Epithelial Membrane Protein 2 (EMP2) Blockade Attenuates Pathological Neovascularization in Murine Oxygen-Induced Retinopathy.

Purpose: Retinopathy of prematurity (ROP) results from postnatal hyperoxia exposure in premature infants and is characterized by aberrant neovascularization of retinal blood vessels. Epithelial membrane protein-2 (EMP2) regulates hypoxia-inducible factor (HIF)-induced vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line and genetic knock-out of Emp2 in a murine oxygen-induced retinopathy (OIR) model attenuates neovascularization. We hypothesize that EMP2 blockade via intravitreal injection protects against neovascularization. Methods: Ex vivo choroid sprouting assay was performed, comparing media and human IgG controls versus anti-EMP2 antibody (Ab) treatment. In vivo, eyes from wild-type (WT) mice exposed to hyperoxia from postnatal (P) days 7 to 12 were treated with P12 intravitreal injections of control IgG or anti-EMP2 Abs. Neovascularization was assessed at P17 by flat mount imaging. Local and systemic effects of anti-EMP2 Ab treatment were assessed. Results: Choroid sprouts treated with 30 µg/mL of anti-EMP2 Ab demonstrated a 48% reduction in vessel growth compared to control IgG-treated sprouts. Compared to IgG-treated controls, WT OIR mice treated with 4 µg/g of intravitreal anti-EMP2 Ab demonstrated a 42% reduction in neovascularization. They demonstrated down-regulation of retinal gene expression in pathways related to vasculature development and up-regulation in genes related to fatty acid oxidation and tricarboxylic acid cycle respiratory electron transport, compared to controls. Anti-EMP2 Ab-treated OIR mice did not exhibit gross retinal histologic abnormalities, vision transduction abnormalities, or weight loss. Conclusions: Our results suggest that EMP2 blockade could be a local and specific treatment modality for retinal neovascularization in oxygen-induced retinopathies, without systemic adverse effects.

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.

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.

Guidelines for parenteral nutrition in preterm infants: The American Society for Parenteral and Enteral Nutrition.

BACKGROUND: Parenteral nutrition (PN) is prescribed for preterm infants until nutrition needs are met via the enteral route, but unanswered questions remain regarding PN best practices in this population. METHODS: An interdisciplinary committee was assembled to answer 12 questions concerning the provision of PN to preterm infants. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used. Questions addressed parenteral macronutrient doses, lipid injectable emulsion (ILE) composition, and clinically relevant outcomes, including PNALD, early childhood growth, and neurodevelopment. Preterm infants with congenital gastrointestinal disorders or infants already diagnosed with necrotizing enterocolitis or PN-associated liver disease (PNALD) at study entry were excluded. RESULTS: The committee reviewed 2460 citations published between 2001 and 2023 and evaluated 57 clinical trials. For most questions, quality of evidence was very low. Most analyses yielded no significant differences between comparison groups. A multicomponent oil ILE was associated with a reduction in stage 3 or higher retinopathy of prematurity (ROP) compared to an ILE containing 100% soybean oil. For all other questions, expert opinion was provided. CONCLUSION: Most clinical outcomes were not significantly different between comparison groups when evaluating timing of PN initiation, amino acid dose, and ILE composition. Future clinical trials should standardize outcome definitions to permit statistical conflation of data, thereby permitting more evidence based recommendations in future guidelines. This guideline has been approved by the ASPEN 2022-2023 Board of Directors.

A Pilot Single-Site Randomized Control Trial: Investigating the Use of Donor Milk in Late Preterm and Term Infants in the Neonatal Intensive Care Unit.

