The Current State of Neonatal Neurodevelopmental Follow-up Programs in North America: A Children's Hospitals Neonatal Consortium Report.

OBJECTIVE: This study aimed to determine neonatal neurodevelopmental follow-up (NDFU) practices across academic centers. STUDY DESIGN: This study was a cross-sectional survey that addressed center-specific neonatal NDFU practices within the Children's Hospitals Neonatal Consortium (CHNC). RESULTS: Survey response rate was 76%, and 97% of respondents had a formal NDFU program. Programs were commonly staffed by neonatologists (80%), physical therapists (77%), and nurse practitioners (74%). Median gestational age at birth identified for follow-up was ≤32 weeks (range 26-36). Median duration was 3 years (range 2-18). Ninety-seven percent of sites used Bayley Scales of Infant and Toddler Development, but instruments used varied across ages. Scores were recorded in discrete electronic data fields at 43% of sites. Social determinants of health data were collected by 63%. Care coordination and telehealth services were not universally available. CONCLUSION: NDFU clinics are almost universal within CHNC centers. Commonalities and variances in practice highlight opportunities for data sharing and development of best practices. KEY POINTS: · Neonatal NDFU clinics help transition high-risk infants home.. · Interdisciplinary neonatal intensive care unit follow-up brings together previously separated outpatient service lines.. · This study reviews the current state of neonatal NDFU in North America..

Study Protocol: Multimodal Longitudinal Assessment of Infant Brain Organization and Recovery in Perinatal Brain Injury.

PURPOSE: Perinatal brain injury is a primary cause of cerebral palsy, a condition resulting in lifelong motor impairment. Infancy is an important period of motor system development, including development of the corticospinal tract (CST), the primary pathway for cortical movement control. The interaction between perinatal stroke recovery, CST organization, and resultant motor outcome in infants is not well understood. METHODS: Here, we present a protocol for multimodal longitudinal assessment of brain development and motor function following perinatal brain injury using transcranial magnetic stimulation and magnetic resonance imaging to noninvasively measure CST functional and structural integrity across multiple time points in infants 3 to 24 months of age. We will further assess the association between cortical excitability, integrity, and motor function. DISCUSSION: This protocol will identify bioindicators of motor outcome and neuroplasticity and subsequently inform early detection, diagnosis, and intervention strategies for infants with perinatal stroke, brain bleeds, and related diagnoses.

Renal tissue oxygenation after caffeine administration in preterm neonates.

BACKGROUND: Caffeine has been associated with reduced rates of acute kidney injury (AKI) in preterm neonates. The effect of caffeine on preterm neonatal renal regional saturation of oxygen (RrSO2) is unknown. METHODS: RrSO2 was recorded continuously in neonates < 32 weeks' gestation until 7 days of age with INVOS™ neonatal near-infrared spectroscopy (NIRS) sensors. Baseline RrSO2 values were established by averaging the saturations in the 20 min prior to caffeine administration. Subgroup analysis was performed based on pre-caffeine RrSO2 averages. Change in RrSO2 was recorded at 0.5, 1, 2, 3, 4, 6, and 12 h after maintenance caffeine administration. RESULTS: Of 35 eligible neonates, 31 (median gestational age 28.4 weeks) received 156 caffeine doses (median 8 mg/kg). Analysis of combined doses showed no significant changes in RrSO2 after caffeine administration at any time. However, neonates with baseline 20-29.9% had significant increases from 1 to 12 h (range of increase 5.9-13.9%), and those with baseline 30-39.9 had significant increases at 1 h (8.06%, p < 0.05). CONCLUSIONS: Maintenance caffeine dosing increased RrSO2 in neonates with low RrSO2 in the first week. Further research is needed to determine the effect of loading doses of caffeine and if increases in RrSO2 correlate with improved clinical kidney outcomes. IMPACT: Caffeine administration is associated with increased renal tissue oxygenation in preterm neonates with low baseline values under 40%. The most significant renal tissue oxygenation changes occur in the first 3 h after IV caffeine administration. With recent studies suggesting low RrSO2 values in preterm neonates are associated with AKI, caffeine should be studied as a potential therapeutic for this common and complex morbidity in preterm neonates.

Non-invasive continuous renal tissue oxygenation monitoring to identify preterm neonates at risk for acute kidney injury.

