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REVIEW ARTICLE |
https://doi.org/10.5005/jp-journals-11002-0097 |
Intracranial Hemorrhage in Neonates: Causes, Diagnosis, and Management
1Department of Neurosurgery, Surgical clinic of Azerbaijan Medical University, Azerbaijan
2Department of Pediatric Radiology, Texas Children’s Hospital, Houston, Texas, United States of America
3Global Newborn Society, Clarksville, Maryland, United States of America, https://www.globalnewbornsociety.org/
4Department of Pediatric Neurology, King Saud Medical City, Kingdom of Saudi Arabia
5Department of Neonatology, King Saud Medical City, Kingdom of Saudi Arabia
Corresponding Author: Roya Huseynova, Department of Neonatology, King Saud Medical City, Kingdom of Saudi Arabia, Phone: +00966508463068, e-mail: huseynova_roya@yahoo.com.
How to cite this article: Huseynov O, Huisman TAGM, Hassan AS, et al. Intracranial Hemorrhage in Neonates: Causes, Diagnosis, and Management. Newborn 2024;3(2):111–123.
Source of support: Nil
Conflict of interest: Dr Thierry AGM Huisman is associated as the Editorial Board Member of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of this Editorial Board Member and his research group.
Received on: 22 May 2024; Accepted on: 20 June 2024; Published on: 21 June 2024
ABSTRACT
The incidence of symptomatic intracranial hemorrhage (ICH) in newborn infants may be up to 1:2,000 spontaneous births, 1:850 vacuum extractions, and 1:650 forceps-assisted deliveries. Intracranial hemorrhage is frequently associated with adverse neurodevelopmental outcomes in neonates as the perinatal period is a crucial window for brain development. In term neonates, ICH usually occurs during labor due to mechanical injury. On the other hand, preterm infants frequently develop ICH due to hemodynamic instability and fragility of the germinal matrix (GM) vasculature. Based on the location of the hemorrhage, ICH is usually described as epidural, subdural, subarachnoid, intraventricular, and parenchymal bleeds. The cause of neonatal ICH is multifactorial and includes hemorrhage related to prematurity, hemorrhagic stroke, infection, vascular malformations, bleeding disorders, and genetic causes. Iatrogenic coagulopathy during cardiopulmonary bypass/extracorporeal membrane oxygenation (ECMO) can also be a cause. Most patients can be managed without surgical intervention. Some symptomatic infants may need neurosurgical procedure(s) such as external ventricular drainage and/or ventriculoperitoneal shunt(s). The neurodevelopmental outcomes vary according to the maturation of the brain, etiology, place, and extent of the hemorrhage. Clinically concerning complications may include developmental delay, leukomalacia, convulsion, cerebral palsy, and other neurological disorders. In this article, we have reviewed the types, etiology, severity, and clinical outcomes of neonatal ICH.
Keywords: Epidural, Germinal matrix vasculature, Hemorrhagic stroke, Infant, Infection, Intraventricular, Newborn, Parenchymal, Subdural, Subarachnoid.
KEY POINTS
Intracranial hemorrhage is a frequently noted finding in neonates. Severe hemorrhages can result in devastating neurodevelopmental outcomes as the neonatal period is a critical window for brain development.
The causes of ICH differ in preterm and term infants. Term neonates tend to develop ICH due to mechanical injury during labor. In preterm infants, ICH may reflect hemodynamic instability, coagulopathy, and/or vascular fragility.
The neurodevelopmental outcomes vary according to the maturation of the brain, etiology, place, and extent of the hemorrhage.
Most patients can be managed without surgical intervention. Some symptomatic infants may need neurosurgical procedure(s) with ventricular drainage.
Neurodevelopmental outcomes of ICH in infants vary according to the maturation of the brain, etiology, place, and extent of the hemorrhage. Developmental delay, cerebral palsy, seizures, and movement disorders are frequently seen.
