Clinical manifestations

Presentation and course

The common clinical setting for intraventricular hemorrhage is the premature infant with respiratory distress requiring mechanical ventilation (96; 21). One study found a bimodal distribution of intraventricular hemorrhage in preterm infants, with just over half occurring within the first 6 hours of life and approximately 40% of cases occurring later but before day 7 to 9 of life (50).

The clinical presentation of intraventricular hemorrhage can vary widely and is often silent. Thus, many cases are only identified on routine brain imaging. However, when symptoms are present, they include abnormal tone or reflexes, apnea, pallor associated with anemia, respiratory distress, temperature instability, altered mental status, and seizures (28; 21). Other clinical characteristics associated with intraventricular hemorrhage include hypotension, hypercarbia, worsening base deficit, hypernatremia, and hypoglycemia (73). Subsequent outcomes depend on the progress of the hemorrhage and its effects on the ventricles and brain parenchyma (12). Extremely low gestational age, chorioamnionitis, being outborn, male gender, lack of antenatal steroids, vaginal birth, intubation at birth, and 5-minute Apgar score of less than 7 have been identified as risk factors for severe intraventricular hemorrhage (96; 21).

There are several classifications of intraventricular hemorrhage severity, although the definitions outlined by Papile are perhaps the most widely used (64). Grade III and IV hemorrhages are typically considered severe, although lesser grades of hemorrhage may also result in severe consequences.

Intraventricular hemorrhage grading (64; 28; 21)

Grade I: hemorrhage confined to the germinal matrix

Grade II: germinal matrix hemorrhage extends occupying less than 50% of the intraventricular space

Grade III: germinal matrix hemorrhage extends occupying more than 50% of the intraventricular space OR hemorrhage into a dilated ventricle

Grade IV: now recognized as periventricular hemorrhagic infarction (PVHI); extension of hemorrhage into the surrounding parenchyma causing venous occlusion

Prognosis and complications

Intraventricular hemorrhage can result in a multitude of long-term sequelae, including posthemorrhagic ventricular dilation, hydrocephalus, cerebral palsy, epilepsy, and cognitive delay (01; 19). One large cohort study reported that severe intraventricular hemorrhage affects 16% of all preterm infants born in the U.S. (79; 65). Data show that seizures are uncommon and accompany grade III or grade IV intraventricular hemorrhage in only about 3% of cases (19). The rate of associated hydrocephalus varies widely among studies, with some reporting rates as low as 25% to 28% and others documenting rates as high as 86%, although only 22% of those required shunt placement (19; 21).

It can be difficult to differentiate between grade III intraventricular hemorrhage and posthemorrhagic ventricular dilation (PHVD). PVHD is an important complication of grade III/IV intraventricular hemorrhage (95) and occurs in approximately 30% to 50% of patients (51; 25). It results from impaired absorption of CSF via two mechanisms. Acute hydrocephalus can occur within days secondary to impaired absorption of CSF due to particulate blood clots. Subacute hydrocephalus can arise within weeks due to an obliterative arachnoiditis in the posterior fossa, where blood collects after intraventricular hemorrhage (73). This obstructs the flow of CSF, most commonly at the level of the fourth ventricle. Of those diagnosed with PHVD, between 10% to 20% go on to require surgical intervention with shunt insertion (25). Traditional signs of increased cranial pressure and hydrocephalus may not be present until days to weeks after ventricular dilation has occurred (51). One sign of elevated increased cranial pressure in the neonate is splaying of the sagittal suture (73). In a premature infant, it takes less pressure to compress white matter than it takes to separate the sutures, which also requires stretching the dura (65), so progressive dilation of the ventricles should be carried out using cranial ultrasound, even in the absence of separation of the sutures.

Grade IV intraventricular hemorrhage can result in porencephalic cysts that communicate with the ventricles, most often affecting the parietal lobe (12). Fluid-filled cysts may cause obstruction to CSF flow, increased intracranial pressure, and reduced total brain volume (87; 42).

