Chapter 13 - Intracranial Hemorrhage

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Neonatology: Clinical Practice and Procedures
Chapter 13: Intracranial Hemorrhage
LuAnn Papile
INTRODUCTION
Periventricular/intraventricular hemorrhage (P/IVH) is the most common intracranial hemorrhage in premature infants. In the United States,
approximately 14,000 very low birth weight (VLBW) infants are diagnosed with P/IVH each year; of these, approximately 7% will develop
posthemorrhagic hydrocephalus (PHH). Numerous risk factors for developing P/IVH have been described, most of which are associated with
premature birth. Because the majority of babies with P/IVH do not manifest clinical signs, the diagnosis relies on screening with noninvasive cranial
imaging. There are no effective neonatal therapies to prevent P/IVH; however, antenatal steroids (ANSs) given to women who are anticipated to deliver
preterm reduces the frequency and severity of P/IVH among their offspring. Infants with extensive P/IVH have an increased risk of later
neurodevelopmental impairment, whereas those with lessextensive P/IVH may not.
EPIDEMIOLOGY
Since the 1990s, the overall incidence of P/IVH has dramatically decreased from 50% to 20%–25%; however, since the mid1990s there has been little, if
any, progress in reducing the overall incidence further.1,2 This, in part, may be explained by an increase in the birth and survival rates of extremely low
birth weight (ELBW) infants (birth weight ≤ 1000 g), the cohort at highest risk for developing not only P/IVH but also the complications associated with
PI/VH.3
Distribution and Frequency
The site of origin of P/IVH typically is the microcirculation of the subependymal germinal matrix (see the discussion of pathogenesis). The hemorrhage
may be isolated or may be accompanied by hemorrhage into the lateral ventricles that may spread throughout the ventricular system, through the
foramina of Magendie and Luscka and into the basilar cisterns in the posterior fossa. The particulate matter in the intraventricular blood may obstruct
the outflow tracks of the third and fourth ventricles or incite an obliterative arachnoiditis in the posterior fossa with obstruction of cerebrospinal fluid
(CSF) flow, resulting in PHH. The reported overall incidence of P/IVH is approximately 20% for infants with a birth weight less than 2000 g and
approximately 25% for those who weigh less than 1500 g.
The most frequently used description of P/IVH was developed in 1978 and demarcated P/IVH into 4 grades: grade I, isolated subependymal
hemorrhage (Figure 131); grade II, intraventricular hemorrhage (IVH); grade III, IVH with cerebral ventricular dilation (Figure 132); and grade IV,
parenchymal hemorrhage (Figure 133).4 Although the description was intended to characterize findings on computed tomographic brain scans, it
continues to be used to describe lesions visualized on cranial ultrasonography (CUS). Isolated subependymal hemorrhage (grade I) is the most
common lesion detected (approximately 40% of lesions), while parenchymal hemorrhage (grade IV) is the least frequent (approximately 10% of
lesions)2 (Figure 134). Since the mid2000s, the frequency of grade II P/IVH has markedly decreased. The most likely explanation relates to the
increasing survival of extremely premature infants whose lateral ventricles are prominent to accommodate the choroid plexus.
FIGURE 131
Subependymal germinal matrix hemorrhage (grade I periventricular/intraventricular hemorrhage) shown in the coronal and
parasagittal planes (arrowheads). A homogeneously echogenic mass consistent with acute hemorrhage is noted in the
caudothalamic groove. (Used with permission of Benjamin Brann IV, MD.)
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FIGURE 131
Subependymal germinal matrix hemorrhage (grade I periventricular/intraventricular hemorrhage) shown in the coronal and
parasagittal planes (arrowheads). A homogeneously echogenic mass consistent with acute hemorrhage is noted in the Access Provided by:
caudothalamic groove. (Used with permission of Benjamin Brann IV, MD.)
FIGURE 132
Intraventricular hemorrhage with ventricular dilation (grade III periventricular/intraventricular hemorrhage) is shown in the
coronal and parasagittal planes (arrowheads). (Used with permission of Benjamin Brann IV, MD.)
FIGURE 133
Periventricular hemorrhagic infarction (grade IV periventricular/intraventricular hemorrhage) is shown in the coronal and sagittal
planes. A hemorrhagic infarction is noted adjacent to the left lateral ventricle that is filled with blood. The right lateral ventricle
also contains a hemorrhagic clot. (Used with permission of Benjamin Brann IV, MD.)
FIGURE 134
Distribution of periventricular/intraventricular hemorrhage (P/IVH) and subsequent development of ventricular dilation and
posthemorrhagic hydrocephalus. (Used with permission of LuAnn Papile, University of Mexico. Unpublished personal data.)
FIGURE 134
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Distribution of periventricular/intraventricular hemorrhage (P/IVH) and subsequent development of ventricular dilation and
posthemorrhagic hydrocephalus. (Used with permission of LuAnn Papile, University of Mexico. Unpublished personal data.)
