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

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.

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