Abstract
-
- Fetal or neonatal brain injury can result in lifelong neurologic disability. Although survival rates for preterm infants have increased dramatically with the advent of modern perinatal and neonatal intensive care, but the rates of neurologic abnormalities in survivors, particularly motor disorders such as cerebral palsy, have not diminished. Antenatal magnesium sulfate may reduce the rates of cerebral palsy in survivors of preterm birth. There are five randomized controlled trials of magnesium sulfate administered to women at risk of preterm delivery before 34 weeks of gestation which have reported neurological outcomes for the child. From meta-analysis of these randomized trials, the rate of cerebral palsy was reduced by magnesium sulfate (RR, ᄋ·69; 95% CI, ᄋ·54-ᄋ·87; five trials; 6,145 infants) as did the moderate/severe cerebral palsy incidence (RR, 0.64; 95% CI, ᄋ·44-ᄋ·92; three trials; 4387 infants). There was no statistically significant difference between the rates of neonatal adverse outcomes of the magnesium administration group and the control group. In most prospective randomized studies, no significant difference in the severe mother-side side effects between the magnesium sul- fate administration group and the control group.
- Antenataᅵ magnesium sulfate therapy is neuroprotective against motor dysfunction in offspring for the preterm infant; however the possibility of an increase in the fetal or neonatal death rate was not completely excluded.
-
Keywords: Cerebral Palsy; Magnesium Sulfate; Mortality; Neroprotection; preterm birth
Table 1.Characteristics of Included Studies
Study |
Centers |
NumbeT of participants |
Gestational age |
Magnesium regimen |
Neuroprotective outcomes |
MagNET |
1 |
149 mothers |
25-33 weeks |
4 gm bolus |
Antenatal MgSO4 was associated with worse perinatal |
Mittendorff et al |
(United States) |
165 fetus |
|
(neuroprotective arm) |
outcome |
ACTOMgSO4
|
16 |
1,062 mothers |
<30 weeks |
4 gm bolus, 1 gm/h |
CP RR:0.83; 95% CI: 0,54-1.27 |
Crowther et al |
(Austrailia and New Zealand) |
1,255 fetuses |
|
maintenance |
|
PreMAG trial + folllow up trial |
18 (France) |
573 mothers
6S8 fetuses |
<33 weeks |
4 gm bolus, no maintenance |
Original trial: Nonsignificant decrease in risk of short-term severe white matter injury, mortality before hospital discharge |
Marret et al |
|
(original trial) |
|
|
|
|
|
472 children |
|
|
Follow-up trial (2 years): Combined death or cerebral palsy |
|
|
(follow-up trial) |
|
|
OR, 0.65; 95% CI: 0.42-1.03 |
|
|
|
|
|
|
|
|
|
|
|
Combined death or gross motor dysfunction OR: 0.62; 95% |
|
|
|
|
|
CI: 0.41-0,95 (siatisiicatly significant) |
BEAM. Rouse et al |
20 (United States) |
2.241 mothers 2,444 fetuses |
24-31 weeks |
6 gm bolus. 2gm/h maintenance |
Significant dcciease in the risk of moderate or severe CP (RR: 0,55; 95% CI: 0,32-0.92) among survival children in the MgSO4 group |
|
|
|
|
|
Death and CP RR: 0.97; 95% CI: |
Magpie trial |
125 |
3.283 children |
<37 weeks c |
4 gm bolus, 1 gm/h IV |
Combined death or neuroseasory disability RR: 1.06; 95% CI: |
