Early blood glucose screening in asymptomatic high-risk neonates.

OBJECTIVES: Detecting and treating severe hypoglycemia promptly after birth is crucial due to its association with adverse long-term neurodevelopmental outcomes. However, limited data are available on the optimal timing of glucose screening in asymptomatic high-risk neonates prone to hypoglycemia. Risk factors associated with asymptomatic high-risk neonates include late prematurity ≥35 and <37 weeks gestation (LPT), small-for-gestational-age (SGA), large-for-gestational-age (LGA), and infant-of-a-diabetic mother (IDM). This study aims to determine the incidence and the impact of individual risk factors on early hypoglycemia (defined as blood glucose ≤25 mg/dL in the initial hour after birth) in asymptomatic high-risk neonates. METHODS: All asymptomatic high-risk neonates ≥35 weeks gestation underwent early blood glucose screening within the first hour after birth (n=1,690). A 2-year retrospective analysis was conducted to assess the incidence of early neonatal hypoglycemia in this cohort and its association with hypoglycemia risk factors. RESULTS: Out of the 9,919 births, 1,690 neonates (17 %) had risk factors for neonatal hypoglycemia, prompting screening within the first hour after birth. Incidence rates for blood glucose ≤25 mg/dL and ≤15 mg/dL were 3.1 and 0.89 %, respectively. Of concern, approximately 0.5 % of all asymptomatic at-risk neonates had a blood glucose value of ≤10 mg/dL. LPT and LGA were the risk factors significantly associated with early neonatal hypoglycemia. CONCLUSIONS: Asymptomatic high-risk neonates, particularly LPT and LGA neonates, may develop early severe neonatal hypoglycemia identified by blood glucose screening in the first hour of life. Additional investigation is necessary to establish protocols for screening and managing asymptomatic high-risk neonates.

From Warm to Cold: Feeding Cold Milk in Preterm Infants with Uncoordinated Oral Feeding Patterns.

Objective: Premature infants frequently face feeding challenges due to disrupted coordination of sucking, swallowing, and breathing, increasing their risk of dysphagia. There are few effective treatment options available for these infants. In adults experiencing dysphagia, consuming cold foods or liquids can be an effective strategy. This method stimulates the sensory receptors in the pharyngeal mucosa, promoting safer and more effective swallowing. We have previously demonstrated that short-duration feeding (5 swallows) with cold liquid significantly reduces dysphagia in preterm infants; however, the impact of extended cold milk feeding remains unexplored. This study aims to assess the safety of cold milk feedings in preterm infants diagnosed with uncoordinated feeding patterns and its effect on feeding performance. Study Design: Preterm infants with uncoordinated feeding patterns (n=26) were randomized to be fed milk at either room or cold temperatures using an experimental, randomized crossover design. We monitored axillary and gastric content temperatures, mesenteric blood flow, and feeding performance. Result: The findings suggest that preterm infants can safely tolerate cold milk without any clinically significant changes in temperature or mesenteric blood flow, and it may enhance certain aspects of feeding performance. Conclusion: These results suggest that cold milk feeding could be a safe therapeutic option for preterm infants. These results highlight the potential for further comprehensive studies to explore the use of cold milk as an effective therapeutic approach for addressing feeding and swallowing difficulties in preterm infants. Registered at clinicaltrials.org #NCT04421482.

Exploiting sweet relief for preeclampsia by targeting autophagy-lysosomal machinery and proteinopathy.

The etiology of preeclampsia (PE), a severe complication of pregnancy with several clinical manifestations and a high incidence of maternal and fetal morbidity and mortality, remains unclear. This issue is a major hurdle for effective treatment strategies. We recently demonstrated that PE exhibits an Alzheimer-like etiology of impaired autophagy and proteinopathy in the placenta. Targeting of these pathological pathways may be a novel therapeutic strategy for PE. Stimulation of autophagy with the natural disaccharide trehalose and its lacto analog lactotrehalose in hypoxia-exposed primary human trophoblasts restored autophagy, inhibited the accumulation of toxic protein aggregates, and restored the ultrastructural features of autophagosomes and autolysosomes. Importantly, trehalose and lactotrehalose inhibited the onset of PE-like features in a humanized mouse model by normalizing autophagy and inhibiting protein aggregation in the placenta. These disaccharides restored the autophagy-lysosomal biogenesis machinery by increasing nuclear translocation of the master transcriptional regulator TFEB. RNA-seq analysis of the placentas of mice with PE indicated the normalization of the PE-associated transcriptome profile in response to trehalose and lactotrehalose. In summary, our results provide a novel molecular rationale for impaired autophagy and proteinopathy in patients with PE and identify treatment with trehalose and its lacto analog as promising therapeutic options for this severe pregnancy complication.