The frequency of P/IVH is influenced by gestational age and birth weight. There is an inverse relationship of gestational age and P/IVH, with the most
immature infants having the highest frequency and severity of P/IVH (Figures 135 and 136). Infants who weigh less than 751 g at birth have a 2fold
greater risk of having P/IVH than those whose birth weight is 1001–1500 g; the risk for infants who weigh 750–100 g is 1.5fold greater.2
FIGURE 135
Frequency of periventricular/intraventricular hemorrhage (P/IVH) as a function of birth weight. (Adapted from Fanaroff et al.2)
FIGURE 136
Frequency of grades I/II periventricular/intraventricular hemorrhage (P/IVH) (light) and grades II/IV P/IVH (dark) for infants 1000 g
or less and greater than 1000 g birth weight. (Adapted from Fanaroff et al.2)
Although the overall reported frequency of P/IVH ranges from 20% to 25%, there is marked variability across centers. Centers participating in the
National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) reported frequencies of 7%–23% (grade I), 1%–
11% (grade II), 3%–11% (grade III), and 3%–8% (grade IV).2 Some of the difference can be attributed to interpretation of the head ultrasound (HUS)
findings. When local interpretation of CUS was compared to that of central readers, the overall discrepancy in interpretation ranged from 21% to 28%,
with the greatest disagreement occurring for grades I and II P/IVH (67% and 71%, respectively).5 Other factors that might influence the frequency of
P/IVH include population characteristics, neonatal practices, and obstetric management.
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Although the overall reported frequency of P/IVH ranges from 20% to 25%, there is marked variability across centers. Centers participating in the
National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) reported frequencies of 7%–23% (grade I), 1%–
11% (grade II), 3%–11% (grade III), and 3%–8% (grade IV).2 Some of the difference can be attributed to interpretation of the head ultrasound (HUS)
findings. When local interpretation of CUS was compared to that of central readers, the overall discrepancy in interpretation ranged from 21% to 28%,
with the greatest disagreement occurring for grades I and II P/IVH (67% and 71%, respectively).5 Other factors that might influence the frequency of
P/IVH include population characteristics, neonatal practices, and obstetric management.
Risk Factors
Studies addressing the etiology of P/IVH have identified numerous environmental and medical risk factors including prematurity, male sex, respiratory
failure and its attendant complication, and lack of exposure to ANS therapy.
Prematurity
The vast majority of P/IVH occurs in infants who are less than 32 weeks of gestational age. This relates to the prominence of the germinal matrix, a
highly cellular and richly vascularized collection of neuronalglial precursor cells in the developing brain where the majority of P/IVH originates. It is a
source of neuronal precursors between 10 and 20 weeks of gestation, and during the third trimester provides glial elements that become
oligodendroglia and astrocytes. The germinal matrix is most prominent between 20 and 25 weeks of gestation and involutes with increasing gestation
as cells leave the region.6 At 20–25 weeks of gestation, the germinal matrix surrounds the ventricular system and gradually involutes to reside over the
body of the caudate nucleus between 25 and 28 weeks of gestation, the head of the caudate nucleus in the thalamusstriate groove between 28 and 34
weeks and usually dissipates at 36 weeks of gestation. The site of hemorrhage within the germinal matrix tends to shift with increasing gestational age.
In infants less than 28 weeks, hemorrhage occurs mainly in the matrix overlying the body of the caudate nucleus, but in more mature infants, the
primary site is at the head of the caudate nucleus at the level of the foramen of Munro.
Male Sex
Male infants have an overall higher rate of medical complications associated with prematurity than do female infants and are twice as likely as their
female counterparts to develop P/IVH. Increased male vulnerability may be caused by relative immaturity of the male infant, increased genetic
endowment related to redundancy in certain Xchromosome genes, genetic and environmental factors, or a combination of these.
PATHOGENESIS
The mechanism of P/IVH is multifactorial and most likely involves multiple environmental and genetic factors that affect the risk of P/IVH independently
or interactively. They include immaturity of the cerebral vasculature, cerebral blood flow (CBF) dynamics, cardiovascular instability, and inflammatory
and genetic factors.
Immaturity of the Cerebral Vasculature
Germinal Matrix Vasculature
Throughout gestation, the density and crosssectional area of blood vessels in the human brain are largest in the germinal matrix.7 This highly vascular
network within the germinal matrix consists of highcaliber, irregular, thinwall vessels that lack basement membrane deposition and glial endfoot
ensheathing, both of which provide structural integrity to blood vessels.8,9 The rich vascularity of the germinal matrix is essential to meeting the high
metabolic demand of proliferating and maturing neuronal and glial precursor cells within the germinal matrix. However, the combination of a rich
vascular network and the lack of structural integrity of these vessels enhances the propensity to hemorrhage.
Cerebral Venous System
The immature cerebral venous system may also contribute to the genesis of P/IVH. At 24 to 28 weeks of gestation, most of the cerebral venous blood
flow is through the deep galenic system, which also drains the germinal matrix and most of the white matter. The major veins of the deep system pass
directly through the germinal matrix, and any hemorrhage within the germinal matrix may result in venous congestion and stasis.