Duley et al |
(International) |
|
preeclampsia |
matnieaance or, 4 gm |
0.40-1.29 |
|
|
|
|
bolus combined wilh 10 |
|
|
|
|
|
gm IM, then 5 gm/4 hrs |
|
|
|
|
|
IM maintenance |
|
Table 2.Meta-Analysis of Mortality, Cerebral Palsy, Substantial Gross Motor Dysfonction an Combined Outcome by Subcategory of Intent23
Outcome and Subcategory |
No. of Studies |
Magnesium n/N (%) |
Control n/N (%) |
RR∗
|
95% CI∗
|
Statistical Significance |
Heterogeneity [I2(%)] |
Mortality |
|
|
|
|
|
|
|
Neuroprotective intent |
4 |
226/2,199(10.3) |
242/2,247 (10.8) |
0.94 |
0.77-1.15 |
Z=0.58,P=.56 |
19.6 |
Other intent |
2 |
217/853 (25.4) |
188/846 (22.2) |
2.86 |
0.23-35.8 |
Z=0.81,P=.42 |
71.2 |
Total |
5†
|
443/3,052 (145) |
430/3,093 (13.9) |
1.01 |
0.82-1.23 |
Z=0.08,P=.94 |
44.9 |
Cerebral palsy |
|
|
|
|
|
|
|
Neuroprotective intent |
4 |
102/2,199(4.6) |
146/2,247 (6.5) |
0.71 |
0.55-0.91 |
Z=2.74,P=006 |
25.2 |
Other intent |
1 |
2/853 (0.2) |
8/846 (0.9) |
0.29 |
0.07-1.16 |
Z=I.75,P=.08 |
0 |
Total |
5†
|
104/3,052 (3.4) |
154/3,093(5.0) |
0.69 |
0.54-0,87 |
Z=3.07,P=.002 |
11.7 |
Mortality or cerebral palsy |
|
|
|
|
|
|
|
Neuroprotective intent |
4 |
528/2,199(14.9) |
387/2,247 (172) |
0.85 |
0.74-0.98 |
Z=2.21,P=.03 |
5.3 |
Other intent |
2 |
219/853 (25.7) |
196/846 (23.2) |
1.28 |
0,68-1.12 |
Z=0.75,P=.45 |
36.5 |
Total |
5†
|
547/3,052(17.9) |
583/3,095 (18.8) |
0.94 |
0.78-1.12 |
z=0.70,p=.48 |
51.3 |
Substantial gross motordysfunction |
|
|
|
|
|
|
|
Neuroprotective intent |
3 |
56/2,169 (2.6) |
94/2.218(4.2) |
0.60 |
0.43-0.83 |
z=3.08,p=.002 |
0 |
Other intent |
1 |
1/798(0.1) |
0/795 (0) |
199 |
0.12-73.3 |
z=0.67,p=.50 |
NA |
Total |
4 |
57/2,967(1,9) |
94/3,013(3.1) |
0.61 |
0.44-0.85 |
z=2.98,p=.003 |
0 |
Mortality or substantial gross motor dysfunction |
|
|
|
|
|
|
|
Netiroprotective intent |
3 |
280/2,169 (12.9) |
335/2,218 (15.1) |
0,84 |
0,71-1.00 |
z=1.95p=.05 |
25.2 |
Other intent |
1 |
210/798 (26.3) |
188/795 (23.6) |
1.11 |
0,94-1.32 |
z=1.23,p=.22 |
NA |
Total |
4 |
490/2,967 (16.5) |
523/3,013(17.4) |
0.92 |
0.75-1.12 |
z=0.87, p=.39 |
65.0 |
Table 3.Effect of magnesium sulfate on cerebral palsy and pediatric mortality24
Outcome |
No. of trials |
No. of events/total number |
Relative risk (95% O) |
I2(°/o)
|
Mngnesium |
No magnesium |
Cerebral palsy |
6 |
104/2658 |
152/2699 |
0.69 (0.55-0,88) |
4.4 |
Moderate/severe cerebral palsy |
3 |
45/2169 |
72/2218 |
0.64 (0.44-0,92) |
0,0 |
Mild cerebral palsy |
3 |
54/2169 |
74/2218 |
0.74 (0.52-1.04) |
0.0 |
Tolal pediatric mortality |
6 |
401/2658 |
400/2699 |
1.01 (0.89-1 J4) |
38.9 |
Fetal mortality |
5 |
17/2254 |
22/2298 |
0,78 (0,42-1.46) |
0,0 |
Under 2 y of corrected age mortality |
5 |
217/2254 |
220/2298 |
1.00 (0.84-1.19) |
47.3 |
Death or cerebral palsy |
6 |
505/2658 |
551/2699 |
0.92 (0.83-1.02) |
43.3 |
Table 4.Meta-Analysis of Other Neurologic Outcomes23
Outcome |
No. of studies |
Magnesium [n/N(%)] |
Control [n/N(%)] |
RR(95% CI)∗
|
Statistical 11 Significance |
Heterogeneity [I2(%)] |
Newborn period |
Apgar less than 7 at 5 minutes |