Vertical transmission of SARS-CoV-2 delta-variant in a preterm infant.

BACKGROUND: As SARS-CoV-2 continues to be relevant and cause illnesses, the effect of emerging virus variants on perinatal health remains to be elucidated. It was demonstrated that vertical transmission of SARS-CoV-2 is a relatively rare event in the original SARS-CoV-2 strain. However, very few reports describe vertical transmission related to the delta-variant. CASE PRESENTATION: We report a case of a preterm male neonate born to a mother with positive SARS-CoV-2 and mild respiratory complications. The neonate was born by cesarean section due to fetal distress. The rupture of the amniotic membrane was at delivery. The neonate had expected prematurity-related complications. His nasopharyngeal swabs for RT-PCR were positive from birth till three weeks of age. RT-ddPCR of the Placenta showed a high load of the SARS-CoV-2 virus with subgenomic viral RNA. RNAscope technique demonstrated both the positive strand of the S gene and the orf1ab negative strand. Detection of subgenomic RNA and the orf1ab negative strand indicats active viral replication in the placenta. CONCLUSIONS: Our report demonstrates active viral replication of the SARS-CoV-2 delta-variant in the placenta associated with vertical transmission in a preterm infant.

Biodistribution of mRNA COVID-19 vaccines in human breast milk.

BACKGROUND: COVID-19 mRNA vaccines play a vital role in the fight against SARS-CoV-2 infection. However, lactating women have been largely excluded from most vaccine clinical trials. As a result, limited research has been conducted on the systemic distribution of vaccine mRNA during lactation and whether it is excreted in human breast milk (BM). Here, we evaluated if COVID-19 vaccine mRNA is detectable in BM after maternal vaccination and determined its potential translational activity. METHODS: We collected BM samples from 13 lactating, healthy, post-partum women before and after COVID-19 mRNA vaccination. Vaccine mRNA in whole BM and BM extracellular vesicles (EVs) was assayed using quantitative Droplet Digital PCR, and its integrity and translational activity were evaluated. FINDINGS: Of 13 lactating women receiving the vaccine (20 exposures), trace mRNA amounts were detected in 10 exposures up to 45 h post-vaccination. The mRNA was concentrated in the BM EVs; however, these EVs neither expressed SARS-COV-2 spike protein nor induced its expression in the HT-29 cell line. Linkage analysis suggests vaccine mRNA integrity was reduced to 12-25% in BM. INTERPRETATION: Our findings demonstrate that the COVID-19 vaccine mRNA is not confined to the injection site but spreads systemically and is packaged into BM EVs. However, as only trace quantities are present and a clear translational activity is absent, we believe breastfeeding post-vaccination is safe, especially 48 h after vaccination. Nevertheless, since the minimum mRNA vaccine dose to elicit an immune reaction in infants <6 months is unknown, a dialogue between a breastfeeding mother and her healthcare provider should address the benefit/risk considerations of breastfeeding in the first two days after maternal vaccination. FUNDING: This study was supported by the Department of Pediatrics, NYU-Grossman Long Island School of Medicine.

Characterization of lipoproteins in human placenta and fetal circulation as well as gestational changes in lipoprotein assembly and secretion in human and mouse placentas.

In the maternal circulation, apoB-containing low-density lipoproteins (LDL) and apoA1-containing high-density lipoproteins (HDL) transport lipids. The production of lipoproteins in the placenta has been suggested, but the directionality of release has not been resolved. We compared apolipoprotein concentrations and size-exclusion chromatography elution profiles of lipoproteins in maternal/fetal circulations, and in umbilical arteries/veins; identified placental lipoprotein-producing cells; and studied temporal induction of lipoprotein-synthesizing machinery during pregnancy. We observed that maternal and fetal lipoproteins are different with respect to concentrations and elution profiles. Surprisingly, concentrations and elution profiles of lipoproteins in umbilical arteries and veins were similar indicating their homeostatic control. Human placental cultures synthesized apoB100-containing LDL-sized and apoA1-containing HDL-sized particles. Immunolocalization techniques revealed that ApoA1 was present mainly in syncytiotrophoblasts. MTP, a critical protein for lipoprotein assembly, was in these trophoblasts. ApoB was in the placental stroma indicating that trophoblasts secrete apoB-containing lipoproteins into the stroma. ApoB and MTP expressions increased in placentas from the 2nd trimester to term, whereas apoA1 expression was unchanged. Thus, our studies provide new information regarding the timing of lipoprotein gene induction during gestation, the cells involved in lipoprotein assembly and the gel filtration profiles of human placental lipoproteins. Next, we observed that mouse placenta produces MTP, apoB100, apoB48 and apoA1. The expression of genes gradually increased and peaked in late gestation. This information may be useful in identifying transcription factors regulating the induction of these genes in gestation and the importance of placental lipoprotein assembly in fetal development.

