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.

Clinical Characteristics of Necrotizing Enterocolitis Diagnosed by Independent Adjudication of Abdominal Radiographs, Laparotomy, or Autopsy in Preterm Infants in the "Connection Trial".

OBJECTIVE: Necrotizing enterocolitis (NEC) classically is diagnosed by radiographic demonstration of pneumatosis intestinalis/portal venous gas (PI/PVG). This study examines clinical characteristics of NEC confirmed by independent evaluation of abdominal radiographs, taken for clinical signs of NEC, or by pathologic findings at laparotomy or autopsy (confirmed NEC [cNEC]). STUDY DESIGN: The investigated cohort included 1,382 extremely low birth weight (BW) infants (BW range: 500-1,000 g) with median 27 weeks (range: 23-32) gestational age (GA) at birth. They were randomized into the placebo-controlled "Connection Trial" of the new biological drug candidate IBP-9414 with cNEC as one primary endpoint. RESULTS: Total 119 infants (8.6%) had cNEC diagnosed at median 14 days of age by confirming PI/PVG at X-ray adjudication (n = 111) and/or by surgery/autopsy (n = 21). Sixteen percent of cNEC cases died. Adverse events of NEC were reported in 8.5% of infants and 4.1% had NEC diagnosed by radiology and surgery/autopsy at the participating centers. Regression analyses showed that the risk of cNEC decreased by 11 to 30% for every 100-g increment in BW and single-week increment in GA and associated cNEC with odds ratios (ORs) > 2.0 for gastrointestinal (GI) perforation and obstruction, hypotension, hypokalemia, hypophosphatemia, and death. Comparing risks of cNEC in infants below and above 750-g BW showed higher ORs (2.7-4.3) for GI perforation, hypotension, hypokalemia, and renal complications in the smaller infants, whereas the bigger infants had higher ORs (1.9-3.2) for serious non-GI events, late-onset sepsis (LOS), and death. Predictors of cNEC (hazard ratio, HR > 1.5) included serious non-GI events (mainly infections), hyponatremia, and hyperglycemia, whereas the HR was 0.52 for intravenous antibiotics. After cNEC diagnosis, there were higher rates of GI perforation and obstruction, hypotension, hypokalemia, and LOS. CONCLUSION: Independent adjudication of abdominal radiographs increased radiological recognition of NEC and proved to be feasible in a multicenter study setting as well as able to diagnose clinically relevant NEC. KEY POINTS: · Independent adjudication of abdominal radiographs in ELBW infants increased NEC recognition.. · Risk of NEC decreased by 11 to 30% with every 100-g increment in BW and GA week.. · In infants with BW 750 to 1,000 g, the risk of death from NEC was almost twice that in infants with BW 500 to 749 g. · Infants with NEC received antibiotics during one-third and parenteral nutrition during half of the first 7 postnatal weeks..

Multiomics, artificial intelligence, and precision medicine in perinatology.

Technological advances in omics evaluation, bioinformatics, and artificial intelligence have made us rethink ways to improve patient outcomes. Collective quantification and characterization of biological data including genomics, epigenomics, metabolomics, and proteomics is now feasible at low cost with rapid turnover. Significant advances in the integration methods of these multiomics data sets by machine learning promise us a holistic view of disease pathogenesis and yield biomarkers for disease diagnosis and prognosis. Using machine learning tools and algorithms, it is possible to integrate multiomics data with clinical information to develop predictive models that identify risk before the condition is clinically apparent, thus facilitating early interventions to improve the health trajectories of the patients. In this review, we intend to update the readers on the recent developments related to the use of artificial intelligence in integrating multiomic and clinical data sets in the field of perinatology, focusing on neonatal intensive care and the opportunities for precision medicine. We intend to briefly discuss the potential negative societal and ethical consequences of using artificial intelligence in healthcare. We are poised for a new era in medicine where computational analysis of biological and clinical data sets will make precision medicine a reality. IMPACT: Biotechnological advances have made multiomic evaluations feasible and integration of multiomics data may provide a holistic view of disease pathophysiology. Artificial Intelligence and machine learning tools are being increasingly used in healthcare for diagnosis, prognostication, and outcome predictions. Leveraging artificial intelligence and machine learning tools for integration of multiomics and clinical data will pave the way for precision medicine in perinatology.

