The flow of the search is shown in . Of the 331 potentially relevant citations identified, 5 studies (6 trials) published in 7 articles fulfilled the inclusion criteria after a detailed review of 92 studies.29–35
Because the study by Mittendorf et al29, 30
had two arms (tocolytic and neuroprotective), it was considered as two separate trials in this review. Of the other four studies included, three31, 33, 35
evaluated magnesium sulfate as an infant neuroprotective agent, and one32
assessed the efficacy of magnesium sulfate for preventing eclampsia. Eighty-seven studies were excluded, the main reason being the lack of data on cerebral palsy and/or pediatric mortality in randomized controlled trials on magnesium sulfate for preventing preterm birth or eclampsia. Overall agreement on the inclusion of studies was 100% (κ, 1.00). The 6 trials included a total of 4796 women and 5357 infants.
The characteristics of included studies are presented in . Two studies were performed in the United States,29, 35
one each in France,33
Australia and New Zealand,31
and the remaining one was conducted in 19 countries across five continents.32
Trials included women with gestational ages <34 weeks29
(165 infants), <33 weeks33
(688 women), <32 weeks35
(2444 infants), and <30 weeks31
(1255 infants). The Magpie trial32
reported data for 3283 infants whose mothers were randomized before delivery. Of these, 805 infants were randomized before 34 weeks of gestational age and 788 between 34 and 36 weeks. Data for the 805 infants randomized before 34 weeks of gestational age included in our meta-analyses were extracted from the review by Doyle et al.22
Multiple pregnancies were included in all trials. Two trials31, 33
included women at high risk of preterm delivery because of expected or planned birth within 24 hours. The trial by Rouse et al35
included women at high risk for spontaneous delivery because of premature rupture of membranes or advanced preterm labor and women with indicated preterm delivery within 2 to 24 hours. The main reasons for preterm birth were preterm labor and premature rupture of the membranes (63 and 9% in the study by Crowther et al,31
85 and 61% in the study by Marret et al,33
and 10 and 87% in the study by Rouse et al,35
respectively), followed by antepartum hemorrhage and chorioamnionitis (14 and 14% in the study by Crowther et al,31
and 19 and 11% in the study by Marret et al,33
respectively). In the study by Crowther et al,31
15% of women enrolled had preeclampsia. One study only included women in active preterm labor with cervical dilation ≤4 cm (tocolytic arm) or >4 cm (neuroprotective arm).29
The Magpie trial32
included only women with preeclampsia. Three trials excluded women with preeclampsia.29, 33, 35
The definition and diagnostic criteria of cerebral palsy were clearly reported in four trials.31, 32, 34, 35
The study by Mittendorf et al30
did not report a definition or details of the diagnosis. A pediatrician made the diagnosis of cerebral palsy in all trials at a corrected age of at least 18 months30, 32
or 24 months.31, 34, 35
Characteristics of studies included in the systematic review
The studies included a range of dosing schedules. In five trials,29, 31–33
women received a loading dose of 4 g of intravenous magnesium sulfate. In the trial by Rouse et al5
women received a loading infusion of 6 g. There was no maintenance infusion of magnesium sulfate in two trials (neuroprotective arm of the study by Mittendorf et al29
and the study by Marret el al33
). The maintenance doses of magnesium sulfate used in four trials were 1 g/h,31
2–3 g/h (tocolytic arm of the study by Mittendorf et al. study29
), and either 1 g/h intravenously or 5 g every four hours intramuscularly.32
The maintenance infusion was continued until birth (if it occurred within 24 hours) or up to 24 hours in the study by Crowther et al,31
or until 24 hours in the Magpie trial.32
In the study by Rouse et al,35
if delivery had not occurred after 12 hours and was no longer considered imminent, the infusion was discontinued and resumed when delivery was deemed imminent again. If at least 6 hours had passed since the discontinuation of the study medication, another loading dose was given. Retreatment with magnesium sulfate was not allowed in three trials31–33
and in the neuroprotective arm of the study by Mittendorf et al.30
There was no information on duration of maintenance infusion and whether retreatment was permitted in the tocolytic arm of the study by Mittendorf et al.30
The median total dose of magnesium sulfate received by women in the magnesium group ranged between 4 and 49.8 g.