OBJECTIVE: We aimed to study donor milk (DM) supplementation when mother's own milk (MOM) was unavailable in term and late preterm infants (LPIs) admitted to the neonatal intensive care unit (NICU). We hypothesized that this study would be feasible, defined by the rate of consent, diet adherence, and study completion. We further hypothesized that compared with formula supplementation, DM supplementation, for no longer than 7 days from birth, would be associated with an increase in breastfeeding attempts and the percentage of MOM (MOM%) without adversely affecting growth. Breastfeeding attempts and MOM% were assessed over 48 hours at the end of the intervention, which was defined as NICU discharge or at the end of supplementation, whichever came sooner. STUDY DESIGN: This was a pilot study (n = 32). Infants with a gestational age > 34 weeks admitted to the NICU were included. Infants were randomized to one of two groups: human milk (MOM + DM) or formula (MOM + F). RESULTS: The consent rate was 52%. Adherence to the study diet was 97%, and completion was 100%. When the MOM + DM group was compared with the MOM + F group, there was no difference in breastfeeding attempts (median [interquartile range]: 3.5 [1.5-6] vs. 1.5 [0.5-4] times, p = 0.1) or MOM% (60 vs. 59%, p = 0.9). Weight and length at multiple time points were similar when the groups were compared. CONCLUSION: A study randomizing term and LPIs in the NICU to DM or formula when MOM was unavailable is feasible. It remains unclear if DM improves breastfeeding success in this population. KEY POINTS: · A study that randomizes term and late preterm infants in the NICU to DM or formula supplementation when mother's own milk is not available is feasible.. · It remains unclear if DM compared to formula supplementation improves direct breastfeeding.. · In general, growth was similar in infants who received DM or formula as a supplement..

Retinopathy of Prematurity: The Role of Nutrition.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. ROP occurs in infants who are born very preterm. In ROP, retinal blood vessel development, which is prematurely arrested in preterm infants, is altered by perinatal exposures like oxygen and inflammation. Optimizing nutritional practices for preterm infants may mitigate the risk of ROP. In this article, we review the evidence that postnatal growth, hyperglycemia, polyunsaturated fatty acids, and breast milk provision may affect ROP risk. We also outline the current management strategies for ROP and describe the vision outcomes of children affected by ROP. [Pediatr Ann. 2023;52(8):e303-e308.].

Parenteral Nutrition in the Neonatal Intensive Care Unit: Intravenous Lipid Emulsions.

Intravenous lipid emulsions (ILEs) are a source of nonprotein calories and fatty acids and help promote growth in preterm infants and infants with intestinal failure. An ILE dose and oil source determines its fatty acid, phytosterol, and vitamin E delivery. These factors play a role in the infant's risk for essential fatty acid deficiency and cholestasis, and help modulate inflammation, immunity, and organ development. This article reviews different ILEs and their constituents and their relationship with neonatal health.

Dilemmas in the delivery of intravenous lipid emulsions and approach to hypertriglyceridemia in very preterm and low birth weight infants.

Intravenous lipid emulsions (ILEs) are an essential component of parenteral nutrition for very preterm and very low birth weight infants (VLBWs). This article offers a perspective on advancements and controversies on ILE use in this population. ILEs prescribed after birth at a dose of 1.5-2 g/kg/day and advanced to 3 g/kg/day enhance growth. Growth appears to be similar for infants who receive an ILE composed of 100% soybean oil or a multi-oil ILE with 15% fish oil. 100% fish oil is the preferred ILE for the management of parenteral nutrition associated cholestasis and intestinal failure associated liver disease. Research is warranted to help determine how we can optimize ILEs to improve neurodevelopment and prematurity complications. Last, we lack a universal definition of hypertriglyceridemia (HTG) and consensus on triglyceride surveillance and HTG management. Investigation is required to determine the health impact of specific triglyceride ranges in very preterm infants and VLBWs.

Gut Microbes and Circulating Cytokines in Preterm Infants with Growth Failure.

