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..

Trends in the early care of infants with myelomeningocele in the United States 2012-2018.

PURPOSE: The early care of children with spina bifida has changed with the increasing availability of fetal surgery and evidence that fetal repair improves the long-term outcomes of children with myelomeningocele. We sought to determine current trends in the prevalence and early care of children with myelomeningocele using a national administrative database. METHODS: This is a retrospective, cross-sectional cohort study of infants with spina bifida admitted within the first 28 days of life using the 2012-2018 Healthcare Cost and Utilization Project National Inpatient Database. Patients with spina bifida were identified by ICD code and stratified into a cohort with a coded neonatal repair of the defect and those without a coded repair. This database had no identifier specific for fetal surgery, but it is likely that a substantial number of infants without a coded repair had fetal surgery. RESULTS: We identified 5,090 patients with a coded repair and 5,715 without a coded repair. The overall prevalence of spina bifida was 3.94 per 10,000 live births. The percentage of patients without neonatal repair increased during the study period compared to those with repair (p = 0.0002). The cohort without neonatal repair had a higher risk of death (p < 0.001), prematurity (p < 0.001), and low birth weight (p < 0.001). More shunts were placed in patients who underwent neonatal repair (p < 0.001). Patients without neonatal repair were less likely to have public insurance (p = 0.0052) and more likely to reside in zip codes within the highest income quartile (p = 0.0002). CONCLUSIONS: The prevalence of spina bifida from 2012 to 2018 was 3.94 per 10,000 live births, with an increasing number of patients without neonatal repair of the defect, suggesting increased utilization of fetal surgery. Patients without neonatal repair had a higher risk of death, prematurity, and low birth weight but were more likely to have commercial insurance and reside in high-income zip codes.

Quality improvement sustainability to decrease utilization drift for therapeutic hypothermia in the NICU.

OBJECTIVES: Therapeutic hypothermia (TH) is now standard of care for the neuroprotection of patients with moderate to severe hypoxic-ischemic encephalopathy (HIE). TH misuse results in increased medical complication rates and high health care resource utilization. Quality improvement (QI) methodology can address drift from clinical guidelines. Assessment of sustainability of any intervention over time is an integral part of the QI methodology. METHODS: Our prior QI intervention improved medical documentation using an electronic medical record-smart phrase (EMR-SP) and demonstrated special cause variation. This study serves as Epoch 3 and investigates the sustainability of our QI methods to decrease TH misuse. RESULTS: A total of 64 patients met the diagnostic criteria for HIE. Over the study period, 50 patients were treated with TH, and 33 cases (66%) used TH appropriately. The number of appropriate TH cases between cases of misuse increased to an average of 9 in Epoch 3 from 1.9 in Epoch 2. Of the 50 cases, 34 (68%) had EMR-SP documentation included. Length of stay and TH complication rates did not vary between cases of TH misuse and appropriate TH use. CONCLUSIONS: Our study confirmed a sustained decrease in TH misuse, despite inconsistent use of EMR-SP. We speculate that culture change involving increased awareness of guidelines through education may have contributed more to a lasting change.

Quality improvement for reducing utilization drift in hypoxic-ischemic encephalopathy management.

OBJECTIVES: Therapeutic hypothermia is an effective neuroprotective intervention for infants with moderate or severe hypoxic-ischemic encephalopathy (HIE). With the introduction of new medical therapy comes a learning curve with regards to its proper implementation and understanding of eligibility guidelines. We hypothesized that variation in patient selection and lack of adherence to established protocols contributed to the utilization drift away from the original eligibility guidelines. METHODS: A retrospective cohort study was conducted including infants who received therapeutic hypothermia in the neonatal intensive care unit (NICU) for HIE to determine utilization drift. We then used QI methodology to address gaps in medical documentation that may lead to the conclusion that therapeutic hypothermia was inappropriately applied. RESULTS: We identified 54% of infants who received therapeutic hypothermia who did not meet the clinical, physiologic, and neurologic examination criteria for this intervention based on provider admission and discharge documentation within the electronic medical record (EMR). Review of the charts identified incomplete documentation in 71% of cases and led to the following interventions: 1) implementation of EMR smartphrases; 2) engagement of key stakeholders and education of faculty, residents, and neonatal nurse practitioners; and 3) performance measurement and sharing of data. We were able to improve both adherence to the therapeutic hypothermia guidelines and achieve 100% documentation of the modified Sarnat score. CONCLUSIONS: Incomplete documentation can lead to the assumption that therapeutic hypothermia was inappropriately applied when reviewing a patient's EMR. However, in actual clinical practice physicians follow the clinical guidelines but are not documenting their medical decision making completely. QI methodology addresses this gap in documentation, which will help determine the true utilization drift of therapeutic hypothermia in future studies.

