Ventilatory Assistance Before Umbilical Cord Clamping in Extremely Preterm Infants: A Randomized Clinical Trial.

Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants. Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death. Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth. Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs. Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort. Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight. Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.

Building a NICU quality & safety infrastructure.

The American Academy of Pediatrics (AAP) Standards for Levels of Neonatal Care, published in 2023, highlights key components of a Neonatal Patient Safety and Quality Improvement Program (NPSQIP). A comprehensive Neonatal Intensive Care Unit (NICU) quality and safety infrastructure (QSI) is based on four foundational domains: quality improvement, quality assurance, safety culture, and clinical guidelines. This paper serves as an operational guide for NICU clinical leaders and quality champions to navigate these domains and develop their local QSI to include the AAP NPSQIP standards.

A clinical informatics approach to bronchopulmonary dysplasia: current barriers and future possibilities.

Bronchopulmonary dysplasia (BPD) is a complex, multifactorial lung disease affecting preterm neonates that can result in long-term pulmonary and non-pulmonary complications. Current therapies mainly focus on symptom management after the development of BPD, indicating a need for innovative approaches to predict and identify neonates who would benefit most from targeted or earlier interventions. Clinical informatics, a subfield of biomedical informatics, is transforming healthcare by integrating computational methods with patient data to improve patient outcomes. The application of clinical informatics to develop and enhance clinical therapies for BPD presents opportunities by leveraging electronic health record data, applying machine learning algorithms, and implementing clinical decision support systems. This review highlights the current barriers and the future potential of clinical informatics in identifying clinically relevant BPD phenotypes and developing clinical decision support tools to improve the management of extremely preterm neonates developing or with established BPD. However, the full potential of clinical informatics in advancing our understanding of BPD with the goal of improving patient outcomes cannot be achieved unless we address current challenges such as data collection, storage, privacy, and inherent data bias.

Transforming neonatal care with artificial intelligence: challenges, ethical consideration, and opportunities.

Artificial intelligence (AI) offers tremendous potential to transform neonatology through improved diagnostics, personalized treatments, and earlier prevention of complications. However, there are many challenges to address before AI is ready for clinical practice. This review defines key AI concepts and discusses ethical considerations and implicit biases associated with AI. Next we will review literature examples of AI already being explored in neonatology research and we will suggest future potentials for AI work. Examples discussed in this article include predicting outcomes such as sepsis, optimizing oxygen therapy, and image analysis to detect brain injury and retinopathy of prematurity. Realizing AI's potential necessitates collaboration between diverse stakeholders across the entire process of incorporating AI tools in the NICU to address testability, usability, bias, and transparency. With multi-center and multi-disciplinary collaboration, AI holds tremendous potential to transform the future of neonatology.

Validity Evidence for a Novel, Comprehensive Bag-Mask Ventilation Assessment Tool.

OBJECTIVE: To develop a comprehensive competency assessment tool for pediatric bag-mask ventilation (pBMV) and demonstrate multidimensional validity evidence for this tool. STUDY DESIGN: A novel pBMV assessment tool was developed consisting of 3 components: a 22-item-based checklist (trichotomized response), global rating scale (GRS, 5-point), and entrustment assessment (4-point). Participants' performance in a realistic simulation scenario was video-recorded and assessed by blinded raters. Multidimensional validity evidence for procedural assessment, including evidence for content, response-process, internal structure, and relation to other variables, was assessed. The scores of each scale were compared with training level. Item-based checklist scores also were correlated with GRS and entrustment scores. RESULTS: Fifty-eight participants (9 medical students, 10 pediatric residents, 18 critical care/neonatology fellows, 21 critical care/neonatology attendings) were evaluated. The pBMV tool was supported by high internal consistency (Cronbach α = 0.867). Inter-rater reliability for the item-based checklist component was acceptable (r = 0.65, P < .0001). The item-based checklist scores differentiated between medical students and other providers (P < .0001), but not by other trainee level. GRS and entrustment scores significantly differentiated between training levels (P < .001). Correlation between skill item-based checklist and GRS was r = 0.489 (P = .0001) and between item-based checklist and entrustment score was r = 0.52 (P < .001). This moderate correlation suggested each component measures pBMV skills differently. The GRS and entrustment scores demonstrated moderate inter-rater reliability (0.42 and 0.46). CONCLUSIONS: We established evidence of multidimensional validity for a novel entrustment-based pBMV competence assessment tool, incorporating global and entrustment-based assessments. This comprehensive tool can provide learner feedback and aid in entrustment decisions as learners progress through training.