BACKGROUND: Near-infrared spectroscopy (NIRS) is an emerging tool to identify signs of inadequate tissue oxygenation in preterm neonates with acute kidney injury (AKI). Previous studies have shown a correlation between low renal tissue oxygenation (RrSO2) in the first 24 hours of age and the later development of AKI. In this prospective clinical trial, NIRS monitoring was used to identify changes in RrSO2 in comparison to traditional AKI markers, serum creatinine (SCr), and urine output (UOP). METHODS: We enrolled 35 preterm neonates born less than 32 weeks' gestation and applied neonatal NIRS sensors at less than 48 hours of age. Neonates underwent 7 days of continuous monitoring. Renal and demographic information were collected for the first 7 days of age. AKI was determined by the modified neonatal Kidney Disease: Improving Global Outcomes (KDIGO) definition including UOP. RESULTS: Three patients experienced AKI, all based on both SCr and UOP criteria. Each neonate with AKI had decreases in RrSO2 over 48 hours prior to changes in SCr and UOP. Patients with AKI had lower median RrSO2 values compared to patients without AKI over the first week of age, (32.4% vs. 60%, p < 0.001). CONCLUSION: RrSO2 monitoring identified preterm neonates at risk for AKI. NIRS detected a decline in RrSO2 prior to changes in SCr and UOP and was significantly lower in patients with AKI compared to those without AKI. Further studies are needed to evaluate the ability of RrSO2 monitoring to detect signs of kidney stress prior to the diagnosis of AKI. Graphical abstract.

Delayed Umbilical Cord Clamping is Not Associated with Acute Kidney Injury in Very Low Birth Weight Neonates.

OBJECTIVE: This study aimed to determine if delayed cord clamping (DCC) is associated with a reduction in neonatal acute kidney injury (AKI). STUDY DESIGN: A retrospective single-center cohort study of 278 very low birth weight (VLBW) neonates was performed to compare the incidence of AKI in the following groups: immediate cord clamping (ICC), DCC, and umbilical cord milking. AKI was diagnosed by the modified neonatal Kidney Diseases and Improving Global Outcomes (KDIGO) definition. RESULTS: The incidence of AKI in the first week was 20.1% with no difference between groups (p = 0.78). After adjustment for potential confounders, the odds of developing AKI, following DCC, compared with ICC was 0.93 (confidence interval [CI]: 0.46-1.86) with no reduction in the stage of AKI between groups. CONCLUSION: In this study, DCC was not associated with a reduced rate of AKI in VLBW neonates. However, the data suggest that DCC is also not harmful to the kidneys, further supporting the safety of DCC in VLBW neonates.

Attitudes Surrounding the Management of Neonates with Severe Necrotizing Enterocolitis.

OBJECTIVES: To assess providers' recommendations as to comfort care versus medical and surgical management in clinical scenarios of newborns with severe bowel loss and to assess how a variety of factors influence providers' decision making. STUDY DESIGN: We conducted a survey of pediatric surgeons and neonatologists via the American Pediatric Surgical Association and American Academy of Pediatrics Section of Neonatal-Perinatal Medicine. We examined how respondents' recommendations were affected by a variety of patient and provider factors. RESULTS: There were 288 neonatologists and 316 pediatric surgeons who responded. Irrespective of remaining bowel length, comfort care was recommended by 73% of providers for a premature infant with necrotizing enterocolitis and 54% for a full-term infant with midgut volvulus. The presence of comorbidities and earlier gestational age increased the proportion of providers recommending comfort care. Neonatologists were more likely to recommend comfort care than surgeons across all scenarios (OR, 1.45-2.00; P < .05), and this difference was more pronounced with infants born closer to term. In making these recommendations, neonatologists placed more importance on neurodevelopmental outcomes (P < .001), and surgeons emphasized experience with long-term quality of life (P < .001). CONCLUSION: Despite a contemporary survival of >90% in infants with intestinal failure, a majority of providers still recommend comfort care in infants with massive bowel loss. Significant differences were identified in clinical decision making between surgeons and neonatologists. These data reinforce the need for targeted education on long-term outcomes in intestinal failure to neonatal and surgical providers.

Focal Brain Injury Associated with a Model of Severe Hypoxic-Ischemic Encephalopathy in Nonhuman Primates.