Risk Factors Linked to Central Catheter-Associated Thrombosis in Critically Ill Infants in the Neonatal Intensive Care Unit.

OBJECTIVE: Our study identified risk factors for the development of clinically identifiable catheter-associated thrombosis (CT). STUDY DESIGN: We performed a retrospective cohort study of neonates in whom a central catheter was present. A total of 1,475 catheters were identified in 766 patients during a 36-month study period. The odds ratio (OR) of thrombi formation in catheterized neonates was modeled using simple (single predictor) and multiple (multiple predictors) logistic regressions as well as simple and multiple Cox's proportional hazard models. RESULT: The incidence of CT was 1.17 per 100 neonates. Unadjusted factors including age at insertion, history of surgery before or during line placement, cholestasis, femoral location, and line size significantly increased the OR or hazards ratio (HR) of developing thrombi formation. In multiple logistic and Cox's regression analyses, three factors continued to be significantly associated with OR or HR of thrombi formation: line size, femoral location, and cholestasis. CONCLUSION: We conclude that clinically identifiable CT is rare in the neonatal population. Furthermore, catheter-specific characteristics are predictive for CT and require further investigation.

IUGR increases chromatin-remodeling factor Brg1 expression and binding to GR exon 1.7 promoter in newborn male rat hippocampus.

Intrauterine growth restriction (IUGR) increases the risk for neurodevelopment delay and neuroendocrine reprogramming in both humans and rats. Neuroendocrine reprogramming involves the glucocorticoid receptor (GR) gene that is epigenetically regulated in the hippocampus. Using a well-characterized rodent model, we have previously shown that IUGR increases GR exon 1.7 mRNA variant and total GR expressions in male rat pup hippocampus. Epigenetic regulation of GR transcription may involve chromatin remodeling of the GR gene. A key chromatin remodeler is Brahma-related gene-1(Brg1), a member of the ATP-dependent SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. Brg1 regulates gene expression by affecting nucleosome repositioning and recruiting transcriptional components to target promoters. We hypothesized that IUGR would increase hippocampal Brg1 expression and binding to GR exon 1.7 promoter, as well as alter nucleosome positioning over GR promoters in newborn male pups. Further, we hypothesized that IUGR would lead to accumulation of specificity protein 1 (Sp1) and RNA pol II at GR exon 1.7 promoter. Indeed, we found that IUGR increased Brg1 expression and binding to GR exon 1.7 promoter. We also found that increased Brg1 binding to GR exon 1.7 promoter was associated with accumulation of Sp1 and RNA pol II carboxy terminal domain pSer-5 (a marker of active transcription). Furthermore, the transcription start site of GR exon 1.7 was located within a nucleosome-depleted region. We speculate that changes in hippocampal Brg1 expression mediate GR expression and subsequently trigger neuroendocrine reprogramming in male IUGR rats.

Effects of interleukin-6 on the expression of tight junction proteins in isolated cerebral microvessels from yearling and adult sheep.

OBJECTIVES: The blood-brain barrier is a selective diffusion barrier between brain parenchyma and the intravascular compartment. Tight junctions are integral components of the blood-brain barrier. Pro-inflammatory cytokines are important in the pathogenesis of brain injury and could modify the protein constituents of tight junctions. We hypothesized that interleukin-6 (IL-6) downregulates key protein constituents of endothelial tight junctions (e.g. occludin and claudin-5). METHODS: We examined the effects of IL-6 on tight junction protein expression using an in vitro blood-brain barrier model. We isolated microvessels from yearling and adult ovine cerebral cortex and placed them into culture with IL-6 concentrations of 0 (control, phosphate-buffered saline), 1, 10, and 100 ng/ml for 24 h. Cerebral microvessels were harvested, Western immunoblot performed for occludin and claudin-5, densitometry performed, and results expressed as a ratio to control values. RESULTS: Western immunoblot analysis showed that treatment with 100 ng/ml of IL-6, but not the lower concentrations, reduced (p < 0.05) occludin expression in microvessels from yearling and adult sheep and claudin-5 in microvessels from adult sheep. However, treatment with 10 ng/ml of IL-6 increased claudin-5 in microvessels from yearling sheep. The percent of lactate dehydrogenase released from the microvessels into the surrounding media was not increased by IL-6 treatment, suggesting that the reductions in tight junction proteins did not result from cell death. Treatment of adult cerebral cortical microvessels with IL-6 preincubated with anti-IL-6 monoclonal antibodies partially attenuated the reduction in claudin-5. CONCLUSION: We conclude that IL-6 modulates tight junction protein expression in cerebral cortical microvessels from yearling and adult sheep.