BACKGROUND: Growth failure (GF) is a multifactorial problem in preterm infants. The intestinal microbiome and inflammation may contribute to GF. OBJECTIVES: This study's objective was to compare the gut microbiome and plasma cytokines in preterm infants with and without GF. METHODS: This was a prospective cohort study of infants with birth weights of <1750 g. Infants with a weight or length z-score change from birth to discharge or death that was less than or equal to -0.8 (GF group) were compared with infants without GF [control (CON) group]. The primary outcome was the gut microbiome (at weeks 1-4 of age), assessed by 16S rRNA gene sequencing using Deseq2. Secondary outcomes included inferred metagenomic function and plasma cytokines. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States determined metagenomic function, which was compared using ANOVA. Cytokines were measured by 2-multiplexed immunometric assays and compared using Wilcoxon tests and linear mixed models. RESULTS: GF (n = 14) and CON group (n = 13) had similar median (IQR) birth weight (1380 [780-1578] g vs. 1275 [1013-1580] g) and gestational age (29 [25-31] weeks vs. 30 [29-32] weeks). Compared with the CON group, the GF group had a greater abundance of Escherichia/Shigella in weeks 2 and 3, Staphylococcus in week 4, and Veillonella in weeks 3 and 4 (P-adjusted < 0.001 for all). Plasma cytokine concentrations did not differ significantly between the cohorts. When all time points are combined, fewer microbes were involved in TCA cycle activity in the GF group compared with the CON group (P = 0.023). CONCLUSIONS: In this study, when compared with CON infants, GF infants had a distinct microbial signature with increased Escherichia/Shigella and Firmicutes and fewer microbes associated with energy production at later weeks of hospitalization. These findings may suggest a mechanism for aberrant growth.

A Pilot Single-Site Randomized Control Trial: Investigating the Use of Donor Milk in the Late Preterm and Term Infant in the Neonatal Intensive Care Unit.

Objective : We aimed to study the use of donor milk (DM) in term and late preterm infants (LPIs) when mother’s own milk (MOM) was unavailable. We hypothesized this study would be feasible and breastfeeding attempts and the percentage of MOM (MOM%) would increase with DM without adversely affecting growth. Study Design : This was a pilot study (n=32). Infants with gestational age >34 weeks admitted to the neonatal intensive care unit were included. Infants were randomized to: the human milk (MOM+DM) or formula (MOM+F) groups. Result : Consent rate was 52%. Breastfeeding attempts increased significantly over time in the MOM+DM group compared to the MOM+F group (group p=0.41, time p =0.02, group*time p=0.01) . Growth at multiple time points was similar when the two groups were compared. Conclusion : A study randomizing term infants and LPIs to DM or formula when MOM is unavailable is feasible. DM may increase breastfeeding attempts without compromising growth.

Using Free-Breathing MRI to Quantify Pancreatic Fat and Investigate Spatial Heterogeneity in Children.

BACKGROUND: MRI acquisition for pediatric pancreatic fat quantification is limited by breath-holds (BH). Full segmentation (FS) or small region of interest (ROI) analysis methods may not account for pancreatic fat spatial heterogeneity, which may limit accuracy. PURPOSE: To improve MRI acquisition and analysis for quantifying pancreatic proton-density fat fraction (pPDFF) in children by investigating free-breathing (FB)-MRI, characterizing pPDFF spatial heterogeneity, and relating pPDFF to clinical markers. STUDY TYPE: Prospective. POPULATION: A total of 34 children, including healthy (N = 16, 8 female) and overweight (N = 18, 5 female) subjects. FIELD STRENGTH AND SEQUENCES: 3 T; multiecho gradient-echo three-dimensional (3D) stack-of-stars FB-MRI, multiecho gradient-echo 3D Cartesian BH-MRI. ASSESSMENT: A radiologist measured FS- and ROI-based pPDFF on FB-MRI and BH-MRI PDFF maps, with anatomical images as references. Regional pPDFF in the pancreatic head, body, and tail were measured on FB-MRI. FS-pPDFF, ROI-pPDFF, and regional pPDFF were compared, and related to clinical markers, including hemoglobin A1c. STATISTICAL TESTS: T-test, Bland-Altman analysis, Lin's concordance correlation coefficient (CCC), one-way analysis of variance, and Spearman's rank correlation coefficient were used. P < 0.05 was considered significant. RESULTS: FS-pPDFF and ROI-pPDFF from FB-MRI and BH-MRI had mean difference = 0.4%; CCC was 0.95 for FS-pPDFF and 0.62 for ROI-pPDFF. FS-pPDFF was higher than ROI-pPDFF (10.4% ± 6.4% vs. 4.2% ± 2.8%). Tail-pPDFF (11.6% ± 8.1%) was higher than body-pPDFF (8.9% ± 6.3%) and head-pPDFF (8.7% ± 5.2%). Head-pPDFF and body-pPDFF positively correlated with hemoglobin A1c. DATA CONCLUSION: FB-MRI pPDFF is comparable to BH-MRI. Spatial heterogeneity affects pPDFF quantification. Regional measurements of pPDFF in the head and body were correlated with hemoglobin A1c, a marker of insulin sensitivity. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Uncertainty-aware physics-driven deep learning network for free-breathing liver fat and R2 * quantification using self-gated stack-of-radial MRI.