Standardizing premedication for non-emergent neonatal tracheal intubations improves compliance and patient outcomes.

OBJECTIVE: We sought to standardize and improve compliance with evidence-based premedication for non-emergent neonatal intubations in two academic-affiliated Neonatal Intensive Care Units. STUDY DESIGN: A multidisciplinary team created guidelines and electronic medical record order sets for intubation. Compliance with recommended premedication, number of intubation attempts, and frequency of bradycardia and desaturation were assessed. RESULTS: 387 intubation procedures were reviewed. Provision of recommended premedication increased by 36% and 75% at the level III and IV units, respectively. Decreased frequency of bradycardia during intubation (p = 0.0003) occurred in the level III unit. A reduction in number of intubation attempts (p ≤ 0.001), improvement in first-attempt intubation success (p ≤ 0.001), and decreased frequency of bradycardia (p = 0.01) and desaturation (p = 0.02) during intubation occurred in the level IV unit. CONCLUSIONS: This quality improvement initiative improved standardized premedication compliance and decreased adverse events associated with non-emergent neonatal intubations in two separate units.

Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction.

Unlike other visceral organs, myocardial weight is maintained in relation to fetal body weight in intrauterine growth restriction (IUGR) fetal sheep despite hypoinsulinemia and global nutrient restriction. We designed experiments in fetal sheep with placental insufficiency and restricted growth to determine basal and insulin-stimulated myocardial glucose and oxygen metabolism and test the hypothesis that myocardial insulin sensitivity would be increased in the IUGR heart. IUGR was induced by maternal hyperthermia during gestation. Control (C) and IUGR fetal myocardial metabolism were measured at baseline and under acute hyperinsulinemic/euglycemic clamp conditions at 128-132 days gestation using fluorescent microspheres to determine myocardial blood flow. Fetal body and heart weights were reduced by 33% (P = 0.008) and 30% (P = 0.027), respectively. Heart weight to body weight ratios were not different. Basal left ventricular (LV) myocardial blood flow per gram of LV tissue was maintained in IUGR fetuses compared to controls. Insulin increased LV myocardial blood flow by ∼38% (P < 0.01), but insulin-stimulated LV myocardial blood flow in IUGR fetuses was 73% greater than controls. Similar to previous reports testing acute hypoxia, LV blood flow was inversely related to arterial oxygen concentration (r(2 )= 0.71) in both control and IUGR animals. Basal LV myocardial glucose delivery and uptake rates were not different between IUGR and control fetuses. Insulin increased LV myocardial glucose delivery (by 40%) and uptake (by 78%) (P < 0.01), but to a greater extent in the IUGR fetuses compared to controls. During basal and hyperinsulinemic-euglycemic clamp conditions LV myocardial oxygen delivery, oxygen uptake, and oxygen extraction efficiency were not different between groups. These novel results demonstrate that the fetal heart exposed to nutrient and oxygen deprivation from placental insufficiency appears to maintain myocardial energy supply in the IUGR condition via increased glucose uptake and metabolic response to insulin, which support myocardial function and growth.

Using in situ simulation to evaluate operational readiness of a children's hospital-based obstetrics unit.

INTRODUCTION: Relocating obstetric (OB) services to a children's hospital imposes demands on facility operations, which must be met to ensure quality care and a satisfactory patient experience. We used in situ simulations to prospectively and iteratively evaluate operational readiness of a children's hospital-based OB unit before it opened for patient care. METHODS: This project took place at a 314-bed, university-affiliated children's hospital. We developed 3 full-scale simulation scenarios depicting a concurrent maternal and neonatal emergency. One scenario began with a standardized patient experiencing admission; the mannequin portrayed a mother during delivery. We ran all 3 scenarios on 2 dates scheduled several weeks apart. We ran 2 of the scenarios on a third day to verify the reliability of key processes. During the simulations, content experts completed equipment checklists, and participants identified latent safety hazards. Each simulation involved a unique combination of scheduled participants who were supplemented by providers from responding ancillary services. RESULTS: The simulations involved 133 scheduled participants representing OB, neonatology, and anesthesiology. We exposed and addressed operational deficiencies involving equipment availability, staffing, interprofessional communication, and systems issues such as transfusion protocol failures and electronic order entry challenges. Process changes between simulation days 1 to 3 decreased the elapsed time between transfusion protocol activation and blood arrival to the operating room and labor/delivery/recovery/postpartum setting. CONCLUSIONS: In situ simulations identified multiple operational deficiencies on the OB unit, allowing us to take corrective action before its opening. This project may guide other children's hospitals regarding care processes likely to require significant focus and possible modification to accommodate an OB service.

