Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Reassessing acquired neonatal intestinal diseases using unsupervised machine learning.

BACKGROUND: Acquired neonatal intestinal diseases have an array of overlapping presentations and are often labeled under the dichotomous classification of necrotizing enterocolitis (which is poorly defined) or spontaneous intestinal perforation, hindering more precise diagnosis and research. The objective of this study was to take a fresh look at neonatal intestinal disease classification using unsupervised machine learning. METHODS: Patients admitted to the University of Florida Shands Neonatal Intensive Care Unit January 2013-September 2019 diagnosed with an intestinal injury, or had imaging findings of portal venous gas, pneumatosis, abdominal free air, or had an abdominal drain placed or exploratory laparotomy during admission were included. Congenital gastroschisis, omphalocele, intestinal atresia, malrotation were excluded. Data was collected via retrospective chart review with subsequent hierarchal, unsupervised clustering analysis. RESULTS: Five clusters of intestinal injury were identified: Cluster 1 deemed the "Low Mortality" cluster, Cluster 2 deemed the "Mature with Inflammation" cluster, Cluster 3 deemed the "Immature with High Mortality" cluster, Cluster 4 deemed the "Late Injury at Full Feeds" cluster, and Cluster 5 deemed the "Late Injury with High Rate of Intestinal Necrosis" cluster. CONCLUSION: Unsupervised machine learning can be used to cluster acquired neonatal intestinal injuries. Future study with larger multicenter datasets is needed to further refine and classify types of intestinal diseases. IMPACT: Unsupervised machine learning can be used to cluster types of acquired neonatal intestinal injury. Five major clusters of acquired neonatal intestinal injury are described, each with unique features. The clusters herein described deserve future, multicenter study to determine more specific early biomarkers and tailored therapeutic interventions to improve outcomes of often devastating neonatal acquired intestinal injuries.

Monitoring and management of hypertriglyceridemia in extremely low birth weight neonates receiving intravenous lipid emulsions: A national survey.

AIM: To assess the practice variation of defining, monitoring and managing hypertriglyceridemia (HTG) in extremely low birth weight neonates receiving intravenous lipid emulsions (IVLE). METHODS: An 8-question survey created via the web survey site Qualtrics was distributed to neonatologists, neonatal nurse practitioners and fellows within the Section of Neonatal-Perinatal Medicine email directory list in the United States and Canada. Survey results were obtained between August and September 2022. RESULTS: There were 249 respondents from approximately 4000 members within the Section of Neonatal-Perinatal Medicine. Responses were documented as a frequency (percentage) with a margin of error of plus or minus 6.2 %. Most respondents were neonatologists, individuals practicing for >10 years and reported a unit-based policy for IVLE initiation and advancement. The definitions of HTG varied among respondents, with the majority (42.7 %) reporting a defining threshold of >200 mg/dL. Nineteen percent of respondents reported not routinely monitoring serum triglyceride concentrations with variable triglyceride monitoring intervals reported by other survey respondents. Regarding elevated triglyceride concentrations, 19.0 % reported decreasing the IVLE rate and checking triglyceride concentrations until normalization; 14.6 % reported IVLE discontinuation and monitoring triglyceride concentrations until normalization; 61.9 % reported using a combination of the above practices; and 4.4 % reported individualized practices for IVLE management with elevated triglyceride concentrations. CONCLUSION: This survey demonstrates a high variation in defining, monitoring and managing HTG in extremely low birth weight neonates and emphasizes the need for studies to better guide this practice.

Antibiotics Use and Its Effects on the Establishment of Feeding Tolerance in Preterm Neonates.

OBJECTIVE: Antibiotics are one of the most widely used medications in today's neonatal intensive care units. Indiscriminate antibiotic usage persists in preterm newborns who are symptomatic due to factors linked to prematurity rather than being septic. Previous studies in older infants suggest that prior antibiotic administration is associated with possible dysmotility and microbial dysbiosis in the intestinal tract. We hypothesize that early antibiotic administration impacts high-risk preterm infants' tolerance to enteral feeding advancement. STUDY DESIGN: As part of the Routine Early Antibiotic Use in SymptOmatic Preterm Neonates study, symptomatic preterm newborns without maternal infection risk factors were randomized to receive or not receive antibiotics, with C1 receiving antibiotics and C2 not. Of the 55 newborns that underwent pragmatic randomization, 28 preterm neonates in group C1 received antibiotics. RESULTS: The premature neonates in the randomized groups who received antibiotics and those who did not showed no differences in sustained feeding tolerance. CONCLUSION: Our investigation of the risk of feeding issues in babies who get antibiotics early in life revealed no differences between neonates who received antibiotics and those who did not when the randomized controlled trial data alone was reviewed. Given the sample sizes, it is uncertain if the preceding analysis is powerful enough to detect differences (a significant percentage of neonates who were randomly assigned to NOT get antibiotics subsequently received early treatment due to changing clinical conditions). This affirms the requirement for a meticulously designed prospective randomized study. KEY POINTS: · Defining feeding tolerance for the first time in neonates.. · Patients from the REASON trial were evaluated.. · Preterm neonates were the focus of this study..

