Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (Triple I): randomized clinical trial

Abstract

BACKGROUND: Intrauterine infection and/or inflammation (Triple I) is an important cause of preterm birth (PTB) and adverse newborn outcomes. N-acetylcysteine (NAC) is a Food and Drug Administration (FDA)-approved drug safely administered to pregnant women with acetaminophen toxicity. METHODS: We conducted a single-center, quadruple-blind, placebo-controlled trial of pregnant women with impending PTB due to confirmed Triple I. Participants (n = 67) were randomized to an intravenous infusion of NAC or placebo mimicking the FDAapproved regimen. Outcomes included clinical measures and mechanistic biomarkers. RESULTS: Newborns exposed to NAC (n = 33) had significantly improved status at birth and required less intensive resuscitation compared to placebo (n = 34). Fewer NAC-exposed newborns developed two or more prematurity-related severe morbidities [NAC: 21% vs. placebo: 47%, relative risk, 0.45; 95% confidence interval (CI) 0.21-0.95] with the strongest protection afforded against bronchopulmonary dysplasia (BPD, NAC: 3% vs. placebo: 32%, relative risk, 0.10; 95% CI: 0.01-0.73). These effects were independent of gestational age, birth weight, sex, or race. Umbilical cord plasma NAC concentration correlated directly with cysteine, but not with plasma or whole blood glutathione. NAC reduced the placental expression of histone deacetylase-2, suggesting that epigenetic mechanisms may be involved. CONCLUSIONS: These data provide support for larger studies of intrapartum NAC to reduce prematurity-related morbidity.

N-Acetylcysteine (NAC): Impacts on Human Health

“…The pregnant women followed the following protocol: infusion of a loading dose of NAC (150 mg/kg) administered in 1 h, followed by continuous infusion of NAC (50 mg/kg) for 4 h, and infusion of 100 mg/kg of NAC in the next 16 h or until delivery versus infusion of dextrose (5%) in water (D5W) in the placebo group. The study showed that maternal intrapartum NAC infusion is feasible, safe, and effective in reducing the mortality rate and severe neonatal morbidity, such as bronchopulmonary dysplasia, in addition to improving Apgar scores at 1 and 5 min and reducing the need for resuscitation with positive pressure ventilation [ 101 ].…”

Maternal N-Acetyl-Cysteine Prevents Neonatal Hypoxia-Induced Brain Injury in a Rat Model

“…NAC is a recommended treatment for disorders resulting from free oxygen radicals [6]. NAC is a class B drug in pregnancy [9], though the NAC effect on the fetal brain in response to hypoxia was not previously addressed. NAC mechanisms of action include increased glutathione peroxidase levels, antioxidant effect by free-radical scavenging, inhibition of the activation of NF-κB, inhibition of TNF toxicity, NOS inhibition, and prevention of mitochondrial dysfunction [34].…”

“…NAC has been shown to prevent fetal brain inflammation and brain damage associated with maternal inflammation in a rat model of lipopolysaccharide exposure [7,8]. In humans, antenatal and postnatal NAC treatments were demonstrated to be safe when used in association with maternal chorioamnionitis [9]. In the current study, we hypothesized that maternal antenatal and offspring-postnatal NAC can protect offspring brain from hypoxic brain damage.…”

Acetaminophen and the Developing Lung: Could There Be Lifelong Consequences?

“…[199][200][201][202][203][204][205][206][207] Interestingly, it has recently been demonstrated that maternal treatment with N-acetylcysteine significantly decreases the incidence of BPD, even in the absence of APAP exposure. 208 These data are not dissimilar from other interventions to enhance nutritional/antioxidant status shown to improve the respiratory health of offspring. 209,210 It is possible that pulmonary CYP2E1 metabolism of APAP stresses these antioxidant stores increasing the risk of injury.…”