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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Safety of N-acetylcysteine in Maternal Chorioamnionitis

Conditions
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Chorioamnionitis, Brain Injury

Intervention / Treatment
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* Drug: N-acetylcysteine
* Drug: Control


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N-acetylcysteine<br>Mother/infant pairs were stratified by gestational age into premature (P) and term (T) cohorts. | Drug: N-acetylcysteine<br>* NAC (100 mg/kg/dose) was given intravenously to mothers within 4 hours of diagnosis of chorioamnionitis, and every 6 hours until delivery. NAC was given to preterm (12.5 mg/kg/dose) and term infants (25 mg/kg/dose) every 12 hours for 5 doses after birth.<br>* Other names: Acetadote, NAC;|
| Active Comparator: Control<br>Mother/infant pairs were stratified by gestational age into premature (P) and term (T) cohorts. | Drug: Control<br>* Saline was given in the same volume, at the same timing as NAC infusions<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NAC Terminal Elimination Half-life |  | prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion | 
| NAC Volume of Distribution |  | 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 | Ratio of NAC concentration in cord to maternal venous blood | At time of delivery | 
| 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 | Resistive index in middle cerebral artery (MCA) | after NAC infusion | 
| Prothrombin Time | prothrombin clotting time | after N-acetylcystiene or saline infusion | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neonatal white matter injury, N-acetylcysteine, NAC, anti-oxidant treatment, chorioamnionitis, maternal chorioamnionitis