Brain Injury, Chorioamnionitis
Conditions
Keywords
chorioamnionitis, maternal chorioamnionitis, neonatal white matter injury, N-acetylcysteine, NAC, anti-oxidant treatment
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.
Interventions
DRUGN-acetylcysteine
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.
DRUGControl
Saline was given in the same volume, at the same timing as NAC infusions
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prothrombin Time | after N-acetylcystiene or saline infusion | prothrombin clotting time |
| 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 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 | At time of delivery | Ratio of NAC concentration in cord to maternal venous blood |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Pre-assignment details
Due two enrolling two sets of twins (one set in the preterm/NAC group, and one set in the preterm/control group), our study included 24 infants and 22 mothers.
Participants by arm
| Arm | Count |
|---|---|
| NAC Infant Infants treated with N-acetylcysteine | 12 |
| Control Infant Infants treated with saline | 12 |
| NAC Maternal Mothers of infants treated with N-acetylcysteine | 11 |
| Control Maternal Mothers of infants treated with saline | 11 |
| Total | 46 |
Baseline characteristics
| Characteristic | Total | Control Maternal | NAC Maternal | Control Infant | NAC Infant |
|---|---|---|---|---|---|
| Age, Customized Mothers aged 18-45years | NA participants | 11 participants | 11 participants | NA participants | NA participants |
| Age, Customized Preterm Infants | NA participants | NA participants | NA participants | 7 participants | 7 participants |
| Age, Customized Term Infants | NA participants | NA participants | NA participants | 5 participants | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 26 Participants | 4 Participants | 8 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 7 Participants | 3 Participants | 7 Participants | 3 Participants |
| Region of Enrollment United States | 46 participants | 11 participants | 11 participants | 12 participants | 12 participants |
| Sex: Female, Male Female | 33 Participants | 11 Participants | 11 Participants | 6 Participants | 5 Participants |
| Sex: Female, Male Male | 13 Participants | 0 Participants | 0 Participants | 6 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 12 | 3 / 12 | 2 / 11 | 2 / 11 |
| serious Total, serious adverse events | 4 / 12 | 3 / 12 | 0 / 11 | 0 / 11 |
Outcome results
Primary
Cerebral Blood Flow
Resistive index in middle cerebral artery (MCA)
Time frame: after NAC infusion
Population: blood flow resistive indices after first dose of N-acetylcysteine or saline
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NAC Maternal | Cerebral Blood Flow | 0.93 units on a scale |
| NAC Preterm Infants | Cerebral Blood Flow | 0.89 units on a scale |
| NAC Term Infants | Cerebral Blood Flow | 0.92 units on a scale |
| Control Maternal | Cerebral Blood Flow | 0.89 units on a scale |
Comparison: Term infant cohort : NAC vs control H0= there will be no difference in resistive index in Middle Cerebral Artery after N-acetylcysteine or saline in the term cohort.p-value: 0.9t-test, 2 sided
Comparison: Preterm infant cohort: NAC vs control H0= there will be no difference in resisitive index in MCA after N-acetylcysteine or saline in preterm cohortp-value: 0.9t-test, 2 sided
Primary
Maternal and Infant Mean Blood Pressure Change
Time frame: Maternal mean BP changes were pre/post dosing prior to delivery. Infant measurements were pre/post their first dosing
Population: The infant and maternal populations analyzed for this portion are incomplete, as not all individuals had paired before/after blood pressure measurements at this time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC Maternal | Maternal and Infant Mean Blood Pressure Change | -1.2 mmHg | Standard Deviation 13 |
| NAC Preterm Infants | Maternal and Infant Mean Blood Pressure Change | 2.1 mmHg | Standard Deviation 11 |