Alterations in Cerebral Blood Flow
Cerebral Pressure Autoregulation
The inability of preterm infants to maintain a relatively constant CBF despite fluctuations in arterial blood pressures (ie, cerebral pressure
autoregulation) was first implicated in the genesis of P/IVH in the 1970s. Clinical studies using the xenon 133 clearance technique to measure CBF
The immature cerebral venous system may also contribute to the genesis of P/IVH. At 24 to 28 weeks of gestation, most of the cerebral venous blood
flow is through the deep galenic system, which also drains the germinal matrix and most of the white matter. The major veins of the deep system pass
directly through the germinal matrix, and any hemorrhage within the germinal matrix may result in venous congestion and stasis.
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Alterations in Cerebral Blood Flow
Cerebral Pressure Autoregulation
The inability of preterm infants to maintain a relatively constant CBF despite fluctuations in arterial blood pressures (ie, cerebral pressure
autoregulation) was first implicated in the genesis of P/IVH in the 1970s. Clinical studies using the xenon 133 clearance technique to measure CBF
demonstrated a statistically significant correlation between CBF and arterial blood pressure in preterm infants, suggesting that cerebral pressure
autoregulation in the preterm infant was impaired.10 It was postulated that such impairment renders the preterm infant susceptible to both
hypoperfusion with resultant ischemia and hyperfusion, which potentially could lead to rupture of germinal matrix vasculature.11 The causal
relationship of pressure passive CBF with P/IVH was reinforced by a subsequent study in which the effects of acute changes in blood pressure and
partial pressure of carbon dioxide (Pco2) on CBF were measured in preterm infants on mechanical ventilation using the xenon 133 clearance
technique. P/IVH was noted only in infants who had pressure passive CBF and reduced CO2 vasoreactivity.12
Nearinfrared spectroscopy (NIRS) and spatially resolved spectroscopy (SRS) have been employed to continuously measure CBF. Used in conjunction
with arterial blood pressure monitoring, NIRS measurements have been helpful in elucidating the role of cerebral pressure passivity in the genesis of
P/IVH. An observational study using NIRS noted a high prevalence of cerebral pressure passivity among sick VLBW infants that waxed and waned over
relatively short periods, being present 20% of the time and increasing in frequency with lower gestational age.13 The investigators did not observe a
relationship of CBF pressure passivity or systemic hypotension and P/IVH. In another observational study using SRS, impaired autoregulation of CBF
was associated with mortality but not P/IVH.14 Recent studies focusing on the magnitude of pressure passivity have shown that the magnitude is
associated with P/IVH.15 Thus, studies utilizing continuous monitoring of CBF suggest that impairment of autoregulation of CBF per se may not be an
antecedent to P/IVH, but that the degree of impairment of autoregulation of CBF may be a factor.
Hemodynamic Factors
In the absence of bedside techniques to continuously measure CBF, it has been assumed that, in sick very preterm infants, maintaining blood pressure
values between certain populationbased normal limits would ensure adequate CBF and minimize the risk for cerebral injury. However, in clinical
studies, neither mean blood pressure nor the duration of low blood pressure has been associated with P/IVH.13,16 In 1 clinical study, CBF was
significantly lower during the first 24 hours after birth in infants who incurred P/IVH compared to those who did not; however, mean arterial blood
pressure was consistently higher.17 Several investigators have suggested that cardiac function may be a more accurate measure of cerebral perfusion
than blood pressure. Kluckow et al, using functional echocardiography to measure cardiac output and superior vena cava (SVC) blood flow
demonstrated that low SVC flow is common in the first 24 hours after birth in extremely premature infants and is associated independently with
subsequent P/IVH.18 Additional studies for the same group indicated that systemic blood pressure measurements did not correlate with lowflow
states in the SVC and were a poor predictor of P/IVH.19,20 In subsequent followup studies, low SVC flow also was associated with poor
neurodevelopmental outcome.21,22 Kusaka and colleagues have measured CBF and left ventricular output simultaneously using multichannel NIRS and
pulse dye densitometry with indocyanine green to show that there is a significant positive relationship between cardiac output and CBF, but not
cardiac output and blood pressure.23
Both blood pressure fluctuations and a decrease in blood pressure variability have been implicated in the pathogenesis of P/IVH.24 However, more
recent studies using NIRS technology suggested that blood pressure variability is not a significant independent predictor for P/IVH.13
Biochemical Factors
Carbon dioxide is a potent and important mediator of CBF independent of autoregulation. Both hypocapnia and hypercapnia induce substantial
alterations in CBF in newborn animal models. The vascular response to CO2 is thought to be secondary to changes in intravascular pH. Hypercarbia as a
risk factor for P/IVH was first proposed in the 1970s. Clinical studies using xenon 133 to measure CBF indicated that hypercarbia is associated with
impaired cerebral autoregulation in ventilated VLBW infants and increased the risk of P/IVH.25 It was postulated that infants who were hypercarbic
were vulnerable to perturbations in blood pressure due to impaired autoregulation and at risk for P/IVH due to transmittance of arterial pressure to
the capillaries in the germinal matrix. Any increase in blood pressure would cause CBF to increase in a passive manner due to ineffective
vasoconstriction. Conversely, with hypotension, additional vasodilation might not be possible, resulting in pressure passive decreases in CBF. It was
suggested that a possible intervention for the prevention of P/IVH would be to limit hypercapnia. However, there is extensive retrospective evidence
that hypocapnia in preterm infants is associated with an increased risk of periventricular leukomalacia (PVL) and cerebral palsy,26, 27, and 28 possibly
due to cerebral vasoconstriction, decreased CBF, and decreased cerebral oxygen delivery.