INTRODUCTION
Intracranial hemorrhage is a leading cause of adverse neurological outcomes in infants as it affects the developing brain during a crucial period of structural–functional maturation.1,2 In term neonates, ICH occurs mainly during labor due to mechanical injury, whereas in preterm infants, it likely results from hemodynamic instability and fragility of the germinal matrix (GM) vasculature.3,4 Based on the location, ICH is usually described in epidural, subdural, subarachnoid, intraventricular, and parenchymal categories.5 The etiopathogenesis of neonatal ICH remains unclear, and it could well be multifactorial with contributions from vascular immaturity, ischemia (hemorrhagic stroke), infection, vascular malformations, the still-evolving coagulation system, and genetics.6 In critically ill infants, there could also be iatrogenic factors such as thoracic overinflation in ventilated infants and extracorporeal membrane oxygenation (ECMO) applied in those with severe cardiorespiratory failure.3,7 Usage of anticoagulant agents for the prevention of thrombus formation in the circuit, and disturbance of cerebral autoregulation secondary to fluctuations in the systemic pressure may predispose to ICH.8,9
The neurodevelopmental outcomes of infants with ICH vary according to the maturation of their brain, and the etiology, place, and extent of the hemorrhage.1 There can be complications such as ventriculomegaly due to adhesions along the Sylvian aqueduct, outlets of the 4th ventricle, or hemosiderosis with obstruction of the pachionic granulations.10,11 Most are managed without surgical intervention.10,12–14 Some require neurosurgical procedure(s) such as external ventricular drainage or ventriculoperitoneal (VP) shunt.15 There might be complications including developmental delay, leukomalacia, seizures, cerebral palsy, and other neurological disorders.16 The seizures can be subclinical, so electroencephalographic monitoring should be considered in all cases with large ICH.17 In this article, we have reviewed the types, etiology, severity, and clinical outcomes of neonatal ICH.
Subdural and Epidural Hemorrhage
During vaginal deliveries, vertical molding of the skull predisposes to stretching and tearing of bridging veins including dural sinuses along may produce subdural hemorrhage (SDH).3,18 Epidural hemorrhage (EH) occurs in neonates mainly after birth-related head trauma with damage to the meningeal artery(-ies) and consequent bleeding into the epidural space.3,16 Most cases result from biomechanical stress related to a relatively-large fetal cranium, breech presentation, rigid maternal pelvis, frontal-occipital elongation, very rapid or prolonged labor, or instrumental deliveries.19,20 SDHs are seen in up to 8% of all term deliveries; EHs occur less frequently (<2%).21,22
Clinical Presentation
Large hematomas may present with signs of brainstem compression such as opisthotonos, fixed pupils, and apnea.3 These infants may present with anemia, and signs of increased intracranial pressure (ICP) such as wide-open sutures and bulging fontanelle(s).23 Hematomas over the cerebral convexity may present with seizures.24 EHs can be associated with large cephalohematomas or skull fractures.25 Most small EHs and SDHs remain asymptomatic.3
Neonates with SDHs/EHs should be closely monitored and have serial imaging to exclude other brain injuries and the progression of these bleeds.26 Some EHs can show both venous and arterial injuries.27 However, the middle meningeal artery is less susceptible to injury than in adults as it is more mobile and usually does not get trapped in osseous grooves close to skull fracture(s).28 Small skull hemorrhages are frequently seen after vaginal delivery but these typically resolve without any intervention or clinical sequelae.29 The size of these hemorrhages is not a major determinant of neurological outcomes in these infants.30
Diagnosis
Magnetic resonance imaging (MRI) is the best tool for diagnosis of SDH or EH.31 Computed tomography (CT) can be considered if the patient is hemodynamically unstable or an MRI cannot be obtained urgently. Lumbar puncture (LP) is contraindicated in cases with suspected large hematomas because of the risk of acute brain herniation due to the loss of cerebrospinal fluid.32 An LP should be considered only after neuroimaging has been done.
Management and Prognosis
Most cases of SDH need only supportive management, including initial stabilization with volume replacement and respiratory support as needed; surgical intervention is usually not needed.33 Only infants with very large SDHs with acute pressure changes and brainstem dysfunction sometimes require surgical evacuation.34 Laboratory investigations to rule out bleeding abnormalities and/or sepsis should be considered in these infants.
