Magnesium reduces cerebral palsy in infants delivered early preterm [Classics Series]

Classics Series, Landmark Trials in Medicine

1. Among women with imminent delivery between 24 and 31 weeks gestation, those randomized to receive magnesium sulfate experienced a decreased risk of moderate or severe cerebral palsy.

2. Risk of fetal death did not differ between groups.

Original date of publication: August 28, 2008

Study Rundown: Cerebral palsy, the leading cause of childhood disability, is a group of syndromes characterized by motor and postural dysfunction. A strong risk factor for cerebral palsy is preterm birth, which is associated with as many as one third of cerebral palsy cases. In the early-mid 2000s, research identified an increased prevalence of cerebral palsy among infants delivered very preterm (see background reading). The incidence of preterm delivery in the United States is 11.5%, contributing to its rank as 6th highest in the world for preterm delivery. At the same time, the survival of preterm and very preterm infants born in the United States has drastically improved in recent decades such that more infants born prematurely are surviving to childhood and adolescence. Improved survival of preterm infants motivated investigation into best ways to protect and prepare this vulnerable population for life, including identification of interventions to reduce cerebral palsy. In this climate, a retrospective investigation identified a lower odds radio of cerebral palsy among premature infants whose mothers received magnesium (OR:0.14, CI:0.05-0.51). Previous studies enrolled women in preterm labor, who are often recommended to receive magnesium for its purposes as a uterine tocolytic. The present study achieved greater parsimony by enrolling women without other indications for magnesium therapy to specifically evaluate the benefit of intrapartum magnesium for fetal neuroprotection in premature infants born between 24 and 31 weeks.

This randomized, placebo-controlled trial evaluated the impact of intrapartum magnesium sulfate in women at risk for imminent preterm delivery between 24 and 31 weeks gestation on neonatal death and cerebral palsy. Results demonstrated that the risk of cerebral palsy was decreased among infants born to women who received magnesium prophylaxis. Incidence of stillbirth and neonatal death were similar between groups. Strengths included randomized, placebo-controlled and double-blinded design and an excellent follow-up rate of 95.6%. Inclusion of women with both singleton and twin gestations receiving care at 20 delivery centers across the United States allows for widely applicable results. Limitations include potential selection bias, with 40% of eligible participants (1602/3843) declining to participate. This landmark study was the first to demonstrate reduction in cerebral palsy incidence among very preterm infants and changed practice recommendations for women with risk for imminent very preterm delivery.

Click to read the article in NEJM

Background reading: Increasing prevalence of cerebral palsy among very preterm infants (Pediatrics)

Study Author, Dr. Alan Peaceman, MD, talks to 2 Minute Medicine: Northwestern University School of Medicine; Chief, Division of Obstetrics and Gynecology-Maternal Fetal Medicine.

“This randomized, placebo controlled trial evaluated the benefit of intrapartum administration of magnesium sulfate for fetal neuroprotection in women at risk of imminent delivery between 24 and 33 weeks gestation.  Follow up examinations at 2 years of age showed a decrease of almost 50% in the diagnosis of moderate or severe cerebral palsy with this treatment.  Together with similar trials of magnesium for this indication, the evidence is strong for a treatment that can significantly reduce the risk of cerebral palsy in the group of infants at highest risk for developing this disabling condition.”

In Depth [randomized placebo-controlled, double-blinded trial]: Multicenter trial of 2241 women at risk for imminent delivery between 24 and 31 weeks of gestation were randomly assigned to receive magnesium sulfate (6g loading dose followed by 2g/hour infusion) or placebo. Women with hypertension, pre-eclampsia or those requiring magnesium for tocolysis were excluded. Outcomes assessed included the primary composite outcome of stillbirth or infant death within 1 year or secondary outcome of moderate or severe cerebral palsy beyond 2 years of corrected age as well as assessment or each of these factors. The diagnosis of cerebral palsy was rigorously determined by an annually certified pediatrician or pediatric neurologist if children met 2 or more strictly defined criteria, including motor delay, abnormal muscle tone or reflexes, persistence of primitive reflexes and movement abnormality.

Among women with imminent delivery between 24 and 31 weeks gestation, those randomized to receive magnesium sulfate experienced a decreased risk of moderate or severe cerebral palsy (1.9% vs. 3.5%, RR:0.55, CI:0.32-0.95, P = 0.03). Risk of fetal death did not differ between groups (9.5 vs. 8.5%, RR:1.12, CI:0.85-1.47, P = 0.41). Risks of adverse outcomes of flushing and sweating were more common in the magnesium group (P < 0.001), though there were no life-threatening events or maternal deaths associated with magnesium. Obstetrical outcomes and a range of neonatal outcomes, including respiratory distress, intraventricular hemorrhage, necrotizing enterocolytis and retinopathy of prematurity were similar between groups (all P > 0.5).

More from this author: Risks of trial of labor after cesarean delivery (TOLAC) [Classics Series], Recurrent pregnancy loss associated with increased cardiovascular morbidity, Home self sonograms for assisted reproduction comparable to in-office imaging, Induction of labor more successful with standardization, The TRINOVA-1 trial: trebananib decreases progression of recurrent ovarian cancer

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