Henrietta S. Bada
Neonatal germinal matrix hemorrhage/intraventricular hemorrhage (GMH/IVH) remains a common form of intracranial hemorrhage in preterm infants. It is an important cause of long-term morbidities among survivors of neonatal intensive care. The hemorrhage is typically located in the cerebral ventricles. However, hemorrhage in its least severe form may be restricted to the germinal matrix area or subependyma without blood in the ventricles. Germinal matrix hemorrhage may evolve to rupture into the ventricular space.
GMH/IVH is a neurological disorder unique to preterm infants.1 Its incidence decreases as gestational age birth weight increase.2 Because of improvement in perinatal and neonatal care, the incidence of GMH/IVH has decreased over the past several years but to a lesser extent than the decline in neonatal mortality.3,4 About 3 decades ago, GMH/IVH was noted in 45% of those with birth weight of 1500 grams or less and in greater than 60% of those with birth weight of 750 grams or less.5 In the 1990s, the incidence of GMH/IVH remained around 40% among the extremely low-birth-weight survivors,6 decreasing to 22% between 2000 and 2002.7 The more severe hemorrhages, grades III and IV, were reported to occur in 12% to 17% of the extremely low-birth-weight infants3 and in as high as 24% of those with birth weight of 750 grams or less.2 These severe hemorrhages occur in 17% to 28% of those with gestational age 22 to 26 weeks and in 9% to 14% of those 27 to 32 weeks’ gestation.8 Also, as to gender predisposition, boys are reported more likely to sustain GMH/IVH and are at higher risk for neurological sequelae.9
PATHOGENESIS AND RISK FACTORS
FIGURE 58-1. Schematic diagram of the pathogenesis of germinal matrix hemorrhage/intraventricular hemorrhage and its consequences.
The pathogenesis of GMH/IVH is complex1 and involves multiple risk factors and disorders that may cause biochemical, inflammatory, and hemodynamic alterations, predisposing to the development of hemorrhage. Further, the mechanisms for predisposition to hemorrhage, and the relationship among GMH/IVH and white matter and neuronal injury have recently been linked to generation of free radicals, reactive oxygen and nitrogen species, and genes-environment interactions.10,11 The origin of hemorrhage is the germinal matrix, a prominent structure in the preterm brain in the second and early third trimesters, which undergoes involution as gestation reaches term. The germinal matrix structure contains neuronal precursor cells prior to 20 weeks of gestation. As development progresses, the differentiating glioblasts give rise to oligodendroglial cells, which are important to myelination. The germinal matrix is supplied by a complex capillary network but is a low blood flow structure.12,13 The susceptibility of the thin-walled germinal matrix capillaries to rupture may be due to their large diameter, which offers lesser resistance to changes in intravascular pressure,14 and to endothelial cell tight junctions, which are still undergoing maturation of their specialized function through the third trimester.15 Rupture of the capillaries results when the endothelial wall loses integrity and or when there is imbalance of pressure between the intravascular lumen and the extravascular space.12 eTable 58.1 lists cerebrovascular factors and alterations in cerebral hemodynamics that may result from a variety of antenatal and postnatal conditions. The antenatal and postnatal conditions are those that are usually associated with hypoxemia, hypercapnea, acidosis, hypotension, and/or ischemia. As seen in the schematic diagram in Figure 58-1, a single factor or a combination of factors may disrupt the cerebral circulation leading to GMH/IVH and its complications.
CLINICAL MANIFESTATIONS AND DIAGNOSIS
GMH/IVH is usually detected in the first 4 to 5 days of life with approximately 40% to 50% occurring in the first day of life.16-18 Early-onset hemorrhage isolated in the germinal matrix may evolve to become more severe and extend into the ventricles within the first week of life.19 Small hemorrhages may be asymptomatic and may only be detected by routine cranial ultrasound. However, larger GMH/IVH may present with sudden clinical deterioration, especially when there is a significant blood loss. Other clinical manifestations include anemia or failure; seizures; tense, full, and/or bulging fontanels; split and wide sutures; apnea and bradycardia with desaturation episodes; poor perfusion; hypotension; severe metabolic acidosis; increase in oxygen requirement; and increase in ventilator support.
Imaging studies will establish the diagnosis of GM/IVH. The current state-of-the-art approach to diagnosis is the use of cranial ultrasonography. Findings on ultrasound have been interpreted with a high level of agreement among practitioners.20 The procedure can be performed at the bedside, thus avoiding the risks of transporting the infant for either computed tomography (CT) scan or magnetic resonance imaging (MRI) procedure. Table 58-1 shows the grading of GMH/IVH, based on Papile criteria from CT scanning,21 still employed by clinicians and researchers for cranial ultrasound findings. Others have added findings such as cystic periventricular leukomalacia to indicate associated white matter injury and measurements of the lateral ventricles to define mild to severe ventriculomegaly.22 Volpe1 also reported modifications to the grading of cranial ultrasound findings, taking into consideration the location of hemorrhage and the amount of blood detected in the ventricles. Examples of cranial ultrasound findings are shown in Figures 58-2A and 58-2B.