Extracellular Vesicle-microRNAs as Diagnostic Biomarkers in Preterm Neonates.

Neonates born prematurely (<37 weeks of gestation) are at a significantly increased risk of developing inflammatory conditions associated with high mortality rates, including necrotizing enterocolitis, bronchopulmonary dysplasia, and hypoxic-ischemic brain damage. Recently, research has focused on characterizing the content of extracellular vesicles (EVs), particularly microRNAs (miRNAs), for diagnostic use. Here, we describe the most recent work on EVs-miRNAs biomarkers discovery for conditions that commonly affect premature neonates.

Is Lactoferrin Supplementation Beneficial for All Preterm Infants?

OBJECTIVE: Human milk (HM) has antibacterial properties due to the presence of immune-modulators, including lactoferrin (LF). This study will determine effect(s) of HM maturation, fortification, and storage conditions on LF levels and its antibacterial properties. STUDY DESIGN: HM samples (n = 30) were obtained from preterm and term mothers. The LF levels were analyzed by ELISA, and the antibacterial activity was measured after inoculation with Escherichia coli. RESULTS: The highest level of LF in preterm HM was observed in the first week of lactation. However, storage of preterm HM at 4°C decreased LF levels significantly. Both LF levels and antibacterial activity in preterm HM was lower compared with term HM, but significantly higher than donor HM even after HM-based fortification. LF supplementation of donor HM improved its antibacterial activity. CONCLUSION: Preterm infants fed donor HM, formula, or stored HM at 4°C may benefits from LF supplementation to improve HM antibacterial properties. KEY POINTS: · Milk LF levels vary with storage and maturity.. · Donor milk is deficient in LF even after adding HM-based fortification.. · Donor HM and formula fed infants may benefit from LF..

Detection of Messenger RNA COVID-19 Vaccines in Human Breast Milk.

This cohort study investigates the presence of COVID-19 vaccine mRNA in the expressed breast milk of lactating individuals who received the vaccination within 6 months after delivery.

Light protection of parenteral nutrition, cholestasis, and other prematurity-related morbidities in premature infants.

Introduction: Parenteral Nutrition (PN) can lead to intestinal failure associated liver disease (IFALD). There are no human studies to date studying specifically the benefits of light-protection on neonatal IFALD. Recently, the European Medicines Agency and the American Society for Parenteral and Enteral Nutrition (ASPEN) both recommended full light protection of PN to reduce the risk of adverse clinical outcomes. Objective: The primary objective of this study was to evaluate the impact of light-protecting PN on the incidence of cholestasis and peak direct bilirubin levels in premature infants. Study design: Retrospective chart review of preterm infants requiring PN for a minimum of 2 weeks with or without light-protection. After light protection of the PN solution, primary outcomes (including cholestasis and direct bilirubin levels) of both groups were compared. Secondary outcomes include evaluation of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis and mortality. Results: A total of 50 preterm infants <37 weeks gestation were included, 25 infants in each group. There was a statistically significant decrease in the rate of cholestasis (12 vs. 3, p = 0.005), median peak direct bilirubin levels (1.7 vs. 0.9 mg/dL, p = 0.02) and total bilirubin levels (4.1 vs. 3.4, p = 0.05) in the light-protection group compared to no light-protection group. There was a decrease in the incidence of severe BPD (with an increase of mild BPD, resulting in the same overall BPD rate) in the light-protection compared to no light-protection group (7 vs. 15, p = 0.0223). There was no difference in NEC, ROP, sepsis or mortality. Conclusion: Our study supports that the practice of light-protecting PN may reduce the incidence of IFALD in premature infants. Moreover, there was a trend toward decreased incidence of severe BPD in the light-protection group. Further light protection studies are needed to confirm these findings.

Breast Milk and Breastfeeding of Infants Born to SARS-CoV-2 Positive Mothers: A Prospective Observational Cohort Study.