Neonatal intubation performance: room for improvement in tertiary neonatal intensive care units.

OBJECTIVE: To describe neonatal tracheal intubation (TI) performance across five neonatal intensive care units. METHODS: This prospective descriptive study was conducted at five level III neonatal intensive care units (NICU) between July 2010 and July 2011. TI performance data were collected using a standardized data collection instrument (provider, procedure, and patient characteristics) and analyzed using descriptive and inferential statistics. The primary outcome of interest was procedural success rate defined as a tube placed in the airway between the vocal cords that could be used to provide ventilation. RESULTS: Forty-four percent of 455 TI attempts (203 patients) were successful. Attending physicians and 3rd year neonatal fellows had the highest success rates; 72.2% and 70%, respectively. Pediatric residents had the lowest success rate (20.3%). The median duration of attempts was 30s for residents, 25s for fellows, and 20s for neonatal attending physicians. The most common reasons cited for failure were inability to visualize the vocal cords (25%), patient decompensation (desaturation/bradycardia, 41%) and esophageal TI (19%). The duration of all TI attempts ranged from 5s to 180s and there was no difference between successful and failed attempts. Impending respiratory failure (46.5%) was the most common indication for TI. Patient factors (weight, gestational age, or number of previous TI attempts) were not associated with TI success. CONCLUSIONS: Overall TI procedure success rates were poor. Providers with advanced training were more likely to be successful. Patient factors were not associated with TI success.

Effect of small for gestational age on hemodynamic parameters in the neonatal period.

OBJECTIVE: The time course over which hypertension develops in children with a history of growth restriction has not been fully elucidated. The purpose of this study was to determine whether commonly obtained hemodynamic parameters were different between small for gestational age (SGA) and appropriate for gestational age (AGA) neonates. METHODS: This was a retrospective case-control study matching 24 SGA neonates in a 1:2 fashion with 48 AGA neonates delivered during the same gestational week. Hemodynamic parameters were evaluated during the first week of life and the week prior to discharge. RESULTS: There were no differences in blood pressure (BP) parameters during the first week of life. Compared to AGA controls, SGA neonates had a significantly lower heart rate (HR) at birth (148.2 ± 19.2 vs. 159.2 ± 17.1, p < 0.001), and a greater need for vasopressor support (OR 5.66; 95% CI 2.28, 14.04). The SGA neonates had a lower systolic BP during the week prior to discharge (68.3 ± 1.2 vs. 73.5 ± 1.2 mmHg, p < 0.001). CONCLUSIONS: SGA newborns had a lower HR at birth and greater need for vasopressor support during the first week of life despite similar BP parameters. SGA newborns had a lower systolic BP prior to discharge. Further studies are needed to understand the progression to adult hypertension.

Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation.