Infants with non-surgical SDH and EH have an excellent prognosis.33 Those requiring aspiration of the hematoma also do well if the procedure is performed in a timely fashion; many of these procedures can now be guided by interventional radiology if no other parenchymal pathology is notable. These patients should be followed for the development of hydrocephalus.35
Subarachnoid Hemorrhage (SAH)
Subarachnoid hemorrhage usually occurs because of the rupture of the leptomeningeal vessels or bridging veins of the subarachnoid space.3 These bleeds usually occur due to injury to pial arteries in the subarachnoid or the subpial space, which rupture into the adjacent subarachnoid space.36 In some cases, SAH may result from the redistribution of intraventricular blood after a GM hemorrhage.37
Clinical Presentation
Neonates with severe SAH may present with lethargy and/or seizures.38 Very mild SAH may be silent. In some cases, SAH may trigger arterial vasospasm and cause ischemic injury in the brain structures perfused by these vessels.39 Such vasospasm can be examined by duplex sonography or digital subtraction angiography.40
Diagnosis
Magnetic resonance imaging is preferred over CT to confirm the diagnosis of SAH as there is no radiation and it is more sensitive for excluding other parenchymal pathologies.41 Cranial ultrasound (CUS) is less sensitive than either for detection of small SAHs and should be used only if the patient is not stable for transport for MRI or CT.42 The image through the mastoid fontanel is preferred for excluding subarachnoid hemorrhages within the basal and peri-mesencephalic cisterns.19 Magnetic resonance angiography (MRA) can help evaluate the degree of vasospasm and may also exclude vascular anomalies such as arteriovenous malformations or aneurysms.43
Management and Prognosis
Management of SAH includes symptomatic support, if needed, usage of anti-seizure medications.44 In severe hemorrhage, blood transfusion, cardiovascular support, and neurosurgical intervention should be considered. Furthermore, moderate-to-severe SAH can be associated with hydrocephalus; serial head circumference measurements and follow-up cUS scans should be done in these neonates.45 Transcranial Doppler and continuous intravenous milrinone infusion may be helpful in the diagnostic approaches and treatment of cerebral vasospasm.46
INTRAPARENCHYMAL HEMORRHAGE (IPH)
Etiology and Pathogenesis
The term intraparenchymal hemorrhage (IPH) refers to bleeding into the cerebral or cerebellar parenchyma.47 Cerebral hemorrhages can be either: (a) primary, which are seen less frequently and are usually related to ruptured aneurysms or arteriovenous malformations; and (b) secondary, which may occur due to venous infarction in large GM hemorrhages-intraventricular hemorrhages (GM-IVHs) in preterm infants, or in IPHs seen in regions affected by hypoxic-ischemic injury. Other causes of IPH may include the extension from large SAHs, SDHs, or due to coagulation disorders, significant trauma, or dural sinus thromboses.
Intracerebellar hemorrhage happens mainly in preterm neonates.48 Some cases show these lesions as an extension of large SAHs or SDHs in the posterior fossa.
Clinical Presentation of IPH
Clinical presentation depends on the location and size of the IPHs. In term neonates, the clinical manifestation may include irritability, lethargy, focal neurological signs, such as asymmetry of the movements/tone, and seizures. Most preterm neonates tend to have very minimal clinical manifestations.47
Diagnosis
Cranial US through the mastoid and posterior fontanelles is a good, convenient tool to detect these bleeds. The best tool for diagnosis of ICH is MRI with magnetic resonance venography/angiography (MRA/MRV) to determine sinus venous thrombosis, lack of flow distal to an arterial embolus, or vascular anomalies.49
Management and Prognosis
Small hemorrhages require observation and symptomatic therapy. Large IPHs may need surgical management. It is essential to rule out dural sinus thrombosis and infection because these may be associated with further progressive injury affecting neurological outcomes.49
The prognosis depends on the size and location of the IPH. Small IPH may have minimal long-term complications, while large ones may result in motor deficits, feeding problems, severe neurodevelopmental impairment (NDI), and seizures.50
In term infants, cerebellar hemorrhage is usually a relatively benign event, although hypotonia, ataxia, nystagmus, and mild cognitive dysfunction may occur.51 In preterm neonates, large cerebellar hemorrhages may result in severe cognitive and motor disability. Cerebellar hemorrhages with subsequent loss of cerebellar tissue have been linked to autism, behavioral disorders, and developmental delay later in life.52 However, there may be minor or no neurological deficit in small cerebellar hemorrhages in both term and preterm neonates.53
Pathogenesis of GMH-IVH in Preterm Neonates
