Germinal Matrix-intraventricular Haemorrhage Research Articles

The miRNA transcriptome of cerebrospinal fluid in preterm infants reveals the signaling pathways that promote reactive gliosis following cerebral hemorrhage.

Germinal Matrix-Intraventricular Haemorrhage (GM-IVH) is one of the most common neurological complications in preterm infants, which can lead to accumulation of cerebrospinal fluid (CSF) and is a major cause of severe neurodevelopmental impairment in preterm infants. However, the pathophysiological mechanisms triggered by GM-IVH are poorly understood. Analyzing the CSF that accumulates following IVH may allow the molecular signaling and intracellular communication that contributes to pathogenesis to be elucidated. Growing evidence suggests that miRs, due to their key role in gene expression, have a significant utility as new therapeutics and biomarkers. The levels of 2,083 microRNAs (miRs) in 15 CSF samples from 10 infants with IVH were measured using miRNA whole transcriptome sequencing. Gene ontology (GO) and miR family analysis were used to uncover dysregulated signalling which were then validated in vitro in human foetal neural progenitor cells treated with IVH-CSF. Five hundred eighty-seven miRs were differentially expressed in the CSF extracted at least 2 months after injury, compared to CSF extracted within the first month of injury. GO uncovered key pathways targeted by differentially expressed miRs including the MAPK cascade and the JAK/STAT pathway. Astrogliosis is known to occur in preterm infants, and we hypothesized that this could be due to abnormal CSF-miR signaling resulting in dysregulation of the JAK/STAT pathway - a key controller of astrocyte differentiation. We then confirmed that treatment with IVH-CSF promotes astrocyte differentiation from human fetal NPCs and that this effect could be prevented by JAK/STAT inhibition. Taken together, our results provide novel insights into the CSF/NPCs crosstalk following perinatal brain injury and reveal novel targets to improve neurodevelopmental outcomes in preterm infants.

Ventriculosubgaleal shunts in the management of neonatal post-haemorrhagic hydrocephalus: technical note.

Germinal matrix / intraventricular haemorrhage (GMIVH) remains a significant complication of prematurity. The more severe grades are associated with parenchymal haemorrhagic infarction (PHI) and hydrocephalus. A temporising procedure is usually the first line in management of neonatal post-haemorrhagic hydrocephalus (nPHH) as the risk of failure of a permanent cerebrospinal fluid (CSF) diversion is higher in the early stage. Our choice of temporising procedure is a ventriculosubgaleal shunt (VSGS). In this technical note, we describe a modification in technique whereby the pocket of the VSGS is fashioned away from the surgical wound. This resulted in lower CSF leak and subsequent infection rates in our centre. We conducted a retrospective analysis of all patients who underwent insertion of a VSGS between September 2014 and February 2023. Twenty children were included in our study with a mean gestational age of 31 weeks + 4 days. Post-operatively, 10% of patients did not need a tap, and 10%, 20%, 15%, 25% and 20% respectively had 1, 2, 3, 4 and 5 taps. Two patients experienced CSF leak from their wounds. In both these patients, the pocket was deemed too close to the wound. None of the patients without suspected pre-existing CNS infection at the time of insertion of VSGS had a subsequent VSGS-related infection. VSGS conversion to permanent ventriculoperitoneal shunts (VPS) was required in 15 (75%) of the patients with an average interval duration of 72 days. On reviewing the literature, the infection rate following VSGS is quoted up to 13.5%. In our own centre, 13 patients had undergone VSGS insertion between 2005 and 2013 with a 30.8% infection rate which seemed related to increased leak rates. Our modified surgical approach seems to be effective in reducing the risk of infection, which we postulate is a direct result of reduction in the risk of leak from the surgical wound.