The quality assessment of trials is shown in . The overall quality of the trials was relatively good. All studies were randomized with the appropriate method to generate the sequence of randomization (computer-generated). Five trials, including the neuroprotective arm of the study by Mittendorf et al,30
were double-blinded in which a placebo was used, and the outcomes were evaluated by individuals who were blinded to treatment group allocation. The tocolytic arm of the study by Mittendorf et al,30
was not double-blinded because the women were randomized to receive magnesium sulfate or other tocolytic therapy such as ritodrine, terbutaline, indomethacin, or nifedipine, although diagnosis of cerebral palsy was made by a pediatrician who was masked to the antenatal treatment. Four trials had adequate methods of allocation sequence concealment.31, 32, 34, 35
The tocolytic arm of the study by Mittendorf et al30
had no concealment of allocation whereas the neuroprotective arm did not report on this item. Information on withdrawals and dropouts was available for four trials.31, 32, 34, 35
In the two trials performed by Mittendorf et al30
there was no statement on numbers and reasons for withdrawals in each group. Three trials reported assessment of primary outcomes in ≥95% of randomized fetuses.31, 34, 35
The Magpie trial32
evaluated the primary outcomes in only 47.4% of fetuses of all gestational ages randomized before delivery. Four trials had a modified Jadad score of 7 or more.31, 32, 34, 35
The two trials performed by Mittendorf et al30
had scores of 2 (tocolytic arm) and 4 (neuroprotective arm).
Modified Jadad score for assessment of methodological quality of included studies
Six trials (5357 infants) reported cerebral palsy, total pediatric mortality, and the combined outcome of death or cerebral palsy. The risk of giving birth to an infant subsequently receiving a diagnosis of cerebral palsy was significantly lower in the group of women who received magnesium sulfate than among women who did not receive magnesium sulfate (3.9% vs 5.6%; RR, 0.69 [95% CI, 0.55–0.88]) () (). There was evidence of low statistical heterogeneity among the trials included in this analysis (I2=4.4%). The funnel plot of trials of antenatal magnesium sulfate in the prevention of cerebral palsy appeared symmetrical either visually or in terms of statistical significance (intercept, 0.23 [95% CI, −1.97 to 2.43]; P = 0.79) () suggesting that there was no evidence of either publication or related biases.
Effect of magnesium sulfate on cerebral palsy.
Effect of magnesium sulfate on cerebral palsy and pediatric mortality
Funnel plot of trials of antenatal magnesium sulfate in the prevention of cerebral palsy. Circles indicate log (relative risks) from trials included in meta-analysis.
The number of women at risk for preterm delivery less than 34 weeks of gestation who needed to be treated with magnesium sulfate rather than with placebo to prevent one case of cerebral palsy in their children was 52 (95% CI, 31–154). The random-effects analysis of the primary outcome of cerebral palsy yielded effect sizes similar in magnitude and direction to those obtained from the fixed-effects analysis ().
Sensitivity and subgroup palsy and pediatric mortality analyses of metaanalysis on effect of magnesium sulfate on cerebral
Antenatal magnesium sulfate significantly decreased the risk of cerebral palsy in sensitivity analyses limited to the 4 trials with modified Jadad quality score >4 (RR, 0.69 [95% CI, 0.54–0.88]; I2=0.0%) and to the 3 trials with completeness of follow-up of randomized fetuses ≥95% (RR, 0.69 [95% CI, 0.54–0.88]; I2=0.0%). The RR for the subgroup of 4 trials (4,446 infants) whose primary aim was neuroprotection was 0.71 (95% CI, [0.55–0.91]; I2=25.2%) and for the subgroup of 2 trials (911 infants) whose primary aim was tocolysis or to prevent eclampsia was 0.37 (95% CI, [0.09–1.58]; I2=0.0%). The lowered risk of cerebral palsy was demonstrated even in the subgroup of 3 trials (3981 infants) that included women with gestational age <32 weeks at trial entry and in the subgroup of 4 trials (4610 infants) that used a median total dose of magnesium sulfate greater than 4 grams. No statistically significant differences between groups treated with antenatal magnesium sulfate and controls in cerebral palsy were seen in the subgroups of 2 trials that used a median total dose of magnesium sulfate ≤4 grams and that included women with gestational age <30 weeks at trial entry.
Three trials (4,387 infants) reported cerebral palsy according to severity.31, 34, 35
Moderate or severe cerebral palsy was significantly reduced in the group who received magnesium sulfate (2.1% vs 3.2%; RR, 0.64 [95% CI, 0.44–0.92]; I2
=0.0%; NNT for benefit, 74 [95% CI, 41–373]). The risk of mild cerebral palsy was reduced by 26% in the group allocated magnesium sulfate rather than placebo, although this did not achieve statistical significance (RR, 0.74 [95% CI, 0.52–1.04]).
