Dorothea D. Jenkins MD

I have been an academic neonatologist for over 20 years at the Medical University of South Carolina and have a primary research interest in brain injury and clinical translational research to neuroprotect infants at high risk for neuroinflammatory and hypoxic ischemic injuries. Working with my colleagues Drs. Wagner and Katikaneni, we conducted and published one of the first randomized, controlled trials of the safety and efficacy of hypothermia in neonates with HIE, an R01 funded by NINDS. I was the lead PI for this multicenter, phase II trial which collected extensive safety and efficacy data, and showed hypothermic neuroprotection was largely safe and effective even for critically ill neonates. Subsequent phase III trials substantiated our preliminary data on efficacy. Hypothermia is now standard of care, and we are excited to continue to advance neuroprotection and neurorehabilitation in neonates and infants with brain injury with many new projects.

In a first in human neonates/infants, we designed a brain stimulation study to pair transcutaneous auricular vagal nerve stimulation (taVNS) with feeding to enhance learning the first motor sequence babies have to master, that of suck, swallow, breath. This novel, non-invasive neuromodulation technique aims to further improve outcomes in our premature and term babies with brain injury by addressing the failure to achieve full oral feeds and the rising gastrostomy tube placement rate in these infants. Our study was supported by a NM4R pilot grant to pair taVNS with feeding over 2-3 weeks in 30 preterm/HIE neonates, who were designated by clinical team to need gastrostomy tube placement. We further quantified the dose effects and effects on swallowing and CNS diffusion imaging more precisely, via funding through a COBRE pilot study at MUSC. Collaborating with pediatric speech pathologists, we continue to study taVNS effects on the mechanisms of swallowing during one of the first and last taVNS paired feedings. In the pilot trail of 30 infants we achieved a 50% response rate for the infants who were slated to receive a G-tube, but notable failure to respond in infants of diabetic mothers who experienced uncontrolled hyperglycemia in utero (8/8 failed). We demonstrated IDMs who are failing oral feeding have persistent oxidative stress on MRS weeks to months after birth, and are now funded to address the oxidative stress by administering NAC 4 days prior to treatment with taVNS paired with feeding for 10days with MRS/DKI before, after 4 days of NAC and after another 10 days of taVNS.  We continue to develop a portable taVNS unit called the BabySTrong bottle system, to enable bedside taVNS-paired feeding in a future multicenter trial.

I have been working with many collaborators in clinical and basic science research projects to develop neurotherapeutics to improve on hypothermia’s neuroprotection. Dr. Inderjit Singh and I have been collaborating for many years on the clinical translation of N-acetylcysteine in chorioamnionitis and other therapeutic interventions in hypothermic neonatal HI model. We have found significant neuroprotection with NAC+1,25(OH)2Vitamin D, and sex differences in response, after severe HI in the neonatal rat model. In addition, we have been investigating this combination in the combined LPS-HI model, as chorioamnionitis exposed infants make up a substantial number of HIE infants currently being treated with hypothermia. We have been working to identify pharmacodynamic measures of treatment effect for clinical translation of these therapies, including MRS measurement of glutathione in vivo in neonatal animals and human HIE neonates with two manuscripts in preparation on this technique. We have two manuscripts on NAC and Vitamin D neuroprotection in animals providing rationale for use of both drugs, and another from our human pilot trial of NAC and vitamin D in 30 HIE neonates treated with hypothermia. The final manuscript with 2-4 year follow up developmental outcomes is in submission. Remarkably, even with cord pH <6.8, we have achieved significant reduction in oxidative stress as measured by MRS glutathione in the basal ganglia on day 5 with NAC and vitamin D infusion, and normal developmental outcomes.

In addressing fetal neuroinflammation, which frequently precedes HI injury, I worked with obstetrical, pharmacology, and neuroimaging collaborators to conduct the first controlled trial of N-acetylcysteine as a neuroprotectant in pregnant mothers with chorioamnionitis and in their infants postnatally for 48 hours. In this R01 work funded by NINDS, we assessed safety and pharmacokinetics in this vulnerable population, and serum and MRS/DTI biomarkers to measure effects of NAC in reducing neuroinflammation. We showed that NAC crosses the placenta rapidly after intravenous infusion in the mother, without changes in cerebral blood flow, cardiac function, clotting studies, or blood pressure in fetuses and /or neonates. Two manuscripts report on maternal, placental and neonatal PK of NAC, and longer-term outcomes at 4 years for this cohort, as well as improvement in inflammatory cytokines, and an increase in an anti-inflammatory, neuroprotective cytokines in the NAC cohort, compared to those who received saline. In collaboration with Drs Koch, Mulvihill and Katikaneni, we have also conducted observational studies into changes in cerebral blood flow, diffusion and MRS metabolites in healthy newborns with confirmed funisitis.