Clinical value of cortical bursting in preterm infants with intraventricular haemorrhage

BackgroundIn healthy preterm infants, cortical burst rate and temporal dynamics predict important measures such as brain growth. We hypothesised that in preterm infants with germinal matrix-intraventricular haemorrhage (GM-IVH), cortical bursting could provide prognostic information. AimsWe determined how cortical bursting was influenced by the injury, and whether this was related to developmental outcome. Study designSingle-centre retrospective cohort study at University College London Hospitals, UK. Subjects33 infants with GM-IVH ≥ grade II (median gestational age: 25 weeks). Outcome measuresWe identified 47 EEGs acquired between 24 and 40 weeks corrected gestational age as part of routine clinical care. In a subset of 33 EEGs from 25 infants with asymmetric injury, we used the least-affected hemisphere as an internal comparison. We tested whether cortical burst rate predicted survival without severe impairment (median 2 years follow-up). ResultsIn asymmetric injury, cortical burst rate was lower over the worst- than least-affected hemisphere, and bursts over the worst-affected hemisphere were less likely to immediately follow bursts over the least-affected hemisphere than vice versa. Overall, burst rate was lower in cases of GM-IVH with parenchymal involvement, relative to milder structural injury grades. Higher burst rate modestly predicted survival without severe language (AUC 0.673) or motor impairment (AUC 0.667), which was partly mediated by structural injury grade. ConclusionsCortical bursting can index the functional injury after GM-IVH: perturbed burst initiation (rate) and propagation (inter-hemispheric dynamics) likely reflect associated grey matter and white matter damage. Higher cortical burst rate is reassuring for a positive outcome.

RISK FACTORS AFFECTING SEVERITY OF INTRAVENTRICULAR HEMORRHAGE IN PRETERM INFANTS OF AN NICU OF A TERTIARY CARE CENTRE

Background: As severe germinal matrix intraventricular haemorrhage (GM-IVH) causes neurological sequelae in 50–75% of preterm survivors, it is still a major global public health problem. [1].By studying the association and severity with risk factors for IVH in preterms we can make preventive measures for the same. Objective: The purpose of this study is to identify the risk factors associated with the development IVH in the preterm infants of an NICU of a tertiary care centre and the relationship of the severity of disease and these risk factors. Methods: It is a retrospective study. A total of 160 premature neonates of gestational age ≤34 weeks were examined by cranial ultrasound (CUS) for detection of GM-IVH among the babies admitted in neonatal intensive care unit of a tertiary teaching hospital at Pune, Maharashtra. The babies were divided into two groups: GM-IVH and non-IVH. The association and severity of neonatal and maternal risk factors were analysed. Results: In our study, out of 160 neonates, 75 neonates (46.8%) developed intraventricular haemorrhage, of which 8% developed severe IVH (grade 3 and 4). Use of inotropes (p = 0.008), surfactant (p < 0.0001), blood transfusions(p=0.005),HsPDA(p=0.006) were highly significant for developing intraventricular haemorrhage. Conclusions: Clinicians and healthcare policy makers should consider these factors during decision-making coverage of (complete) antenatal steroid therapy, early diagnosis and treatment of PDA with paracetamol/ibuprofen, delayed cord clamping in labour room to prevent hypotension hence, use of inotropes and boluses can prevent GM-IVH in preterms.

Stem cell-based interventions for the prevention and treatment of intraventricular haemorrhage and encephalopathy of prematurity in preterm infants.

Germinal matrix-intraventricular haemorrhage (GMH-IVH) and encephalopathy of prematurity (EoP) remain substantial issues in neonatal intensive care units worldwide. Current therapies to prevent or treat these conditions are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. This is an update of the 2019 review, which did not include EoP. To evaluate the benefits and harms of stem cell-based interventions for prevention or treatment of GM-IVH and EoP in preterm infants. We used standard, extensive Cochrane search methods. The latest search was April 2022. We attempted to include randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing 1. stem cell-based interventions versus control; 2. mesenchymal stromal cells (MSCs) of type or source versus MSCs of other type or source; 3. stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or 4. MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH or EoP; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH or with EoP. We used standard Cochrane methods. Our primary outcomes were 1. all-cause neonatal mortality, 2. major neurodevelopmental disability, 3. GM-IVH, 4. EoP, and 5. extension of pre-existing non-severe GM-IVH or EoP. We planned to use GRADE to assess certainty of evidence for each outcome. We identified no studies that met our inclusion criteria. Three studies are currently registered and ongoing. Phase 1 trials are described in the 'Excluded studies' section. No evidence is currently available to evaluate the benefits and harms of stem cell-based interventions for treatment or prevention of GM-IVH or EoP in preterm infants. We identified three ongoing studies, with a sample size range from 20 to 200. In two studies, autologous cord blood mononuclear cells will be administered to extremely preterm infants via the intravenous route; in one, intracerebroventricular injection of MSCs will be administered to preterm infants up to 34 weeks' gestational age.

