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

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.

Conflict of interest statement

The authors declare no conflicts of interest.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Mean fetal umbilical cord and MCA blood flow velocity (TAMX) before and after NAC dosing by treatment and GA (n = 4 preterm, n = 2−3 term) with 95% CIs. Doppler measures could not be obtained in preterm control fetuses.

Figure 2

Systolic, diastolic, and mBPs before and after first NAC/saline dose (0–6 HOLs) by GA. Reference line represents normal BP measure for first week of life by GA.P, preterm infants; T, term infants.

Figure 3

A, Infant CBF velocity (TAMX) and resistive indices (corrected resistive index [CRI]) in the ACA, MCA, and BA before and after initial dose of NAC or saline in preterm (n = 6 NAC, n = 5 control), and B, term (n = 5 NAC, n = 4 control) cohorts (mean, 95% CI). No significant differences in TAMX or CRI between NAC and control infants in any vessel. *P < .016; †P < .007; ‡P < .05, all versus predosing (0 hour).

Figure 4

CRIs in BA and MCA over 48 HOLs by sex for individual preterm and term infants, regardless of treatment (preterm: n = 6 females, n = 5 males; term: n = 5 females, n = 4 males). Preterm males have higher CRI than females, whereas term males have lower CRI than females, as previously reported by Koch et al.CRI, corrected resistive index.

Figure 5

A, CBF and B, cardiac function in preterm infants with IVH in the first week of life vs those with no insult (mean, 95% confidence intervals, CI). A, CBF velocity (TAMX) and resistance (CRI) in ACA, MCA, and BA before and after treatment with NAC or saline (n = 4 IVH, n = 7 control). B, Echocardiographic measurements before and after NAC/saline (n = 4 IVH, n = 7 control). All were not significant. CO, cardiac output index (ml/kg/min); EF, ejection fraction; LVASMV (mL/s); StokeVol, stroke volume index (mL/kg); SVCFlow, superior vena cava flow velocity (mL/kg/min).

Figure 6

Echocardiographic measures before and after dosing of NAC or saline in preterm and term infants. Cardiac output (mL/kg/min), EF, LVASMV (mL/s,) and LVMPI, stroke volume (mL/kg), and SVC flow (mL/kg/min) were not significantly different before or after dosing of NAC or saline (mean, 95% CI; preterm: n = 6 NAC, n = 5 control; term: n = 4 NAC, n = 4 control).

Figure 7

Median, IQR of serum cytokine concentrations (pg/mL): A, FGF-2 before and after NAC/saline dosing in mothers (NAC n = 11; saline n = 7, P = .02); B, VEGF and IL-1Ra in infants over 0–48 hours after delivery with GA and time in mixed model (n = 12 NAC, n = 9 saline; P ≤ .014). For IL-6, there was a significant NAC treatment*time interaction effect (P = .014), from 36–48 HOL. FGF-2, fibroblast growth factor 2.