Worldwide, hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. To better understand the mechanisms contributing to brain injury and improve outcomes in neonates with HIE, better preclinical animal models that mimic the clinical situation following birth asphyxia in term newborns are needed. In an effort to achieve this goal, we modified our nonhuman primate model of HIE induced by in utero umbilical cord occlusion (UCO) to include postnatal hypoxic episodes, in order to simulate apneic events in human neonates with HIE. We describe a cohort of 4 near-term fetal Macaca nemestrina that underwent 18 min of in utero UCO, followed by cesarean section delivery, resuscitation, and subsequent postnatal mechanical ventilation, with exposure to intermittent daily hypoxia (3 min, 8% O2 3-8 times daily for 3 days). After delivery, all animals demonstrated severe metabolic acidosis (pH 7 ± 0.12; mean ± SD) and low APGAR scores (<5 at 10 min of age). Three of 4 animals had both electrographic and clinical seizures. Serial blood samples were collected and plasma metabolites were determined by 2-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC-TOFMS). The 4 UCO animals and a single nonasphyxiated animal (delivered by cesarean section but without exposure to UCO or prolonged sedation) underwent brain magnetic resonance imaging (MRI) on day 8 of life. Thalamic injury was present on MRI in 3 UCO animals, but not in the control animal. Following necropsy on day 8, brain histopathology revealed neuronal injury/loss and gliosis in portions of the ventrolateral thalamus in all 4 UCO, with 2 animals also demonstrating putamen/globus pallidus involvement. In addition, all 4 UCO animals demonstrated brain stem gliosis, with neuronal loss present in the midbrain, pons, and lateral medulla in 3 of 4 animals. Transmission electron microscopy imaging of the brain tissues was performed, which demonstrated ultrastructural white matter abnormalities, characterized by perinuclear vacuolation and axonal dilation, in 3 of 4 animals. Immunolabeling of Nogo-A, a negative regulator of neuronal growth, was not increased in the injured brains compared to 2 control animals. Using GC × GC-TOFMS, we identified metabolites previously recognized as potential biomarkers of perinatal asphyxia. The basal ganglia-thalamus-brain stem injury produced by UCO is consistent with the deep nuclear/brainstem injury pattern seen in human neonates after severe, abrupt hypoxic-ischemic insults. The UCO model permits timely detection of biomarkers associated with specific patterns of neonatal brain injury, and it may ultimately be useful for validating therapeutic strategies to treat neonatal HIE.

Long-Term Neuropathological Changes Associated with Cerebral Palsy in a Nonhuman Primate Model of Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited. METHODOLOGY: Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed. RESULTS: All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP. CONCLUSIONS/SIGNIFICANCE: In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.

Group B streptococcal infection of the choriodecidua induces dysfunction of the cytokeratin network in amniotic epithelium: a pathway to membrane weakening.

Early events leading to intrauterine infection remain poorly defined, but may hold the key to preventing preterm delivery. To determine molecular pathways within fetal membranes (chorioamnion) associated with early choriodecidual infection that may progress to preterm premature rupture of membranes (PPROM), we examined the effects of a Group B Streptococcus (GBS) choriodecidual infection on chorioamnion in a nonhuman primate model. Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term = 172 days) received choriodecidual inoculation of either GBS (n = 5) or saline (n = 5). Cesarean section was performed in the first week after GBS or saline inoculation. RNA extracted from chorioamnion (inoculation site) was profiled by microarray. Single gene, Gene Set, and Ingenuity Pathway Analysis results were validated using qRT-PCR (chorioamnion), Luminex (amniotic fluid, AF), immunohistochemistry, and transmission electron microscopy (TEM). Despite uterine quiescence in most cases, significant elevations of AF cytokines (TNF-α, IL-8, IL-1ß, IL-6) were detected in GBS versus controls (p<0.05). Choriodecidual infection resolved by the time of cesarean section in 3 of 5 cases and GBS was undetectable by culture and PCR in the AF. A total of 331 genes were differentially expressed (>2-fold change, p<0.05). Remarkably, GBS exposure was associated with significantly downregulated expression of multiple cytokeratin (CK) and other cytoskeletal genes critical for maintenance of tissue tensile strength. Immunofluorescence revealed highly significant changes in the CK network within amniocytes with dense CK aggregates and retraction from the cell periphery (all p = 0.006). In human pregnancies affected by PPROM, there was further evidence of CK network retraction with significantly shorter amniocyte foot processes (p = 0.002). These results suggest early choriodecidual infection results in decreased cellular membrane integrity and tensile strength via dysfunction of CK networks. Downregulation of CK expression and perturbations in the amniotic epithelial cell intermediate filament network occur after GBS choriodecidual infection, which may contribute to PPROM.

Choriodecidual Group B Streptococcal Infection Induces miR-155-5p in the Fetal Lung in Macaca nemestrina.