| NAC Term Infants | Maternal and Infant Mean Blood Pressure Change | 1 mmHg | Standard Deviation 12 |
| Control Maternal | Maternal and Infant Mean Blood Pressure Change | 2 mmHg | Standard Deviation 10 |
Primary
NAC Concentrations
Time frame: Peak: 30 minutes after NAC infusion. Cord: at delivery
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NAC Maternal | NAC Concentrations | Peak NAC concentration in plasma | 1222 micromol/L | Standard Deviation 415 |
| NAC Maternal | NAC Concentrations | NAC cord concentration | NA micromol/L | — |
| NAC Preterm Infants | NAC Concentrations | Peak NAC concentration in plasma | 49.0 micromol/L | Standard Deviation 14.9 |
| NAC Preterm Infants | NAC Concentrations | NAC cord concentration | 370.7 micromol/L | Standard Deviation 199.2 |
| NAC Term Infants | NAC Concentrations | Peak NAC concentration in plasma | 92.3 micromol/L | Standard Deviation 69.2 |
| NAC Term Infants | NAC Concentrations | NAC cord concentration | 639.7 micromol/L | Standard Deviation 409.4 |
Primary
NAC Terminal Elimination Half-life
Time frame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC Maternal | NAC Terminal Elimination Half-life | 1.2 hours | Standard Deviation 0.2 |
| NAC Preterm Infants | NAC Terminal Elimination Half-life | 7.5 hours | Standard Deviation 2 |
| NAC Term Infants | NAC Terminal Elimination Half-life | 5.1 hours | Standard Deviation 1.3 |
Primary
NAC Total Body Clearance
Time frame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC Maternal | NAC Total Body Clearance | 255 mL/h/kg | Standard Deviation 61 |
| NAC Preterm Infants | NAC Total Body Clearance | 45.0 mL/h/kg | Standard Deviation 8.2 |
| NAC Term Infants | NAC Total Body Clearance | 53.7 mL/h/kg | Standard Deviation 11.3 |
Primary
NAC Volume of Distribution
Time frame: prior to delivery in mothers, and in newborn after delivery during 2 days of NAC infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC Maternal | NAC Volume of Distribution | 0.41 L/kg | Standard Deviation 0.07 |
| NAC Preterm Infants | NAC Volume of Distribution | 0.47 L/kg | Standard Deviation 0.04 |
| NAC Term Infants | NAC Volume of Distribution | 0.38 L/kg | Standard Deviation 0.09 |
Primary
Placental Transfer Ratio
Ratio of NAC concentration in cord to maternal venous blood
Time frame: At time of delivery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC Maternal | Placental Transfer Ratio | 1.4 ratio | Standard Deviation 0.8 |
Primary
Prothrombin Time
prothrombin clotting time
Time frame: after N-acetylcystiene or saline infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC Maternal | Prothrombin Time | 19.5 seconds | Standard Deviation 2.5 |
| NAC Preterm Infants | Prothrombin Time | 19.0 seconds | Standard Deviation 4 |
| NAC Term Infants | Prothrombin Time | 14.2 seconds | Standard Deviation 0.6 |
| Control Maternal | Prothrombin Time | 14.4 seconds | Standard Deviation 1.2 |
Comparison: Maternal cohort: NAC versus control l H0= PT will not be different in mothers after NAC or salinep-value: 0.9t-test, 2 sided
Comparison: Infant cohort: NAC versus control H0= prothrombin time will not be different in the infants after NAC or salinep-value: 0.9t-test, 2 sided
Secondary
Cytokine Level IL-1Ra in Plasma
anti-inflammatory cytokine Interleukin -1 Receptor alpha (IL-1Ra)
Time frame: after N-acetylcysteine infusion
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| NAC Maternal | Cytokine Level IL-1Ra in Plasma | 745 pg/ml |
| NAC Preterm Infants | Cytokine Level IL-1Ra in Plasma | 8.3 pg/ml |
p-value: 0.014t-test, 2 sided
Secondary
Magnetic Resonance Spectroscopy of Infants
ratio of myoInositol / NAA concentrations in basal ganglia
Time frame: 36 - 40 weeks gestational age
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC Maternal | Magnetic Resonance Spectroscopy of Infants | 1.09 ratio | Standard Deviation 0.31 |
| NAC Preterm Infants | Magnetic Resonance Spectroscopy of Infants | 1.34 ratio | Standard Deviation 0.2 |
Comparison: correcting for gestational age at birthp-value: 0.072t-test, 2 sided