Intracerebral hemorrhages in premature infants typically begin in the GM.4 This is a highly vascularized neuroepithelial zone with metabolically active, proliferating neuroblasts and glia.6 Germinal matrix is prominent along the full extent of the lateral ventricles in the fetal brain beginning at 7–8 weeks and peaks around 24 weeks’ gestation. It then begins to involute and almost disappears by 36–37 weeks.54 In extremely premature infants, the hemorrhage can be seen in adjoining regions all around the lateral ventricles. With advancing gestation, the region around the caudothalamic groove persists the longest during gestation and consequently, most GMH occur in this region in mid-gestation infants.55,56
The pathogenesis of these hemorrhages is complex and likely multifactorial.57,58 The technological and scientific advances in neonatal intensive care have improved the survival of extremely preterm neonates and hence, by extension, led to a relative increase in the number of preterm neonates at high risk of developing GM-IVH.59 The incidence of these hemorrhages is inversely related to gestational age and most commonly occurs in neonates of ≤32 weeks’ gestation. The incidence range of GM-IVH has been reported at 5–52% (Asia-5–36%, North America up to 22%, and Europe 5–52%).60 Mild GV-IVHs constitute about 60% and 25% are severe.61 Nearly, half of all GM-IVHs occur in the first 6 hours, and the occurrence becomes very uncommon after the 5th postnatal day.62
Germinal matrix hemorrhage-intraventricular hemorrhagecan be restricted to the GM, involve lateral cerebral ventricle(s), or cause periventricular hemorrhagic infarction (PVHI).63 Most affected infants are asymptomatic. The neurodevelopmental outcomes are determined by the underlying etiology, maturity of the brain, site, and extension of the hemorrhage. Abnormal neurodevelopmental outcomes such as post hemorrhagic hydrocephalus (PHH), seizures, cerebral palsy, and impaired cognitive, hearing, and visual impairment may occur. No optimal treatment exists; potential interventions currently under evaluation include stem cell treatment and endoscopic removal of clots.64 Our current understanding of the pathogenesis of these hemorrhages is summarized below:
(a) Fragility of the Cerebral Vasculature
Germinal matrix contains an immature, extensive vascular rete, a network of fragile, irregular vessels that are not supported by a robust-looking basement membrane; the endothelium contains only a few tight junctions; and the surrounding astrocytes contain lesser-than-usual glial fibrillary acidic protein in the end-feet. These structural deficiencies make the GM vasculature more fragile, and consequently, increase the risk of hemorrhage.54 The high vascularity in the GM increases the risk of hemorrhage in these regions as compared with the lesser vascularity regions in other parts of the brain. Furthermore, this fine capillary network drains into the deep venous system, which forms a terminal vein that deviates in a U-turn and drains into the internal vein circulation. These flow patterns increase the risk of GM-IVH even more.65
The etiopathogenesis of GM-IVH is still being elucidated. It is likely multifactorial; the three most important risk factors are prematurity, fragility of GM vasculature, and fluctuations in cerebral blood flow (CBF).56,66,67 Increased expression of several factors during hypoxia and hypotension, such as cyclo-oxygenase 2 (COX-2), prostaglandins (PGs), epidermal growth factor receptor, and inflammatory modulators such as transforming growth factor, interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF) is likely to be important.6,68–70 These mediators may disrupt tight junctions, modulate the blood–brain barrier, and activate microglia. Microglial activation can stimulate the release of reactive oxygen species (ROS), which can damage the endothelium, alter hemostasis, and increase anaerobic metabolism.71 This feed-forward loop may increase the risk of periventricular parenchymal infarction.72–74 Hemorrhagic events can also alter vascular lumina and impair brain perfusion. Venous stasis within the periventricular white matter can lead to parenchymal venous infarction.75 Coagulation or platelet disorders may also predispose to hemorrhage.54
Clinically, low-birth weight, low Apgar scores, and the presence of hypercapnia, acidosis, hypoxemia, infection, and systemic hypotension have been associated with GM-IVH.76,77 Bleeding in the GM can disrupt the ependyma leading to the filling of the cerebral ventricles with blood. Antenatal steroid therapy in women at risk of premature delivery is protective. Factors that likely increase the risk of severe IVH include 5-minute Apgar scores <7, extremely low gestational age, need for intubation, and vasopressors within the first 24 hours after birth.78 The pathogenesis of IVH and IPH in term neonates include hypoxic-ischemic encephalopathy (HIE),79 traumatic delivery, platelet/coagulation abnormalities,80 sinovenous thrombosis,81 rupture of vascular malformation, and mutations in collagen genes.82
(b) Autoregulation of CBF
In mature infant, cerebral brain vessels maintain a stable blood flow despite changes in systemic blood pressures (BPs). In contrast, this autoregulation of CBF is mostly unpredictable and transient in premature infants.4,83 There is a “pressure-passive” dependence of CBF on systemic BPs in infants born at lower gestational ages, with low-birth weights, and who have fluctuations in the systolic and diastolic blood flow velocity.83,84