Periventricular white matter injury secondary to intraventricular hemorrhage is caused by ventricular dilation and subsequent compression of white matter, ischemia, and inflammatory cytokine response, all of which cause injury to pre-oligodendrocytes and subsequently compromise myelination (22; 65). White matter injury can be differentiated into two different categories: periventricular leukomalacia and punctate white matter lesions (PWML). Periventricular leukomalacia is characterized by focal coagulation necroses, white matter gliosis, and impaired myelination resulting in compromised grey matter. Periventricular leukomalacia with large areas of focal necrosis can result in the formation of cysts, ultimately designated cystic periventricular leukomalacia. PWML is caused by small areas of diffuse gliosis. The presence of cystic periventricular leukomalacia is strongly associated with later neuromotor dysfunction, such as cerebral palsy (28; 42).

The effects of low-grade hemorrhage are controversial. Some studies conclude that the neurodevelopmental outcomes of low-grade hemorrhage in extremely low gestational age infants do not differ from those without hemorrhage (66; 19). Others suggest an association between low-grade intraventricular hemorrhage and lower IQ at school age (70). One study found that preterm infants with cerebellar hemorrhage are more likely to need physical therapy sooner than preterm infants with intraventricular hemorrhage, but those with intraventricular hemorrhage are more likely to have attention deficits at 3 years of age compared to those with cerebellar hemorrhage (85). Although there is wide and often confusing variation among the studies of sequelae, the general pattern reveals greater levels of permanent disability with larger hemorrhages (89).

Clinical vignette

A 29-week premature infant was born following early labor with a birth weight of 1400 g. The infant required mechanical ventilation to maintain blood gases, and a chest x-ray showed hyaline membrane disease. The baby had been relatively stable since birth, but a routine cranial ultrasound on day 4 of life demonstrated a right germinal matrix hemorrhage (grade I). A scan 3 days later revealed blood extending into the ventricle and possibly into the parenchyma (grade IV). Ventricular size was followed by serial cranial ultrasounds and gradually increased for several weeks. The problem was temporized by ventriculoperitoneal shunt placement, and the ventricular size stabilized. At developmental follow-up at 18 months of life, delays were identified in multiple domains.

Biological basis

Etiology and pathogenesis

Intraventricular hemorrhage usually occurs in the clinical setting of the sick, premature infant who is receiving mechanical ventilation or is otherwise unstable. It may rarely occur in term infants.

Intraventricular hemorrhage in preterm infants is generally believed to arise from the germinal matrix (29; 67; 65; 95). The germinal matrix is an embryological structure lying below the lateral ventricles over the caudate nucleus. It is most prominent between 8 and 28 weeks’ gestation (51). It gives rise to both neuronal and glial cells and is important for grey matter development. Blood enters the microvessels of the germinal matrix via the Heubner artery (the distal medial striate branch of the anterior cerebral artery) and drains into the terminal veins, then onto the subependymal venous system. The germinal matrix evolutes by 36 to 37 weeks’ gestation.

Preterm infants are at risk of bleeding from the germinal matrix due to their immaturity, including reduced amounts of collagen IV, laminin, and fibronectin around the microvessels and reduced autoregulation of cerebral blood flow (91; 25; 65). Cerebral blood flow in preterm infants appears to be pressure-passive, so it is directly related to systemic blood pressure, especially in those of lower birth weight and gestational age (84; 78; 80). Increased cerebral blood flow passivity is associated with an increased risk of intraventricular hemorrhage (63; 80; 65). Preterm infants are prone to spikes in blood pressure in response to even minimal handling (eg, diaper changes), and the maximum peaks in blood pressure are higher in preterm infants who develop intraventricular hemorrhage (68). Blood pressure fluctuations may also be worsened by anatomical variants in the terminal veins, subependymal veins, or deeper venous systems that may impact venous drainage (82; 83; 46).

Once bleeding occurs in the germinal matrix, venous drainage can be impaired, which increases the risk of hemorrhage extension or intraparenchymal hemorrhage (65). PVHD can result from obstructed CSF flow by the hemorrhage, adhesive arachnoiditis, fibrosis of basal cistern or arachnoid granulation, or subependymal gliosis (65). The largest hemorrhages are seen in the least mature infants (less than 28 weeks’ gestation). Intraventricular hemorrhage may extend into the lateral ventricular system, frequently obstructing CSF flow in the posterior fossa and basilar cisterns and occasionally causing obstruction at the aqueduct of Sylvius and at the arachnoid villi. In addition to the mechanical insults to the brain parenchyma caused by blood products, adverse chemical reactions may also be initiated. Ventricular tissue can be exposed to reactive oxygen species formed by the release of iron, thereby damaging the neuronal axons and pre-oligodendrocytes that are important for myelination. Accumulation of thrombin and fibrin also contribute to parenchymal injury (13).

