Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis.

Dorothea D Jenkins, Donald B Wiest, Denise M Mulvihill, Anthony M Hlavacek, Sarah J Majstoravich, Truman R Brown, Joseph J Taylor, Jason R Buckley, Robert P Turner, Laura Grace Rollins, Jessica P Bentzley, Kathryn E Hope, Andrew B Barbour, Danielle W Lowe, Renee H Martin, Eugene Y Chang

Journal: The Journal of pediatrics 2016;168():67-76.e6

PMID: 26545726

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Abstract

OBJECTIVE

To evaluate the clinical safety of antenatal and postnatal N-acetylcysteine (NAC) as a neuroprotective agent in maternal chorioamnionitis in a randomized, controlled, double-blinded trial.

STUDY DESIGN

Twenty-two mothers >24 weeks gestation presenting within 4 hours of diagnosis of clinical chorioamnionitis were randomized with their 24 infants to NAC or saline treatment. Antenatal NAC (100 mg/kg/dose) or saline was given intravenously every 6 hours until delivery. Postnatally, NAC (12.5-25 mg/kg/dose, n = 12) or saline (n = 12) was given every 12 hours for 5 doses. Doppler studies of fetal umbilical and fetal and infant cerebral blood flow, cranial ultrasounds, echocardiograms, cerebral oxygenation, electroencephalograms, and serum cytokines were evaluated before and after treatment, and 12, 24, and 48 hours after birth. Magnetic resonance spectroscopy and diffusion imaging were performed at term age equivalent. Development was followed for cerebral palsy or autism to 4 years of age.

RESULTS

Cardiovascular measures, cerebral blood flow velocity and vascular resistance, and cerebral oxygenation did not differ between treatment groups. Cerebrovascular coupling was disrupted in infants with chorioamnionitis treated with saline but preserved in infants treated with NAC, suggesting improved vascular regulation in the presence of neuroinflammation. Infants treated with NAC had higher serum anti-inflammatory interleukin-1 receptor antagonist and lower proinflammatory vascular endothelial growth factor over time vs controls. No adverse events related to NAC administration were noted.

CONCLUSIONS

In this cohort of newborns exposed to chorioamnionitis, antenatal and postnatal NAC was safe, preserved cerebrovascular regulation, and increased an anti-inflammatory neuroprotective protein.

TRIAL REGISTRATION

ClinicalTrials.gov: NCT00724594.

Address: Department of Pediatrics, Medical University of South Carolina, Charleston, SC. Electronic address: [email protected].; Department of Clinical Pharmacy and Outcome Science, Medical University of South Carolina, Charleston, SC.; Department of Pediatrics, Medical University of South Carolina, Charleston, SC.; Department of Neuroscience's Center for Advanced Imaging Research, Medical University of South Carolina, Charleston, SC.; Department of Neuroscience's Center for Advanced Imaging Research, Medical University of South Carolina, Charleston, SC; Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC.; Department of Clinical Pediatrics and Neurology, University of South Carolina School of Medicine and Palmetto Health Richland Children's Hospital, Columbia, SC.; Department of Clinical Psychology, University of Massachusetts, Boston, MA.; Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.; Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC.

DOI: 10.1016/j.jpeds.2015.09.076

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MeSH Terms: Acetylcysteine, Cerebrovascular Circulation, Chorioamnionitis, Double-Blind Method, Echoencephalography, Electroencephalography, Female, Fetus, Humans, Infant, Infant, Newborn, Magnetic Resonance Imaging, Male, Mothers, Neuroprotective Agents, Pregnancy, Prospective Studies, Ultrasonography, Doppler