Unstable CBF can enhance the risk of GMH.85 Factors associated with fluctuations in CBF velocity include systemic hypotension, irritability, and asynchrony between spontaneous and ventilator breaths. Hemodynamically significant patent ductus arteriosus (PDA) can also increase the variability in CBF.86 Hypoglycemia, hypoxia, and hypercarbia can also cause cerebral vasodilatation and have been correlated with the development of GMH.87,88
Unstable BPs increase the risk of GM-IVH,89 especially when the initial low blood pressure (BP) readings are followed by high, fluctuating BPs.90 Very low-birth weight (VLBW) neonates show pressure-passive cerebral perfusion in up to 20% of the time. In extremely low-birth weight (ELBW) infants, this pressure passivity might be seen in more than 50% of the time.91 Even minor steps of routine clinical care such as tracheal suctioning, diaper changes, changing position/posture;89,92 and rapid infusion of intravenous fluids can alter CBF.93 These deficiencies in CBF autoregulation can prolong ischemic and hyperperfusion phases of brain injury and consequently, increase the risk of GM-IVH.94 In critically ill neonates, pulmonary hypoxia, hypercarbia, bradycardia, acidosis, apnea, persistent patency of the ductus arteriosus, and changing thoracic distension with high-pressure ventilation can destabilize the systemic and cerebral hemodynamics, cause ischemic alterations in cerebral perfusion, and have been associated with GM-IVH.83,89,95,96 These changes can also contribute to reperfusion following cerebral ischemia.97
(c) Disorders of Hemostasis due to Immature Coagulation and Platelet Function
The role of thrombocytopenia in the development of GMH in neonates has been reported.98 However, other studies found no correlation. Studies on the severity of the thrombocytopenia and its association with GMH have been limited with varying results.99,100 However, low gestation age and birth weight are known to affect platelet function and hence, it is quite plausible that platelet dysfunction and related coagulation disorders may contribute to the risk of GM-IVH in preterm neonates.98,101 Thrombocyte hyporeactivity together with fragility of the GM and hemodynamic instability may contribute to the risk of GMH in preterm neonates. Studies on adhesion, aggregation, and activation of the thrombocytes in preterm neonates have shown functional improvement of platelets after 4–10 postnatal days.102,103
(d) Genetic Factors
Genetic risk factors include prothrombin gene mutations, methylenetetrahydrofolate reductase polymorphism, and factor V Leiden gene mutations.104,105 Screening for polymorphisms or mutations should be considered in neonates with an atypical presentation of PVHI.106
(e) Mode of Delivery
Some studies reported that elective cesarean section is associated with a decrease in the risk of severe grades of GMH in preterm neonates when presenting with preterm labor. However, recent data showed no correlation. Therefore, the mode of delivery could be decided based on the obstetrical indications.107
Clinical Presentation
Approximately, 50% of GMH are asymptomatic and are detectable only during routine screening by the cranial US.108 Infants with symptoms are more likely to have a severe grade of GM-IVH. Symptomatic infants may present with acidosis, hyper/hypoglycemia, and sudden reduction in hematocrit level. Clinical examinations may reveal lethargy, tense fontanelle, respiratory distress, apnea, temperature instability, unexplained pallor, and convulsions. Uncommonly, progression can be fast with progress to stupor, coma, decerebrate posturing, and death. Infants with a severe type of GMH are more likely to have clinically detectable convulsions109 and inappropriate antidiuretic hormone (ADH) release.110
Grading of GM-IVH
The severity of GM-IVH is graded based on localization, the extent of bleeding, and the presence of acute ventricular dilatation. GM-IVH can be mild or severe, unilateral or bilateral, and can also be classified based on localization, the extent of bleeding, and the presence of acute ventricular dilatation. Mild GM-IVH includes grades I and II, while severe hemorrhages include grade III and PVHI (previously graded as GMH grade IV).111 Hemorrhages restricted to the subependymal zone are classified as grade I. Extension of bleeding into the non-distended lateral ventricle(s), where the hemorrhage occupies <50% of the ventricular(s) diameter is classified as grade II. Grade III hemorrhages occupy >50% of the ventricular diameter. Periventricular hemorrhagic infarction112 involves compression of the terminal vein by the GM hemorrhage and consequent congestion of the draining medullary veins. These events predispose to ischemia, infarction, and then to hemorrhagic changes in the periventricular white matter.113
Grading of GMH was first described by Papile et al.114 and presented in Table 1 and later modified by Volpe.88 The information in Table 2 is routinely used in clinical practice.
