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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