Magnetic resonance imaging evaluation of foetal intracranial haemorrhage and the correlation with ultrasound findings and postnatal outcomes.

The aim of the study was to compare the magnetic resonance imaging (MRI) findings of intracranial haemorrhage (ICH) in the middle- and late trimesters and to explore the relationship between the MRI features of foetal ICH and postnatal outcomes. This was a retrospective study which recruited foetal ICH diagnosed by MRI in one tertiary centre from 2015 to 2019. The prenatal and postnatal medical records were reviewed. Of 39 ICH cases, 82.1% (32) had germinal matrix intraventricular haemorrhage (GM-IVH), and 18.9% (7) were diagnosed with non-GM-IVH. The cerebellum, corpus callosum and subdural space were affected in 5, 1 and 1 non-GM-IVH cases, respectively. MRI confirmed possible ICH on sonogram in 10 cases (35.7%) and the remaining 19 added ICH diagnoses that were not obtained on initial ultrasound imaging. Pregnancy outcome data were available in 82.1% of (32) cases, of which 21 were terminated pregnancies, 1 was foetal demise and 10 were delivered. One neonate died after birth and one infant suffered from hearing loss. The remaining eight patients had favourable outcome. In our study, evaluation of the relationship between MRI findings and outcomes remains challenging, depending on the timing of examination and the hematoma itself. MRI was an adjunct to US in diagnosing ICH in utero which helps to assess postnatal development.

Intraventricular haemorrhage and posthaemorrhagic ventricular dilatation: moving beyond CSF diversion

Advances in medical care have led to more premature babies surviving the neonatal period. In these babies, germinal matrix haemorrhage (GMH), intraventricular haemorrhage (IVH) and posthaemorrhagic ventricular dilatation (PHVD) are the most important determinants of long-term cognitive and developmental outcomes. In this review, we discuss current neurosurgical management of IVH and PHVD, including the importance of early diagnosis of PHVD, thresholds for intervention, options for early management through the use of temporising measures and subsequent definitive CSF diversion. We also discuss treatment options for the evolving paradigm to manage intraventricular blood and its breakdown products. We review the evidence for techniques such as drainage, irrigation, fibrinolytic therapy (DRIFT) and neuroendoscopic lavage in the context of optimising cognitive, neurodevelopmental and quality of life outcomes in these premature infants.

Head midline position for preventing the occurrence or extension of germinal matrix-intraventricular haemorrhage in preterm infants.