| Grade I | Germinal matrix hemorrhage |
| Grade II | Hemorrhage extent to lateral ventricle without dilatation |
| Grade III | Ventricle hemorrhage with ventricle dilatation |
| Grade IV | Intraparenchymal hemorrhage |
| Grade I | Germinal matrix hemorrhage |
| Grade II | Hemorrhage extent to lateral ventricle without dilatation and or hemorrhage occupying less than 50% of the ventricle |
| Grade III | Ventricle hemorrhage with ventricle dilatation |
| Grade IV | Also, called an intraparenchymal hemorrhage |
Diagnosis of GM-IVH
Cranial US is a widely used, non-invasive, and easily accessible diagnostic tool to diagnose/monitor GM-IVH. It is performed using the cranial fontanels as sonographic windows for assessing the ventricular system and periventricular white matter. All preterm infants <32 weeks’ gestation and/or those born VLBW should be considered for GM-IVH screening.115 Infants born at ≥32 weeks are considered for screening if they need critical care, have sepsis, necrotizing enterocolitis (NEC), abnormal neurological manifestations, and require major surgical intervention(s). The cranial US should include descriptions of findings on both left and right sides in parasagittal and coronal views; the location, size, and extension of the lesions should be determined.116 The anterior fontanelle is the most frequently described site for the cranial US, although the mastoid and posterior fontanelles can be useful.115 Grade I GMH images show focal hyperechogenic, rounded/nodular lesions in the caudothalamic groove. Grade II bleeds are similarly hyperechogenic but with additional blood products within non-distended ventricles. Grade III GM-IVH shows blood clots within the GM and enlarged ventricles. PVHI shows focal enlarged GMH(s) at the level of caudothalamic notches and notable hyperechogenicity of the periventricular white matter within the distribution of the venous drainage117 (Figs 1 to 7).
Fig. 1: Coronal and sagittal ultrasound of the normal brain through the anterior fontanel of a preterm 28-weeks’ gestational age newborn. The surface of both hemispheres appears smooth, the Sylvian fissures are wide open, the cavum septum pellucidum is present, all findings are compatible with prematurity. On the midsagittal image, the corpus callosum (outlined) as well as the tectal plate (outlined) are easily identified. The Sylvian aqueduct (arrow) is seen anterior to the tectal plate. Within the posterior fossa the brainstem and hyperechogenic vermis (asterisk) are noted
Fig. 2: Mastoid views of the normal posterior fossa in two newborns [left at 27 weeks’ gestational (outlined) and right at 35 weeks’ GA]. The progressing foliation of the cerebellum is noted, smooth at 27 weeks’ gestation and progressively complex at 35 weeks’ gestation. The fourth ventricle is filled with hypoechogenic CSF
Figs 3A to C: Coronal (A), Sagittal; (B) and high-resolution coronal; (C) Ultrasound images of newborn with bilateral grade I GM-IVH in the region of the caudothalamic grooves (arrows). The groove between head of the caudate nucleus (outlined by the solid line) and the thalamus (outlined by the dashed line) harbor the germinal matrix hemorrhage. The ventricles are of normal size
Fig. 4: Coronal view of the posterior fossa through the mastoid fontanel show a focal hyperechogenic hemorrhage in the GM of the right cerebellar hemisphere. The choroid plexus is physiologic large within the occipital horn of the supratentorial lateral ventricles in this premature newborn
Fig. 5: Coronal ultrasound images through the anterior fontanel show a bilateral grade II GMH located within the caudothalamic grooves (long arrows) with additional hyperechogenic blood products within the temporal horn of the left lateral ventricle as well as on top of the choroid plexus within the right lateral ventricle (short arrows) in a 2-day-old, 29-weeks’ gestation infant
Figs 6A and B: Coronal and sagittal ultrasound images acquired through the anterior fontanel in a 1-week-old preterm newborn show a mid-sized GM-IVH within the left caudothalamic groove. Blood products are also noted within the temporal horns bilaterally (short arrows). The ventricles are moderately widened. Constellation of findings are compatible with a grade III GM-IVH. The ependymal lining appears hyperechogenic (long arrows) secondary to the intraventricular blood products
Fig. 7: Coronal and sagittal and high-resolution coronal ultrasound images acquired through the anterior fontanel show a left sided GM-IVH with adjacent fan shaped hyperechogenicity within the adjacent periventricular white matter (outlined by a dashed line). The area of white matter hyperechogenicity matches the area of white matter that drains over the intramedullary veins into the subependymal deep venous system which is obstructed/compressed by the GM-IVH. In the sagittal view, the dilated or partially thrombosed intramedullary veins are reality identified along the periphery of the hyperechogenic area. The ventricles are dilated; additional blood clots are noted within the right lateral ventricle. Constellation of findings are consistent with a PVHI previously known as a grade IV GM-IVH