Skin microbiome sampling in the preterm neonate.

Despite advances in our understanding of the human microbiome, there exist significant knowledge gaps in our understanding of the skin microbiome of the preterm neonate. Herein, we describe skin microbiome sampling of six preterm neonates at multiple timepoints, and compare the skin microbiome samples to environmental (crib/isolette swabs) and negative controls. Samples of the same type (skin, crib, control) were more similar than when compared by week or by patient.

A Scoping Review of the Oral Microbiome in Preterm Infants.

The purpose of this scoping review was to examine the oral microbiome composition in preterm infants, sampling and collection methods, as well as exposures associated with oral microbiome composition and health implications. We conducted a scoping review of the literature using the Arskey and O'Malley framework. We identified a total of 13 articles which met our inclusion criteria and purpose of this scoping review. Articles included in this review compared the oral microbiome in preterm infants to term infants, examined alterations to the oral microbiome over time, compared the oral microbiome to different body site microbiomes, and explored associations with clinically relevant covariates and outcomes. Exposures associated with the diversity and composition of the oral microbiome in preterm infants included delivery mode, oral feeding, oropharyngeal care, skin-to-skin care, and antibiotics. Day of life and birth weight were also associated with oral microbiome composition. The oral microbiome may be associated with the composition of the tracheal and gut microbiomes, likely due to their proximity. Alpha and beta diversity findings varied across studies as well as the relative abundance of taxa. This is likely due to the different sampling techniques and timing of collection, as well as the wide range of infant clinical characteristics. Multiple factors may influence the composition of the oral microbiome in preterm infants. However, given the heterogeneity of sampling techniques and results within this review, the evidence is not conclusive on the development as well as short- and long-term implications of the oral microbiome in preterm infants and needs to be explored in future research studies. KEY POINTS: · Day of life is a critical factor in oral microbiome development in preterm infants.. · The oral microbiome may be associated with tracheal and gut microbiome colonization.. · Future research should examine sampling methodology for examining the oral microbiome.. · Future research should explore associations with the oral microbiome and adverse health outcomes..

Progression of Enteral Feeding Volumes in Extremely Low Birth Weight Infants in the "Connection Trial".

OBJECTIVE: Investigate daily feeding volumes and their association with clinical variables in the early postnatal care of premature infants of the "Connection Trial." STUDY DESIGN: A total of 641 infants of 510 to 1,000-g birth weight (BW, mean: 847 g) and mean 27 weeks' gestational age at birth (GA) were analyzed for total daily enteral (TDE) feeding volumes of 10, 20, 40, 80, and 120 mL/kg/d and their association with 24 clinical variables. Uni- and multivariable Cox regression models were used to calculate hazard ratios (HR) with 95% confidence intervals as a measure of the chance of reaching each of the TDE volumes. RESULTS: Daily feeding volumes were highly variable and the median advancement from 10 to 120 mL/kg/d was 11 mL/kg/d. Univariable analyses showed the lowest chance (HR, 0.22-0.81) of reaching the TDE volumes for gastrointestinal (GI) serious adverse events (SAEs), GI perforation, GI obstruction, and necrotizing enterocolitis, as well as respiratory SAEs, persistent ductus arteriosus, and hypotension. Each GA week, 100-g BW, and point in 5-minute Apgar score at birth associated with 8 to 20% increased chance of reaching the TDE volumes. Multivariable analyses showed independent effects for BW, GA, Apgar score, GI SAEs, abdominal symptoms/signs, respiratory SAEs, days on antibiotics, and hypotension. CONCLUSION: This observational analysis demonstrates the variable and cautious progression of enteral feedings in contemporary extremely low BW infants and the extent to which clinical variables associate with this progression. KEY POINTS: · Total feedings of 10 and 120 mL/kg/d were reached at median 4 and 14 day of age, respectively, and at a daily increase of 11 mL/kg.. · Each incremental GA week, 100-g BW, and point in 5-minute Apgar score associated with 8 to 20% increased chance of reaching enteral feedings of 10 to 120 mL/kg/d.. · Progression of enteral feeding associated with several clinical events and was slower than advocated in common feeding protocols..

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..

Tachygastria in Preterm Infants: A Longitudinal Cohort Study.