PURPOSE: To develop a deep learning-based method for rapid liver proton-density fat fraction (PDFF) and R2 * quantification with built-in uncertainty estimation using self-gated free-breathing stack-of-radial MRI. METHODS: This work developed an uncertainty-aware physics-driven deep learning network (UP-Net) to (1) suppress radial streaking artifacts because of undersampling after self-gating, (2) calculate accurate quantitative maps, and (3) provide pixel-wise uncertainty maps. UP-Net incorporated a phase augmentation strategy, generative adversarial network architecture, and an MRI physics loss term based on a fat-water and R2 * signal model. UP-Net was trained and tested using free-breathing multi-echo stack-of-radial MRI data from 105 subjects. UP-Net uncertainty scores were calibrated in a validation dataset and used to predict quantification errors for liver PDFF and R2 * in a testing dataset. RESULTS: Compared with images reconstructed using compressed sensing (CS), UP-Net achieved structural similarity index >0.87 and normalized root mean squared error <0.18. Compared with reference quantitative maps generated using CS and graph-cut (GC) algorithms, UP-Net achieved low mean differences (MD) for liver PDFF (-0.36%) and R2 * (-0.37 s-1 ). Compared with breath-holding Cartesian MRI results, UP-Net achieved low MD for liver PDFF (0.53%) and R2 * (6.75 s-1 ). UP-Net uncertainty scores predicted absolute liver PDFF and R2 * errors with low MD of 0.27% and 0.12 s-1 compared to CS + GC results. The computational time for UP-Net was 79 ms/slice, whereas CS + GC required 3.2 min/slice. CONCLUSION: UP-Net rapidly calculates accurate liver PDFF and R2 * maps from self-gated free-breathing stack-of-radial MRI. The pixel-wise uncertainty maps from UP-Net predict quantification errors in the liver.

Outcomes in preterm infants who received a lipid emulsion with fish oil: An observational study.

BACKGROUND: 100% soybean oil emulsions (SO100) are associated with poor docosahexaenoic acid (DHA) and arachidonic acid (ARA) status in extremely low birth weight (ELBW) infants. A multi-oil emulsion with 15% fish oil (FO15) contains more DHA and ARA than SO100. This study compares clinical outcomes, namely growth and fatty acids, in ELBW infants who received S0100 or FO15. METHODS: This observational study included ELBW infants born between 2014 and 2019 who received SO100 or FO15 for >7 days. Gas chromatography/mass spectrometry was used to measure erythrocyte fatty acids. RESULTS: The mean ± SD gestational age was 27 ± 3 and 26 ± 2 weeks for SO100 (n = 43) and FO15 (n = 43), respectively (P = 0.2). DHA (-0.3 ± 0.10% per week, P = 0.026, for FO15 vs -0.2 ± 0.05% per week, P < 0.001, for SO100) and ARA (-0.8 ± 0.21% per week for FO15 vs -0.9 ± 0.17% per week for SO100; P < 0.001 for both) declined in both groups with no difference between groups (P interaction > 0.7 for both). After controlling for days to reach full feeds, the mean difference in weight z score trajectories was similar (Est = -0.08; 95% CI, -0.82 to 0.04; P = 0.2), and SO100 was associated with a nonsignificant increased odds for cholestasis (odds ratio, 3.1; 95% CI, 0.96-10.2; P = 0.059). There was no difference in other clinical comorbidities. CONCLUSIONS: In comparison with ELBW infants who received SO100, infants who received FO15 still demonstrated a decline in DHA and ARA. Growth and other clinical outcomes were unchanged.

Pregnancies complicated by gestational diabetes and fetal growth restriction: an analysis of maternal and fetal body composition using magnetic resonance imaging.