Head position during care may affect cerebral haemodynamics and contribute to the development of germinal matrix-intraventricular haemorrhage (GM-IVH) in very preterm infants. Turning the head toward one side may occlude jugular venous drainage while increasing intracranial pressure and cerebral blood volume. It is suggested that cerebral venous pressure is reduced and hydrostatic brain drainage improved if the infant is cared for in the supine 'head midline' position. To assess whether head midline position is more effective than other head positions for preventing (or preventing extension) of GM-IVH in very preterm infants (< 32 weeks' gestation at birth). We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), MEDLINE via PubMed (1966 to 12 September 2019), Embase (1980 to 12 September 2019), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 12 September 2019). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles. Randomised controlled trials (RCTs) comparing caring for very preterm infants in a supine head midline position versus a prone or lateral decubitus position, or undertaking a strategy of regular position change, or having no prespecified position. We included trials enrolling infants with existing GM-IVH and planned to assess extension of haemorrhage in a subgroup of infants. We planned to analyse horizontal (flat) versus head elevated positions separately for all body positions. We used standard methods of Cochrane Neonatal. For each of the included trials, two review authors independently extracted data and assessed risk of bias. The primary outcomes were GM-IVH, severe IVH, and neonatal death. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data; and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of evidence. Three RCTs, with a total of 290 infants (either < 30 weeks' gestational age or < 1000 g body weight), met the inclusion criteria. Two trials compared supine midline head position versus head rotated 90° with the cot flat. One trial compared supine midline head position versus head rotated 90° with the bed tilted at 30°. We found no trials that compared supine versus prone midline head position. Meta-analysis of three trials (290 infants) did not show an effect on rates of GM-IVH (RR 1.11, 95% confidence interval (CI) 0.78 to 1.56; I² = 0%) and severe IVH (RR 0.71, 95% CI 0.37 to 1.33; I² = 0%). Neonatal mortality (RR 0.49, 95% CI 0.25 to 0.93; I² = 0%; RD -0.09, 95% CI -0.16 to -0.01) and mortality until hospital discharge (typical RR 0.50, 95% CI 0.28 to 0.90; I² = 0%; RD -0.10, 95% CI -0.18 to -0.02) were lower in the supine midline head position. The certainty of the evidence was very low for all outcomes because of limitations in study design and imprecision of estimates. We identified one ongoing study. We found few trial data on the effects of head midline position on GM-IVH in very preterm infants. Although meta-analyses suggest that mortality might be reduced, the certainty of the evidence is very low and it is unclear whether any effect is due to cot tilting (a co-intervention in one trial). Further high-quality RCTs would be needed to resolve this uncertainty.

Altered cortical processing of somatosensory input in pre-term infants who had high-grade germinal matrix-intraventricular haemorrhage.

High-grade (large) germinal matrix-intraventricular haemorrhage (GM-IVH) is one of the most common causes of somatomotor neurodisability in pre-term infants. GM-IVH presents during the first postnatal week and can impinge on somatosensory circuits resulting in aberrant somatosensory cortical events straight after injury. Subsequently, somatosensory circuits undergo significant plastic changes, sometimes allowing the reinstatement of a somatosensory cortical response. However, it is not known whether this restructuring results in a full recovery of somatosensory functions. To investigate this, we compared somatosensory responses to mechanical stimulation measured with 18-channels EEG between infants who had high-grade GM-IVH (with ventricular dilatation and/or intraparenchymal lesion; n=7 studies from 6 infants; mean corrected gestational age=33 weeks; mean postnatal age=56 days) and age-matched controls (n=9 studies from 8 infants; mean corrected gestational age=32 weeks; mean postnatal age=36 days). We showed that infants who had high-grade GM-IVH did not recruit the same cortical source configuration following stimulation of the foot, but their response to stimulation of the hand resembled that of controls. These results show that somatosensory cortical circuits are reinstated in infants who had GM-IVH, during the several weeks after injury, but remain different from those of infants without brain injury. An important next step will be to investigate whether these evidences of neural reorganisation predict neurodevelopmental outcome.

Neonatal care bundles are associated with a reduction in the incidence of intraventricular haemorrhage in preterm infants: a multicentre cohort study

ObjectiveTo investigate the effect of a nursing intervention bundle, applied during the first 72 hours of life, on the incidence of germinal matrix-intraventricular haemorrhage (GMH-IVH) in very preterm infants.DesignMulticentre cohort...

