Subamniotic haemorrhage, a possible new presentation of fetal and neonatal alloimmune thrombocytopenia

Background: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare fetal disease in which maternal antibodies directed towards fetal human platelet antigens (HPA) are formed during pregnancy and cause fetal thrombocytopenia. The diagnosis FNAIT is suspected when a fetus or neonate presents with signs of bleeding. Case: We describe a pregnancy complicated by a placental hematoma in the 20th week of gestation as the first manifestation of FNAIT. Further evaluation showed signs of germinal matrix haemorrhage and HPA-5b allo-antibodies. After the diagnosis, intravenous immunoglobulin was administered weekly and a healthy daughter was born at 37 weeks. Histopathological analysis revealed that the hematoma was caused by a subamniotic haemorrhage of fetal origin. Conclusion: A subamniotic hematoma appears to be the first manifestation of FNAIT.

Predictive Risk Factors for Mild and Severe Germinal Matrix Hemorrhage and Associated Neurodevelopmental Prognosis: A Retrospective Study

Aims: To compare commonly mentioned risk factors between mild germinal matrix hemorrhage-Intraventricular hemorrhage (GMH-IVH) (grade I & II) and severe GMH-IVH (grade III & IV) and to study the long-term neurodevelopmental outcomes in relation to severe GMH-IVH. Study Design: Retrospective cohort study. Place and Duration of Study: Neonatal intensive care unit, King Fahad University Hospital, between 2000 and 2020. Methodology: We included 54 premature infants at ≤36 weeks of gestation and with birth weight <2500g admitted to our neonatal intensive care unit. Premature neonates were divided into two subgroups: mild GMH-IVH (grade I and II) and severe (grade III and IV). We investigated the risk factors and neurodevelopmental outcomes in association with GMH-IVH. Results: Amnionitis (OR: 1.190, 95% CI 0.515-2.749), lower genital tract infection (OR: 1.190, 95% CI 0.515-2.749), antenatal infection (OR: 1.406, 95% CI 0.866-2.283), gestational diabetes mellitus (OR: 1.815, 95% CI 1.410-2.337), usage of inotropes (OR: 1.731, 95% CI 1.348-2.222), APGAR score <7 (OR: 0.806, 95% CI 0.493-1.316), birth trauma (OR: 1.767, 95% CI 1.396-2.236), catecholamines (OR: 1.470, 95% CI 0.903-2.393), intubation (OR: 1.300, 95% CI 0.686-2.464), asphyxia (OR: 1.135, 95% CI 0.718-1.794), Abnormal coagulation (OR: 1.197, 95% CI 0.756-1.896), congenital heart disease (OR: 1.727, 95% CI 1.124-2.653), low hematocrit (OR: 1.140, 95% CI 0.688-1.889), resuscitation (OR: 1,193, 95% CI 0.748- 1.904) and ventriculoperitoneal (VP) shunt as a prognosis of hydrocephalus (P-value: 0.005) all showed a higher incidence with severe GMH-IVH Conclusion: Amnionitis, lower genital tract infection, antenatal infections, GDM, usage of inotropes, APGAR score <7, birth trauma, catecholamines, intubation, asphyxia, resuscitation, abnormal coagulation parameters, congenital heart disease, low hematocrit and hydrocephalus with VP shunt were higher in severe GMH-IVH.

Complement Inhibition Reduces Post-Hemorrhagic Hydrocephalus in Mouse Neonatal Germinal Matrix Hemorrhage

IntroductionGerminal matrix hemorrhage (GMH) is a devastating disease of infancy that results in intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), periventricular leukomalacia and neurocognitive deficits. There are no curative treatments and limited surgical options. We developed a novel mouse model of GMH and investigated the role of complement in PHH development.MethodsWe utilized a neonatal mouse model of GMH involving injection of collagenase into the subventricular zone of post-natal day four (P4) pups. Animals were randomized into four experimental arms: Naïve, sham injured, injured and vehicle (PBS) treated, and injured and CR2Crry-treated (a pan-complement inhibitor). Histopathologic and immunofluorescence analyses were performed at P14 with a focus on parameters of neuroinflammation and neuroprotection. Survival was monitored through day 45, prior to which cognitive and motor function was analyzed.ResultsThe complement inhibitor CR2Crry, which binds C3 complement activation products, localized specifically in the brain following systemic administration after GMH. Compared to vehicle treatment, CR2Crry treatment reduced PHH and lesion size, which was accompanied by decreased perilesional complement deposition, decreased astrocytosis and microgliosis, and the preservation of dendritic and neuronal density. Progression to PHH and neuronal loss was linked to microglial phagocytosis of complement opsonized neurons, which was reversed with CR2Crry treatment. Complement inhibition also improved survival and weight gain, and improved motor performance and cognitive outcomes measured in adolescent GMH mice. ConclusionComplement plays an important role in the pathological sequelae of GMH. Complement inhibition represents a novel therapeutic approach to reduce disease progression in neonatal GMH and PHH, for which there is currently no treatment outside of surgical intervention.