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants with Necrotizing Enterocolitis.

INTRODUCTION: The neonatal sequential organ failure assessment (nSOFA) score is a tool for calculating mortality risk of infants in the neonatal intensive care unit. The utility of the nSOFA in determining the risk of mortality or the association with surgical intervention among infants with necrotizing enterocolitis (NEC) has not been investigated. METHODS: We performed a retrospective, cohort study of preterm (<37 weeks) infants with NEC Bell's stage ≥ IIA at six hospitals from 2008 to 2020. An nSOFA score (range 0-15) was assigned to each patient at nine time points from 48 h before or after clinical illness was suspected. RESULTS: Of the 259 infants, nSOFA scores for infants who died (n = 39) or had the composite outcome of surgery or death (n = 114) were significantly higher (p < 0.05) early in the NEC course compared to nSOFA scores for infants who survived medical NEC. Twelve hours after evaluation, the area under the receiver operating characteristic curve was 0.87 (95% confidence interval [CI], 0.80-0.93) to discriminate for mortality and 0.84 (95% CI, 0.79-0.90) for surgery or death (p < 0.001). A maximum nSOFA score of ≥4 at -6, 0, 6, or 12 h following evaluation was associated with a 20-fold increase in mortality and 19-fold increase in surgery or death compared with a score of <4 (p < 0.001). CONCLUSION: In this multicenter cohort, the nSOFA score was able to discriminate well for death as well as surgery or death among infants with NEC. The nSOFA is a clinical research tool that may be used in infants with NEC to improve classification by objective quantification of organ dysfunction.

Gastrointestinal and feeding issues for infants <25 weeks of gestation.

Appropriate nutrition is essential for optimal development and growth of preterm infants. Infants less than 25 weeks corrected gestational age are frequently the most difficult group for which to provide adequate nutrition due to minimal energy stores and high fluid losses. Nutrient delivery becomes an integral, but also very challenging part in their management. Early administration of intravenous nutrients provides a critical bridge to full enteral nutrition. However, enteral feeding is challenging due to immaturities of the intestinal tract, feeding intolerance and the risk of catastrophic gastrointestinal disease such as necrotizing enterocolitis (NEC). Decreased gastric acid production, increased gut permeability, reduced immunoglobulins, immature intestinal epithelia and a decreased mucin barrier all contribute to weakness to gastrointestinal insult. This review aims to illustrate the importance of enteral feeding and the common challenges and approaches in the nutrition of infants born at this age.

Hourly Kinetics of Critical Organ Dysfunction in Extremely Preterm Infants.

Rationale: Use of severity of illness scores to classify patients for clinical care and research is common outside of the neonatal ICU. Extremely premature (<29 weeks' gestation) infants with extremely low birth weight (<1,000 g) experience significant mortality and develop severe pathology during the protracted birth hospitalization. Objectives: To measure at high resolution the changes in organ dysfunction that occur from birth to death or discharge home by gestational age and time, and among extremely preterm infants with and without clinically meaningful outcomes using the neonatal sequential organ failure assessment score. Methods: A single-center, retrospective, observational cohort study of inborn, extremely preterm infants with extremely low birth weight admitted between January 2012 and January 2020. Neonatal sequential organ failure assessment scores were calculated every hour for every patient from admission until death or discharge. Measurements and Main Results: Longitudinal, granular scores from 436 infants demonstrated early and sustained discrimination of those who died versus those who survived to discharge. The discrimination for mortality by the maximum score was excellent (area under curve, 0.91; 95% confidence intervals, 0.88-0.94). Among survivors with and without adverse outcomes, most score variation occurred at the patient level. The weekly average score over the first 28 days was associated with the sum of adverse outcomes at discharge. Conclusions: The neonatal sequential organ failure assessment score discriminates between survival and nonsurvival on the first day of life. The major contributor to score variation occurred at the patient level. There was a direct association between scores and major adverse outcomes, including death.

