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Magnesium sulfate in pregnancy cuts CP in preemies: risk of death at 2 years did not decrease.

DALLAS -- Magnesium sulfate during pregnancy protects the survivors of early preterm birth against cerebral palsy, but not death, according to results of a large phase III multicenter trial.

The composite primary outcome of moderate to severe palsy or death at 2 years was not reduced by magnesium sulfate in the BEAM (Beneficial Effects of Antenatal Magnesium Sulfate) trial, Dr. Dwight Rouse, principal investigator, and associates reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The composite outcome occurred in 11.3% of the infants of 1,041 women treated with magnesium sulfate during labor versus 11.7% of the infants of 1,095 women who received placebo (relative risk 0.97).

However, when analyzed separately, the benefits of magnesium sulfate were substantial, Dr. Rouse said, with moderate to severe cerebral palsy occurring in significantly fewer offspring of magnesium sulfate pregnancies than of placebo pregnancies (1.9% vs. 3.5%, RR 0.55). The rate of stillbirth or death was not significantly different between groups (9.5% vs. 8.5%, RR 1.12).

"We conclude that magnesium sulfate protects the survivors of early preterm birth from cerebral palsy, and that its use for this purpose should be considered," said Dr. Rouse of the University of Alabama at Birmingham.

This association has biologic plausibility, said Dr. Rouse, who explained that magnesium sulfate may improve vascular stability, prevent hypoxic damage, and mitigate cytokine and amino acid damage in the preterm fetal brain. About one in three cases of cerebral palsy is associated with prematurity.

When asked by an audience member if the results were any less robust because of the negative primary outcome, Dr. Rouse explained that death had to be included as part of the primary outcome because it's much more common in fetuses in the study's gestational age range of 24-31 weeks, but that it made it difficult to determine the significance of the lesser component of cerebral palsy (CP).

He noted that the benefits of magnesium sulfate against CP remained significant after excluding 80 cases with previously unrecognized major congenital anomalies (1.8% vs. 3.2%, RR 0.56) and when milder forms of cerebral palsy were included in the analysis (P = .004).

"Magnesium sulfate is inexpensive, easy to administer, safe, and used regularly by obstetricians throughout the world," Dr. Rouse said. "Indeed, the principal reason for the lengthy duration of recruitment to our trial was the frequency with which otherwise eligible women were already receiving magnesium sulfate for commonly accepted clinical indications."

Between December 1997 and May 2004, 2,241 women presenting at 24 weeks to 31 weeks 6 days' gestation with advanced preterm labor or premature rupture of the membranes were randomized at 20 institutions to receive either a 6-g bolus of intravenous magnesium sulfate followed by 2 g per hour, or a masked placebo. No other parenteral tocolytics were allowed. Neonatal cranial ultrasounds were performed, and reviewed centrally.

There were no significant differences between groups in baseline maternal outcomes including gestational age at randomization (mean 28 weeks), need for corticosteroids, chorioamnionitis diagnosis, and cesarean delivery, or in immediate fetal outcomes including birth weight, 5-minute Apgar scores, and periventricular leukomalacia.

Because it's been claimed that magnesium sulfate increases the risk of stillbirth and death in a dose-related fashion, Dr. Rouse said a regression analysis was performed and indicated that neither maternal magnesium sulfate dose nor cord magnesium was significantly associated with stillbirth or death. The data also suggest that 63 women would need to be treated to prevent one case of moderate or severe CP, which Dr. Rouse said compares favorably with the 100 women needed to be treated to prevent preeclampsia from pro gressing to eclampsia.

Dr. Rouse said the BEAM findings are consistent with an earlier Australian trial of 1,047 women in which combined death or cerebral palsy trended in favor of magnesium sulfate and the rate of substantial gross motor dysfunction was significantly lower in the magnesium sulfate group (JAMA 2003;290:2669-76).

However, results of the recent PREMAG trial, evaluating whether a single infusion of magnesium sulfate given to mothers would be neuroprotective in preterm newborns, were inconclusive (BJOG 2007;114:310-8), and a Cochrane Review concluded that the role for "antenatal magnesium sulfate therapy as a neuroprotective agent for the preterm fetus is not yet established" (Cochrane Database Syst. Rev. 2007 Jul 18[3];CD004661).

The review did note that ongoing trials would provide additional information, and suggested that outcomes in later childhood should be evaluated given the possible beneficial effects of magnesium sulfate on gross motor function in early childhood.

The BEAM trial was sponsored by the National Institute of Child Health and Human Development in collaboration with the National Institute of Neurological Disorders and Stroke. Dr. Rouse and his coinvestigators reported no relevant financial conflicts of interest.

BY PATRICE WENDLING

Chicago Bureau
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Author:Wendling, Patrice
Publication:OB GYN News
Date:Feb 15, 2008
Words:804
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