A more recent clinical study utilizing transcranial Doppler ultrasound suggested that autoregulation of CBF in ventilated preterm infants was intact at
risk factor for P/IVH was first proposed in the 1970s. Clinical studies using xenon 133 to measure CBF indicated that hypercarbia is associated with
impaired cerebral autoregulation in ventilated VLBW infants and increased the risk of P/IVH.25 It was postulated that infants who were hypercarbic
were vulnerable to perturbations in blood pressure due to impaired autoregulation and at risk for P/IVH due to transmittance of arterial pressure to
the capillaries in the germinal matrix. Any increase in blood pressure would cause CBF to increase in a passive manner due to ineffective Access Provided by:
vasoconstriction. Conversely, with hypotension, additional vasodilation might not be possible, resulting in pressure passive decreases in CBF. It was
suggested that a possible intervention for the prevention of P/IVH would be to limit hypercapnia. However, there is extensive retrospective evidence
that hypocapnia in preterm infants is associated with an increased risk of periventricular leukomalacia (PVL) and cerebral palsy,26, 27, and 28 possibly
due to cerebral vasoconstriction, decreased CBF, and decreased cerebral oxygen delivery.
A more recent clinical study utilizing transcranial Doppler ultrasound suggested that autoregulation of CBF in ventilated preterm infants was intact at
Paco2 (partial pressure of carbon dioxide, arterial) values of 30 to 44 mm Hg, but there was a progressive loss of autoregulation between 45 and 60 mm
Hg.29 Because the study was cross sectional in design, data regarding brain injury are lacking. In a multicenter clinical trial of permissive hypercapnea
(Paco2 > 52 mm Hg) compared to routine ventilation (Paco2 < 48 mm Hg), there was a small, but not significant, difference in the incidence of P/IVH and
no difference in survival without neurodevelopmental impairment.30 A singlecenter retrospective review of clinical and blood gas data during the first
4 days after birth suggested that extreme values of Paco2, whether high or low, and the wide variations in Paco2 values for an individual infant are
associated with grades III and IV P/IVH; the association persisted after adjustment for major perinatal variables.31
Genetic Factors
Since the mid2000s, there has been an increasing interest in the potential role of genetic factors in the genesis of P/IVH. Twin studies suggested that
shared environmental and genetic risk factors explain 41% of risk for developing P/IVH.32 Observational studies of genetic association with P/IVH have
focused primarily on genes related to inflammation or infection, mechanisms thought to be important in the pathophysiology of perinatal brain injury.
Additional studies have focused on genes related to complement coagulation because of the possibility that increased fibrinolytic activity and
decreased levels of clotting factors may contribute to the extent of the P/IVH lesion. IL1b511T, IL4590T, IL6174C, and TNFa308 have been associated
with P/IVH.33,34 The coagulation factor V Leiden mutation, a coagulation factor II, and prothrombin polymorphism have also been implicated.35, 36, 37, 38,
and 39 Although factor V Leiden mutation is associated with an increased risk of P/IVH, several studies suggested that the P/IVH is limited to grades I and
II.35,38,39 However, many of the associations have not been evaluated in large cohorts of VLBW infants and have not been replicated across studies.
DIFFERENTIAL DIAGNOSIS
Germinal matrix hemorrhage and IVH are distinct entities that are readily detected with CUS. However, distinguishing parenchymal hemorrhage
secondary to venous congestion (grade IV IVH) from hemorrhagic PVL may be challenging, and in some instances both lesions may be present.40
The typical HUS appearance of early parenchymal hemorrhage is that of a large, asymmetric, triangular, fanshaped lesion that is located in the
periventricular area just dorsal and lateral to the external angle of the lateral ventricle (Figure 132). Subependymal or IVH is almost always present on
the same side as a parenchymal hemorrhage and is considered to be the underlying cause of venous compromise by compression of terminal veins
underlying the germinal matrix. The lesion is usually unilateral and involves 2 or more lobar territories, typically the frontal and parietal regions.
Bilateral lesions, although rare, are characterized by a grossly asymmetric appearance.41 Approximately 50% of lesions are associated with a midline
shift of cerebral structures. Eventually, the parenchymal hemorrhage evolves into multiple coalescent cysts or a large cyst that may or may not
communicate with the lateral ventricle. In some cases, the lesion may resolve, resulting in ex vacuo dilation of the ipsilateral ventricle.