OBJECTIVES: Tachygastria is a gastric dysrhythmia (>4 to ≤9 cycles per minute, cpm) associated with gastric hypomotility and gastrointestinal disorders. Healthy preterm infants spend more time in tachygastria than adults; however, normative values are not defined. We sought to determine the percent of time preterm infants spend in tachygastria. METHODS: We conducted a longitudinal, prospective cohort study with weekly electrogastrography (EGG) recordings in 51 preterm <34 weeks' gestation and 5 term (reference) infants. We calculated percentage recording time in tachygastria (% tachygastria) and determined the mean ± standard deviation (SD) across EGG sessions. Mixed effects model was performed to test weekly variance in % tachygastria and gestational age effect. Successive pre- and post-prandial measurements were obtained to assess reproducibility of % tachygastria. We compared time to achieve full feeds between subjects with % tachygastria within 1 SD from the mean versus % tachygastria >1 SD from mean. RESULTS: Three hundred seventy-six EGG sessions were completed (N = 56). Mean % tachygastria was 40% with SD ±5%. We demonstrated no change in % tachygastria across 9 postnatal weeks (P = 0.70) and no gestational age effect. No difference was demonstrated between successive pre- (P = 0.91) and post-prandial (P = 0.96) % tachygastria. Infants with 35%-45% tachygastria (within 1 SD from mean) had higher gestational age and less time to achieve full feeds than infants with <35% or >45% tachygastria. CONCLUSIONS: EGG is a reproducible tool to assess % tachygastria in preterm infants. Clinical significance of increased or decreased % tachygastria needs further investigation to validate if 35%-45% tachygastria is safe for feeding.

Integrating longitudinal clinical and microbiome data to predict growth faltering in preterm infants.

Preterm birth affects more than 10% of all births worldwide. Such infants are much more prone to Growth Faltering (GF), an issue that has been unsolved despite the implementation of numerous interventions aimed at optimizing preterm infant nutrition. To improve the ability for early prediction of GF risk for preterm infants we collected a comprehensive, large, and unique clinical and microbiome dataset from 3 different sites in the US and the UK. We use and extend machine learning methods for GF prediction from clinical data. We next extend graphical models to integrate time series clinical and microbiome data. A model that integrates clinical and microbiome data improves on the ability to predict GF when compared to models using clinical data only. Information on a small subset of the taxa is enough to help improve model accuracy and to predict interventions that can improve outcome. We show that a hierarchical classifier that only uses a subset of the taxa for a subset of the infants is both the most accurate and cost-effective method for GF prediction. Further analysis of the best classifiers enables the prediction of interventions that can improve outcome.

Effect of Routine Gastric Residual Aspiration on the Preterm Infant Fecal Microbiome.

OBJECTIVE: Enteral feeding tubes are used in neonatal intensive care units (NICUs) to assess feeding tolerance by utilizing preprandial gastric residual aspiration. This study evaluates the effect of gastric residual aspiration on the preterm infant fecal microbiome and gastrointestinal inflammation. STUDY DESIGN: Fifty-one very low birth weight (VLBW) infants (≤32 weeks' gestational age and ≤1,250 g) enrolled in a larger single-center randomized controlled trial evaluating the effects of routine and nonroutine gastric residual aspiration were selected for further analysis. Of those infants, 30 had microbiome analysis performed on stools collected at 6 weeks by sequencing the bacterial V1 to V3 variable regions of the genes encoding for 16S rRNA. In an additional 21 infants, stool samples collected at 3 and 6 weeks were analyzed for intestinal inflammation using a cytokine multiplex panel. RESULTS: Microbial communities between groups were not distinct from each other and there was no difference in intestinal inflammation between groups. Analyses using gene expression packages DESeq2 and edgeR produced statistically significant differences in several taxa, possibly indicating a more commensal intestinal microbiome in infants not undergoing gastric residual aspiration. CONCLUSION: Omission of routine gastric residual aspiration was not associated with intestinal dysbiosis or inflammation, providing additional evidence that monitors preprandial gastric residuals is unnecessary. KEY POINTS: · Omission of routine gastric residual aspiration was not associated with intestinal dysbiosis or inflammation.. · Existing literature indicates preprandial gastric aspiration does not reliably correlate with development of necrotizing enterocolitis but does correlate with delayed enteral nutrition.. · Further study is required but this data that suggest monitoring preprandial gastric residuals are unnecessary..

