School-Age Outcomes of Very Preterm Infants After Antenatal Treatment With Magnesium Sulfate vs Placebo

Abstract

Survival rates for infants born at less than 28 weeks’ gestation have increased, but rates of adverse long-term neurodevelopmental outcomes remain high compared with outcomes for term infants. The ACTOMgSO4 (Australasian Collaborative Trial of Magnesium Sulphate) study was designed to determine whether antenatal magnesium sulfate given to women at risk of preterm birth at less than 30 weeks’ gestation was related to mortality and neurosensory morbidity, particularly cerebral palsy (CP), in early childhood. The aim of the present study was to determine outcomes into school age from antenatal magnesium sulfate compared with placebo. Of 1062 parturients at less than 30 weeks’ gestation with birth planned or expected within 24 hours, 535 were randomized to receive intravenously administered magnesium sulfate and 527 to receive normal saline placebo. These women had a total of 1255 fetuses alive at randomization, and 1066 survived to hospital discharge (n = 544 exposed, n = 522 placebo). The outcomes for the school-age follow-up were CP, motor function, general intellectual ability, academic skills, attention, executive function, behavior, growth, functional and other neurosensory outcomes, and mortality. The severity of gross motor dysfunction in children with CP was classified according to the Gross Motor Function Classification System or by the Movement Assessment Battery for Children (MABC). General cognitive ability was assessed using the Wechsler Intelligence Scale for Children. Academic skills were assessed using the Wide Range Achievement Test. Attention and executive function were assessed with tests sensitive to specific attentional and executive processes. Attention-deficit/hyperactivity disorder symptoms were evaluated with parent and teacher versions of the Conners’ ADHD/DSM-IV Scales. Of the 1255 fetuses alive at randomization, the known mortality rate to school age was 14.0% in the magnesium sulfate group (88/629) compared with 17.6% in the placebo group (110/626), not a statistically significant difference. The final analysis included 867 children (443 magnesium sulfate and 424 placebo) for follow-up at school age; outcomes were determined for 669 (77%). Both groups were assessed at a mean age of 8.4 ±1.0 years, corrected for prematurity. The groups were similar for important perinatal, sociodemographic, and 2-year outcome variables. The 2 groups had no statistically significant differences in proportions with CP or in its severity (8% vs 7%; odds ratio, 1.26; 95% confidence interval [CI], 0.84–1.91). A 96% agreement was found between a diagnosis or not of CP at age 6 to 11 years with that at age 2 years in children assessed at both ages; 11 children with CP at age 2 years no longer had the diagnosis at age 6 to 11 years, and 16 children with no CP at age 2 years had the diagnosis at 8 years. Motor function on the Gross Motor Function Classification System and distribution on the MABC centiles (29 vs 32 centile; mean difference, −2.8; 95% CI, −9.1 to 3.5) were similar between groups. The proportions with abnormal motor function based on the MABC and definite motor dysfunction were similar (27% vs 27%; odds ratio, 1.16; 95% CI, 0.88–1.52). The groups did not differ in cognitive, academic, attention, executive function, or behavioral outcomes or in any of the growth, functional, or other neurosensory outcomes. Potentially confounding social variables and sex of the child had little effect and changed no conclusions. In this study, antenatal magnesium sulfate was not associated with any long-term benefits or harms compared with placebo. Magnesium sulfate given to mothers just before preterm birth for fetal neuroprotection has been one of the few measures available to possibly improve neurologic outcome for preterm survivors. Other adequately powered studies are needed to evaluate long-term benefit of magnesium for fetal neuroprotection.