Two-dimensional ultrasound measurements vs. magnetic resonance imaging-derived ventricular volume of preterm infants with germinal matrix intraventricular haemorrhage

BackgroundPost-haemorrhagic ventricular dilatation can be measured accurately by MRI. However, two-dimensional (2-D) cranial US can be used at the bedside on a daily basis.ObjectiveTo assess whether the ventricular volume can be determined accurately using US.Materials and methodsWe included 31 preterm infants with germinal matrix intraventricular haemorrhage. Two-dimensional cranial US images were acquired and the ventricular index, anterior horn width and thalamo-occipital distance were measured. In addition, cranial MRI was performed. The ventricular volume on MRI was determined using a previously validated automatic segmentation algorithm. We obtained the correlation and created a linear model between MRI-derived ventricular volume and 2-D cranial US measurements.ResultsThe ventricular index, anterior horn width and thalamo-occipital distance as measured on 2-D cranial US were significantly associated with the volume of the ventricles as determined with MRI. A general linear model fitted the data best: ∛ventricular volume (ml) = 1.096 + 0.094 × anterior horn width (mm) + 0.020 × thalamo-occipital distance (mm) with R2 = 0.831.ConclusionThe volume of the lateral ventricles of infants with germinal matrix intraventricular haemorrhage can be estimated using 2-D cranial US images by application of a model.

Stem cell-based interventions for the prevention and treatment of germinal matrix-intraventricular haemorrhage in preterm infants.

Germinal matrix-intraventricular haemorrhage (GMH-IVH) remains a substantial issue in neonatal intensive care units worldwide. Current therapies to prevent or treat GMH-IVH are limited. Stem cell-based therapies offer a potential therapeutic approach to repair, restore, and/or regenerate injured brain tissue. These preclinical findings have now culminated in ongoing human neonatal studies. To determine the benefits and harms of stem cell-based interventionsfor prevention or treatment of germinal matrix-intraventricular haemorrhage (GM-IVH) in preterm infants. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1), in the Cochrane Library; MEDLINE via PubMed (1966 to 7 January 2019); Embase (1980 to 7 January 2019); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 7 January 2019). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We attempted to identify randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing (1) stem cell-based interventions versus control; (2) mesenchymal stromal cells (MSCs)of type or source versus MSCs of other type or source; (3) stem cell-based interventions other than MSCs of type or source versus stem cell-based interventions other than MSCs of other type or source; or (4) MSCs versus stem cell-based interventions other than MSCs. For prevention studies, we included extremely preterm infants (less than 28 weeks' gestation), 24 hours of age or less, without ultrasound diagnosis of GM-IVH; for treatment studies, we included preterm infants (less than 37 weeks' gestation), of any postnatal age, with ultrasound diagnosis of GM-IVH. For each of the included trials, two review authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, type and source of MSCs, other stem cell-based interventions) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). Primary outcomes considered in this review are all-cause neonatal mortality, major neurodevelopmental disability, GM-IVH, and extension of pre-existing non-severe GM-IVH. We planned to use the GRADE approach to assess the quality of evidence. Our search strategy yielded 769 references. We did not find any completed studies for inclusion. One randomised controlled trial is currently registered and ongoing. Five phase 1 trials are described in the excluded studies. Currently no evidence is available to show the benefits or harms of stem cell-based interventions for treatment or prevention of GM-IVH in preterm infants.

Does an elevated midline head position prevent periventricular-intraventricular haemorrhage in extremely low birth weight neonates?