There was no overall difference in the risk of total pediatric mortality, including fetal mortality and under two years of corrected age mortality, between infants exposed to magnesium sulfate and those non exposed (15.1% versus 14.8%; RR, 1.01 [95% CI, 0.89–1.14; I2
= 38.9%) (). The lack of evidence for any overall effect of magnesium sulfate on total pediatric mortality was found in all sensitivity and subgroup analyses performed except one (subgroup of two trials by Mittendorf et al30
with modified Jadad quality score ≤4 (RR, 6.61; 95% CI, 1.12–36.11; I2
=31.0%) (). The combined outcome of death or cerebral palsy was slightly lower for children in the magnesium sulfate group (19.0% versus 20.4%), although this was not a statistically significant difference.
There were no significant differences between the groups in the risk of adverse neonatal outcomes (), although a non-significant increase was seen in the risk of necrotizing enterocolitis in the magnesium group compared with the control group (7.1% vs 5.9%; RR, 1.23 [95% CI, 0.98–1.54]; I2=0.0%)
Effect of magnesium sulfate on neonatal outcomes
With regard to infant neurodevelopmental outcomes, the risk of substantial gross motor dysfunction at the corrected age of 2 years was significantly lower among children whose mothers received magnesium sulfate than among children whose mothers did not receive magnesium sulfate (3 trials; 4387 infants; 2.6% vs 4.2%; RR, 0.60 [95% CI, 0.43–0.83]; I2=0.0%; NNT for benefit, 53 [95% CI, 32–146]). There were no significant effects of antenatal magnesium sulfate treatment on other infant neurodevelopmental outcomes such as major neurologic disability, any neurological impairment, Bayley mental and psychomotor development indexes, blindness, and deafness ().
Effect of magnesium sulfate on infant neurodevelopmental outcomes
There was no evidence of an effect of magnesium sulfate on the risk of maternal death (3 trials; 3,867 women), cardiac or respiratory arrest (3 trials; 3867 women), pulmonary edema (1 trial; 2,241 women), respiratory depression (2 trials; 3,303 women), severe postpartum hemorrhage (2 trials; 1626 women), and cesarean section (3 trials; 3,867 women) (). Compared with women receiving placebo, those exposed to magnesium sulfate had about a 50% increased risk of both hypotension and tachycardia (RR, 1.51 [95% CI, 1.09–2.09]; NNT for harm, 30 [95% CI, 17–156] and RR, 1.53 [95% CI, 1.03–2.29; NNT for harm, 28 [95% CI, 14–379], respectively). Maternal side effects secondary to study medication were significantly more common among women allocated magnesium sulfate rather than placebo, including flushing (58.4% vs 8.3%; NNT for harm, 2 [95% CI, 2–2]), nausea or vomiting (16.3% vs 3.9%; NNT for harm, 8 [95% CI, 7–10]), sweating (25.2% vs 3.4%; NNT for harm, 5 [95% CI, 4–5]), problems at injection site (37.6% vs 4.1%; NNT for harm, 3 [95% CI, 3–3]), stopping of infusion because of adverse effects (7.5% vs 2.6%; NNT for harm, 20 [95% CI, 16–29]), and any side effect (70.7% vs 17.6%; NNT for harm, 2 [95% CI, 2–2]). All funnel plots showed no asymmetry, either visually or in terms of statistical significance (P>.10 for all, by Egger test).
Effect of magnesium sulfate on maternal outcomes
Impact and economic evaluation of the intervention
The United Cerebral Palsy Foundation has estimated that about 8,000 babies and infants are diagnosed with cerebral palsy each year in the US6
of which about 25% (n=2,000) are born before 34 weeks of gestational age.5, 8
Therefore, if all women who deliver before 34 weeks of gestation receive antenatal magnesium sulfate, the estimated number of new cases of cerebral palsy that hypothetically could be prevented annually is 620 (95% CI, 240–900).
The number of women at risk of preterm delivery before 34 weeks of gestation who needed to receive magnesium sulfate to prevent one case of cerebral palsy was 52 (95% CI, 31–154). A recent cost decision analysis from the US revealed that the total cost for administrating magnesium sulfate as a tocolytic agent, including costs attributable to the evaluation and treatment of its adverse events, was $197.90 per patient in 2005.36
Thus, if magnesium sulfate was given to all women at risk of preterm delivery before 34 weeks of gestation, the incremental cost of preventing one case of cerebral palsy would be $10,291 (95% CI, 6,135–30,477).