Safety of N-acetylcysteine in Maternal Chorioamnionitis (NAC in Chorio)

Phase 1

Completed

Brief Summary: The purpose of this trial was to find the best dose of N-acetylcysteine (NAC) to decrease brain injury in babies exposed to intrauterine infection without causing significant side effects.

Detailed Description: Chorioamnionitits is an infection in the fluid and membranes surrounding the baby in utero. Intrauterine infection is associated with significant white and grey matter brain injury in newborns and is particularly important in the pathogenesis of periventricular leukomalacia (PVL) and cerebral palsy (CP). CP has been shown to be 4-9 times higher in babies exposed to intrauterine infection than in normal infants. Antibiotics have not changed the risk for brain injury in the newborn.

NAC is a promising anti-oxidant therapy that has shown effective neuroprotection in an animal model of chorioamnionitis, and has a favorable safety profile with limited and manageable side effects.

In this trial, intravenous NAC was given to mothers antenatally and to their infants postnatally, who presented with the diagnosis of chorioamnionitis, to evaluate safety and pharmacokinetics (PK) in mothers and infants. Mothers at ≥24 weeks gestation and their infants were randomized to receive either saline NAC within 4 hours of a clinical diagnosis of chorioamnionitis. Infants were stratified into term (≥ 33wk) and preterm (24-32wk) cohorts, due to different expected rates of metabolism and clearance.

Information gained from this trial will be used to determine how rapidly NAC is metabolized by mother, fetus, infant, and the ability of NAC to cross placenta. This study will also elucidate the safety of NAC in the setting of chorioamnionitis for fetal neuroprotection.

Recruitment & Eligibility

Inclusion Criteria

Participants had all of the following to qualify:

Chorioamnionitis, defined as either 1) clinical diagnosis of choriomanionitis 2) maternal fever greater than or equal to 100 degrees F in the presence of rupture of membranes or 2 of the following: uterine tenderness, maternal WBC > 15,000 cells/mm, fetal tachycardia > 160 bpm, malodorous amniotic fluid, or in preterm group only, rupture of membranes and active preterm labor.
Gestational age ≥ 24 completed weeks, by first trimester ultrasound or date of last menstrual period.
No greater than 4 hours from onset of fever or diagnosis.

Exclusion Criteria

Participants had none of the following:

Asthma, steroid-dependent
Clinical sepsis, whether viral or bacterial in nature, defined as fever with signs of cardiovascular compromise in mother (blood pressure < 90/50, heart rate > 120 bpm, need for oxygen due to maternal saturations below 92%, pneumonia, pyelonephritis, or meningitis)
Seizure disorder
Fetal weight or biparietal diameter less than the 10th% for gestational age
Suspected major genetic or congenital abnormality
Fetal distress which demands immediate delivery (poor fetal biophysical profile, late decelerations, sinusoidal fetal heart rate pattern)
Participation in another therapeutic clinical trial

Arm && Interventions

Group	Intervention	Description
Control	Control	Mother/infant pairs were stratified by gestational age into premature (P) and term (T) cohorts.
N-acetylcysteine	N-acetylcysteine	Mother/infant pairs were stratified by gestational age into premature (P) and term (T) cohorts.

Primary Outcome Measures

Name	Time	Method
Maternal and Infant Mean Blood Pressure Change	Maternal mean BP changes were pre/post dosing prior to delivery. Infant measurements were pre/post their first dosing
Cerebral Blood Flow	after NAC infusion	Resistive index in middle cerebral artery (MCA)
NAC Volume of Distribution	prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
NAC Terminal Elimination Half-life	prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
NAC Total Body Clearance	prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
NAC Concentrations	Peak: 30 minutes after NAC infusion. Cord: at delivery
Placental Transfer Ratio	At time of delivery	Ratio of NAC concentration in cord to maternal venous blood
Prothrombin Time	after N-acetylcystiene or saline infusion	prothrombin clotting time

Secondary Outcome Measures

Name	Time	Method
Cytokine Level IL-1Ra in Plasma	after N-acetylcysteine infusion	anti-inflammatory cytokine Interleukin -1 Receptor alpha (IL-1Ra)
Magnetic Resonance Spectroscopy of Infants	36 - 40 weeks gestational age	ratio of myoInositol / NAA concentrations in basal ganglia