The mechanisms underlying fetal lung injury remain poorly defined. MicroRNAs (miRNAs) are small noncoding, endogenous RNAs that regulate gene expression and have been implicated in the pathogenesis of lung disease. Using a nonhuman primate model of choriodecidual infection, we sought to determine if differentially expressed miRNAs were associated with acute fetal lung injury. After inoculating 10 chronically catheterized pregnant monkeys (Macaca nemestrina) with either group B streptococcus (GBS) at 1 × 10(6) CFU (n = 5) or saline (n = 5) in the choriodecidual space, we extracted fetal lung mRNA and miRNA and profiled the changes in expression by microarray analysis. We identified 9 differentially expressed miRNAs in GBS-exposed fetal lungs, but of these, only miR-155-5p was validated by quantitative reverse transcription-PCR (P = 0.02). Significantly elevated miR-155-5p expression was also observed when immortalized human fetal airway epithelial (FeAE) cells were exposed to proinflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNF-α]). Overexpression of miR-155-5p in FeAE cells in turn increased the production of IL-6 and CXCL10/gamma interferon-induced protein 10, which are implicated in leukocyte recruitment but also in protection from lung injury. Interestingly, while miR-155-5p decreased fibroblast growth factor 9 (FGF9) expression in a luciferase reporter assay, FGF9 levels were actually increased in GBS-exposed fetal lungs in vivo. FGF9 overexpression is associated with abnormal lung development. Thus, upregulation of miR-155-5p may serve as a compensatory mechanism to lessen the increase in FGF9 and prevent aberrant lung development. Understanding the complicated networks regulating lung development in the setting of infection is a key step in identifying how to prevent fetal lung injury leading to bronchopulmonary dysplasia.

Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats.

BACKGROUND: The α2-adrenergic agonist dexmedetomidine (DEX) is increasingly used for prolonged sedation of critically ill neonates, but there are currently no data evaluating possible consequences of prolonged neonatal DEX exposure. We evaluated the pharmacokinetics and histological consequences of neonatal DEX exposure. METHODS: DEX was administered (s.c.) to naive (uninjured) neonatal Lewis rats to provide acute (25 µg/kg, ×1) or prolonged (25 µg/kg three times daily, ×2 or ×4 d) exposure. Therapeutic hypothermia was simulated using a water-cooled blanket. Cranial temperatures were measured using an infrared thermometer. DEX concentrations were measured by LC-MS in plasma and homogenized brainstem tissue for pharmacokinetic analysis. Cortex, cerebellum, and brainstem were evaluated for evidence of inflammation or injury. RESULTS: Prolonged neonatal DEX exposure was not associated with renal or brain pathology or indices of gliosis, macrophage activation, or apoptosis in either hypothermic or control rats. Plasma and brain DEX concentrations were tightly correlated. DEX peaked within 15 min in brain and reduced cranial temperature from 32 to 30 °C within 30 min after injection in cooled rats. CONCLUSION: Prolonged DEX treatment in neonatal rats was not associated with abnormal brain histology. These data provide reassuring preliminary results for using DEX with therapeutic hypothermia to treat near-term brain injury.

A quality of life quandary: a framework for navigating parental refusal of treatment for co-morbidities in infants with underlying medical conditions.

Parental refusal of a recommended treatment is not an uncommon scenario in the neonatal intensive care unit. These refusals may be based upon the parents' perceptions of their child's projected quality of life. The inherent subjectivity of quality of life assessments, however, can exacerbate disagreement between parents and healthcare providers. We present a case of parental refusal of surgical intervention for necrotizing enterocolitis in an infant with Bartter syndrome and develop an ethical framework in which to consider the appropriateness of parental refusal based upon an infant's projected quality of life.

Demographics, clinical characteristics and neonatal outcomes in a rural Ugandan NICU.

BACKGROUND: Ninety-six percent of the world's 3 million neonatal deaths occur in developing countries where the majority of births occur outside of a facility. Community-based approaches to the identification and management of neonatal illness have reduced neonatal mortality over the last decade. To further expand life-saving services, improvements in access to quality facility-based neonatal care are required. Evaluation of rural neonatal intensive care unit referral centers provides opportunities to further understand determinants of neonatal mortality in developing countries. Our objective was to describe demographics, clinical characteristics and outcomes from a rural neonatal intensive care unit (NICU) in central Uganda from 2005-2008. METHODS: The NICU at Kiwoko hospital serves as a referral center for three rural districts of central Uganda. For this cross sectional study we utilized a NICU clinical database that included admission information, demographics, and variables related to hospital course and discharge. Descriptive statistics are reported for all neonates (<28 days old) admitted to the NICU between December 2005 and September 2008, disaggregated by place of birth. Percentages reported are among neonates for which data on that indicator were available. RESULTS: There were 809 neonates admitted during the study period, 68% (490/717) of whom were inborn. The most common admission diagnoses were infection (30%, 208/699), prematurity (30%, 206/699), respiratory distress (28%, 198/699) and asphyxia (22%, 154/699). Survival to discharge was 78% (578/745). Mortality was inversely proportional to birthweight and gestational age (P-value test for trend <0.01). This was true for both inborn and outborn infants (p < 0.01). Outborn infants were more likely to be preterm (44%, (86/192) vs. 33%, (130/400), P-value <0.01) and to be low birthweight (58%, (101/173) vs. 40%, (190/479), P-value <0.01) than inborn infants. Outborn neonates had almost twice the mortality (33%, 68/208) as inborn neonates (17%, 77/456) (P-value <0.01). CONCLUSIONS: Understanding determinants of neonatal survival in facilities is important for targeting improvements in facility based neonatal care and increasing survival in low and middle income countries.

