The NICU Antibiotics and Outcomes (NANO) trial: a randomized multicenter clinical trial assessing empiric antibiotics and clinical outcomes in newborn preterm infants

Abstract

Background Early-onset sepsis is an important cause of neonatal morbidity and mortality in the preterm population. Infants perceived to be at increased risk for early-onset sepsis are often treated empirically with broad-spectrum antibiotics while awaiting confirmatory blood cultures, despite an overall incidence of early-onset sepsis of 2–3% among extremely-low-birthweight (ELBW) infants. Recent observational studies associate perinatal antibiotic use with an increased incidence of necrotizing enterocolitis, late-onset sepsis, and mortality among ELBW infants. Given currently available data and variability in clinical practice, we designed a prospective multi-institutional randomized controlled trial to determine the safety of early antibiotic use in ELBW infants. Methods The NICU Antibiotics and Outcomes (NANO) trial is a multicenter, double-blinded, randomized controlled trial. A sample of 802 ELBW preterm infants will undergo web-based stratified block randomization to receive empiric antibiotics (EA; ampicillin and gentamicin) or placebo during routine evaluation for early-onset sepsis. Participating sites will use preexisting institutional protocols for antibiotic dosage and duration. Infants born at participating sites with a gestational age of 29 weeks or less are eligible for enrollment. Exclusion criteria include maternal intrauterine infection, hemodynamic or respiratory instability, delivery by caesarean section for maternal indications without labor or prolonged rupture of membranes, and prior administration of antibiotics. The primary outcome is the composite incidence of necrotizing enterocolitis, late-onset sepsis, or death during participants’ index hospitalization. Maternal and infant samples will be collected longitudinally and assessed for differences in microbiome composition and diversity. Discussion The NANO trial is designed to compare the rate of adverse outcomes of EA use at birth versus placebo in ELBW preterm infants. If EA at birth worsens clinical outcomes, then the results of the trial may help providers decrease antibiotic utilization in the NICU and subsequently decrease the incidence of complications associated with early antibiotic use in ELBW infants. If we instead find that EA improve outcomes, then the trial will validate a longstanding clinical practice that has not previously been supported by high-quality data. Future studies will assess long-term clinical and microbial outcomes in infants who received empiric antibiotics following delivery. Trial registration Trial registration data: June 25, 2019 NCT03997266.

Early antibiotics and risk for necrotizing enterocolitis in premature infants: A narrative review

“…Ultimately, the inherent limitations of existing human studies warrant large prospective RCTs ( 105 ) as well as well-designed prospective observational studies ( 106 ) to study the impact of withholding early antibiotic use or limiting duration of exposure on NEC as well as other outcomes including late-onset sepsis and bronchopulmonary dysplasia. The NICU Antibiotics and Outcomes Trial (NANO) as well as other studies are beginning to address this question ( 106 – 108 ). Future clinical practice on early antibiotics use will likely be impacted by these ongoing studies.…”

Early initiation of antibiotic therapy and short-term outcomes in preterm infants: a single-centre retrospective cohort analysis

“…This would only be possible with a prospective study design. In this regard, the NICU Antibiotics and Outcome (NANO) trial is currently recruiting for a placebo-controlled prospective randomised trial investigating the effect of early empirical antibiotic therapy, which may provide answers 50. Another limitation is that our dataset was not complete.…”

“…In this regard, the NICU Antibiotics and Outcome (NANO) trial is currently recruiting for a placebo-controlled prospective randomised trial investigating the effect of early empirical antibiotic therapy, which may provide answers. 50 Another limitation is that our dataset was not complete. For most variables we used for our analyses, there were significantly less than 10% missing values.…”

Microbiome and its impact on fetal and neonatal brain development: current opinion in pediatrics

“…Judicious antibiotic use in preterm infants, given their frequent empirical antibiotic treatment, can positively impact gut microbiota and subsequent neurocognitive outcomes [ 45 ]. In an observational study – with inherent limitations and therefore not proving causation – we observed that prolonged empirical antibiotic treatment in preterm infants was associated with below-average gross-motor development at 24 MCA [ 46 ].…”