Other pathophysiological factors that may be associated with intraventricular hemorrhage include impaired coagulation, reduced circulating platelet mass, or monogenetic factors (98; 25; 65).

Isolation of Ureaplasma spp in amniotic fluid, or from the placental or amniotic membrane, has been associated with increased rates of intraventricular hemorrhage and bronchopulmonary dysplasia (45). Ureaplasma organisms may cross the immature blood-brain barrier in very low birth weight infants. PCR detection in serum is associated with a 2.5-fold increase in intraventricular hemorrhage; however, there was no association when Ureaplasma was isolated from the CSF (88). Ureaplasma spp may also provoke preterm labor and prolonged rupture of membranes, both of which are risk factors for intraventricular hemorrhage (45).

Intraventricular hemorrhage in term or near-term infants. Although the vast majority of intraventricular hemorrhage cases are preterm infants, it can rarely be seen in term or near-term infants. The reported incidence of intraventricular hemorrhage in term infants varies based on the definition and inclusion criteria. In one population-based study, two symptomatic cases of grade III or IV intraventricular hemorrhage were identified in nearly 36,000 term newborns, resulting in an incidence of 0.006% (81). A smaller study, also limited to symptomatic infants, found 33 cases and yielded a population incidence of approximately 0.05% (32). When asymptomatic infants are included, intraventricular hemorrhage incidence increases significantly. A study of 505 asymptomatic term infants who received cranial ultrasounds as part of a research study found intracranial bleeds in 4.6% of patients, primarily bilateral subependymal hemorrhages (35). Infants with hemorrhages had similar Apgar scores and resuscitation needs compared to those without but were more likely to be Black, small for gestational age, and delivered vaginally.

Symptoms of intracranial hemorrhage in term infants include seizures, apnea, poor feeding, and respiratory distress (32; 08; 02). Neurologic abnormalities may include irritability, truncal hypotonia, hypertonicity of extremities, and hyperreflexia (81). The location of intracranial hemorrhage varies and includes subependymal hemorrhage, choroid plexus, germinal matrix, thalamic hemorrhage, lobar hemorrhage, and intraventricular hemorrhage (74; 08; 02). Sinovenous thrombosis may be seen in association with intraventricular hemorrhage, especially in those with hemorrhagic involvement of the thalamus (94). Another study emphasized the strong association between intraventricular hemorrhage and thalamic hemorrhage. The authors reported that 12 of 19 infants who became symptomatic for intracranial hemorrhage during the first week of life were diagnosed with thalamic hemorrhage on CT imaging during the first month of life (74).

A prospective study from a single tertiary center identified several risk factors associated with intracranial hemorrhage in term and late preterm infants, including placental abruption, congenital heart disease, extracorporeal membrane oxygenation, or systemic anticoagulation of the infant (08). Perinatal depression and hypoxic-ischemic encephalopathy are also associated with increased intraventricular hemorrhage risk (33; 26).

The risk of intraventricular hemorrhage significantly rises in term infants requiring extracorporeal life support (ECLS), especially when combined with therapeutic hypothermia (18; 09). Hypothermia's impact on platelet function and the coagulation cascade, along with ECLS-related anticoagulation, contribute to increased intraventricular hemorrhage incidence (03; 09). Hemorrhage was more frequently observed in infants treated with therapeutic hypothermia (3/31) than in those who were not treated (1/31), even in the absence of ECLS, although these differences were not statistically significant (26).

The role of preeclampsia in intraventricular hemorrhage is inconsistent across studies, with some reporting it as protective and others as an associated risk factor (02; 56). More recent studies report no relationship between preeclampsia and intraventricular hemorrhage (90; 09). The role of thrombocytopenia and intraventricular hemorrhage in term infants is also inconclusive (10).

