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September 2006
Feature Story
NIH funds $1.9 million to collaborative trial to protect newborns
Unique, multi-departmental teamwork has resulted in a $1.9 million grant from the NIH to conduct a three-year pilot project to protect the brains
of children from damage by the intrauterine infection, chorioamnionitis.
Basic scientific discoveries, made in Dr. Inderjit Singh's laboratory in the Darby Children's Research Institute, and strong pediatric clinical
research have resulted in this award funded by the National Institute of Neurologic Disorders and Stroke.
The study was designed to test whether giving N-acetylcysteine, or NAC, to pregnant women with the chorioamnionitis can decrease their baby's
baseline level of brain inflammation and improve the fetal tolerance of labor and delivery, thereby resulting in less injury to the brains of the unborn babies.
The study is part of an overall effort at MUSC to reduce brain damage and neonatal mortality, says Dr. Lyndon Key. The facility's Neonatal
Intensive Care Unit is currently highly ranked by several organizations and publications, including Child Magazine.
The initial investigation started when Drs. Key and Singh suggested that neuroprotection using agents such as NAC could prevent perinatal
brain injury in a variety of diseases in neonates.
This led the team to fund a study with remarkable results: a reduction in the level of inflammatory damage in the brains of animals with
chorioamnionitis, published in the Journal of Neuroscience Research (2004 Nov 1;78(3):347-61).
Dr. Doe Jenkins, principal investigator on the grant, had conducted previous research on the prevention of neonatal brain injury after
hypoxic-ischemic injury, and began to collaborate with Dr. Singh to develop a program to reduce neonatal inflammation. The effort progressed
quickly from the realm of bench research into a grant proposal for an investigational clinical pilot trial.
Drs. Singh, Ernie Barbosa and Eugene Chang's basic science work formed the basis for the preliminary data for the grant.
"We took Dr. Singh's animal data and developed a clinical pilot proposal to give NAC to pregnant woman to prevent the fetal brain inflammation
that we know accompanies chorioamnionitis," says Dr. Jenkins. Within hours of the umbilical cord becoming infected, the fetal rat brain shows
evidence of inflammation as well.
"The baby's brain is already inflamed due to the maternal Infection, and the baby has to yet to go through the birth process, which is relatively
hypoxic, with interrupted umbilical blood flow," continues Dr. Jenkins. The newborn may suffer further brain injury from the birth process.
"We have long known that term and preterm infants who are exposed to infection (chorioamnionitis) in labor--or even just to maternal fever--are
at greater risk of neurological injury up to and including cerebral palsy, despite prompt initiation of antibiotics on delivery," explains
Dr. Roger Newman, a co-investigator from the Department of Obstetrics and Gynecology.
"It's a new and innovative approach which we've developed as a collaborative group involving bench and clinical researchers from five different
departments," explains neonatologist Dr. Jenkins. "Everyone's role is invaluable- this is a team of incredible people."
"We've been working for about two years with Epidemiology and Biostatistics, (Drs. Renne Martin, John Schwacke and Thomas Hulsey), Pediatric
Radiology, (Drs. Mulvihill and Lee), Obstetrics, (Drs. Chang, Newman, and Goetzl), and with pharmocologists (Drs.Wiest, Garner and Cox) to
develop this protocol," Dr. Jenkins continues. While some of these are new collaborations, Drs. Mulvihill, Lee and Jenkins have been working
in the clinical field of hypoxic-ischemic injury and neuroprotection in infants and collaborated on previous clinical trials.
Part of the study design requires complex pharmacological data, with multiple dynamics to consider, including placental transport of NAC to
the fetus at different gestation ages. Drs. Schwacke and Martin from biostatistics helped model the pharmacokinetics of NAC after various
doses given to the mother.
"The complex, multi-compartment pharmacokinetic models are important to make sure fetal serum levels would not be in the toxic range, and to
allow us to test the effect of different doses of NAC safely," adds Dr. Jenkins. Although NAC has been used for decades to treat Tylenol
overdosage in pregnant women, there is little data on fetal levels.
"Working together, we have come up with much more than we would have working in isolation," she says.
Collaboration leads to innovation
With so many disciplines involved, the group was able to develop several innovative ideas and approaches. For instance, the study will use
magnetic resonance spectroscopy, or MRS, to detect NAC in baby brains.
While Dr. Jenkins initiated the idea of using MRS to measure NAC in brain tissue, collaborative brainstorming led to the solution.
"We included this in the grant as one of the innovative ways that we might actually measure neuro-therapeutics in the brain," she says.
It's also unique, she points out, that investigators are dosing the mother to achieve a level of NAC in the fetal brain before delivery.
"Although we are dosing the mother, the fetal brain is really our target tissue. This is a new area for neuro-protection, but to protect
the infant's brain from oxidative injury in chorioamnionitis, therapies may well have to be given antenatally to be effective."
The study will monitor both baby and mother for possible side effects, gather pharmacological data for both preterm and near term babies,
measure NAC in the brain of infants after birth, and record responses to NAC In blood flow, cytokine levels and brain imaging.
"We expect to see that NAC decreases brain inflammation in a dose or concentration-dependent manner," explains Dr. Jenkins. "If we show it's
effective in short-term outcomes, then we would prove long-term outcome effectiveness in a phase III trial. It could be a safe and effective
therapy for almost any mother with chorioamnionitis prior to delivery to help protect her baby's brain. NAC may prove to be one of only a
few therapies for preterm babies that is both safe and neuro-protective."
"We feel that this study could be ground-breaking in establishing a new form of clinical intervention (anti-inflammatory and anti-oxidant)
for pregnant women," agrees Dr. Newman.
"We've found a lot of stuff we didn't expect to find," says co-principal obstetric investigator Dr. Chang, clinician-scientist in Obstetrics.
"We're very convinced NAC is safe, and hope this will lead to more research down the road. Ultimately, we hope it will prevent some cases of cerebral palsy."
To do infant-related studies involves a huge collaborative effort and requires the type of NICU facility that is currently underway for MUSC
Children's Hospital. "Our challenge," says Dr. David Annibale, director of the division of Neonatology, "is to expand and improve neonatal /
obstetric facilities and resources to support innovative investigations like this one."
"The ability to rally a group of experts, basic scientists and clinical trialists who all are interested in the perinatal period make studies
like this possible," notes Dr. Key. "A host of collaborative projects emanating from Dr. Singh's studies in blocking inflammation will result
from this, proving that research in childhood diseases benefits both children and adults."
"This is exactly the type of translational research that Institute benefactors and investigators hoped for. Now that everyone is hard at work
in linking basic research findings to children's diseases, we see the Darby Children's Research Institute (DCRI) developing as a model for
children's research in the Carolinas and nationwide, said Dr. Maria, DCRI Executive Director.
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