OBJECTIVE: There are limited published data on the transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus from mothers to newborns through breastfeeding or from breast milk. The World Health Organization released guidelines encouraging mothers with suspected or confirmed COVID-19 to breastfeed as the benefits of breastfeeding outweighs the possible risk of transmission. The objective of this study was to determine if SARS-CoV-2 was present in the breast milk of lactating mothers who had a positive SARS-CoV-2 nasopharyngeal swab test prior to delivery, and the clinical outcomes for their newborns. STUDY DESIGN: This was a single-center, observational, prospective cohort study. Maternal-newborn dyads that delivered at New York University Langone Hospital Brooklyn with confirmed maternal SARS-CoV-2 positive screen test at the time of admission were recruited for the study. Breast milk samples were collected during postpartum hospitalization and tested for the presence of SARS-CoV-2 genes N1 and N2 by two-step reverse transcription polymerase chain reaction. Additionally, the clinical characteristics of the maternal newborn dyad, results of nasopharyngeal SARS-CoV-2 testing, and neonatal follow-up data were collected. RESULTS: A total of 19 mothers were included in the study and their infants who were all fed breast milk. Breast milk samples from 18 mothers tested negative for SARS-CoV-2, and 1 was positive for SARS-CoV-2 RNA. The infant who ingested the breast milk that tested positive had a negative nasopharyngeal test for SARS-CoV-2, and had a benign clinical course. There was no evidence of significant clinical infection during the hospital stay or from outpatient neonatal follow-up data for all the infants included in this study. CONCLUSION: In a small cohort of SARS-CoV-2 positive lactating mothers giving birth at our institution, most of their breast milk samples (95%) contained no detectable virus, and there was no evidence of COVID-19 infection in their breast milk-fed neonates. KEY POINTS: · Breast milk may rarely contain detectable SARS-CoV-2 RNA and was not detected in asymptomatic mothers.. · Breast milk with detectable SARS-CoV-2 RNA from a symptomatic mother had no clinical significance for her infant.. · Breast feeding with appropriate infection control instructions appears to be safe in mother with COVID infection..

Placental extracellular vesicles-associated microRNA-519c mediates endotoxin adaptation in pregnancy.

BACKGROUND: Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring a balance between immunosuppression, which is essential for the maintenance of a semiallogeneic fetus, and proinflammatory host defense to protect the maternal-fetal interface from invading organisms. Adaptation to repeated inflammatory stimuli (endotoxin tolerance) may be critical in preventing inflammation-induced preterm birth caused by exaggerated maternal inflammatory responses to mild or moderate infections that are common during pregnancy. However, the exact mechanisms contributing to the maintenance of tolerance to repeated infections are not completely understood. MicroRNAs play important roles in pregnancy with several microRNAs implicated in gestational tissue function and in pathologic pregnancy conditions. MicroRNA-519c, a member of the chromosome 19 microRNA cluster, is a human-specific microRNA mainly expressed in the placenta. However, its role in pregnancy is largely unknown. OBJECTIVE: This study aimed to explore the role of "endotoxin tolerance" failure in the pathogenesis of an exaggerated inflammatory response often seen in inflammation-mediated preterm birth. In this study, we investigated the role of microRNA-519c, a placenta-specific microRNA, as a key regulator of endotoxin tolerance at the maternal-fetal interface. STUDY DESIGN: Using a placental explant culture system, samples from term and second-trimester placentas were treated with lipopolysaccharide. After 24 hours, the conditioned media were collected for analysis, and the placental explants were re-exposed to repeated doses of lipopolysaccharide for 3 days. The supernatant was analyzed for inflammatory markers, the presence of extracellular vesicles, and microRNAs. To study the possible mechanism of action of the microRNAs, we evaluated the phosphodiesterase 3B pathway involved in tumor necrosis factor alpha production using a microRNA mimic and phosphodiesterase 3B small interfering RNA transfection. Finally, we analyzed human placental samples from different gestational ages and from women affected by inflammation-associated pregnancies. RESULTS: Our data showed that repeated exposure of the human placenta to endotoxin challenges induced a tolerant phenotype characterized by decreased tumor necrosis factor alpha and up-regulated interleukin-10 levels. This reaction was mediated by the placenta-specific microRNA-519c packaged within placental extracellular vesicles. Lipopolysaccharide treatment increased the extracellular vesicles that were positive for the exosome tetraspanin markers, namely CD9, CD63, and CD81, and secreted primarily by trophoblasts. Primary human trophoblast cells transfected with a microRNA-519c mimic decreased phosphodiesterase 3B, whereas a lack of phosphodiesterase 3B, achieved by small interfering RNA transfection, led to decreased tumor necrosis factor alpha production. These data support the hypothesis that the anti-inflammatory action of microRNA-519c was mediated by a down-regulation of the phosphodiesterase 3B pathway, leading to inhibition of tumor necrosis factor alpha production. Furthermore, human placentas from normal and inflammation-associated pregnancies demonstrated that a decreased placental microRNA-519c level was linked to infection-induced inflammatory pathologies during pregnancy. CONCLUSION: We identified microRNA-519c, a human placenta-specific microRNA, as a novel regulator of immune adaptation associated with infection-induced preterm birth at the maternal-fetal interface. Our study serves as a basis for future experiments to explore the potential use of microRNA-519c as a biomarker for infection-induced preterm birth.