A small subset of hemorrhages may have underlying monogenetic causes (35; 27; 61; 43; 48). Mutations in COL4A1 and COL4A2 (which encode for collagen chains integral to the basement membrane of vascular structures in the brain, eyes, and kidneys) are associated with porencephaly and intraventricular hemorrhage (35; 27; 43). A work-up for a genetic etiology of disease, including for mutations in COL4A1 and COL4A2, should be considered in any patient with an antenatal parenchymal hemorrhage or porencephaly present at birth. Testing can be performed postnatally or prenatally using fetal DNA obtained by amniocentesis (16; 53; 56). To date, at least 21 COL4A1 and three COL4A2 pathogenic mutations have been identified (57).

Mutations in JAM3, which codes for a tight junction protein, are associated with severe hemorrhagic destruction of the brain as well as congenital cataracts and subependymal calcification. One Middle Eastern study describes a family (eight members) that each presented with devastating intracranial hemorrhage, resulting in death (61). All members had mutations in JAM3. Other possible genetic causes associated with intraventricular hemorrhage include MTHFR variants and endothelial nitric oxide synthase promoter polymorphisms (86; 47; 56). Interrogation of factor V Leiden mutations implicated in the pathomechanism of intraventricular hemorrhage has yielded variable and inconclusive results (34; 56).

Survival rates for term infants with intraventricular hemorrhage grades I and II are above 90% (19). Neurologic impairment at follow-up is common in those with symptomatic intraventricular hemorrhages (08), especially those with venous hemorrhagic infarcts. A Canadian systematic review evaluated data collected from 240 cases across 80 studies to better establish morbidity risks associated with neonatal intraventricular hemorrhage (19). Adverse outcomes were rare in grade I and II hemorrhages, but motor impairments were seen in 7%, developmental delays in 6%, and shunt placement in 12% in worse hemorrhages (grade III). Outcomes were worse in those with periventricular hemorrhagic infarction (motor impairment 10%; developmental delays 17%; seizure disorders 7%; shunt placement 17%).

Epidemiology

Current estimates suggest that intraventricular hemorrhage affects between 12,000 and 15,000 preterm infants in the U.S. annually and that roughly 45% of infants born at extremely low birth weight (< 1000 grams) will develop intraventricular hemorrhage (25; 50; 80). However, reported incidence rates are inconsistent, in part, due to variability in screening standards and differences among study cohorts (eg, average gestational age and birth weight). One study found the incidence of intraventricular hemorrhage to be extremely high in very low birth weight patients (71%), with an observed incidence of severe intraventricular hemorrhage at 29% (41). Conversely, another study diagnosed 20.2% of very low birth weight infants with intraventricular hemorrhage and only 5.2% with severe intraventricular hemorrhage (96). One study examining the presence of intraventricular hemorrhage among preterm infants documented autopsies between the years 1914 and 2015. The incidence of intraventricular hemorrhage was approximately 5% prior to 1960 but increased significantly to 50% after 1975, after the introduction of assisted ventilation in neonatal care. The incidence fell to 12% in 2005, a reduction the authors associated with antenatal steroids, “gentler” resuscitation and ventilation, and the use of surfactant (36; 96).

Although mortality has remained unchanged at approximately 30% to 40% (12; 55), a greater number and percentage of preterm and very low birth weight infants survive without major complications. The sum of these data is that the overall occurrence rate of intraventricular hemorrhage is less, but the clinical problem continues as more very low birth weight babies survive (89).

Prevention

Antenatal prevention. The most effective prevention of intraventricular hemorrhage is the prevention of premature birth, which may include the use of tocolytic agents (69). Magnesium is often given to mothers at risk for preterm delivery for fetal neuroprotection in addition to being a tocolytic. However, the evidence that magnesium reduces the risk of intraventricular hemorrhage in preterm newborns is poor (60; 23; 20). Alternatively, antenatal steroids, which are primarily given to enhance lung maturation, are clearly effective in reducing the risk and severity of intraventricular hemorrhage, regardless of which steroid (betamethasone or dexamethasone) is used (52; 60; 17; 31; 96; 41; 93). Additionally, some evidence suggests that exposure to the second stage of labor may increase the risk of intraventricular hemorrhage (24); however, data that cesarean section reduces intraventricular hemorrhage are contradictory (72; 14; 97; 50).