On CUS, hemorrhagic PVL typically appears as symmetrical bilateral lesions that are located in the regions adjacent to the trigone of the lateral
ventricle or adjacent to the ventricles at the level of the foramina of Monro. The characteristic evolution of hemorrhagic PVL is the formation of
multiple small cysts. The clinical usefulness of HUS criteria to distinguish grade IV P/IVH from hemorrhagic PVL has been evaluated. In a retrospective
HUS study, 77% of lesions could be differentiated as either grade IV P/IVH or hemorrhagic PVL, with coexisting features noted in 11%. An additional
12% with persistent periventricular echo densities without cystic changes could not be classified.40 In contrast, the results of a subsequent
retrospective study indicated that only 53% of infants with white matter lesions on HUS could be allocated to periventricular hemorrhagic infarction or
PVL. It was postulated that periventricular hemorrhagic infarction contributes to the risk of PVL.42
DIAGNOSTIC TESTS
Because most infants who develop P/IVH do not manifest clinical signs attributable to P/IVH, the diagnosis relies on screening with noninvasive cranial
imaging. Some infants may exhibit subtle abnormalities in the level of consciousness, movement, tone, respirations, and eye movement; rarely, P/IVH
will be accompanied by a catastrophic deterioration consisting of stupor, coma, decerebrate posturing, and generalized seizures. The majority of
P/IVH is initiated within the first 24 hours after birth, and hemorrhages can progress over 48 hours or more. By the end of the first postnatal week, 98%
of P/IVH has occurred. The time frame in which P/IVH occurs is independent of gestational age, although extremely preterm infants tend to
hemorrhage earlier than more mature infants. In 1 series, 62% of P/IVH in infants between 500 and 700 g birth weight occurred in the first 18 hours
after birth.43
DIAGNOSTIC TESTS
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Because most infants who develop P/IVH do not manifest clinical signs attributable to P/IVH, the diagnosis relies on screening with noninvasive cranial
imaging. Some infants may exhibit subtle abnormalities in the level of consciousness, movement, tone, respirations, and eye movement; rarely, P/IVH
will be accompanied by a catastrophic deterioration consisting of stupor, coma, decerebrate posturing, and generalized seizures. The majority of
P/IVH is initiated within the first 24 hours after birth, and hemorrhages can progress over 48 hours or more. By the end of the first postnatal week, 98%
of P/IVH has occurred. The time frame in which P/IVH occurs is independent of gestational age, although extremely preterm infants tend to
hemorrhage earlier than more mature infants. In 1 series, 62% of P/IVH in infants between 500 and 700 g birth weight occurred in the first 18 hours
after birth.43
Cranial Sonography
In 2002, the American Academy of Neurology and the Child Neurology Society published a joint practice parameter for neuroimaging of the neonate.44
In this report, screening with CUS was recommended for all preterm infants less than 30 weeks of gestational age at 2 time points. The first screening
ultrasound was to be done at 7–14 days of age to detect P/IVH and the second ultrasound at 36–40 weeks’ postmenstrual age to assess for cerebral
ventriculomegaly and PVL. Because of its ease of use, CUS remains the imaging modality of choice to screen for P/IVH shortly after birth. Older studies
have shown that the correlation of lesions noted on screening CUS and those detected at necropsy are excellent for both the frequency and extent of
P/IVH.
Magnetic Resonance Imaging
Since the publication of the practice parameter in 2002, improvements in scanning procedures, the technique of bundling infants to minimize the use
of sedative and anesthetic agents during a procedure, and the development of incubators compatible with magnetic resonance imaging (MRI) have
enhanced the safety of MRI studies and, as a result, have led to its widespread use in ill neonates. Several observational studies have suggested that
MRI is superior to CUS in the detection of brain lesions, especially in the extremely preterm infant, and should replace HUS as a screening tool for the
detection of brain injury.45,46 However, HUS data used for comparison in these reports were obtained early (2 to 6 weeks of age), precluding the
inclusion of late CUS findings, such as diffuse gray and white matter loss and impaired brain growth, whereas the MRI data were obtained weeks later
at term gestation. When comparing MRI and CUS evaluations done at term gestation and on the same day, cerebral lesions were detected equally well
with both modalities.47 A major drawback of using MRI routinely to diagnose neonatal brain injury is the lack of radiologists even in tertiary care
centers with sufficient expertise in both neonatal neuroimaging and the interpretation of the MRI images. Based on available data, HUS remains the
preferred modality for P/IVH screening shortly after birth. Whether CUS or MRI is used for the evaluation at 36 to 40 weeks’ corrected age will depend
on available equipment and expertise at a given center (see Figure 136).
MANAGEMENT
Management of P/IVH can be considered in terms of prevention of P/IVH and the treatment of PHH.
Prevention of P/IVH
The most effective strategy to prevent P/IVH would be to prevent preterm birth. Despite concerted efforts directed toward this end, there has been little
change in the rate of premature birth, especially for infants who are less than 28 weeks of gestational age.48 Strategies for the prevention of P/IVH have
focused primarily on pharmacological interventions administered shortly before birth to women who are threatening premature birth or to premature
infants shortly after birth (Table 131).
Table 131
Effective Pharmacological Intervention for the Prevention of Periventricular/Intraventricular Hemorrhage
Antenatal therapy
Antenatal steroids (betamethasone and dexamethasone)
Postnatal therapy
Pancuronium bromide
Indomethacin
Antenatal Pharmacological Intervention
Because factors related to labor and delivery or the immediate postnatal period potentially may play a role in the pathogenesis of P/IVH, several
The most effective strategy to prevent P/IVH would be to prevent preterm birth. Despite concerted efforts directed toward this end, there has been little
change in the rate of premature birth, especially for infants who are less than 28 weeks of gestational age.48 Strategies for the prevention of P/IVH have
focused primarily on pharmacological interventions administered shortly before birth to women who are threatening premature birth or to premature
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infants shortly after birth (Table 131).