3 |
351/2469(16.2) |
351/2,218(15.8) |
1.03 (0.90-1.18) |
Z=0.42,P=.68
|
7 |
Ongoing respiratory support |
3 |
980/2,169(45,2) |
1,069/2,218(48.2) |
0,94 (0.89 L00) |
Z=1.91, P=.06
|
24 |
Any imraventricular heinontiage |
4 |
467/2,254(20,7) |
493/2,298 (21,5) |
0,96(0.86 1.08) |
Z=0.65,P=.51
|
20 |
Periventricular Icukomalacia |
4 |
71/2,254(3.1) |
76/2,298 (3.3) |
0.93 (0.68 1.28) |
Z=0.43,P=.67
|
0 |
Neonatal convulsions |
3 |
55/2,169(2.5) |
70/2,218(3.2) |
0.80(0.56-1.13) |
Z=1.28,P=.20
|
0 |
Follow-up |
Blindness |
3 |
3/1,779 (0,2) |
4/1,757(0.2) |
0.74(0.17 3.30) |
2=0.40, p=m
|
0 |
Deafness |
3 |
9/1,779 (0.5) |
12/1,757(0.7) |
0.79 (0.24-2.56) |
z=0.40, p=.69 |
17 |
Devctopmcnlal delay |
4 |
647/2,967(21.8) |
670/3,013 (22.2) |
0.99(0.91 1.09) |
z=0.11, p=.91 |
0 |
Table 5.Effect of magnesium sulfate on neonatal outcomes24
Outcome |
No. of trials |
No, of events/total number |
Relative risk (95% CI) |
I2/(%) |
Magnesium |
No magnesium |
Intraventricular hemorrhage (ala grades) |
5 |
467/2254 |
493/2298 |
0,96 (0.86-1.08) |
20.1 |
Grade III/IV intraventricular hemorrhage |
4 |
74/1902 |
91/1962 |
0.83(0.61-1.11) |
0.0 |
Periventricular leukomalacia |
5 |
71/2254 |
76/2298 |
0.93 (0.68-1,28) |
0.0 |
Apgar score < 7 at 5 min |
3 |
351/2169 |
351/2218 |
1.03 (0.90-1.18) |
7.3 |
Neonatal seizures |
3 |
55/2169 |
70/2218 |
0.80(0.56-1.13) |
0 |
Respiratory distress syndrome |
2 |
730/1540 |
779/1592 |
1.01 (0.85-1,19) |
65.8 |
Need for supplemental oxygen at 36wk |
2 |
220/981 |
195/962 |
1.12(0.95-132) |
23.1 |
Bronchopulmonary dysplasia |
1 |
213/188 |
218/1256 |
1.03(0.87-1.23) |
NA |
Mechanical ventilation |
3 |
1381/2169 |
1446/2218 |
0,99 (0.89-1.09) |
82.1 |
Necrotizing enterocolitis |
3 |
155/2169 |
131/2218 |
1.23 (0.98-1.54) |
0.0 |
Table 6.Effect of magnesium sulfate on maternal outcomes24
Outcome |
No. of trials |
No. of events/total number |
Relative risk (95% CI) |
I2 (%) |
Magnesium |
No magnesium |
Death |
3 |
0/1917 |
1/1950 |
0.32 (0.01-7.92) |
0.0 |
Cardiac or respiratory arrest |
3 |
0/1917 |
35 0/1950 |
Not estimable |
NA |
Fulmonary edema |
1 |
8/1096 |
3/1145 |
2.79(0.74-10.47) |
NA |
Respiratory depression |
2 |
41/1631 |
31/1672 |
1.31 (0.83-2.07) |
0.0 |
Hypotension |
2 |
80/821 |
52/S05 |
1.51 (1,09-2.09) |
3.6 |
Tachycardia |
1 |
56/535 |
36/527 |
1.53 (1.03-2.29) |
NA |
Severe postpartum hemorrhage |
2 |
28/821 |
26/805 |
1.06(0,63-1.79) |
0.0 |
Cesarean section |
3 |
822/1917 |
BM/1950 |
1.00 (0.93-1.07) |
21.6 |
Clinical and self-assessed maternal side effects of the infusion |
|
|
|
|
|
Flushing |
3 |
1119/1917 |
162/1950 |
7.56(339-16.88) |
93,8 |
Nausea or vomiting |
3 |
312/1917 |
76/1950 |
4.60(1.54-13,75) |
91.5 |
Sweating |
2 |
411/1631 |
57/1672 |
6.37(1.96-20.68) |
94,6 |
Problems at injection site |
2 |
614/1631 |
68/1672 |
9.12 (7J9-11.57) |
0.0 |
Stopping of infusion because of adverse effects |
2 |
125/J631 |
44/1672 |
2.81 (2.01-3.93) |
0.0 |
Any side effect |
3 |
1356/1917 |
343/1950 |
105 (2.06-12.39) |
983 |
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