Protein supplementation during human pregnancy does not improve fetal growth and may increase small-for-gestational-age birth rates and mortality. To define possible mechanisms, sheep with twin pregnancies were infused with amino acids (AA group, n = 7) or saline (C group, n = 4) for 4 days during late gestation. In the AA group, fetal plasma leucine, isoleucine, valine, and lysine concentrations were increased (P < 0.05), and threonine was decreased (P < 0.05). In the AA group, fetal arterial pH (7.365 +/- 0.007 day 0 vs. 7.336 +/- 0.012 day 4, P < 0.005), hemoglobin-oxygen saturation (46.2 +/- 2.6 vs. 37.8 +/- 3.6%, P < 0.005), and total oxygen content (3.17 +/- 0.17 vs. 2.49 +/- 0.20 mmol/l, P < 0.0001) were decreased on day 4 compared with day 0. Fetal leucine disposal did not change (9.22 +/- 0.73 vs. 8.09 +/- 0.63 micromol x min(-1) x kg(-1), AA vs. C), but the rate of leucine oxidation increased 43% in the AA group (2.63 +/- 0.16 vs. 1.84 +/- 0.24 micromol x min(-1) x kg(-1), P < 0.05). Fetal oxygen utilization tended to be increased in the AA group (327 +/- 23 vs. 250 +/- 29 micromol x min(-1) x kg(-1), P = 0.06). Rates of leucine incorporation into fetal protein (5.19 +/- 0.97 vs. 5.47 +/- 0.89 micromol x min(-1) x kg(-1), AA vs. C), release from protein breakdown (4.20 +/- 0.95 vs. 4.62 +/- 0.74 micromol x min(-1) x kg(-1)), and protein accretion (1.00 +/- 0.30 vs. 0.85 +/- 0.25 micromol x min(-1) x kg(-1)) did not change. Consistent with these data, there was no change in the fetal skeletal muscle ubiquitin ligases MaFBx1 or MuRF1 or in the protein synthesis regulators 4E-BP1, eEF2, eIF2alpha, and p70(S6K). Decreased concentrations of certain essential amino acids, increased amino acid oxidation, fetal acidosis, and fetal hypoxia are possible mechanisms to explain fetal toxicity during maternal amino acid supplementation.

Insulin is required for amino acid stimulation of dual pathways for translational control in skeletal muscle in the late-gestation ovine fetus.

During late gestation, amino acids and insulin promote skeletal muscle protein synthesis. However, the independent effects of amino acids and insulin on the regulation of mRNA translation initiation in the fetus are relatively unknown. The purpose of this study was to determine whether acute amino acid infusion in the late-gestation ovine fetus, with and without a simultaneous increase in fetal insulin concentration, activates translation initiation pathway(s) in skeletal muscle. Fetuses received saline (C), mixed amino acid infusion plus somatostatin infusion to suppress amino acid-stimulated fetal insulin secretion (AA+S), mixed amino acid infusion with concomitant physiological increase in fetal insulin (AA), or high-dose insulin infusion with euglycemia and euaminoacidemia (HI). After a 2-h infusion period, fetal skeletal muscle was harvested under in vivo steady-state conditions and frozen for quantification of proteins both upstream and downstream of mammalian target of rapamycin (mTOR). In the AA group, we found a threefold increase in ribosomal protein S6 kinase (p70(S6k)) and Erk1/2 phosphorylation; however, blocking the physiological rise in insulin with somatostatin in the AA+S group prevented this increase. In the HI group, Akt, Erk1/2, p70(S6k), and ribosomal protein S6 were highly phosphorylated and 4E-binding protein 1 (4E-BP1) associated with eukaryotic initiation factor (eIF)4E decreased by 30%. These data show that insulin is a significant regulator of intermediates involved in translation initiation in ovine fetal skeletal muscle. Furthermore, the effect of amino acids is dependent on a concomitant increase in fetal insulin concentrations, because amino acid infusion upregulates p70(S6k) and Erk only when amino acid-stimulated increase in insulin occurs.

Glucose replacement to euglycemia causes hypoxia, acidosis, and decreased insulin secretion in fetal sheep with intrauterine growth restriction.

Nutritional interventions for intrauterine growth restriction (IUGR) have raised concerns for fetal toxicity, the mechanisms of which are unknown. Most of these attempts did not aim to normalize fetal metabolic conditions. Therefore, we used a model of IUGR to determine whether normalization of fetal hypoglycemia for 2 wks would be tolerated and increase insulin concentrations and pancreatic beta-cell mass. IUGR fetuses received either a direct saline infusion (Sal, the control group) or a 30% dextrose infusion (Glu) to normalize glucose concentrations. Neither insulin concentrations (0.11 +/- 0.01 Glu vs. 0.10 +/- 0.01 ng/mL Sal) nor beta-cell mass (65.2 +/- 10.3 Glu vs. 74.7 +/- 18.4 mg Sal) changed. Glucose stimulated insulin secretion (GSIS) was lower in the Glu group. Glu fetuses became progressively more hypoxic: O2 content 1.4 +/- 0.5 Glu vs. 2.7 +/- 0.4 mM Sal, p < 0.05. Partial pressure of carbon dioxide (Paco2) (53.6 +/- 0.8 Glu vs. 51.6 +/- 0.8 Sal, p < 0.05) and lactate (7.74 +/- 3.82 Glu vs. 2.47 +/- 0.55 mM Sal, p < 0.0001) were greater and pH lower (7.275 +/- 0.071 Glu vs. 7.354 +/- 0.003 Sal, p < 0.01) in the Glu group. We conclude that correction of fetal hypoglycemia is not well tolerated and fails to increase insulin concentrations or beta-cell mass in IUGR fetuses.