Application of Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling in Preterm Neonates to Guide Gentamicin Dosing Decisions and Predict Antibacterial Effect.

Clinical studies in preterm neonates are rarely performed due to ethical concerns and difficulties associated with trials and recruitment. Consequently, dose selection in this population is primarily empirical. Scaling neonatal doses from adult doses does not account for developmental changes and may not accurately predict drug kinetics. This is especially important for gentamicin, a narrow therapeutic index aminoglycoside antibiotic. While gentamicin's bactericidal effect is associated with its peak plasma concentration, keeping trough concentrations below 1 µg/mL prevents toxicity and also helps to counteract adaptive resistance in bacteria such as Escherichia coli. In this study, physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) modeling was used to support and/or guide dosing decisions and to predict the antibacterial effect in preterm neonates. A gentamicin PBPK model was successfully verified in healthy adults and preterm neonates across all gestational ages. Clinical data from a neonatal intensive care unit at NYU Langone Hospital-Long Island was used to identify dosing regimens associated with increased incidence of elevated gentamicin trough concentrations in different preterm patient cohorts. Model predictions demonstrated that a higher dose with an extended-dosing interval (every 36 hours) in neonates with a postmenstrual age of 30 to 34 weeks and ≥35 weeks, with postnatal age 8 to 28 days and 0 to 7 days, respectively, were more likely to have a trough <1 µg/mL when compared with once-daily (every 24 hours) dosing. PBPK-PD modeling suggested that a higher dose administered every 36 hours may provide effective antibacterial therapy.

A quality improvement initiative to reduce hypothermia in a Baby-Friendly nursery - our story of algorithms, K-cards, and Key cards.

BACKGROUND: Baby-Friendly hospitals encourage rooming-in newborns with mothers. In our institution, we noticed increased incidence of hypothermia following Baby-Friendly designation. We aimed to reduce the incidence of hypothermia in the mother-baby-unit to <15% and to decrease the rate of isolated hypothermia admissions to the neonatal intensive care unit (NICU) by 20% over two years. METHODS: After a retrospective review of newborns ≥35 weeks gestation in the mother-baby-unit with hypothermia, we implemented multiple interventions such as nursing education, hypothermia algorithm, Kamishibai cards, and Key cards. RESULTS: Hypothermia incidence in the mother-baby-unit decreased from 20.9 to 14.5% (p < 0.001) and infants requiring NICU admission decreased by 71% (p < 0.001) following all interventions. Apart from nursing education, all interventions led to significant reductions in both outcomes from baseline. CONCLUSION: Instituting a hypothermia algorithm and utilizing K-cards and Key cards reduces the incidence of hypothermia in the mother-baby-unit and NICU admissions for isolated hypothermia.

A Quality Improvement Initiative to Improve Perioperative Hypothermia Rates in the NICU Utilizing Checklists.

Premature infants are at high risk for heat loss. Infants undergoing surgical procedures outside of the neonatal intensive care unit have an increased risk of hypothermia. Hypothermia can lead to delayed recovery, hypoglycemia, metabolic acidosis, sepsis, and emotional stress for the parents. We aimed to reduce the incidence of hypothermia for infants undergoing surgical procedures from a baseline of 44.4% to less than 25% over 3 years (2016-2018) with the utilization of a checklist and education. METHODS: We conducted a retrospective chart review for all infants undergoing surgical procedures from 2014 to 2015 and prospective data for 2016-2018. Next, we created a multidisciplinary team, educated staff members, and instituted a checklist comprising 9 tasks. We conducted Plan-Do-Study-Act cycles quarterly and audited checklist compliance monthly. RESULTS: From 2014 to 2015, the total incidence of perioperative hypothermia was 44.4% (n = 54). After the initiation of the checklist, the overall incidence of hypothermia decreased to 23.4% (n = 124, P = 0.007). Hypothermia occurred most frequently while the patient was in the operating room. Furthermore, we noticed that hypothermia was significantly associated with neonates requiring emergency procedures. There was an inverse correlation between overall compliance with checklist usage and the incidence of hypothermia. CONCLUSION: A checklist is a useful and simple tool for maintaining an optimal temperature for postsurgical neonates. Frequent re-education and enforcement of the protocol is necessary. Overall, implementation of the checklist, along with regular education, decreased the total incidence of perioperative hypothermia in the neonatal intensive care unit.