Table 131
Effective Pharmacological Intervention for the Prevention of Periventricular/Intraventricular Hemorrhage
Antenatal therapy
Antenatal steroids (betamethasone and dexamethasone)
Postnatal therapy
Pancuronium bromide
Indomethacin
Antenatal Pharmacological Intervention
Because factors related to labor and delivery or the immediate postnatal period potentially may play a role in the pathogenesis of P/IVH, several
investigators have explored the efficacy of interventions that could be instituted when premature delivery was imminent. Antenatal therapies that have
been studied include glucocorticosteroids, phenobarbital, magnesium sulfate, and vitamin K.
Antenatal administration of glucocorticoids is the most effective antenatal strategy to prevent P/IVH. Interestingly, the initial report regarding the
beneficial effect of corticosteroids for the prevention of P/IVH was based on metaanalysis of data from studies in which antenatal glucocorticoids were
used to promote fetal lung maturation.49 Numerous retrospective observational studies since the initial report have shown that ANSs reduce not only
the overall incidence but also the severity of P/IVH. Multivariate analyses indicated that the beneficial effect of ANS on the incidence of P/IVH is
independent of its beneficial effect of reducing respiratory disease. The mechanism of beneficial effect is not known, but it is thought to be related to
maturation of brain structures and improved cardiovascular stability. The effectiveness of an ANS is greatest when a complete course is given;
however, a partial course is also associated with a decrease in the frequency and severity of P/IVH. In addition, there does not appear to be any benefit
accrued from repeated courses of ANS.50 Retrospective analyses in which the outcome of infants exposed to antenatal betamethasone was compared
to those exposed to dexamethasone suggested that betamethasone is associated with a reduced risk of death and less respiratory distress and chronic
lung disease; however, there was no statistical difference in the frequency and severity of P/IVH.51,52 Thus, it would appear that both pharmacological
agents are equally effective in the prevention of P/IVH.
Coagulation disorders have been described in infants with P/IVH, and it is known that the function of vitamin K–dependent clotting factors in preterm
infants is 30% to 60% of the function in adults. There have been 8 published trials of vitamin K given as an injection to women immediately before a
very preterm birth. Comprehensive metaanalyses of these published trials showed no significant difference in the risk of having any grade of P/IVH
between babies exposed to prenatal vitamin K and control babies.53 The apparent lack of effect of vitamin K is most likely explained by poor placental
transfer of vitamin K and therefore poor effect on fetal coagulation factors.
The beneficial effect of antenatal magnesium sulfate in the prevention of P/IVH is unproven. In several large randomized, placebocontrolled trials,
antenatal magnesium sulfate did not reduce the incidence of P/IVH or PVL.54,55 Despite this, there was a significant reduction in the risk of cerebral
palsy among children who survived early preterm birth. The mechanism of neuroprotection is unknown.
Postnatal Pharmacological Intervention
Because a good proportion of P/IVH occurs within the first postnatal 12 hours after birth, postnatal strategies to prevent P/IVH need to be given at or
shortly after birth to be effective. Pharmacological interventions that have been evaluated include phenobarbital, pavulon, vitamin E, ethamsylate,
indomethacin, and ibuprofen. Of these, only pancuronium bromide and indomethacin therapy have proved effective in multiple clinical trials.
Before the availability of synchronous ventilation, it was noted that ventilated infants who “fought the ventilator” had a fluctuating pattern of CBF
velocity that was associated with a high risk of developing P/IVH. Several small clinical trials were conducted after it was observed that abolishing this
fluctuating pattern with muscle paralysis using pancuronium bromide markedly reduced the risk of developing P/IVH. A 2004 comprehensive review of
published clinical trials using pancuronium bromide for shortterm muscle paralysis of ventilated infants concluded that this intervention leads to a
reduction in the incidence, but not the severity, of P/IVH.55 However, since the studies were completed the use of synchronous and assist control
ventilation has been widely implemented in the United States, making this strategy somewhat dated.
Initial trials of prophylactic indomethacin therapy to prevent P/IVH noted a significant decrease in the frequency and severity of P/IVH. The potentially
beneficial effects of indomethacin include accelerated maturation of microvessels within the germinal matrix, alterations in CBF, and inhibition of the
Before the availability of synchronous ventilation, it was noted that ventilated infants who “fought the ventilator” had a fluctuating pattern of CBF
velocity that was associated with a high risk of developing P/IVH. Several small clinical trials were conducted after it was observed that abolishing this
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fluctuating pattern with muscle paralysis using pancuronium bromide markedly reduced the risk of developing P/IVH. A 2004 comprehensive review of
published clinical trials using pancuronium bromide for shortterm muscle paralysis of ventilated infants concluded that this intervention leads to a
reduction in the incidence, but not the severity, of P/IVH.55 However, since the studies were completed the use of synchronous and assist control
ventilation has been widely implemented in the United States, making this strategy somewhat dated.