The timing of screening is usually based on institutional protocols. As most cases of GMH occur in the 1st week after birth, the American Academy of Neurology (2020) recommends performing the initial cUS at 7–14 days after birth and a repeat scan at 36–40 corrected gestational age.56,67 However, it is essential to consider that GMH may progress and the grade may change over the period, justifying the need for cUS screening for infants with abnormal sonographic findings adjusted according to the clinical presentation.118 Cranial US is limited to GM hemorrhages >5 mm; smaller GMHs are better detected by CT and MRI. MRI is superior to cUS at detecting small GMHs <5 mm, white matter lesions, and cystic and hemorrhagic abnormalities. However, GMH lesions <5 mm usually do not alter outcomes, resolve and do not need an MRI study to confirm. MRI could be considered for infants whose cranial US reveals severe GMH-PVH, periventricular leukomalacia (PVL), post hemorrhagic ventricular dilatation (PHVD), and other abnormalities associated with the risk of white matter infarction.119
Management of GMH-IVH
We still do not have a specific therapy for GM-IVH.97 Therefore, we need to focus on preventing these hemorrhages. A multi-pronged approach, with steps during the pre-, peri-, and postnatal periods is needed.120 The most important way to prevent GM-IVH will be to prevent preterm delivery, as the premature brain has high levels of vascular fragility and poor regulation of CBF.111 Preterm deliveries can be prevented in some cases by using tocolytics and cervical cerclage.121 Avoidance of tobacco and treatment of bacterial vaginosis may have some effect.122 Head vibrations during neonatal transportation could increase the risk of hemorrhage, although there have been some reassuring advancements in the last few years.123 Hence, it might be safer to conduct high-risk deliveries in a tertiary unit.123
Antenatal Steroids
Treatment of pregnant women with steroids (betamethasone or dexamethasone) prior to delivery can reduce the risk of GM-IVH through stabilization of GM vasculature; these changes are likely achieved through suppression of vascular endothelial growth factor and increased transforming growth factor-β levels.57 Furthermore, administration of steroids to birth interval of 24 hours prior to birth to 7 days then after has been shown to reduce the risk of hemorrhage in preterm neonates.124
DCC can prevent GM-IVH.125 It might optimize the cardiac preload following placental transfusion and consequently, increase CBF.126 The American Academy of Pediatrics (2020) recommends at least a 30–60-second delay prior to clamping the cord.127
Volume Guarantee Ventilation
Volume targeted/guarantee ventilation can achieve nearly stable tidal volumes through automatic weaning of peak inspiratory pressures while improving lung compliance.128 Such an e-targeted mode can limit the episodes of hypocarbia that may predispose to GMH.129
Pharmacologic Prophylaxis
Indomethacin is a prostaglandin inhibitor, a drug that inhibits free radical formation and stimulates the maturation of the GM vasculature.130 In ELBW neonates, prophylactic administration of 3–6 doses of indomethacin after birth can reduce the incidence of high-grade GM-IVH.131,132 However, a reduction in NDI has not been consistently documented (aOR 1.1, 95% CI, 0.8–1.4).133 Numerous studies have suggested that prophylactic indomethacin may have a better therapeutic effect on the incidence of GM-IVH in carefully chosen high-risk target groups of infants.134,135 The authors developed a predictive model for severe GM-IVH based on clinical characteristics that would encourage targeted prophylactic indomethacin therapy in high-risk infants. However, the conducted studies did not support selective prophylactic indomethacin treatment to improve the NDI in ELBW infants at high risk for severe GMH.136,137 The optimal timing and broad applicability is still controversial. Considering such contradictory evidence regarding the benefits and a lack of conclusive improvement in developmental outcomes, and a concern for side effects, this drug is not universally accepted. Pharmacological drugs like vitamin K, phenobarbitone, and vitamin E have shone some promise.138 However, further studies are also needed here to demonstrate the safety and evidence of the benefit of these agents.
Postnatal prevention of GM-IVH should be aimed toward avoiding risk factors of hemorrhage. Stabilization of respiratory status, BP, fluid and nutritional support, assisted ventilation, control of seizures, and timely correction of acidosis could prevent the progression of GM-IVH.57 Some of the most promising strategies are summarized in Table 3.
| Prenatal | Perinatal | Postnatal |
|---|---|---|
| Prevention of preterm delivery111 Corticosteroids (World Health Organization 2015) |
Delivery at a tertiary neonatal intensive care unit Delayed cord clamping |
Prevent conditions that interfere with autoregulation: Hypo/hypercarbia Hypoxia Acidosis Prevent conditions that overcome autoregulatory abilities: hypertension Prevent conditions that contribute to rapid fluctuations of cerebral blood flow: Avoidance inter-hospital transportation Minimize vigorous handling, stimulation Pharmacologic prophylaxis (Indomethacin) Avoid unnecessary frequent suction, rapid volume expansion, ventilatory asynchrony Prevention and treatment sepsis Correction of the bleeding disorders |
Long-term follow-up includes neurologic and developmental follow-up.