Peri-birth factors. Being born “out of hours” (eg, between midnight and 7 AM) may increase the risk of intraventricular hemorrhage in preterm infants, as may the need for early postnatal transfer (44; 37; 39).

The practice of immediately clamping the umbilical cord after delivery developed as a matter of convenience, but the practice is now being actively reassessed. Delayed cord clamping may lessen the need for red blood cell transfusion and also appears to decrease rates of intraventricular hemorrhage, bronchopulmonary dysplasia, and possibly overall mortality in preterm infants (05; 49). Conversely, immediate clamping may lead to hypotension and poor perfusion (38). The Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists recommends delayed cord clamping in preterm infants for at least 30 to 60 seconds, when feasible (04). A meta-analysis comparing immediate cord clamping, delayed cord clamping, and umbilical cord milking found that although deferral of cord clamping reduced overall mortality in preterm infants, it did not significantly reduce the incidence of intraventricular hemorrhage (76).

Postnatal factors. Many neonatal intensive care units have developed “neurointensive care units” with the intent to reduce the incidence of intraventricular hemorrhage (31). The units incorporate a range of different nursing and medical practices; however, randomized controlled trials that critically examined these interventions show little good evidence in support of them (76). Head positioning, for example, has not been shown to affect the probability of intraventricular hemorrhage (15; 51).

The strongest evidence in support of intraventricular hemorrhage prevention is for the use of prophylactic indomethacin, which appears to reduce the risk and severity of intraventricular hemorrhage (54; 59; 76; 95). Research describing the use of other COX-inhibitors (eg, ibuprofen) is less conclusive (54; 59; 95). Early screening for, and treatment of, coagulation abnormalities may also reduce intraventricular hemorrhage, as well as the targeted use of fresh frozen plasma in coagulopathic infants (14; 62). Neither ethamsylate, phenobarbital, or caffeine appear to reduce the incidence of intraventricular hemorrhage (54; 40; 58; 75).

Differential diagnosis

Confusing conditions

Intraventricular hemorrhage should be suspected in any premature infant who deteriorates, and screening for intraventricular hemorrhage detection should be a routine part of the care of all premature infants less than 32 weeks’ gestation at birth. Symptoms, such as seizures, apnea, bradycardia, or encephalopathy, are nonspecific for intraventricular hemorrhage. Therefore, the differential for intraventricular hemorrhage is broad and includes infection, such as meningitis and sepsis, apnea of prematurity, seizures due to other causes, drug withdrawal, metabolic disorder, and many others. Intraventricular hemorrhage in preterm (and term) infants may often be asymptomatic.

Diagnostic workup

The test of choice to screen for intraventricular hemorrhage is cranial ultrasound using anterior fontanelle (coronal), posterior fossa, and mastoid (parasagittal) views, which detect germinal matrix hemorrhage, hemorrhage into the ventricles, and parenchymal hemorrhage with good sensitivity and specificity (30). Routine cranial ultrasound is recommended in the first 4 to 7 days of life for infants born before 32 weeks’ gestational age, with repeat imaging at 4 to 6 weeks and once more at term. If abnormalities are detected, such as intraventricular hemorrhage or PHVD, a repeat cranial ultrasound is recommended 7 to 10 days later (28; 30; 50).

Cranial ultrasound is a good diagnostic tool for intraventricular hemorrhage due to its bedside accessibility and low cost. However, there are also limitations, such as low sensitivity for detecting white matter injury and abnormalities in myelination (42). MRI is not routinely indicated for infants born at less than 30 weeks’ gestational age but may be offered to high-risk infants (30). MRI is more sensitive than cranial ultrasound for reporting the presence and severity of white matter injury and is, therefore, better able to inform prognosis regarding neurodevelopmental outcomes (51; 28; 42). However, MRI may be difficult to perform on critically ill patients and may not always be readily available (21). CT imaging is no longer recommended as part of routine screening for intraventricular hemorrhage (30).

For late and moderately preterm infants, routine cranial ultrasound is not recommended but can be considered based on risk factors, such as placental abruption, need for vigorous resuscitation, hypotension requiring pressor support, severe acidosis, prolonged mechanical ventilation, confirmed sepsis, or pneumothorax (28; 30).