Routine Early Antibiotic Use in SymptOmatic Preterm Neonates: A Pilot Randomized Controlled Trial.

We enrolled 98 infants (gestational age <33 weeks) in a pilot randomized trial of antibiotics vs no antibiotics; 55 were randomized (lower maternal infectious risk; symptoms expected for gestation). Adverse events did not differ significantly between the randomization arms. This trial establishes a framework for a larger multicentered trial.

Perspectives of pregnant and breastfeeding women on longitudinal clinical studies that require non-invasive biospecimen collection - a qualitative study.

BACKGROUND: Investigation of the microbiome during early life has stimulated an increasing number of cohort studies in pregnant and breastfeeding women that require non-invasive biospecimen collection. The objective of this study was to explore pregnant and breastfeeding women's perspectives on longitudinal clinical studies that require non-invasive biospecimen collection and how they relate to study logistics and research participation. METHODS: We completed in-depth semi-structured interviews with 40 women who were either pregnant (n = 20) or breastfeeding (n = 20) to identify their understanding of longitudinal clinical research, the motivations and barriers to their participation in such research, and their preferences for providing non-invasive biospecimen samples. RESULTS: Perspectives on research participation were focused on breastfeeding and perinatal education. Participants cited direct benefits of research participation that included flexible childcare, lactation support, and incentives and compensation. Healthcare providers, physician offices, and social media were cited as credible sources and channels for recruitment. Participants viewed lengthy study visits and child protection as the primary barriers to research participation. The barriers to biospecimen collection were centered on stool sampling, inadequate instructions, and drop-off convenience. CONCLUSION: Women in this study were interested in participating in clinical studies that require non-invasive biospecimen collection, and motivations to participate center on breastfeeding and the potential to make a scientific contribution that helps others. Effectively recruiting pregnant or breastfeeding participants for longitudinal microbiome studies requires protocols that account for participant interests and consideration for their time.

Preterm neonatal immunology at the intestinal interface.

Fetal and neonatal development represents a critical window for setting a path toward health throughout life. In this review, we focus on intestinal immunity, how it develops, and its implications for subsequent neonatal diseases. We discuss maternal nutritional and environmental exposures that dictate outcomes for the developing fetus. Although still controversial, there is evidence in support of an in utero microbiome. Specific well-intentioned and routine applications of antibiotics, steroids, and surgical interventions implemented before, during, and after birth skew the neonate towards pro-inflammatory dysbiosis. Shortly after birth, a consortium of maternal and environmentally derived bacteria, through cross-talk with the developing host immune system, takes center stage in developing or disrupting immune homeostasis at the intestinal interface. We also examine subsequent immunological cross-talks, which involve neonatal myeloid and lymphoid responses, and their potential impacts on health and disease such as necrotizing enterocolitis and sepsis, especially critical disease entities for the infant born preterm.

Duration of neonatal intensive care unit exposure associated with decreased risk of atopic dermatitis.

BACKGROUND/OBJECTIVES: Premature infants have lower rates of atopic dermatitis (AD) compared with full-term infants, though little is known about the factors contributing to this association. We explored the infant and environmental factors that may contribute to the association between prematurity and atopic dermatitis, including mode of delivery, birthweight, gestation, and duration of stay in the neonatal intensive care unit (NICU). METHODS: This was a single-center retrospective study. Independent samples t tests or chi-square tests were used to compare groups on continuous and categorical variables, respectively. Logistic regression then examined the association of the predictor variables with AD. RESULTS: Four thousand sixteen mother-infant dyads were included. Infants had a higher risk of developing AD if they were delivered vaginally (P = .013), did not stay in the NICU (P < .001), had a longer gestation (P = .001), or had a higher birthweight (P = .002). In modeling atopic dermatitis with the predictor variables, only NICU length of stay remained significantly associated with a lower risk of AD (P = .004). CONCLUSION: Infants had a lower risk of developing AD if they had a longer stay in the NICU.

Implications of the vaginal microbiome and potential restorative strategies on maternal health: a narrative review.