An animal model of placental insufficiency-induced intrauterine growth restriction.

Intrauterine growth restriction (IUGR), often associated with functional placental insufficiency, results in increased perinatal mortality and morbidity. For obvious reasons, many questions regarding the progression of IUGR pregnancies cannot be addressed experimentally in humans, predicating the use of animal models. Although no animal model fully recapitulates human pregnancy, the pregnant sheep has been used extensively to investigate maternal-fetal interactions. In sheep, surgical placement of catheters in both the maternal and fetal vasculature allows repeated sampling from nonanesthetized pregnancies. Considerable insight has been gained on placental oxygen and nutrient transfer and utilization from use of pregnant sheep, often confirmed in the human once appropriate technologies became available. This review will focus on one sheep model, used to examine the impact of placental insufficiency-induced IUGR on oxygen and nutrient transport and utilization.

Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1alpha mRNA and phosphorylated CREB in fetal sheep.

Hepatic glucose production is normally activated at birth but has been observed in response to experimental hypoglycemia in fetal sheep. The cellular basis for this process remains unknown. We determined the impact of 2 wk of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin-signaling pathway, transcription factors, and coactivators that regulate gluconeogenesis. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNA increased 12-fold and 7-fold, respectively, following chronic hypoglycemia with no change in hepatic glycogen. Chronic hypoglycemia decreased fetal plasma insulin with no change in glucagon but increased plasma cortisol 3.5-fold. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha mRNA and phosphorylation of cAMP response element binding protein at Ser(133) were both increased, with no change in Akt, forkhead transcription factor FoxO1, hepatocyte nuclear factor-4alpha, or CCAAT enhancer binding protein-beta. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver.

Developmental changes in ovine myocardial glucose transporters and insulin signaling following hyperthermia-induced intrauterine fetal growth restriction.

Developmental changes in ovine myocardial glucose transporters and insulin signaling following hyperthermia-induced intrauterine fetal growth restriction (IUGR) were the focus of our study. Our objective was to test the hypothesis that the fetal ovine myocardium adapts during an IUGR gestation by increasing glucose transporter protein expression, plasma membrane-bound glucose transporter protein concentrations, and insulin signal transduction protein concentrations. Growth measurements and whole heart tissue were obtained at 55 days gestational age (dGA), 90 dGA, and 135 dGA (term = 145 dGA) in fetuses from control (C) and hyperthermic (HT) pregnant sheep. Additionally, in 135 dGA animals, arterial blood was obtained and Doppler ultrasound was used to determine umbilical artery systolic (S) and diastolic (D) flow velocity waveform profiles to calculate pulsatility (S - D/mean) and resistance (S - D/S) indices. Myocardial Glut-1, Glut-4, insulin signal transduction proteins involved in Glut-4 translocation, and glycogen content were measured. Compared to age-matched controls, HT 90-dGA fetal body weights and HT 135-dGA fetal weights and gross heart weights were lower. Heart weights as a percent of body weights were similar between C and HT sheep at 135 dGA. HT 135-dGA animals had (i) lower fetal arterial plasma glucose and insulin concentrations, (ii) lower arterial blood oxygen content and higher plasma lactate concentrations, (iii) higher myocardial Glut-4 plasma membrane (PM) protein and insulin receptor beta protein (IRbeta ) concentrations, (iv) higher myocardial glycogen content, and (v) higher umbilical artery Doppler pulsatility and resistance indices. The HT ovine fetal myocardium adapts to reduced circulating glucose and insulin concentrations by increasing plasma membrane Glut-4 and IRbeta protein concentrations. The increased myocardial Glut-4 PM and IRbeta protein concentrations likely contribute to or increase the intracellular delivery of glucose and, together with the increased lactate concentrations, enhance glycogen synthesis, which allows for maintained myocardial growth commensurate with fetal body growth.