Maximum vasoactive-inotropic score and mortality in extremely premature, extremely low birth weight infants.

OBJECTIVE: To determine the relationship between maximum vasoactive-inotropic (VISmax) and mortality in extremely premature (<29 weeks completed gestation), extremely low birth weight (ELBW, <1000 g) infants. STUDY DESIGN: Single center, retrospective, and observational cohort study. RESULTS: We identified 436 ELBW, <29 week, inborn infants cared for during the study period. Compared to infants with VISmax of 0, the frequency of mortality based on VISmax ranged from 3.3-fold to 46.1-fold. VISmax > 30 was associated with universal mortality. Multivariable modeling that included gestational age, birth weight, and VISmax revealed significant utility to predict mortality with negative predictive value of 87.0% and positive predictive value of 84.8% [adjusted AUROC: 0.90, (0.86-0.94)] among patients that received vasoactive-inotropic treatment. CONCLUSION: VISmax is an objective measure of hemodynamic/cardiovascular support that was directly associated with mortality in extremely premature ELBW infants. The VISmax represents an important step towards neonatal precision medicine and risk stratification of extremely premature ELBW infants.

Antibiotics and the developing intestinal microbiome, metabolome and inflammatory environment in a randomized trial of preterm infants.

Antibiotic use in neonates can have detrimental effects on the developing gut microbiome, increasing the risk of morbidity. A majority of preterm neonates receive antibiotics after birth without clear evidence to guide this practice. Here microbiome, metabolomic, and immune marker results from the routine early antibiotic use in symptomatic preterm Neonates (REASON) study are presented. The REASON study is the first trial to randomize symptomatic preterm neonates to receive or not receive antibiotics in the first 48 h after birth. Using 16S rRNA sequencing of stool samples collected longitudinally for 91 neonates, the effect of such antibiotic use on microbiome diversity is assessed. The results illustrate that type of nutrition shapes the early infant gut microbiome. By integrating data for the gut microbiome, stool metabolites, stool immune markers, and inferred metabolic pathways, an association was discovered between Veillonella and the neurotransmitter gamma-aminobutyric acid (GABA). These results suggest early antibiotic use may impact the gut-brain axis with the potential for consequences in early life development, a finding that needs to be validated in a larger cohort.Trial Registration This project is registered at clinicaltrials.gov under the name "Antibiotic 'Dysbiosis' in Preterm Infants" with trial number NCT02784821.

Using machine learning analysis to assist in differentiating between necrotizing enterocolitis and spontaneous intestinal perforation: A novel predictive analytic tool.

PURPOSE: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are devastating diseases in preterm neonates, often requiring surgical treatment. Previous studies evaluated outcomes in peritoneal drain placement versus laparotomy, but the accuracy of the presumptive diagnosis remains unknown without bowel visualization. Predictive analytics provide the opportunity to determine the etiology of perforation and guide surgical decision making. The purpose of this investigation was to build and evaluate machine learning models to differentiate NEC and SIP. METHODS: Neonates who underwent drain placement or laparotomy NEC or SIP were identified and grouped definitively via bowel visualization. Patient characteristics were analyzed using machine learning methodologies, which were optimized through areas under the receiver operating characteristic curve (AUROC). The model was further evaluated using a validation cohort. RESULTS: 40 patients were identified. A random forest model achieved 98% AUROC while a ridge logistic regression model reached 92% AUROC in differentiating diseases. When applying the trained random forest model to the validation cohort, outcomes were correctly predicted. CONCLUSIONS: This study supports the feasibility of using a novel machine learning model to differentiate between NEC and SIP prior to any intended surgical interventions. LEVEL OF EVIDENCE: level II TYPE OF STUDY: Clinical Research Paper.

Antibiotics Effects on the Fecal Metabolome in Preterm Infants.