Variability in neurosurgical management and associated comorbidities and complications among preterm patients with posthemorrhagic hydrocephalus in the United States.

OBJECTIVE: Posthemorrhagic hydrocephalus (PHH) remains a major morbidity of premature birth resulting from intraventricular hemorrhage (IVH). National consensus guidelines for the timing of surgical interventions are lacking, which leads to considerable variations in management among neonatal intensive care units (NICUs). Early intervention (EI) has been shown to improve outcomes, but the authors hypothesized that the timing from IVH to intervention affects the comorbidities and complications associated with PHH management. The authors used a large national inpatient care data set to characterize comorbidities and complications associated with PHH management in premature infants. METHODS: The authors used hospital discharge data from the 2006-2019 Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) to conduct a retrospective cohort study of premature pediatric patients (weight < 1500 g) with PHH. The predictor variable was the timing of the PHH intervention (EI ≤ 28 days vs late intervention [LI] > 28 days). Hospital stay data included hospital region, gestational age, birth weight (BW), length of stay (LOS), PHH treatment procedures, comorbidities, surgical complications, and death. Statistical analysis included chi-square and Wilcoxon rank-sum tests, Cox proportional hazards regression, logistic regression, and a generalized linear model with Poisson and gamma distributions. Analysis was adjusted for demographic characteristics, comorbidities, and death. RESULTS: Of the 1853 patients diagnosed with PHH, 488 (26%) had documented timing of surgical interventions during their hospital stay. More patients had LI than EI (75%). The patients in the LI group of patients had younger gestational age and lower BW. There were significant regional differences in the timing of treatment: hospitals in the West performed EI, whereas hospitals in the South performed LI, even after adjustment for gestational age and BW. The LI group was associated with longer median LOS and more total hospital charges compared with the EI group. More temporary CSF diversion procedures occurred in the EI group, whereas more permanent CSF-diverting shunts were placed in the LI group. Shunt/device replacement and complications did not differ between the two groups. The LI group had 2.5-fold higher odds of sepsis (p < 0.001) and almost 2-fold higher odds of retinopathy of prematurity (p < 0.05) than the EI group. CONCLUSIONS: The timing of PHH interventions differs by region in the United States, whereas the association of potential benefits with treatment timing suggests the importance of national consensus guidelines. Development of these guidelines can be informed by data regarding treatment timing and patient outcomes available in large national data sets, which provide insights into comorbidities and complications of PHH interventions.

A pause in pediatrics: implementation of a pediatric diagnostic time-out.

OBJECTIVES: Diagnostic errors are frequently the product of cognitive biases that arise when heuristic-based approaches fail. The efficiency-thoroughness tradeoff (ETTO) principle states sacrificing thoroughness for efficiency is normal and occurs frequently in medicine. The goal of a diagnostic timeout was to provide an actionable template for when providers transition to an analytical mindset and to help incorporate the ETTO principle during the diagnostic process. METHODS: A diagnostic time-out was adapted for use in pediatric hospital medicine (PHM). In this prospective study, a group of eight PHM providers piloted the time-out in the hospitalized setting. Data was collected over 12 months and descriptive statistics were used for analysis. RESULTS: Cases were most frequently chosen for time-out use due to clinician intuition. In more than half the cases the time-out didn't confirm the initial diagnosis and alternate diagnoses for the wrong diagnosis were pursued. There was only one case of the time-out being burdensome from a time perspective. Learners participated in all cases. As a result of the diagnostic time-out, new actions were taken in all cases. CONCLUSIONS: Implementation of a diagnostic time out provides an actionable template for providers to actively change their mindset to an analytical thinking process to counteract cognitive biases and potentially reduce diagnostic errors in the pediatric inpatient setting.