INTRODUCTION: Maternal body composition may influence fetal body composition. OBJECTIVE: The objective of this pilot study was to investigate the relationship between maternal and fetal body composition. METHODS: Three pregnant women cohorts were studied: healthy, gestational diabetes (GDM), and fetal growth restriction (FGR). Maternal body composition (visceral adipose tissue volume (VAT), subcutaneous adipose tissue volume (SAT), pancreatic and hepatic proton-density fat fraction (PDFF) and fetal body composition (abdominal SAT and hepatic PDFF) were measured using MRI between 30 to 36 weeks gestation. RESULTS: Compared to healthy and FGR fetuses, GDM fetuses had greater hepatic PDFF (5.2 [4.2, 5.5]% vs. 3.2 [3, 3.3]% vs. 1.9 [1.4, 3.7]%, p = 0.004). Fetal hepatic PDFF was associated with maternal SAT (r = 0.47, p = 0.02), VAT (r = 0.62, p = 0.002), and pancreatic PDFF (r = 0.54, p = 0.008). When controlling for maternal SAT, GDM increased fetal hepatic PDFF by 0.9 ([0.51, 1.3], p = 0.001). CONCLUSION: In this study, maternal SAT, VAT, and GDM status were positively associated with fetal hepatic PDFF.

Decreased Levels of Erythrocyte Membrane Arachidonic and Docosahexaenoic Acids Are Associated With Retinopathy of Prematurity.

Purpose: Retinopathy of prematurity (ROP) can lead to blindness. Arachidonic acid (ARA) and docosahexaenoic acid (DHA) regulate retinal inflammation and angiogenesis. The aim of this study was to investigate red blood cell membrane (RBCM) ARA and DHA in preterm infants. Methods: This prospective observational study divided infants into groups by ROP severity and RBCM ARA and DHA means and terciles. Results: Although the mean ± SD RBCM ARA was different between groups (no ROP, 17.9% ± 0.7%, vs. type 2 ROP, 17.4% ± 0.8%, vs. type 1 ROP, 16.7% ± 1.0%; P < 0.001), the mean RBCM DHA was similar (P = 0.161). Infants with type 1 ROP were more likely to be in the lowest ARA and DHA terciles than in the highest (ARA, 44% vs. 5.6%; DHA, 22% vs. 5.6%). ARA and DHA declined over the first month of life in all ROP groups. At week 1, ARA was lower in the type 1 and type 2 ROP groups compared with the no-ROP group (18% ± 2% and 19% ± 3% vs. 21% ± 2%, respectively; P < 0.05 for all). At week 2, DHA and ARA were lower in the type I ROP group compared with the no-ROP group (3% ± 1% vs. 4% ± 1%, P = 0.03 and 16% ± 1% vs. 19% ± 1%, respectively; P < 0.01). A RBCM ARA% ≥ 17 was associated with a 45% reduction in any ROP. As the estimated 4-week ARA% mean increased by 1%, the odds of ROP decreased by 70% (odds ratio = 0.30; 95% confidence interval, 0.1-0.7). Conclusions: Infants with severe ROP have lower ARA and DHA levels than infants without ROP. ARA and DHA may act synergistically to protect against ROP.

Hypertriglyceridemia in Preterm Infants.

Preterm and critically ill infants are at risk for hypertriglyceridemia (HTG). Common risk factors for HTG include prematurity, intravenous lipid emulsion dose and oil composition, reduced lipoprotein lipase activity, fetal growth restriction, sepsis, and renal failure. Despite these risk factors, clinicians lack a universally agreed upon definition for HTG and evidence-based approach to HTG management. This review provides a detailed overview of triglyceride and intravenous lipid emulsion metabolism and how this relates to specific HTG risk factors, along with some practical considerations for managing HTG in the neonatal population.

Neonatal Hyperbilirubinemia.

Neonatal hyperbilirubinemia (NH) is a common phenomenon. In most cases, NH is benign and transient. However, in severe NH cases, neonates can develop encephalopathy and kernicterus. With appropriate screening and treatment, these adverse sequelae can be prevented. This article aims to provide the reader with an in-depth understanding of (1) bilirubin metabolism, (2) risk factors for severe NH, (3) NH screening and treatment, (4) various etiologies of severe NH, and (5) consequences of severe, untreated NH. [Pediatr Ann. 2022;51(6):e219-e227.].