Within a randomized prospective pilot study of preterm infants born at less than 33 weeks' gestation, weekly fecal samples from 19 infants were collected and metabolomic analysis was performed. The objective was to evaluate for differences in fecal metabolites in infants exposed to antibiotics vs. not exposed to antibiotics in the first 48 h after birth. Metabolomics analysis was performed on 123 stool samples. Significant differences were seen in the antibiotics vs. no antibiotics groups, including pathways related to vitamin biosynthesis, bile acids, amino acid metabolism, and neurotransmitters. Early antibiotic exposure in preterm infants may alter metabolites in the intestinal tract of preterm infants. Broader multi-omic studies that address mechanisms will guide more prudent antibiotic use in this population.

Neonatal Dieulafoy Lesion Requiring Massive Transfusion Protocol and Surgical Intervention.

Neonatal Dieulafoy lesion is a rare but severe condition that can be life-threatening if not intervened upon in a timely fashion. In the general population, the majority of lesions are successfully treated with endoscopic or angiographic intervention. Surgery is usually reserved for cases that fail endoscopic or angiographic intervention. We present a case of neonatal Dieulafoy lesion that occurred less than 24 h after delivery with hematemesis. The patient required large volume resuscitation and massive transfusion of blood products for acute blood loss. The lesion was successfully treated with surgical ligation after a failed attempt at endoscopic intervention.

Pediatric Healthcare Needs and Barriers Self-Reported by a Rural Hispanic Community.

Purpose Hispanic immigrants in rural communities can be a hard-to-reach population with many unmet medical needs that have yet to be properly identified. This is particularly true for rural immigrant children. This study focused on documenting self-reported healthcare barriers among this isolated population to identify methods for reducing health disparities among this vulnerable population. Methods Participants at recurrent mobile health fairs were anonymously surveyed from June 2016 to January 2018. Differences between the US and foreign-born Hispanic participants were investigated in bivariate analyses. Findings We received 35 completed surveys. The majority (79.3%) of participants reported household incomes below the federal poverty line for a family of four. Only 4.5% of foreign-born children were insured, compared with 77% of US-born children (p<0.001). Greater than 85% of foreign-born and 100% of US-born children were fully vaccinated, but half of the participants were seeking preventative care. Most patients identified insurance and cost as the most significant barriers to healthcare. Conclusions Access to insurance was the largest barrier identified by this population, with a significant difference between foreign and US-born children. This gap is further compounded by many responders living below the federal poverty line, limiting their ability to pay for the growing costs of uninsured treatment. This study also indicates this Hispanic community's prioritized desire for access to preventative healthcare and high uptake of childhood immunizations.

Food Protein-Induced Enterocolitis Instead of Necrotizing Enterocolitis? A Neonatal Intensive Care Unit Case Series.

Necrotizing enterocolitis is an important disease in infants born premature. However, other disease entities present with similar signs and symptoms. This series reviews 5 atypical cases initially diagnosed as necrotizing enterocolitis that may be more consistent with food protein-induced enterocolitis. Food protein-induced enterocolitis may be underdiagnosed in this population.

Meconium microbiome analysis identifies bacteria correlated with premature birth.

BACKGROUND: Preterm birth is the second leading cause of death in children under the age of five years worldwide, but the etiology of many cases remains enigmatic. The dogma that the fetus resides in a sterile environment is being challenged by recent findings and the question has arisen whether microbes that colonize the fetus may be related to preterm birth. It has been posited that meconium reflects the in-utero microbial environment. In this study, correlations between fetal intestinal bacteria from meconium and gestational age were examined in order to suggest underlying mechanisms that may contribute to preterm birth. METHODS: Meconium from 52 infants ranging in gestational age from 23 to 41 weeks was collected, the DNA extracted, and 16S rRNA analysis performed. Resulting taxa of microbes were correlated to clinical variables and also compared to previous studies of amniotic fluid and other human microbiome niches. FINDINGS: Increased detection of bacterial 16S rRNA in meconium of infants of <33 weeks gestational age was observed. Approximately 61·1% of reads sequenced were classified to genera that have been reported in amniotic fluid. Gestational age had the largest influence on microbial community structure (R = 0·161; p = 0·029), while mode of delivery (C-section versus vaginal delivery) had an effect as well (R = 0·100; p = 0·044). Enterobacter, Enterococcus, Lactobacillus, Photorhabdus, and Tannerella, were negatively correlated with gestational age and have been reported to incite inflammatory responses, suggesting a causative role in premature birth. INTERPRETATION: This provides the first evidence to support the hypothesis that the fetal intestinal microbiome derived from swallowed amniotic fluid may be involved in the inflammatory response that leads to premature birth.