EPCO-11. SINGLE-NUCLEI TRANSCRIPTOMICS RELATES GLIOBLASTOMA INFILTRATION TO DISTINCT GLIAL PROGENITOR STATES

Our understanding of glioblastoma (GBM) intratumoral heterogeneity, particularly in the context of neurodevelopment, has thus far been primarily focused on the more surgically accessible tumor core niche. In contrast, the biology of GBM cells at the infiltrative edge, which evade surgical resection and drive tumor recurrence, remains poorly characterized. To this end, we microdissected and performed single-nuclei RNA sequencing (snRNA-seq) on approximately 62,000 nuclei taken from the tumor core and from the infiltrative edge of six GBM tumors with diverse genomic drivers, including IDH1, EGFR, PDGFRA, FGFR3, and NF1. Unbiased clustering reveals distinct neoplastic and non-neoplastic populations, further distinguished using copy number variation analysis. After projecting previously defined signatures taken from snRNA-seq analysis of human adult neocortex/subventricular zone and prenatal germinal matrix, we find that approximately 90% of tumor cells recapitulate a neurodevelopment-like molecular phenotype, reprising gene expression signatures of prenatal astrocytes and of a distinct glial intermediate progenitor cell population (g-IPC) that precedes both astrocyte and oligodendrocyte lineage differentiation. Examining the infiltrative edge of samples with the most confident microdissection (n=4), we see that while distinct populations of tumor cells in this niche express proneural and classical signatures, these cells are overall enriched for a g-IPC-like phenotype, relative to the tumor core, irrespective of the tumors’ genomic alterations. A subset of cells at the infiltrative edge, in particular, recapitulates the signature of an uncommitted g-IPC subtype, expressing both astroglial and oligodendroglial markers. Trajectory analyses also reveal distinct branches of core and edge tumor cells, which are predominantly astrocyte- and g-IPC-like, respectively. Differential gene expression analysis of GBM cells at the infiltrative edge vs. tumor core reveals a migration signature, dominated by EGFR, ERBB4, PCDH9, and PCDH15. Ultimately, this high resolution analysis of heterogeneity at the infiltrative edge allows us to uncover potentially targetable drivers of invasion in GBM.

White matter injury but not germinal matrix hemorrhage induces elevated osteopontin expression in human preterm brains

Osteopontin (OPN) is a matricellular protein that mediates various physiological functions and is implicated in neuroinflammation, myelination, and perinatal brain injury. However, its expression in association with brain injury in preterm infants is unexplored. Here we examined the expression of OPN in postmortem brains of preterm infants and explored how this expression is affected in brain injury. We analyzed brain sections from cases with white matter injury (WMI) and cases with germinal matrix hemorrhage (GMH) and compared them to control cases having no brain injury. WMI cases displayed moderate to severe tissue injury in the periventricular and deep white matter that was accompanied by an increase of microglia with amoeboid morphology. Apart from visible hemorrhage in the germinal matrix, GMH cases displayed diffuse white matter injury in the periventricular and deep white matter. In non-injured preterm brains, OPN was expressed at low levels in microglia, astrocytes, and oligodendrocytes. OPN expression was significantly increased in regions with white matter injury in both WMI cases and GMH cases. The main cellular source of OPN in white matter injury areas was amoeboid microglia, although a significant increase was also observed in astrocytes in WMI cases. OPN was not expressed in the germinal matrix of any case, regardless of whether there was hemorrhage. In conclusion, preterm brain injury induces elevated OPN expression in microglia and astrocytes, and this increase is found in sites closely related to injury in the white matter regions but not with the hemorrhage site in the germinal matrix. Thus, it appears that OPN takes part in the inflammatory process in white matter injury in preterm infants, and these findings facilitate our understanding of OPN’s role under both physiological and pathological conditions in the human brain that may lead to greater elucidation of disease mechanisms and potentially better treatment strategies.