Kochan M, Leonardi B, Firestine A, McPadden J, Cobb D, Shah TA, et al. Elevated midline head positioning of extremely low birth weight infants: effects on cardiopulmonary function and the incidence of periventricular-intraventricular hemorrhage. J Perinatol 2019, 39(1): 54-62. Germinal matrix-intraventricular haemorrhage (IVH) of the premature infant is the most common form of neonatal intracranial haemorrhage. A portion of infants with IVH suffer a related parenchymal injury called periventricular haemorrhagic infarction. Fluctuations in cerebral blood flow and increases in cerebral venous pressure have been implicated in the pathogenesis of these injuries 1. Head position can affect cerebral haemodynamics and has been evaluated for preventing IVH 2. A recent systematic review evaluated trials involving head positioning strategies to prevent IVH, reviewed two trials (n = 110), and found insufficient evidence to determine the effectiveness of a particular strategy 3. Both trials reviewed and examined the effect of head rotation. No trials were identified which investigated head elevation 3, 4. The current study aims to close this knowledge gap. This single-centre, prospective, randomized trial compared the use of an elevated midline head position to a flat head position for the prevention of intracranial haemorrhage in neonates <1000 g at birth. Baseline characteristics differed among the groups with more pre-eclampsia in the treatment group and more prolonged rupture in the control group. There was no difference in the primary outcome. However, there was improved survival and decreased grade IV (but not grade III) IVH in the treatment group. There was a trend towards escalating respiratory support in the treatment group. Of interest, none of the infants with grade IV IVH developed cystic PVL. A strength of the study included the early enrolment by four hours of life. Although enrolment at birth (with prenatal consent) would be preferred, this may be impractical as flat positioning may be required during initial stabilization procedures. There is a risk for bias with this study as it is unclear if allocation was concealed. Although the interpreting radiologists were blinded, blinding of all caretakers is not possible when evaluating this intervention. It is unclear if the effect of the intervention was due to the absence of periodic turning or the elevation, as infants in the two groups were treated differently in both regards. In fact, the control group may have been affected by compromised venous return due to turning the head only rather than head and body. A weakness of the study is the lack of long-term developmental follow-up. As demonstrated in the largest trial of prophylactic indomethacin, a decrease in severe IVH does not always produce an improvement in long-term developmental outcome 5. Another weakness is the lack of magnetic resonance imaging (MRI) to assess for periventricular leukomalacia (PVL). Mean blood pressures were slightly higher in the elevated group, but cerebral perfusion may have been affected by the elevation placing the infants at risk for PVL. These results suggest that an elevated head position may be beneficial over flat supine head positioning with periodic turning for improving survival and decreasing grade IV IVH. Further, the results suggest that the control and intervention conditions are both safe with no harm shown in either group. With the differences in baseline characteristics, lack of allocation concealment, lack of MRI to assess for PVL, and most importantly, lack of developmental follow-up, it is not possible to strongly suggest a practice change from the results of this trial. However, these results should inform the design of a large, multicentre trial of this simple intervention. https://ebneo.org/2019/06/head-position-intraventricular-hemorrhage/ None. None.

Stem cell-based interventions for the prevention and treatment of germinal matrix-intraventricular haemorrhage in preterm infants

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine the efficacy and safety of stem cell‐based interventions for the prevention or treatment of germinal matrix‐intraventricular haemorrhage (GM‐IVH) in preterm infants.

The effects of mild germinal matrix-intraventricular haemorrhage on the developmental white matter microstructure of preterm neonates: a DTI study.

To evaluate white matter (WM) microstructural changes in preterm neonates (PN) with mild germinal matrix-intraventricular haemorrhage (mGMH-IVH) (grades I and II) and no other associated MRI abnormalities, and correlate them with gestational age (GA) and neurodevelopmental outcome. Tract-based spatial-statistics (TBSS) was performed on DTI of 103 patients studied at term-equivalent age, to compare diffusional parameters (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD)) between mGMH-IVH neonates (24/103) and controls matched by GA at birth and sex. The relationship between DTI abnormalities, GA and neurodevelopmental outcome assessed with Griffiths' Developmental Scale-Revised:0-2 was explored using TBSS and Spearman-correlation analysis (p < .05). Affected neonates had lower FA, higher RD and MD of the corpus callosum, limbic pathways and cerebellar tracts. Extremely preterm neonates (GA < 29 weeks) presented more severe microstructural impairment (higher RD and MD) in periventricular regions. Neonates of GA ≥ 29 weeks had milder WM alterations (lower FA), also in subcortical WM. DTI abnormalities were associated with poorer locomotor, eye-hand coordination and performance outcomes at 24 months. WM microstructural changes occur in PN with mGMH-IVH with a GA-dependent selective vulnerability of WM regions, and correlate with adverse neurodevelopmental outcome at 24 months. • DTI-TBSS analysis identifies WM microstructural changes in preterm neonates with mGMH-IVH. • Extremely preterm neonates with mGMH-IVH presented more severe impairment of WM microstructure. • Extremely preterm neonates with mGMH-IVH presented microstructural impairment of periventricular WM. • mGMH-IVH affects subcortical WM in preterm neonates with gestational age ≥ 29 weeks. • WM microstructural alterations are related to neurodevelopmental impairments at 24 months.