COMPLICATIONS OF GMH/IVH
Events that may result from GMH/IVH are listed in Figure 58-1. Associated brain injury may be secondary to the destruction of germinal matrix structure, injury to periventricular white matter, and/or neuronal injury. Large echodensities noted on cranial ultrasound adjacent to the GMH/IVH are due to venous drainage obstruction, termed hemorrhagic periventricular hemorrhagic infarction.23Periventricular hemorrhagic infarction may be unilateral or bilateral. The area of infarction evolves into tissue loss such that a large porencephalic cyst is noted on later follow-up cranial ultrasound.
Table 58-1. Cranial Ultrasound Findings and Grades of Hemorrhages
In some instances, white matter injury results from ischemia, and damage is noted pathologically as softening or deterioration of the white matter; this is called periventricular leukomalacia (PVL). Early PVL may be noted as echodense lesions in the periventricular area with or without blood in the ventricles. A few weeks after an ischemic insult, the echodense areas become cystic, and these findings are referred to as cystic PVL. Cystic PVL noted on cranial ultrasound is not always associated with GMH/IVH (see Figure 58-3).
About 2 to 3 weeks after detection of GMH/IVH, some infants may present with increasing head circumference, separation of sutures, full and tense fontanels, and sun-setting appearance. A repeat cranial ultrasound in the presence of these manifestations of increased intracranial pressure will reveal prominence and enlargement of the cerebral ventricles (ventriculomegaly), and thus a diagnosis of posthemorrhagic hydrocephalus.24 Posthemorrhagic hydrocephalus results from disturbance in cerebrospinal fluid (CSF) dynamics because of the obstruction of the CSF pathway by blood clots, in the posterior fossa cisterns, aqueduct of Sylvius, or foramen of Monroe. Postinflammatory changes in the arachnoid villi may impair CSF absorption. Obstruction and delayed absorption of CSF leads to progressive increase in ventricular size.24 Among those with GM/IVH who survive for more than 14 days, 50% will develop ventricular dilation, which will progress in half of these infants.25 In 62% of those with progressive ventricular dilation, spontaneous arrest occurs, while the remaining 38% will require nonsurgical or surgical treatment.25 Surgical intervention to relieve the increase in intracranial pressure and ameliorate associated clinical manifestations, will be necessary for rapidly increasing head size, frequent apnea and bradycardia, and the need for increasing ventilatory support.
Ventriculomegaly may also occur without increased intracranial pressure (hydrocephalus ex-vacuo). This differs from posthemorrhagic hydrocephalus and may be a result of brain atrophy from periventricular white matter injury. It rarely requires surgical treatment. Preterm infants with GMH/IVH without obvious parenchymal involvement may have evidence of white matter injury detected by MRI diffusion-weighted imaging at term postmenstrual age; diffuse, excessive, high signal intensity is noted in the cerebral white matter on T2-weighted images.10,26
MANAGEMENT OF GMH/IVH
The treatment of GMH/IVH is primarily supportive. Management strategies include initiation of mechanical ventilation or increase in ventilatory support and/or administration of oxygen in order to maintain optimal levels of PaCO2and PaO2, treatment of hypotension with slow volume expansion and administration of pressors if unresponsive to volume expansion, blood transfusion to correct anemia from blood loss, correction of metabolic acidosis, anticonvulsant therapy for seizures, and administration of fresh frozen plasma, platelets, and other products if there is associated coagulopathy. Progression or evolution of GMH/IVH is monitored by a repeat cranial ultrasound especially when needed for decision making and parental counseling in the face of rapid clinical deterioration.
During early posthemorrhagic hydrocephalus, interventions such as diuretics and intraventricular fibrinolytic therapy have been used.24 Investigation is ongoing to assess the combination use of ventricular drainage, irrigation, and fibrinolytic therapy. Ventriculomegaly with increased intracranial pressure may occasionally respond to serial lumbar punctures, repeated ventricular taps through a ventricular reservoir, or drainage of cerebrospinal fluid by ventriculostomy. Ventriculoperitoneal shunt is the definitive surgical treatment when there is continued progression of ventriculomegaly accompanied by increase in intracranial pressure. Shunt obstruction, malfunction, and infection can complicate shunt placement and long-term function.
