(COLUMBUS, Ohio) - A large randomized controlled trial showed in 2008 that when pregnant women at imminent risk of preterm delivery were given magnesium sulfate, their children had reduced rates of moderate or severe cerebral palsy. As a result of the trial, funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH), many delivery hospitals implemented magnesium administration policies.
But a new study from Nationwide Children’s Hospital and The Ohio State University Wexner Medical Center calls into question whether these labor-intensive magnesium administrations – which are given intravenously in a hospital over a 12 hour span before birth -- have an effect outside of the controlled environment of a trial.
The research, published today in JAMA Pediatrics, shows that more mothers of infants ultimately diagnosed with cerebral palsy received magnesium beginning in 2009, but there were also more infants diagnosed with cerebral palsy. And while the proportion of severe cerebral palsy decreased at the two hospitals after magnesium administration policies were instituted, this effect happened independent of magnesium.
The authors hypothesize that the decrease in severe cerebral palsy may instead be a result of advances in neonatal care over the last decade, along with efforts to diagnose cerebral palsy and intervene with patients as early as possible at Nationwide Children’s. Other factors may also be at work.
“Magnesium sulfate is not a benign medication, and we do not want moms at immediate risk of preterm birth to go through this if it is not helping,” says Bethany Stetson, MD, who was lead author of the study while a fellow at the OSU Wexner Medical Center Division of Maternal Fetal Medicine. “This should lead institutions to question the utility of prenatal magnesium administration related to cerebral palsy, and to consider that postnatal follow-up with infants has a larger role to play.”
The study considered 110 children who were born at the Wexner Medical Center from 2002 to 2014 at less than 32 weeks gestation who were then diagnosed with cerebral palsy. The hospital began a magnesium administration protocol in 2009, and about 52 percent of those children were exposed to the medication.
Robust data from Nationwide Children’s Early Developmental Clinic and Comprehensive Cerebral Palsy Program enabled the authors to evaluate cerebral palsy severity over time. Severity has decreased overall since 2009, but infants exposed to magnesium did not have reduced severity. Notably, infants born in 2009 and later were diagnosed with cerebral palsy at a younger age, particularly those born after 2012.
So while magnesium does not appear to reduce severity, reduced severity may be associated with diagnosing (and intervening) with children earlier, says Nathalie Maitre, MD, PhD, director of Neonatal Follow-up Programs at Nationwide Children’s and senior author of the study. Nationwide Children’s reported in 2017 that it was the first hospital in the world to implement new cerebral palsy diagnosis and intervention guidelines. While diagnosis often occurs when children are 2 years of age or older, Nationwide Children’s had decreased its average age of diagnosis to 13 months by 2016. More recently, its average age of diagnosis has decreased to 10.5 months as the coordinating site of the Cerebral Palsy Foundation’s Early Detection and Intervention for Cerebral Palsy Network.
Nationwide Children’s has been the site of three NIH-funded studies since 2013 on interventions for cerebral palsy patients. The combination of earlier diagnosis and evidence-driven early intervention may well have made an impact on outcomes when magnesium sulfate did not.
“The development of a child between 1 year of age and 2 is exponential, so diagnosing a child with cerebral palsy at 1 instead of 2 really matters,” says Dr. Maitre, who is also a principal investigator at Nationwide Children’s Center for Perinatal Research. “Along with the possibility of earlier therapeutic interventions, an earlier diagnosis allows for greater family awareness and for parents to begin advocating for their children at a younger age.”
Beyond the specific findings, the study highlights the knowledge that can develop when a maternal fetal medicine program at a birth hospital works in concert with a neonatal follow-up program at a children’s institution. This study began with a conversation among physicians and faculty members at Nationwide Children’s and Ohio State: Dr. Maitre; Irina Buhimschi, MD, Director of the Center for Perinatal Research at Nationwide Children’s; and Catalin Buhimschi, MD, Professor of Pediatrics, Obstetrics and Gynecology and Pediatrics, and holder of the Frederick Zuspan Endowed Chair in Obstetrics and Gynecology at Ohio State.
“We all have the same goal of improving outcomes, but we are not able to provide optimal care unless we collaborate across the continuum, from pregnancy to child follow-up,” says Irina Buhimschi. “We had the ability to do that here.”
Catalin Buhimschi was seeking evidence on the impact of magnesium administration in imminent preterm births at the Wexner Medical Center, and together with Irina Buhimschi, they conceptualized the kinds of research that could be completed combining Ohio State’s records with Nationwide Children’s. Dr. Maitre’s work to implement cerebral palsy guidelines at Nationwide Children’s allowed for a detailed examination of child outcomes.
“We must evaluate the long-term impact of clinical interventions adopted following large randomized trials, a mandate not unique to magnesium trials for prevention of cerebral palsy,” says Catalin Buhimschi. “Because we have done that in this case, we now have a new understanding of what we should be doing to help these children.”