOLOGY
group (I
2
71.2%) between studies, largely due to the
different results from the other intent (tocolytic) arm of
the MagNET study
17
(relative risk [RR] 15.8, 95%
confidence interval [CI] 0.93267; 106 infants).
There was a significant effect of antenatal magne-
sium sulfate treatment on cerebral palsy, both overall
(Table 3; risk difference 0.016, 95% CI 0.026 to
0.006; five trials; 6,145 infants) and for the neuropro-
tective intent subgroup (risk difference 0.019, 95% CI
0.032 to 0.006; four trials; 4,446 infants), but not for
the other intent subgroup (Table 3). Overall, the number
needed to treat to prevent one case of cerebral palsy was
63 (95% CI 43155), assuming a baseline risk of 5% for
cerebral palsy in the control group. There was also a
Table 3. Meta-Analysis of Mortality, Cerebral Palsy, Substantial Gross Motor Dysfunction and Combined
Outcomes by Subcategory of Intent
Outcome and Subcategory
No. of
Studies
Magnesium
n/N (%)
Control
n/N (%) RR* 95% CI*
Statistical
Significance
Heterogeneity
[I
2
(%)]
Mortality
Neuroprotective intent 4 226/2,199 (10.3) 242/2,247 (10.8) 0.94 0.771.15 Z0.58, P.56 19.6
Other intent 2 217/853 (25.4) 188/846 (22.2) 2.86 0.2335.8 Z0.81, P.42 71.2
Total 5

443/3,052 (14.5) 430/3,093 (13.9) 1.01 0.821.23 Z0.08, P.94 44.9


Cerebral palsy
Neuroprotective intent 4 102/2,199 (4.6) 146/2,247 (6.5) 0.71 0.550.91 Z2.74, P.006 25.2
Other intent 2 2/853 (0.2) 8/846 (0.9) 0.29 0.071.16 Z1.75, P.08 0
Total 5

104/3,052 (3.4) 154/3,093 (5.0) 0.69 0.540.87 Z3.07, P.002 11.7


Mortality or cerebral palsy
Neuroprotective intent 4 328/2,199 (14.9) 387/2,247 (17.2) 0.85 0.740.98 Z2.21, P.03 5.3
Other intent 2 219/853 (25.7) 196/846 (23.2) 1.28 0.681.12 Z0.75, P.45 36.5
Total 5

547/3,052 (17.9) 583/3,093 (18.8) 0.94 0.781.12 Z0.70, P.48 51.3


Substantial gross motor
dysfunction
Neuroprotective intent 3 56/2,169 (2.6) 94/2,218 (4.2) 0.60 0.430.83 Z3.08, P.002 0
Other intent 1 1/798 (0.1) 0/795 (0) 2.99 0.1273.3 Z0.67, P.50 NA
Total 4 57/2,967 (1.9) 94/3,013 (3.1) 0.61 0.440.85 Z2.98, P.003 0
Mortality or substantial gross
motor dysfunction
Neuroprotective intent 3 280/2,169 (12.9) 335/2,218 (15.1) 0.84 0.711/00 Z1.95, P.05 25.2
Other intent 1 210/798 (26.3) 188/795 (23.6) 1.11 0.941.32 Z1.23, P.22 NA
Total 4 490/2,967 (16.5) 523/3,013 (17.4) 0.92 0.751.12 Z0.87, P.39 65.0
RR, relative risk; CI, confidence interval; NA, not applicable.
* Values obtained from meta-analysis, which is not obtained simply by comparing pooled rates of events.