The vaginal microbiome undergoes dramatic shifts before and throughout pregnancy. Although the genetic and environmental factors that regulate the vaginal microbiome have yet to be fully elucidated, high-throughput sequencing has provided an unprecedented opportunity to interrogate the vaginal microbiome as a potential source of next-generation therapeutics. Accumulating data demonstrates that vaginal health during pregnancy includes commensal bacteria such as Lactobacillus that serve to reduce pH and prevent pathogenic invasion. Vaginal microbes have been studied as contributors to several conditions occurring before and during pregnancy, and an emerging topic in women's health is finding ways to alter and restore the vaginal microbiome. Among these restorations, perhaps the most significant effect could be preterm labor (PTL) prevention. Since bacterial vaginosis (BV) is known to increase risk of PTL, and vaginal and oral probiotics are effective as supplemental treatments for BV prevention, a potential therapeutic benefit exists for pregnant women at risk of PTL. A new method of restoration, vaginal microbiome transplants (VMTs) involves transfer of one women's cervicovaginal secretions to another. New studies investigating recurrent BV will determine if VMTs can safely establish a healthy Lactobacillus-dominant vaginal microbiome. In most cases, caution must be taken in attributing a disease state and vaginal dysbiosis with a causal relationship, since the underlying reason for dysbiosis is usually unknown. This review focuses on the impact of vaginal microflora on maternal outcomes before and during pregnancy, including PTL, gestational diabetes, preeclampsia, and infertility. It then reviews the clinical evidence focused on vaginal restoration strategies, including VMTs.

Effect of Aspiration and Evaluation of Gastric Residuals on Intestinal Inflammation, Bleeding, and Gastrointestinal Peptide Level.

OBJECTIVE: To determine the effect of gastric residual aspiration and evaluation on preterm very low birth weight infants' gastrointestinal function, intestinal inflammation, and gastrointestinal mucosal bleeding. STUDY DESIGN: This single-center, randomized trial compared omission of gastric residuals vs prefeed gastric residuals in 143 infants ≤32 weeks of gestation with a birthweight of ≤1250 g for 6 weeks after birth. Serum levels of gastrin and motilin were collected between 14 and 21 days of life. Stools were collected at 3 and 6 weeks of age and analyzed for calprotectin and S100A12 levels. All stools were tested for occult blood for 6 weeks. RESULTS: Means for gastrin (P = .999) and motilin (P = .694) were similar between groups and there were no statistically significant differences in adjusted means for transformed calprotectin (P = .580), and S100A12 (P = .212). Both calprotectin (P = .003) and S100A12 (P = .002) increased from week 3 to week 6. The mean percentage of stools positive for occult blood (P = .888) were similar between the groups. CONCLUSIONS: Gastrointestinal function, intestinal inflammation, and gastrointestinal mucosal bleeding were similar whether aspiration and evaluation of gastric residuals were eliminated or not, suggesting routinely evaluating gastric residuals before every feeding may be unnecessary. TRIAL REGISTRATION CLINICALTRIALS.GOV:: NCT01863043.

Gut microbiota maturation during early human life induces enterocyte proliferation via microbial metabolites.

BACKGROUND: The intestinal tract undergoes a period of cellular maturation during early life, primarily characterized by the organization of epithelial cells into specialized crypt and villus structures. These processes are in part mediated by the acquisition of microbes. Infants delivered at term typically harbor a stable, low diversity microbiota characterized by an overrepresentation of various Bacilli spp., while pre-term infants are colonized by an assortment of bacteria during the first several weeks after delivery. However, the functional effects of these changes on intestinal epithelium homeostasis and maturation remain unclear. To study these effects, human neonate feces were obtained from term and pre-term infants. Fecal 16S rDNA sequencing and global untargeted LC-MS were performed to characterize microbial composition and metabolites from each population. Murine enteral organoids (enteroids) were cultured with 0.22 µm filtered stool supernatant pooled from term or pre-term infants. RESULTS: Term and pre-term microbial communities differed significantly from each other by principle components analysis (PCoA, PERMANOVA p < 0.001), with the pre-term microbiome characterized by increased OTU diversity (Wilcox test p < 0.01). Term communities were less diverse and dominated by Bacilli (81.54%). Pre-term stools had an increased abundance of vitamins, amino acid derivatives and unconjugated bile acids. Pathway analysis revealed a significant increase in multiple metabolic pathways in pre-term samples mapped to E. coli using the KEGG database related to the fermentation of various amino acids and vitamin biosynthesis. Enteroids cultured with supernatant from pre-term stools proliferated at a higher rate than those cultured with supernatant from term stools (cell viability: 207% vs. 147.7%, p < 0.01), grew larger (area: 81,189µm2 vs. 41,777µm2, p < 0.001), and bud at a higher rate (6.5 vs. 4, p < 0.01). Additionally, genes involved in stem cell proliferation were upregulated in pre-term stool treated enteroid cultures (Lgr5, Ephb2, Ascl2 Sox9) but not term stool treated enteroids. CONCLUSIONS: Our findings indicate that microbial metabolites from the more diverse gut microbiome associated with pre-term infants facilitate stem cell proliferation. Therefore, perturbations of the pre-term microbiota may impair intestinal homeostasis.

