Early antibiotic use and incidence of necrotising enterocolitis in very preterm infants: a protocol for a UK based observational study using routinely recorded data

Abstract

IntroductionNecrotising enterocolitis (NEC) remains a major contributor to preterm mortality and morbidity. Prolonged duration of antibiotic therapy after delivery is associated with later NEC development but recent evidence suggests that absence of antibiotic treatment after delivery may also increase NEC risk. We will explore this controversy using a large pre-existing dataset of preterm infants in the UK.Methods and analysisThis is a retrospective cohort study using data from UK National Neonatal Research Database (NNRD) for infants born 1 January 2012 to 31 December 2020. Eligible infants will be <32 weeks gestation, alive on day 3. Primary outcome is development of severe NEC, compared in infants receiving early antibiotics (days 1–2 after birth) and those not. Subgroup analysis on duration of early antibiotic exposure will also occur. Secondary outcomes are: late onset sepsis, total antibiotic use, predischarge mortality, retinopathy of prematurity, intraventricular haemorrhage, bronchopulmonary dysplasia, focal intestinal perforation and any abdominal surgery. To address competing risks, incidence of death before day 7, 14 and 28 will be analysed. We will perform logistic regression and propensity score matched analyses. Statistical analyses will be guided by NEC risk factors, exposures and outcome presented in a causal diagram. These covariates include but are not limited to gestational age, birth weight, small for gestational age, sex, ethnicity, delivery mode, delivery without labour, Apgar score, early feeding and probiotic use. Sensitivity analyses of alternate NEC definitions, specific antibiotics and time of initiation will occur.Ethics and disseminationWe will use deidentified data from NNRD, which holds permissions for the original data, from which parents can opt out and seek study-specific research ethics approval. The results will help to determine optimal use of early antibiotics for very preterm infants.ImplicationsThis data will help optimise early antibiotic use in preterm infants.Trial registration numberISRCTN55101779.

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

“…In addition to antibiotic-induced changes on the gut microbiome, additional research into the direct effects of antibiotics on intestinal immunity is also needed. 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 ).…”

“…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.…”

Enterocolitis Necrosante neonatal: Factores de riesgo y medidas de prevención

“…Terapias con antibióticos postnatales: Los antibióticos empíricos se usan en los bebés prematuros inmediatamente después del nacimiento debido a la posibilidad de que una infección haya ocasionado el parto prematuro y por el alto riesgo de sepsis en bebés con muy bajo peso al nacer (Jin et al, 2019). Una corta duración de un tratamiento con antibióticos intravenosos después del nacimiento puede retardar la colonización, permitiendo al sistema inmunológico intestinal un periodo corto de adaptación lo que reduce el riesgo de ECN, en contraste un tratamiento prolongado causa disbiosis intestinal persistente lo que aumenta el riesgo de ECN (Jin et al, 2019) (Shen et al, 2022). En un estudio se menciona que del total de 11222 neonatos prematuros, el 89,1% tuvo exposición a antibióticos empíricos (EAE) por sospecha de sepsis de inicio tardío, de los cuales el 63,7% tuvieron EAE ≤ a 72h y el 25,4% a EAE prolongados >72h.…”

Identification of immune-related genes in diagnosing retinopathy of prematurity with sepsis through bioinformatics analysis and machine learning

“…Premature infants with low birth weight were more susceptible to infections, and there was evidence of an increased risk of ROP in these cases. Several studies have demonstrated an association between the incidence of early-onset sepsis in premature infants and an elevated risk as well as severity of ROP (Huang et al, 2019;Bonafiglia et al, 2022;Shen et al, 2022). This indicates that infections and inflammatory responses may have a vital role in the pathogenesis of ROP.…”