Initial trials of prophylactic indomethacin therapy to prevent P/IVH noted a significant decrease in the frequency and severity of P/IVH. The potentially
beneficial effects of indomethacin include accelerated maturation of microvessels within the germinal matrix, alterations in CBF, and inhibition of the
formation of free radicals. A recent detailed metaanalysis of published data of prophylactic indomethacin found no evidence of an effect on the
overall incidence of P/IVH but did confirm a beneficial effect on the incidence of severe P/IVH.56 However, despite the fact that indomethacin reduces
the frequency of severe P/IVH, it does not improve the rate of survival without neurosensory impairment. Both mortality and neurosensory impairment
in early childhood did not differ between children treated with prophylactic indomethacin and those who were not. It has been suggested that the
beneficial effects of indomethacin prophylaxis may be restricted to male infants since secondary analyses of several studies have shown a differential
effect of indomethacin by sex on the frequency of P/IVH.57,58
Posthemorrhagic Hydrocephalus
Prevention
Efforts to prevent the development of PHH have included repeated lumbar punctures at the time of diagnosis of IVH and the use of intraventricular
fibrinolytic therapy in infants developing posthemorrhagic ventricular dilation. When repeated lumbar punctures were compared to conservative
treatment, there was no difference in the relative risks for shunt placement, death, or disability.59 Likewise, when intraventricular instillation of
streptokinase was compared to conservative management of posthemorrhagic ventricular dilation, the numbers of deaths and infants who required
the placement of a permanent shunt were similar.60
Management
Ventricular dilation occurs in approximately 50% of infants who develop an IVH (Figure 134). Approximately half of affected infants will undergo
spontaneous arrest or resolution of the dilation; the other half will develop progressive ventricular dilation (ie, PHH) (see Figure 134). PHH may be
communicating or noncommunicating. Noncommunicating PHH occurs when a large intraventricular clot or ependymal scarring impedes the flow of
CSF through the outflow tracts of the lateral, third, and fourth ventricles. Communicating PHH is thought to be secondary to an impairment of CSF
absorption caused by an obliterative arachnoiditis at the posterior fossa or a chemical arachnoiditis caused by blood within the CSF.
Since progressive ventricular dilation typically occurs before there is clinical evidence of hydrocephalus (eg, increased rate of head growth and the
presence of a full anterior fontanelle), early diagnosis is dependent on serial CUS evaluations (Figure 137). The main therapeutic dilemma in the
management of ventricular dilation is identifying early which infants will develop PHH and will need intervention to minimize additional brain injury
that may be caused by increasing distortion of the ventricles. However, because there are no universally accepted criteria for deciding when
intervention is needed, the decision for treatment varies by center and surgeon and is generally dictated by local experience.
FIGURE 137
Management of periventricular/intraventricular hemorrhage. MRI, magnetic resonance imaging.
intervention is needed, the decision for treatment varies by center and surgeon and is generally dictated by local experience.
FIGURE 137
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Management of periventricular/intraventricular hemorrhage. MRI, magnetic resonance imaging.
Despite many treatment options, there is no consensus on the management of PHH in VLBW infants. The large amount of blood and protein in the CSF,
combined with the infant’s small size, are deterrents to early ventriculoperitoneal shunt placement because of the high risk of blockage and infection.
The most common initial approach to the management of PHH is the placement of a temporary CSF diversion device, usually either a
ventriculosubgaleal (VSG) shunt, in which CSF is shunted into the subgaleal space of the scalp and absorbed into the bloodstream, or a ventricular
reservoir that is intermittently tapped. In a large multicenter retrospective observational study, the use of VSG shunts was associated with a greater
need for permanent CSF diversion compared to the use of intermittent tapping of ventricular reservoirs.61 The rates of infection during temporization
and for the initial 6 months after conversion to a ventriculoperitoneal (VP) shunt system were comparable for both groups.
OUTCOME
Prognosis can be considered in terms of shortterm outcome, especially mortality, and the somewhat longer outcome of neurodevelopmental
impairment in early childhood. The shortterm outcome relates to the extent of the P/IVH and the degree of prematurity. The reported mortality rates
for VLBW infants with isolated germinal matrix hemorrhages (grade I) are comparable to those of infants of the same gestational age without P/IVH.
With both IVHs and normal ventricular size (grade II P/IVH) and IVHs with ventricular dilation (grade III P/IVH), the reported mortality rates are higher
only for infants of extremely low gestational age. For those infants with P/IVH and parenchymal hemorrhage (grade IV P/IVH), the reported mortality
rate is approximately 40%, a rate that is much higher than that for comparable infants without P/IVH.62
Although the spectrum and attendant complications of P/IVH have been well documented with noninvasive cranial imaging techniques, data regarding
the impact of P/IVH on neurological and developmental outcome of affected infants are sparse. In addition, the heterogeneity between published
studies makes interpretation of the data difficult. Two factors, the extent of hemorrhage and ventricular dilation, appear to be critical determinants of
neurodevelopmental outcome.