FIGURE 58-2. (A) The top panel shows coronal (left) and sagittal (right) views from a normal preterm brain (V, ventricle; CP, choroids plexus). The bottom panel (left) shows a coronal view with a left germinal matrix hemorrhage, or grade I. On the right is a sagittal section showing blood in the lateral ventricle (intraventricular hemorrhage) and filling less than 50% of the ventricular space; it is therefore a grade II germinal matrix hemorrhage/intraventricular hemorrhage. (B) The top panel on the left shows a coronal view of bilateral hemorrhage (intraventricular hemorrhage) in the anterior ventricles and almost filling the ventricles. On the right is a sagittal view of the hemorrhage or blood cast (intraventricular hemorrhage) filling and distending the lateral ventricle. This is a grade III hemorrhage. The bottom panel shows on the left a coronal view of hemorrhage with parenchymal involvement (see arrows) representing periventricular hemorrhagic infarction. The area of periventricular hemorrhagic infarction is also noted in the sagittal view (note arrow) on right bottom panel. By Papile criteria, this would be a grade IV GMH/IVH, since the periventricular echodensity appears to be an extension of the intraventricular hemorrhage. By Volpe criteria, the hemorrhage will be classified as a grade III with periventricular hemorrhagic infarction.
PROGNOSIS AND LONG-TERM OUTCOMES
In severe GMH/IVH, sudden deterioration may be observed with no response to any attempt at escalation of support. Mortality in severe GMH/IVH, especially with associated periventricular hemorrhagic infarction, is 40%.27Among those who survive for weeks after detection of hemorrhage and with complicating progressive and persistent ventricular dilation, death occurs in 18%.25 In extremely low-birth-weight infants, after excluding deaths due to extreme immaturity, 7% to 9% of the deaths are attributed to hemorrhage.6
Survivors with grades III or IV GMH/IVH who had birth weight of 1000 grams or less were found to be 3 times more likely to have cerebral palsy.28 Among those with periventricular hemorrhagic infarction who had follow-up at 30 months corrected age, 70% had abnormal gross motor, and 59% had abnormal fine motor development. Fifty percent had delay in cognitive development.29 Those children with extremely low birth weight with grades I and II hemorrhages were found to have lower scores on mental development at 20 months of age corrected for prematurity and a higher rate of neurodevelopmental impairment (47% vs 28%) compared to those children of similar birth weight but normal cranial ultrasound.30 However, even in the absence of GMH/IVH, among the low-birth-weight children, a rate of nearly 30% of either cerebral palsy or abnormal mental developmental index has been reported.31
FIGURE 58-3. The top panel shows the coronal and sagittal views of early periventricular leukomalacia, which appears echodense as indicated by the arrows. A week later on the same child, the echodense areas have turned into multiples cysts in the periventricular area (cystic periventricular leukomalacia).
There is no “silver bullet” for the prevention of GMH/IVH. However, several studies have addressed prevention from the antenatal through the postnatal period.32 Antenatal prevention is directed toward prevention of preterm birth through use of tocolytics, the treatment of maternal complications (bleeding, chorioamnionitis, conditions that may predispose to preterm delivery), intrapartum fetal surveillance, and preference for epidural anesthesia, controlled vaginal delivery, and administration of antenatal steroids. A large randomized clinical trial on the antenatal use of phenobarbital for prevention of GMH/IVH did not show reduction of hemorrhages.33
Postnatal preventive strategies include supportive measures such as resuscitative measures as indicated at delivery with a goal of preventing hyperoxia, maintenance of optimal oxygenation and acid-base balance, gentle ventilation to prevent pneumothoraces and other air-leak syndromes, minimizing abrupt hemodynamic alterations by stabilizing blood pressure, minimal handling, slow volume expansion for low blood pressure, inotopric agents for better blood pressure control, and careful surfactant administration to improve respiratory status and oxygenation. Studies of pharmacologic agents such as pancuronium,34 ethamsylate,35 vitamin E,36 phenobarbital, and indomethacin37,38 do not demonstrate clear benefit.
Muscle paralysis in a ventilated infant with severe respiratory distress will result in normalization of the fluctuating cerebral blood flow velocity pattern.39 Ethamsylate is a nonsteroidal agent used to reduce capillary bleeding during surgical procedures. It inhibits prostaglandins, promotes platelet adhesiveness, and polymerizes capillary basement membrane. Results from clinical trials have not provided support for its routine use for GMH/IVH prophylaxis. Vitamin E may prevent GMH/IVH because of its antioxidant properties. Postnatal phenobarbital for prevention of GMH/IVH may attenuate increases in cerebral blood flow secondary to motor activity, procedures, or handling. Phenobarbital may also protect against free radical injury; studies, however, have shown conflicting results.
Indomethacin, a prostaglandin H synthase inhibitor, also inhibits generation of oxygen free radicals, promotes maturation of the germinal matrix, stabilizes cerebral blood flow, and attenuates the hyperemic response to hypoxia and hypercapnia. A meta-analysis of studies40 and a large multicenter trial41 showed a lower incidence of grades III to IV GMH/IVH with indomethacin prophylaxis compared to placebo treatment. However, administration of indomethacin is not without complications.40,42 Renal insufficiency, ileal perforation, and chronic lung disease are some of the reported complications of indomethacin use. Because of the significant vasoconstrictive effect of this drug, it has to be administered slowly and cautiously, especially during episodes of hypoxia, hypercapnia, acidosis, hypothermia, or hypotension.