Assigning a severity or grade is important in the characterization of intraventricular hemorrhage. The grade of intraventricular hemorrhage is determined by both the presence and amount of blood and is determined by coronal ultrasound scan and parasagittal scan, respectively.

Management

Follow-up with serial compression ultrasonography is the best way to monitor for ventricular dilation and guide management considerations (22). Assessments should be done every 5 to 10 days after diagnosis. This is important because the signs and symptoms of hydrocephalus often declare themselves weeks after ventricular dilation (89; 28).

Infants with rapid head growth and progressive ventricular dilation, apnea, change in consciousness, full anterior fontanelle, or separated cranial sutures may require ventricular drainage or shunt placement. One of the mainstays of interventional therapy for ventricular dilation in the setting of intraventricular hemorrhage is lumbar puncture. Although lumbar puncture is typically a useful method of stabilization while neurosurgical assessment and coordination occurs, some studies have shown that performing up to three lumbar punctures can be adequate in preventing any further neurosurgical management in up to 25% of PVHD cases (13; 22). A Cochrane review concluded that early CSF drainage results in better neurodevelopmental outcomes when compared with late drainage of severely dilated ventricles (92). This was reaffirmed by the later ELVIS trial, which demonstrated that a low intervention threshold for lumbar puncture is associated with decreased mortality and morbidity in preterm patients with significant PHVD (13). There are a number of neurosurgical options, such as ventricular reservoir, temporary ventriculosubgaleal shunt, or permanent ventriculoperitoneal shunt (22; 55; 21). These interventions are associated with significant risk; in one study, 57% of patients treated with a ventricular reservoir for PHVH developed serious complications, including new intraventricular hemorrhage and ventriculitis (21). Approximately 20% to 40% of patients with PHVH later require ventriculoperitoneal shunt (06; 25). Risks associated with ventriculoperitoneal shunt include over-drainage (ie, slit ventricle syndrome), obstruction, or subsequent failure of the shunt (21).

An alternative surgical approach involves septostomy or neuroendoscopic fenestration of the foramen of Monro (11). This approach avoids more invasive procedures and may decrease the size of the affected ventricle and lead to an improved neurologic exam. One Chinese meta-analysis found that endoscopic surgery delivered better outcomes than treatment with extraventricular drainage alone, resulting in lower rates of ventriculoperitoneal shunt, intracranial rebleeding, and infection risk (55).

Nonsurgical management, such as the intraventricular administration of urokinase, has yielded conflicting results. The burden of cognitive impairment is lower amongst treated infants, but there is no decrease in need for ventriculoperitoneal shunt or improvement in overall mortality (21; 65). Acetazolamide reduces production of CSF and has been theorized as a useful temporizing treatment. However, research has found that the use of acetazolamide in patients with PHVH is associated with high rates of neurosurgical intervention and poorer neurodevelopmental outcomes (21; 65).

Although PHVD cannot be prevented, earlier CSF drainage based on modestly increased ventricular size, prior to the manifestation of any clinical symptoms, appears to be associated with improved neurodevelopmental outcomes (07; 51).

Outcomes

Long-term outcomes are defined by the associated major neurologic sequelae. Infants born at extremely low gestational ages (≤ 28 weeks) who suffer an intraventricular hemorrhage are at the highest risk for neurodevelopmental disabilities. Intraventricular hemorrhage in preterm infants can lead to motor impairment, developmental delay, hydrocephalus, and epilepsy (19). Risk factors associated with poor outcomes include neonatal brain injury, lung disease, sepsis, necrotizing enterocolitis, and exposure to surgery. Rates of impairment (cognitive delays 35%, abnormal motor outcomes 31%, cerebral palsy 42%) in infants diagnosed with intraventricular hemorrhage have improved (12); however, they tend to be worse in infants requiring surgical intervention for progressive ventricular dilation secondary to severe intraventricular hemorrhage (71).These patients are at an increased risk for cerebral palsy (76%), hearing impairment (8%), and vision impairment (13%) (77).

The mortality rate related to intraventricular hemorrhage remains unchanged from previous decades (30% to 40%), likely due, in part, to a shift towards more extremely preterm infants with higher neonatal death risk. High redirection of care rates in patients with PVHI also impacts survival.