Extent of Hemorrhage
In the majority of published studies, the incidence of neurodevelopmental impairment for infants who develop grades I or II P/IVH is essentially the
same as that for infants with no evidence of P/IVH on CUS.63, 64, and 65 However, there are several reports that suggested the occurrence of these lesions
is associated with a 2 to 5fold higher odds of cerebral palsy and intellectual disability.66, 67, and 68
Shortterm outcome studies of preterm children who sustained a neonatal grade IV IVH (periventricular hemorrhagic infarction) have reported a high
rate of cerebral palsy, ranging from 40% to 90%; however, there has been no consensus regarding cognitive outcome, with normal cognition noted in
20% to 79%.69, 70, 71, and 72 Although available data on longterm outcome are sparse, published studies suggested that despite a high rate of cerebral
palsy, the majority of affected children have limited functional impairment and attend regular education classes.69,73 The discrepancy between
outcome in early childhood and later childhood most likely relates to the shortcomings of infant neurodevelopmental testing. Because the successful
completion of many test items relies heavily on intact motor function, the scores achieved by infants with motor impairment, such as cerebral palsy,
same as that for infants with no evidence of P/IVH on CUS.63, 64, and 65 However, there are several reports that suggested the occurrence of these lesions
is associated with a 2 to 5fold higher odds of cerebral palsy and intellectual disability.66, 67, and 68
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Shortterm outcome studies of preterm children who sustained a neonatal grade IV IVH (periventricular hemorrhagic infarction) have reported a high
rate of cerebral palsy, ranging from 40% to 90%; however, there has been no consensus regarding cognitive outcome, with normal cognition noted in
20% to 79%.69, 70, 71, and 72 Although available data on longterm outcome are sparse, published studies suggested that despite a high rate of cerebral
palsy, the majority of affected children have limited functional impairment and attend regular education classes.69,73 The discrepancy between
outcome in early childhood and later childhood most likely relates to the shortcomings of infant neurodevelopmental testing. Because the successful
completion of many test items relies heavily on intact motor function, the scores achieved by infants with motor impairment, such as cerebral palsy,
underestimate their true ability and may lead to an unduly pessimistic view regarding their ultimate outcome. An additional finding that has not been
emphasized is the risk for a visual field defect due to injury to the optic radiation. In 1 study, the frequency of a visual field defect was 25%.74
Acute Ventricular Dilation
Ventricular dilation can occur acutely, as seen with grade III P/IVH, or it may not be evident for weeks or months after birth. Later ventricular dilation
may be progressive or nonprogressive. Nonprogressive ventriculomegaly is presumed to be a surrogate for white matter injury.
When the data from multiple published studies are combined, the pooled probability of an abnormal motor outcome when IVH is accompanied by
acute ventricular dilation (grade III P/IVH) is approximately 26%, with a range of 13% to 45%.75 In the largest published series of P/IVH, 35% of infants
with grade III who did not develop PHH had cerebral palsy, and 55% were determined to have a neurodevelopmental impairment in early childhood.72
Nonprogressive Ventricular Dilation
The frequent association of IVH with cystic PVL and late ventricular dilation raises the possibility that intraventricular blood may cause periventricular
white matter injury. In 1 study, cystic PVL was accompanied by IVH in 67% of cases.76 Nonprogressive ventricular dilation was associated with an
increased risk of neurodevelopmental impairment in infants with IVH in 1 study and impaired cognitive function in another.77,78
Progressive Ventricular Dilation
Historical data suggest that only 5% to 30% of surviving children with PHH were free of neurodevelopmental impairment. If only recent studies are
considered, the rate of neurodevelopmental impairment is remarkably lower and ranges from 40% to 64%.72,79 Among infants with PHH, there is a
strong connection between the severity of P/IVH and outcome. In a study that included 128 infants with P/IVH who underwent surgical placement of a
shunt, 60% of infants with grade III P/IVH and hydrocephalus were neurodevelopmentally impaired compared to 92% of infants with grade IV P/IVH and
hydrocephalus.72 A smaller study of 5 to 8yearold children who required neurosurgical intervention for posthemorrhagic hydrocephalus as infants
noted that none of the children with grade III P/IVH and 53% of those with grade IV P/IVH developed cerebral palsy.79 The mean IQ of the cohort was
93.4, and 29% of the children had an IQ less than 85.
Comparison of children with and without PHH suggests that PHH per se may pose an additional risk for poor neurodevelopmental outcome beyond
that associated with P/IVH. The rate of neurodevelopmental impairment for infants with uncomplicated grade III P/IVH was 55% compared to 78% for
infants who had a shunt placed for PHH; the rates for infants with grade IV P/IVH were 63% and 92%, respectively.72
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Chapter 13 - Intracranial Hemorrhage

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43. Perlman JM, Volpe JJ. Intraventricular hemorrhage in extremely preterm infants. Am J Dis Child . 1986;140(11):1122–1126. [PubMed: 3532761]

48. Martin JA, Hamilton BE, Ventura SJ et al. Births: final data for 2009. Natl Vital Stat Rep . 2011;60(1):1–70. [PubMed: 22670489]

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