Heparin for the prevention of intraventricular haemorrhage in preterm infants.

Preterm birth remains the major risk factor for the development of intraventricular haemorrhage, an injury that occurs in 25% of very low birth weight infants. Intraventricular haemorrhage is thought to be venous in origin and intrinsic thromboses in the germinal matrix are likely to play a triggering role. Heparin activates antithrombin and promotes the inactivation of thrombin and other target proteinases. The administration of anticoagulants such as heparin may offset the increased risk of developing intraventricular haemorrhage and may also reduce the risk of developing parenchymal venous infarct, a condition known to complicate intraventricular haemorrhage. To assess whether the prophylactic administration of heparin reduces the incidence of germinal matrix-intraventricular haemorrhage in very preterm neonates when compared to placebo, no treatment, or other anticoagulants. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2015), MEDLINE (1996 to 22 November 2015), EMBASE (1980 to 22 November 2015) and CINAHL (1982 to 22 November 2015), applying no language restrictions. We searched the abstracts of the major congresses in the field (Perinatal Society of Australia and New Zealand and Pediatric Academic Societies) from 2000 to 2015. Randomised controlled trials, quasi-randomised controlled trials and cluster trials comparing the administration of early, i.e. within the first 24 hours of life, heparin in very preterm infants (gestational age < 32 weeks). For each of the included trials, two authors independently extracted data (e.g. number of participants, birth weight, gestational age, dose of heparin, mode of administration, and duration of therapy, etc.) and assessed the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow up). The primary outcomes considered in this review are intraventricular haemorrhage, severe intraventricular haemorrhage and neonatal mortality. Two randomised controlled trials enrolling a total of 155 infants met the inclusion criteria of this review. Both trials compared low-dose heparin to the same solution without heparin in very preterm newborns requiring umbilical catheterisation. No trials were identified that specifically studied the use of heparin in infants at risk of germinal matrix-intraventricular haemorrhage.We found no differences in the rates of intraventricular haemorrhage (typical RR 0.93, 95% CI 0.61 to 1.41; typical RD -0.03, 95% CI -0.17 to 0.12; 2 studies, 155 infants; I² = 57% for RR and I² = 65% for RD), severe intraventricular haemorrhage (typical RR 1.01, 95% CI 0.46 to 2.23; typical RD 0.00, 95% CI -0.11 to 0.11; 2 studies, 155 infants; I² = 0% for RR and I² = 0% for RD) and neonatal mortality (typical RR 0.69, 95% CI 0.28 to 1.67; typical RD -0.04, 95% CI -0.14 to 0.06; 2 studies, 155 infants; I² = 28% for RR and I² = 50% for RD). We judged the quality of the evidence supporting these findings as very low (rates of intraventricular haemorrhage) and low (severe intraventricular haemorrhage and neonatal mortality) mainly because of limitations in the study designs and the imprecision of estimates. We found very few data on other relevant outcomes, such as bronchopulmonary dysplasia, pulmonary haemorrhage and patent ductus arteriosus; and no study assessing long-term outcomes (e.g. neurodevelopmental disability). There is very limited data on the effect of prophylactic administration of heparin on the incidence and severity of IVH in very preterm neonates. Both the identified trials used heparin in the context of maintaining umbilical line patency and not specifically as an agent to prevent germinal matrix-intraventricular haemorrhage. Given the imprecision of our estimates, the results of this systematic review are consistent with either a benefit or a detrimental effect of heparin and do not provide a definitive answer to the review question. Limited evidence is available on other clinically relevant outcomes.