Germinal Matrix -Intraventricular Hemorrhage: Current Concepts and Future Direction

Germinal Matrix Hemorrhage -Intraventricular hemorrhage (IVH) is a bleed of multifactorial etiology involving the highly vascular and delicate neuro-glial precursors in the developing brain. It poses a challenging complication in preterm newborns. This chapter provides a focused discussion on the current concepts in pathogenesis, management, and complications of IVH. The radiological findings at diagnosis and follow-up and the cytological features of CSF will be valuable to both frontline and diagnostic healthcare providers. The chapter also reviews the ongoing scientific development in the field. The authors believe that this chapter will be a valuable tool for all healthcare providers (students, physicians, and in nursing care) in managing this challenging condition.

Risk Factors for Germinal Matrix Haemorrhage-Intraventricular Haemorrhage in Very Low Birth Weight Infants

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) mainly occurs in preterm neonates and is an important cause of brain injury in them. In this retrospective cross-sectional study from march 2017 to march 2018 in our teaching hospitals, we investigated 250 newborns who were admitted to NICU with a birth weight under 1500 grams with ultrasonographic study for presence and grade of GMH-IVH in their first week of life. Risk factors for GMH-IVH were collected from their records and results been analyzed with SPSS software. From 250 neonates who had inclusion criteria of the study, 22 cases had GMH-IVH in ultrasonographic evaluation. 37.6% of all cases and 31.8% of newborns with GMH-IVH had a 5-minute APGAR score of less than six. 91 cases (39.9%) of the control group and 15 cases (68.1%) of the GMH-IVH group need resuscitation at birth. Of 250 cases 54 (21.6%) died, that 14 cases (63.6%) had GMH-IVH. Our study shows significant differences for birth weight, 5 minute APGAR score, and the need for resuscitation at birth as risk factors for the development of GMH-IVH in very low birth weight neonates, but we do not find a significant difference group in terms of gestational age, gender, route of delivery, fetal presentation, maternal parity, CBC parameters, sepsis, RDS, endotracheal tube suctioning and multiple pregnancies for them. In our study, the protective value for antenatal steroid therapy depends on the completion of the course of treatment for mothers.

The role of the brain-sparing effect of growth-restricted fetuses in newborn germinal matrix/intraventricular hemorrhage

Objectives The aim of the study was to evaluate the effect of the brain-sparing effect (BSE) of fetal growth restriction (FGR) in newborn germinal matrix/intraventricular hemorrhage (GM/IVH). Methods A total of 320 patients who delivered prior to the 34th gestational week were analyzed from data records. 201 patients were divided into two groups according to cerebro-placental ratio (CPR): early fetal growth restriction (FGR) with abnormal CPR group (n=104) and appropriate for gestational age with normal Doppler group (control) (n=97). Using the normal middle cerebral artery (MCA) Doppler as a reference, multivariate logistic regression analysis was used to assess the association between the BSE and the primary outcome. Results The rate of Grade I–II Germinal matrix/intraventricular hemorrhage (GM/IVH) was 31(29.8%) in the group possessing early FGR with abnormal CPR and 7(7.2%) in the control group, showing a statistically significant difference. The rate of grade III–IV GM/IVH was 7(6.7%) in the group possessing early FGR with abnormal CPR and 2 (2.1%) in the control group, showing no statistically significant difference. We found that gestational age at delivery <32 weeks was an independent risk factor for GM/IVH. In addition, we found that other variables such as the presence of preeclampsia, fetal weight percentile <10, emergency CS delivery, 48-h completion after the first steroid administration and 24-h completion rate after MgSO4 administration were not independently associated with the primary outcome. Conclusions Our results indicate that the rate of GM-IVH was increased in the group possessing early FGR with abnormal CPR; however, multivariate logistic regression analysis showed that BSE was not an independent risk factor for GM/IVH.