One study
17
represented in both subgroups; hence, there are only five studies overall.
Death or Cerebral Palsy Substantial Motor Dysfunction
Death or Substantial
Motor Dysfunction
Mg Pl Mg Pl Mg Pl
5 (16.7) 1 (3.4) NA NA NA NA
123 (19.6) 149 (23.8) 18 (2.9) 34 (5.4) 105 (16.7) 141 (22.5)
56 (15.9) 67 (19.9) 18 (5.1) 22 (6.5) 52 (14.8) 60 (17.9)
144 (12.1) 170 (13.5) 20 (1.7) 38 (3.0) 123 (10.4) 134 (10.7)
328 (14.9) 387 (17.2) 56 (2.5) 94 (4.2) 280 (12.7) 335 (14.9)
8 (14.5) 3 (5.9) NA NA NA NA
211 (26.4) 193 (24.3) 1 (0.1) 0 (0) 210 (26.3) 188 (23.6)
219 (25.7) 196 (23.2) 1 (0.1) 0 (0) 210 (24.6) 188 (22.2)
547 (17.9) 583 (18.8) 57 (1.9) 94 (3.0) 490 (16.1) 523 (16.9)
VOL. 113, NO. 6, JUNE 2009 Doyle et al Magnesium Sulfate and Cerebral Palsy 1331
significant reduction in cerebral palsy in the BEAM
study
13
(RR 0.71, 95% CI 0.550.91).
Antenatal magnesium sulfate treatment had no
overall significant effect on the combined outcome of
pediatric mortality or cerebral palsy (Table 3), but
there was substantial heterogeneity overall (I
2
51.3%).
However, there was a significant reduction in the com-
bined outcome of pediatric mortality or cerebral palsy in
the neuroprotection subgroup (Table 3; risk difference
0.024, 95% CI 0.046 to 0.003; four trials; 4,446
infants), with little evidence of heterogeneity (I
2
5.3%),
but not the other intent subgroup (Table 3). The number
needed to treat for an extra survivor free of cerebral
palsy in the neuroprotective subgroup was 42 (95% CI
24346), assuming a baseline risk of 17% for death or
cerebral palsy in the control group.
Four studies (4,552 infants) reported other neuro-
logic outcomes during the newborn period; MagNET,
17
ACTOMgSO
4
,
18
PREMAG
1921
and BEAM.
13
Four stud-
ies (5,980 infants) reported other neurologic outcomes
at follow-up: ACTOMgSO
4
,
18
MAGPIE 2006,
22,23
PREMAG,
1921
and BEAM.
13
There were no substantial
effects of antenatal magnesium sulfate therapy on any
other newborn effects, notably lower Apgar scores at 5
minutes, the ongoing need for assisted ventilation, or
major cerebroventricular abnormalities (Table 4). The
were no substantial effects on other neurosensory out-
comes (blindness, deafness, developmental delay) at fol-
low-up (Table 4), with the exception that substantial gross
motor dysfunction was significantly less common with
magnesium, both overall (Table 3), in the subgroup with
neuroprotective intent (Table 3), and in the individual
studies ACTOMgSO
4
,
18
(RR 0.53, 95% CI 0.300.92)
and BEAM
13
(RR 0.56, 95% CI 0.330.95).
There were no statistically significant effects of
antenatal magnesium sulfate treatment on the com-
bined rate of death or substantial gross motor dys-
function overall (Table 3), but there was significant
heterogeneity (I
2
65.0%). In the neuroprotective in-
tent subgroup there was less heterogeneity (I
2
25.2%)
as well as a possible reduction in the rate of death or
substantial gross motor dysfunction (Table 3) and in
the individual study ACTOMgSO
4
,
18
(RR 0.74, 95%
CI 0.590.93).
CONCLUSION
There is little doubt that antenatal magnesium sulfate
therapy given to women at risk of preterm birth is a
neuroprotective agent against motor disorders for the
preterm fetus. It reduced the rates of cerebral palsy
and substantial gross motor dysfunction in early child-
hood, both overall and in the neuroprotective sub-
group, and also the rates of the combined outcomes of
death or cerebral palsy and death or substantial gross
motor dysfunction in the neuroprotective subgroup. It is
important that there were no obvious harmful pediatric
effects; in particular, there was little evidence of respira-
tory depression caused by magnesium sulfaterates of
low Apgar scores at 5 minutes or ongoing respiratory
support were similar between treatment groups. It was
not possible to evaluate fully the effects of magnesium
on other neurologic outcomes, or their combined rates
with mortality, because these outcomes were not re-
ported for all studies.
It should be noted that the follow-up of children
has thus far only been reported to the first few years
of life. It is not always possible to be sure of neuro-
logic diagnoses such as cerebral palsy until children
are older.
26
Moreover, it is vital that survivors en-
rolled in the RCTs of antenatal magnesium sulfate are
reassessed later in childhood, at least into school-age,
particularly to determine motor and higher cognitive
outcomes, such as executive function and academic
progress, if possible.
There are well-described maternal side effects,
such as hypotension and tachycardia, which are more
Table 4. Meta-Analysis of Other Neurologic Outcomes
Outcome
No. of
studies
Magnesium
[n/N (%)]
Control
[n/N (%)] RR (95% CI)*
Statistical
Significance
Heterogeneity
[I
2
(%)]
Newborn period
Apgar less than 7 at 5 minutes 3 351/2,169 (16.2) 351/2,218 (15.8) 1.03 (0.901.18) Z0.42, P.68 7
Ongoing respiratory support 3 980/2,169 (45.2) 1,069/2,218 (48.2) 0.94 (0.891.00) Z1.91, P.06 24
Any intraventricular hemorrhage 4 467/2,254 (20.7) 493/2,298 (21.5) 0.96 (0.861.08) Z0.65, P.51 20
Periventricular leukomalacia 4 71/2,254 (3.1) 76/2,298 (3.3) 0.93 (0.681.28) Z0.43, P.67 0
Neonatal convulsions 3 55/2,169 (2.5) 70/2,218 (3.2) 0.80 (0.561.13) Z1.28, P.20 0
Follow-up
Blindness 3 3/1,779 (0.2) 4/1,757 (0.2) 0.74 (0.173.30) Z0.40, P.69 0
Deafness 3 9/1,779 (0.5) 12/1,757 (0.7) 0.79 (0.242.56) Z0.40, P.69 17
Developmental delay 4 647/2,967 (21.8) 670/3,013 (22.2) 0.99 (0.911.09) Z0.11, P.91 0
RR, relative risk; CI, confidence interval.
* Values obtained from meta-analysis, which is not obtained simply by comparing pooled rates of events.
1332 Doyle et al Magnesium Sulfate and Cerebral Palsy OBSTETRICS & GYNECOLOGY
common with antenatal magnesium sulfate
27
these
are, however, short-lived when treatment ceases.
More serious maternal effects, such as death or car-
diac arrest are rare in the doses used in the RCTs
described in this review.
27
It is reassuring that the systematic review of RCTs
in humans is consistent with some of the animal and
observational human data suggesting a neuroprotec-
tive role for antenatal magnesium sulfate therapy in
preterm pregnancy. More human RCTs designed
specifically to assess long-term effects of magnesium
sulfate on the fetal brain are warranted, especially to
assess the effects of variables such as gestational age
exposed, dosage used, and timing before preterm
birth. Also, diagnostic techniques such as magnetic
resonance imaging of the brain might help to deter-
mine how magnesium affects the brain, particularly
the motor system, to reduce the rate of adverse motor
outcomes.
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