Hypoxia: A teratogen underlying a range of congenital disruptions, dysplasias, and malformations.

In this review, we explore evidence that hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects, but also patterns of anomalies that suggest that hypoxia can exert a more classic teratogenic effect, using the brain as one example. We review neuropathology in the context of intrauterine hypoxia, particularly as it relates to carbon monoxide poisoning, in utero strokes, and homozygous alpha-thalassemia. In general, the associated brain injuries resemble those seen with other causes of hypoxic-ischemic injury. Fetal strokes during development usually lead to loss of brain tissue in areas that do not follow a typical embryologic pattern, and therefore are considered disruptions. However, there is also evidence that fetal brain ischemia can cause more classically recognized patterns of abnormal embryonic neuronal migration and organization such as polymicrogyria, cortical dysplasia, or dysgenesis, including select types of focal cortical dysplasia. This study summarizes available literature and evidence to raise clinicians' awareness regarding the association between hypoxia and congenital anomalies, including brain malformations.

Non-Cystic Fibrosis-Related Meconium Ileus: GUCY2C-Associated Disease Discovered through Rapid Neonatal Whole-Exome Sequencing.

Meconium ileus is caused by cystic fibrosis; however, mutations in the GUCY2C gene also cause this disease. We report non-cystic fibrosis meconium ileus in an infant of non-Middle Eastern origin with compound heterozygous mutations in GUCY2C.

Covariation of Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Management and In-Neonatal Intensive Care Unit Outcomes Following Preterm Birth.

OBJECTIVE: To test the hypothesis that neonatal intensive care unit (NICU)-specific changes in patent ductus arteriosus (PDA) management are associated with changes in local outcomes in preterm infants. STUDY DESIGN: This retrospective repeated-measures study of aggregated data included infants born 400-1499 g admitted within 2 days of delivery to NICUs participating in the California Perinatal Quality Care Collaborative. The period 2008-2015 was divided into four 2-year epochs. For each epoch and NICU, we calculated proportions of infants receiving cyclooxygenase inhibitor (COXI) or PDA ligation and determined NICU-specific changes in these therapies between consecutive epochs. Generalized estimating equations were used to examine adjusted relationships between NICU-specific changes in PDA management and contemporaneous changes in local outcomes. RESULTS: We included 642 observations of interepoch change at 119 hospitals summarizing 32 094 infants. NICU-specific changes in COXI use and ligation showed significant dose-response associations with contemporaneous changes in adjusted local outcomes. Each percentage point decrease in NICU-specific proportion treated with either COXI or ligation was associated with a 0.21 percentage point contemporaneous increase in adjusted local in-hospital mortality (95% CI 0.06, 0.33; P = .005) among infants born 400-749 g. In contrast, decreasing NICU-specific ligation rate among infants 1000-1499 g was associated with decreasing adjusted local bronchopulmonary dysplasia (P = .009) and death or bronchopulmonary dysplasia (P = .01). CONCLUSIONS: NICU-specific outcomes of preterm birth co-vary with local PDA management. Treatment for PDA closure may benefit some infants born 400-749 g. Decreasing NICU-specific rates of COXI use or ligation were not associated with increases in local adjusted rates of examined adverse outcomes in larger preterm infants.

28 NICUs participating in a quality improvement collaborative targeting early-onset sepsis antibiotic use.

OBJECTIVE: There is widespread overuse of antibiotics in neonatal intensive care units (NICUs). The objective of this study was to safely reduce antibiotic use in participating NICUs by targeting early-onset sepsis (EOS) management. STUDY DESIGN: Twenty-eight NICUs participated in this statewide multicenter antibiotic stewardship quality improvement collaborative. The primary aim was to reduce the total monthly mean antibiotic utilization rate (AUR) by 25% in participant NICUs. RESULT: Aggregate AUR was reduced by 15.3% (p < 0.001). There was a wide range in improvement among participant NICUs. There were no increases in EOS rates or nosocomial infection rates related to the intervention. CONCLUSION: Participation in this multicenter NICU antibiotic stewardship collaborative targeting EOS was associated with an aggregate reduction in antibiotic use. This study informs efforts aimed at sustaining improvements in NICU AURs.

Blood culture procedures and practices in the neonatal intensive care unit: A survey of a large multicenter collaborative in California.

OBJECTIVE: To describe variation in blood culture practices in the neonatal intensive care unit (NICU). DESIGN: Survey of neonatal practitioners involved with blood culturing and NICU-level policy development. PARTICIPANTS: We included 28 NICUs in a large antimicrobial stewardship quality improvement program through the California Perinatal Quality Care Collaborative. METHODS: Web-based survey of bedside blood culture practices and NICU- and laboratory-level practices. We evaluated adherence to recommended practices. RESULTS: Most NICUs did not have a procedural competency (54%), did not document the sample volume (75%), did not receive a culture contamination report (57%), and/or did not require reporting to the provider if <1 mL blood was obtained (64%). The skin asepsis procedure varied across NICUs. Only 71% had a written procedure, but ≥86% changed the needle and disinfected the bottle top prior to inoculation. More than one-fifth of NICUs draw a culture from an intravascular device only (if present). Of 13 modifiable practices related to culture and contamination, NICUs with nurse practitioners more frequently adopted >50% of practices, compared to units without (92% vs 50% of units; P < .02). CONCLUSIONS: In the NICU setting, recommended practices for blood culturing were not routinely performed.

Vignette Research Methodology: An Essential Tool for Quality Improvement Collaboratives.