Supportive Management of GM-IVH
Supportive care includes maintaining stable cerebral perfusion by maintaining normal blood volume and BP.97 Correction of anemia, thrombocytopenia, or coagulation disturbances should be considered.139 Transplantation of the allogeneic mesenchymal stem cells (MSCs) is a promising intervention as documented to reduce brain injury and PHH following GMH, although more trials are needed to evaluate the efficacy.140
Clinical Outcomes and Prognosis
The prognosis of cases with GMH depends on the severity of bleeding, parenchymal injury, occurrence of seizure(s), and the need/type/timing of intervention.141 Improving the quality of life of the patients should be targeted through appropriate management and follow-up.
Neurologic complications like PVHIs, PVL, PVHD, cerebral palsy, convulsions, and cognitive disabilities are more prominent in infants with severe GM-IVH, although these can sometimes be associated also with low-grade GMH cases.142,143 Approximately, 50–80% of premature neonates with severe GMH develop severe developmental disabilities and require special education in school.144 The pathogenesis of the two major complications of GMH such as PVHI and PHVD are discussed below.
Post Hemorrhagic Ventricular Dilatation (PHVD)
Post hemorrhagic ventricular dilatationis a frequent complication seen in 1–3 weeks following a severe hemorrhage.120 The incidence of PHH in mild GMH may reach 1–4%, while in severe types of GMH up to 30–50%.58,145 It is usually a transient, spontaneously recovering disorder that can be diagnosed by cUS. Around 30% of PHVD may develop progressive hydrocephalus, and 15% of these cases require surgical intervention.58,142
The primary cause of PHVD is the formation of fibrin during hemorrhage, which causes obstruction in the acute period and platelet activation in the chronic period that evokes/accentuates inflammation.88 Most cases presented with a communicating hydrocephalus due to obliteration of the arachnoid villi by microthrombi and consequently, altered cerebrospinal fluid (CSF) reabsorption.14 However, non-communicating hydrocephalus can also occur due to obstruction of the Sylvian aqueduct or foramen of Monro by a blood clot or due to subependymal scarring.14 Early diagnosis by serial cranial US screenings and timely intervention can minimize the severity of the PHVD.120
The results of serial cranial US should be followed.56 Based on the Fenton growth chart (2003),146 HC should normally increase by 1 mm per day in neonates from 26 to 32 weeks’ gestation and by 0.7 mm in the 32–40 postnatal weeks.146 A persistent increase of ≥2 mm/day or 14 mm in a week is abnormal.147 Besides the rapidly increasing HC, other findings include bulging fontanelle, widely separated sutures, apnea, hypo-/hypertonia, irritability, and altered consciousness.148
Management of PVHD is targeted at preventing secondary injury due to increased ICP.149 At present, a VP shunt is accepted as the most-effective surgical intervention in PVHD.150 However, the insertion of a shunt may have to be deferred in infants who are too small or sick.151 In these patients, the ICP can be controlled by applying a ventricular-subgaleal shunt or ventricular reservoir.152,153 Many other methods including repeated lumbar punctures, drug therapy (acetazolamide/furosemide), choroid plexus coagulation, and intravenous fibrinolytic therapy have been tried but not found to be as beneficial as VP shunts in minimizing neurologic injury.147,154 Furthermore, acetazolamide and furosemide often predispose to electrolyte disturbance and nephrocalcinosis,155,156 and might also independently cause long-term neurologic abnormalities.157 The most frequently seen complications of VP shunts are infection and obstruction.158
Periventricular Hemorrhagic Infarction (PVHI)
Periventricular hemorrhagic infarctionhas been considered as GM-IVH grade IV due to the extension of a large grade III hemorrhage.159 However, further studies have shown it can often be a separate and an asymmetric/unilateral lesion. PVHI mainly includes frontal and parietal areas and can evolve into a porencephalic cyst.65 The outcomes of the PVHI depend on the site of the lesion; approximately half of all infants with a large unilateral infarction may develop contralateral hemiparesis; those with bilateral PVHI may develop spastic quadriparesis.160 Other clinical findings include epilepsy, cerebral palsy, visual disturbance, and cognitive dysfunctions.161
Follow-up of Survivors of Neonates with GM-IVH
Neonates with a history of GM-IVH are at risk for cognitive and/or motor deficits.143 Therefore, outpatient follow-up should be considered to identify associated morbidities and those at risk should be provided appropriate management through a comprehensive neuro-rehabilitation program.162
ORCID
Roya Huseynova https://orcid.org/0000-0002-8914-5892
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