Characterization of health care provider attitudes toward parental involvement in neonatal resuscitation-related decision making in Mongolia.

The aim of this study was to characterize attitudes and practices among health care providers (HCPs) in Mongolia regarding parental involvement in neonatal resuscitation (NR)-related decisions. A voluntary, anonymous questionnaire was administered to 210 HCPs across 19 of 21 Mongolia provinces. Eligible HCPs included midwives, neonatologists, pediatricians, and obstetricians involved in neonatal-perinatal care in both rural and urban hospitals. A total of 210 pediatric HCPs were surveyed and 100 % completed all questions (response rate 100 %). Despite the absence of nation-wide guidelines, NR is uniformly performed at 32-weeks gestation across HCP professions and across rural/urban settings. Most HCPs (67 %) indicate that parents should be counseled about resuscitation, but only 9 % ask the parents if they want their extremely premature child resuscitated and only 17 % counsel the parents prior to birth of an at-risk infant. Most HCPs (72 %) prefer to unilaterally decide when to withdraw NR, and only 28 % indicated that both parents should be involved in the decision. Following a newborn's death, 75 % of all HCPs reported that they do explain the death to parents, although only 28 % reported receiving any training in parental grief counseling. For HCPs in Mongolia, a discrepancy exists between the perceived value of parental involvement and the actual practice of NR-related counseling. This report is a necessary first step toward understanding the factors that influence NR-related practices in Mongolia, and may serve as model for collecting these types of data in other low and middle income countries.

Using Virtual Reality-Based Simulation in Neonatal Resuscitation Program Training.

In this article, we investigate the incorporation of virtual reality (VR) into Neonatal Resuscitation Program (NRP) training. We describe the potential advantages and challenges of the use of VR with NRP. We compare conventional training approaches to VR-based simulation, reviewing diverse VR platforms and their specific roles in neonatal resuscitation education. In addition, technological and ethical aspects in medical training, current research, and prospective developments in this innovative educational tool are discussed.

A pilot study of a virtual reality-based simulation platform for Neonatal Resuscitation Program training.

OBJECTIVE: This pilot implementation study introduces a novel, neonatal-specific virtual reality (VR) simulation platform for resuscitation training and assesses its initial feasibility and reception in a neonatal intensive care unit setting. STUDY DESIGN: We developed a custom VR model simulating a resuscitation scenario for a 30-week neonate. Neonatal providers completed individualized training sessions and post-training surveys. RESULTS: Thirty-eight neonatal providers participated in the study. The VR platform was well-received, with 97% willing to use it again and 95% recommending it. Most participants (70.3%) found VR more realistic than traditional methods, with an average usefulness rating of 4.5/5. However, 40.5% reported adverse effects like eye strain and motion sickness. Feedback led to three significant VR platform upgrades. CONCLUSION: This study demonstrates strong enthusiasm for VR among neonatal providers. While promising, further research with larger samples and comparisons to traditional methods is needed to fully evaluate VR's effectiveness in neonatal resuscitation training.

Equitable Artificial Intelligence in Obstetrics, Maternal-Fetal Medicine, and Neonatology.

Artificial intelligence (AI) offers potential benefits in the interconnected fields of obstetrics, maternal-fetal medicine, and neonatology to bridge disciplinary silos for a unified approach. Artificial intelligence has the capacity to improve diagnostic accuracy and clinical decision making for the birthing parent-neonate dyad. There is an inherent risk of ingrained biases in AI that perpetuate existing inequalities; thus, care must be taken to include diverse data sets with interdisciplinary collaboration that centers equitable AI implementation. As AI plays an increasingly important role in perinatal care, we advocate for its cautious, equity-focused application to benefit the perinatal dyad while avoiding the intensification of health care disparities and disciplinary silos.