Necrotizing Enterocolitis: A Multi-omic Approach and the Role of the Microbiome.

Necrotizing enterocolitis (NEC) is a poorly defined disease that primarily affects preterm infants. There has not been much progress in the prevention or treatment of NEC since it became recognized as a common problem in preterm infants. Reasons for this lack of progress include the likelihood that different diseases are being put under the same moniker of "NEC," similar to using "diabetes" for the different diseases it represents. In order to make progress, better delineation of the phenotypes that present as NEC will be necessary to clearly establish their pathophysiology, find specific and sensitive biomarkers, and establish preventative regimens. In this review, we summarize some of the entities that are being called NEC, discuss the pathophysiology of the most classic form of NEC, and provide an overview of how we might proceed in the future to make progress in this field.

Metabolomic Profile of Personalized Donor Human Milk.

Human milk could be considered an active and complex mixture of beneficial bacteria and bioactive compounds. Since pasteurization drastically reduces the microbial content, we recently demonstrated that pasteurized donor human milk (DHM) could be inoculated with different percentages (10% and 30%) of mother's own milk (MOM) to restore the unique live microbiota, resulting in personalized milk (RM10 and RM30, respectively). Pasteurization affects not only the survival of the microbiota but also the concentration of proteins and metabolites, in this study, we performed a comparative metabolomic analysis of the RM10, RM30, MOM and DHM samples to evaluate the impact of microbial restoration on metabolite profiles, where metabolite profiles clustered into four well-defined groups. Comparative analyses of DHM and MOM metabolomes determined that over one thousand features were significantly different. In addition, significant changes in the metabolite concentrations were observed in MOM and RM30 samples after four hours of incubation, while the concentration of metabolites in DHM remained constant, indicating that these changes are related to the microbial expansion. In summary, our analyses indicate that the metabolite profiles of DHM are significantly different from that of MOM, and the profile of MOM may be partially restored in DHM through microbial expansion.

Consumption of Mother's Own Milk by Infants Born Extremely Preterm Following Implementation of a Donor Human Milk Program: A Retrospective Cohort Study.

OBJECTIVE: To compare mothers' own milk (MOM) consumption by infants born extremely preterm before and after implementation of a donor human milk (DHM) program and determine healthcare provider's knowledge and practices regarding DHM. STUDY DESIGN: One hundred fifty-seven infants born at <30 weeks of gestation were enrolled during 3 time-periods. Group 1: before DHM program implementation, Group 2: the year following implementation, and Group 3: the second year after implementation. The proportion of feeds consisting of MOM for 6 weeks following birth was analyzed using a generalized linear mixed model. The study's second phase surveyed healthcare providers regarding knowledge and practices concerning DHM. RESULTS: Group 1 consumed feeds with a greater proportion of MOM than Group 3 during weeks 1 (P < .001) and 3 (P = .007) and more than both Group 2 (P = .033) and 3 (P = .021) in week 4. During the first 14 days, Group 1 consumed feeds with 23.6% more MOM than Group 3 (P = .002) and had a greater odds of consuming feeds with > 90% MOM (P < .001) than Group 3. During days 1-28, Group 1 consumed feeds with 22% more MOM than Group 3 (P = .003) and had greater odds of consuming feeds with >90% MOM than Group 2 (P = .020) and 3 (P = .004). Knowledge regarding DHM was inconsistent among providers and they were unlikely to communicate potential risks and benefits of DHM to mothers. CONCLUSIONS: Following implementation of a DHM program, MOM consumption decreased over 2 years. Strategies focused on lactation success are necessary to increase MOM consumption.