Sociodemographic disparities in fetal surgery for myelomeningocele: a single-center retrospective review.

OBJECTIVE: Fetal surgery for myelomeningocele has become an established treatment that offers less risk of requiring a ventricular shunt and improved functional outcomes for patients. An increasing body of literature has suggested that social determinants of health have a profound influence on health outcomes. The authors sought to determine the socioeconomic and racial and ethnic backgrounds of patients who were treated with fetal surgery versus those who underwent postnatal repair. METHODS: Demographic data, the method of myelomeningocele repair, insurance status, and zip code data for patients entered into the National Spina Bifida Patient Registry (NSBPR) from Children's Wisconsin were collected. The zip code was used to determine the Distressed Communities Index (DCI) score, a composite socioeconomic ranking with scores ranging from 0 (no distress) to 100 (severe distress). The zip code was also used to determine the median household income for each patient based on the US Census Bureau 2013-2017 American Community Survey 5-year estimates. RESULTS: A total of 205 patients were identified with zip code and insurance data. There were 23 patients in the fetal surgery group and 182 patients in the postnatal surgery group. All patients were born between 2000 and 2019. Patients in the fetal surgery group were more likely to have commercial insurance (100% vs 52.2%, p < 0.001). Fetal surgery patients were also more likely to be non-Hispanic White (95.7% vs 68.7%, p = 0.058), just missing the level of statistical significance. Patients who underwent fetal surgery tended to reside in zip codes with a higher median household income (mean $66,507 vs $59,133, p = 0.122) and less-distressed communities (mean DCI score 31.3 vs 38.5, p = 0.289); however, these differences did not reach statistical significance. CONCLUSIONS: Patients treated with fetal surgery were more likely to have commercial insurance and have a non-Hispanic White racial and ethnic background. The preliminary data suggest that socioeconomic and racial and ethnic disparities may exist regarding access to fetal surgery, and investigation of a larger population of spina bifida patients is warranted.

Regulation of Cerebral Blood Flow: Response to Cytochrome P450 Lipid Metabolites.

There have been numerous reviews related to the cerebral circulation. Most of these reviews are similar in many ways. In the present review, we thought it important to provide an overview of function with specific attention to details of cerebral arterial control related to brain homeostasis, maintenance of neuronal energy demands, and a unique perspective related to the role of astrocytes. A coming review in this series will discuss cerebral vascular development and unique properties of the neonatal circulation and developing brain, thus, many aspects of development are missing here. Similarly, a review of the response of the brain and cerebral circulation to heat stress has recently appeared in this series (8). By trying to make this review unique, some obvious topics were not discussed in lieu of others, which are from recent and provocative research such as endothelium-derived hyperpolarizing factor, circadian regulation of proteins effecting cerebral blood flow, and unique properties of the neurovascular unit. © 2018 American Physiological Society. Compr Physiol 8:801-821, 2018.

Impaired cerebral angiogenesis in the fetal lamb model of persistent pulmonary hypertension.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is associated with increased risk of neuro-developmental impairments. Whether relative fetal hypoxia during evolution of PPHN renders the fetal brain vulnerable to perinatal brain injury remains unclear. We hypothesized that in utero ductal constriction, which induces PPHN also impairs cerebral angiogenesis. METHODS: Fetal lambs with PPHN induced by prenatal ligation of the ductus arteriosus were compared to gestation matched twin controls. Freshly collected or fixed brain specimens were analyzed by immunohistochemistry, Western blot analysis, and RT-PCR. RESULTS: Cortical capillary density was decreased in PPHN lambs compared to controls (Glut-1, isolectin B-4 and factor VIII, n=6, p<0.05). Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels were decreased in cortical cell lysates of PPHN lambs. PPHN increased angiopoetin-1 (Ang-1) and tyrosine-protein kinase receptor (Tie-2) protein expression while angiopoetin-2 (Ang-2) protein levels were decreased (n=6, p<0.05). PPHN did not change mRNA levels of these proteins significantly (n=6). CONCLUSIONS: PPHN decreased cortical capillary density in fetal lamb brain. PPHN decreased the expression of proteins involved in angiogenesis. These findings suggest that PPHN is associated with impaired cortical angiogenesis.