Different gestational ages and changing vulnerability of the premature brain

In recent decades, there has been a general increase in survival rates of preterm and low birth weight infants, but this overall decrease in perinatal mortality has not been accompanied by a decrease in long-term physical and mental disability. In order to reduce the long-term sequelae of prematurity and to establish preventive measures, it is important to identify risk factors since the main determinant of specific vulnerability to different types of lesions is gestational age. The regional tissue vulnerability at a given gestational age is probably determined by the local metabolic requirements together with specific cell characteristics and their level of maturation. In this article, we discuss the most common neonatal cerebral lesions (cerebellar haemorrhage, germinal matrix intraventricular haemorrhage, periventricular leukomalacia, arterial ischaemic stroke, cerebral vein sinus thrombosis and hypoxic-ischaemic encephalopathy) related to the gestational age-dependent vulnerability of the premature brain.

From germinal matrix to cerebellar haemorrhage

For many years cerebellar development after preterm birth has been poorly investigated and has been studied without taking germinal matrix-intraventricular haemorrhage into account. Advanced neuroimaging techniques like magnetic resonance imaging, as well as the use of various acoustic windows (mastoid fontanelle, occipital foramen) have allowed for in vivo diagnosis of acquired focal haemorrhagic lesions in the cerebellum of very preterm babies. The vulnerability of the cerebellum also seems to be related to specific gestational ages, i.e., between 23 and 27 weeks, when rapid growth in cerebellar volume occurs and at a much faster rate than mean brain volume increase. In this paper, the contribution of the cerebellum in long-term motor cognitive, learning and behavioural functions, including psychiatric ones, is discussed.

Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair?

As clinicians attempt to understand the underlying reasons for the vulnerability of different regions of the developing brain to injury, it is apparent that little is known as to how hypoxia-ischemia may affect the cerebrovasculature in the developing infant. Most of the research investigating the pathogenesis of perinatal brain injury following hypoxia-ischemia has focused on excitotoxicity, oxidative stress and an inflammatory response, with the response of the developing cerebrovasculature receiving less attention. This is surprising as the presentation of devastating and permanent injury such as germinal matrix-intraventricular haemorrhage (GM-IVH) and perinatal stroke are of vascular origin, and the origin of periventricular leukomalacia (PVL) may also arise from poor perfusion of the white matter. This highlights that cerebrovasculature injury following hypoxia could primarily be responsible for the injury seen in the brain of many infants diagnosed with hypoxic-ischemic encephalopathy (HIE). Interestingly the highly dynamic nature of the cerebral blood vessels in the fetus, and the fluctuations of cerebral blood flow and metabolic demand that occur following hypoxia suggest that the response of blood vessels could explain both regional protection and vulnerability in the developing brain. However, research into how blood vessels respond following hypoxia-ischemia have mostly been conducted in adult models of ischemia or stroke, further highlighting the need to investigate how the developing cerebrovasculature responds and the possible contribution to perinatal brain injury following hypoxia. This review discusses the current concepts on the pathogenesis of perinatal brain injury, the development of the fetal cerebrovasculature and the blood brain barrier (BBB), and key mediators involved with the response of cerebral blood vessels to hypoxia.

Hidrocefalia poshemorrágica asociada a la prematuridad: evidencia disponible diagnóstica y terapéutica

Intraventricular haemorrhage and posthemorrhagic hydrocephalus are the most important neurological complications in preterm infants during the neonatal period. The prevalence of germinal matrix intraventricular haemorrhage widely varies depending on the population of study, but it is in any case increasing due both to the higher incidence of multiple and preterm deliveries as well as the longer survival of preterm infants favoured by recent advances in perinatal care. It is therefore of the utmost convenience to be familiar with the most important clinical evidence regarding this entity. However, the available evidence is often incomplete and piecemeal. The objective of the present review is to summarise the main diagnostic and therapeutic points regarding preterm related posthemorrhagic hydrocephalus. The participants of the working-group in Pediatric Neurosurgery of the Spanish Society of Neurosurgery were asked to write these recommendations down. This hopefully represents the first step towards the definition of a clinical guide in the treatment of complications related to periventricular hemorrhage of the preterm infants.