Variation in patient outcomes among institutions and within institutions is a major problem in healthcare. Some of this variation is due to differences in practice, termed practice variation. Some practice variation is expected due to appropriately personalized care for a given patient. However, some practice variation is due to the individual preference or style of the clinicians. Quality improvement collaboratives are commonly used to disseminate quality care on a wide scale. Practice variation is a notable barrier to any quality improvement effort. A detailed and accurate understanding of practice variation can help optimize the quality improvement efforts. The traditional survey methods do not capture the complex nuances of practice variation. Vignette methods have been shown to accurately measure the actual practice variation and quality of care delivered by clinicians. Vignette methods are cost-effective relative to other methods of measuring quality of care. This review describes our experience and lessons from implementing vignette research methods in quality improvement collaboratives in California neonatal intensive care units. Vignette methodology is an ideal tool to address practice variation in quality improvement collaboratives, actively engage a large number of participants, and support more evidence-based practice to improve outcomes.

The Term Newborn: Congenital Infections.

Maternal pathogens can be transmitted to the fetus resulting in congenital infection with sequelae ranging from asymptomatic infection to severe debilitating disease and still birth. The TORCH pneumonic (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) is used widely, but it provides a limited description of the expanding list of pathogens associated with congenital infection. This article focuses on the evaluation and management of infants with common congenital infections such as cytomegalovirus, and infections that warrant early diagnosis and treatment to prevent serious complications, such as toxoplasmosis, human immunodeficiency virus, and syphilis. Zika virus and Chagas disease remain uncommon.

Vignettes Identify Variation in Antibiotic Use for Suspected Early Onset Sepsis.

BACKGROUND AND OBJECTIVES: There is widespread unwarranted antibiotic use and large individual provider variation in antibiotic use in NICUs. Vignette-based research methodology offers a unique method of studying variation in individual provider decisions. The objective with this study was to use a vignette-based survey to identify specific areas of provider antibiotic use variation in newborns being evaluated for early onset sepsis. METHODS: This study was undertaken as part of a statewide multicenter neonatal antibiotic stewardship quality improvement project led by a perinatal quality improvement collaborative. A web-based vignette survey was administered to identify variation in decisions to start and discontinue antibiotics in cases of early onset sepsis. RESULTS: The largest variation was noted in 3 of the 6 vignette cases. These cases highlighted variation in (1) decisions to start antibiotics in a case describing a well-appearing newborn with risk factors and an elevated C-reactive protein, (2) decisions to start antibiotics in the case of a newborn with risk factors plus mild respiratory signs at birth, and (3) decisions to stop antibiotics in the case of the newborn with a history of sepsis risk factors and mild clinical respiratory signs that resolved after 72 hours. CONCLUSIONS: Clinical vignette assessment identified specific areas of variation in individual provider antibiotic use decisions in cases of suspected early onset sepsis. Vignettes are a valuable method of describing individual provider variation and highlighting antibiotic stewardship improvement opportunities in NICUs.

Antioxidant status alters levels of Fas-associated death domain-like IL-1B-converting enzyme inhibitory protein following neonatal hypoxia-ischemia.

Activation of Fas death receptor (Fas DR) signaling cascade is seen after neonatal hypoxia-ischemia (HI). Cell survival is favored when signaling through the death-inducing signaling complex and cleavage of caspase 8 to its active form is blocked by FLIP, a dominant negative of caspase 8. H2O2 quickly downregulates expression of FLIP. Neonatal mice overexpressing glutathione peroxidase (GPx) have less injury and less H2O2 accumulation compared with neonatal mice overexpressing superoxide dismutase (SOD) or wild-type (WT) littermates. Expression of both FLIP(L) and FLIP(S) is increased in GPx-oxerexpressing mice relative to WT mice at 24 h and relative to SOD-overexpressing mice at 2 and 24 h following neonatal HI (ANOVA, p < 0.05). There is an increase in Fas DR expression at 24 h in both WT and GPx-overexpressing mice and significant differences between WT and SOD-overexpressing mice (ANOVA, p < 0.01). There is no difference in FADD expression among the 3 groups 24 h after HI. At 24 h following HI, the ratio of FLIP to Fas DR expression supports a significant negative correlation with injury score (r2 = 0.99, slope = -4.01), and expression of both the active fragment of caspase 8 and caspase 8 activity is increased in SOD overexpressors compared to GPx overexpressors at 24 h after HI (ANOVA, p < 0.05). The overall degree of injury previously seen in these 3 strains correlates well with changes in expression of Fas DR signaling proteins favoring neuroprotection in the GPx-overexpressing mice, i.e. increased FLIP expression and decreased caspase 8 activity compared to SODtg mice. The mechanism by which antioxidant status alters FLIP levels following neonatal HI may be related to the ability to detoxify H2O2 produced following neonatal HI.

Platelet count and associated morbidities in VLBW infants with pharmacologically treated patent ductus arteriosus.

OBJECTIVE: Characterize the diagnosis of PDA and the distribution of pretreatment platelet count in pharmacologically managed PDA in infants ≤1500 g and assess the relationship of platelet count to serious morbidities. STUDY DESIGN: This is a retrospective, observational study. In 40 hospitals, data were collected on PDA, including pretreatment platelet count. Distribution of platelet count was examined. The association of platelet count and clinical outcomes of IVH, NEC and PDA closure prior to discharge were examined. Chi-square test was used to compare outcomes by platelet count groups. RESULTS: There were 311 patients treated with medically treated PDA. Pretreatment platelet counts were categorized as 0-119 K, 120-199 K, 200-299 K, >300 K. Incidence and grade of IVH were not significantly different by platelet group. Across all groups: No IVH 62-83%, Grades 1-2 IVH 13-25%, Grades 3-4 IVH 2-13%. NEC occurred in 0-11% of all patients studied. PDA closure rate was 33-45%. CONCLUSION: PDA closure was not significantly affected by platelet count. Platelet count was not a statistically significant factor for development of IVH and NEC in infants born <1500 g with pharmacologically treated PDA.