Pediatrics

Intraventricular hemorrhage

OVERVIEW: What every practitioner needs to know

Are you sure your patient has an intraventricular hemorrhage? What are the typical findings?

The key sign is evidence of blood in the lateral ventricles on cranial ultrasonography done in a preterm infant between 0 and 7 days of age.

The clinical presentation depends on the severity of the hemorrhage. Many infants do not present with symptoms. For infants who do present with clinical symptoms and signs, they are the following:

Full, tense anterior fontanelle

Acute decrease in hematocrit or hemoglobin concentration

Altered neurologic status: lethargy, hypotonia, apnea, seizures

Additional clinical signs and laboratory findings

In 1981, Dubowitz and colleagues published results of a prospective study of 100 preterm infants, comparing cranial ultrasonographic findings with neurologic examinations. They noted that impaired visual tracking, a tight popliteal angle, and roving eye movements all correlated with the presence of intraventricular hemorrhage (IVH). Additional clinical signs and laboratory findings generally correlate with the extent/severity of the hemorrhage. These include the following:

Hemodynamic instability (hypotension, bradycardia)

Respiratory deterioration (including pulmonary hemorrhage)

General coagulopathy

Hyperglycemia

Hyperkalemia

What other disease/condition shares some of these symptoms?

Sepsis/meningitis

CNS malformations (e.g., congenital hydrocephalus)

Other types of CNS hemorrhage (e.g., subdural or subgaleal hemorrhage)

Other, non-CNS hemorrhage (e.g., abdominal)

What caused this disease to develop at this time?

Epidemiology

Approximately 20% of preterm infants weighing less than 1500 g at birth are diagnosed with IVH and both the incidence and the severity increase with decreasing gestational age. This incidence declined from 40%-50% in the early 1980s to 20% in the late 1990s as a result of changing practices in perinatal care and newborn resuscitation. However, the incidence of severe IVH (grades 3-4) has remained the same for the past decade, suggesting that there are other genetic or environmental factors that could be addressed. Most IVH occurs within the first 72 hours after birth and 90%-95% are detected within the first week.

Pathogenesis

The key reasons why preterm infants are so vulnerable to IVH follow:

Anatomic: Preterm infants have a highly vascularized germinal matrix that harbors neuronal and glial precursor cells. The capillaries within the germinal matrix have weak supportive basement membranes, thus making the vessels fragile and vulnerable to rupture. The germinal matrix is located at the head of the caudate nucleus beneath the ependymal lining of the lateral ventricles (i.e., subependymal), so a substantial germinal matrix bleed can break through the ependyma and blood can then enter the ventricle. If blood fills the ventricle, this can cause periventricular venous infarction (which can become hemorrhagic) and/or white matter injury (periventricular leukomalacia)

Physiologic: Critically ill preterm infants often have fluctuating cerebral bood flow (CBF) from hypoxia, hypercapnia, and hypotension associated with the delivery, respiratory distress syndrome, and/or sepsis. Cerebrovascular autoregulation is poorly developed in very preterm infants so that changes in blood pressure are accompanied by same-direction changes in CBF, the so-called pressure-passive circulation. Fluctuating CBF in preterm infants is clearly associated with the development of IVH.

Pathologic: Preterm infants may have hemostatic abnormalities, including thrombocytopenia, altered platelet function or coagulopathy associated with sepsis or maternal preeclampsia, or mutations in various thrombophilic factors such as factor V Leiden. These hemostatic abnormalities may combine with inflammation and/or increased fibrinolytic activity within the germinal matrix to increase the vulnerability of the preterm infant to IVH.

Risk factors include the following:

Extremely young gestational age

Absence of antenatal steroid exposure

Poor condition at birth and need for aggressive resuscitation (low Apgar scores)

Outborn status (transferred to a tertiary care center after birth)

Hypotension (but corrective blood pressure treatment does not affect the risk)

Pneumothorax

Chorioamnionitis/neonatal sepsis

Coagulation abnormalities and thrombophilia mutations

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Hematocrit: A significant hematocrit drop over a short period (e.g., 40% to 25% within 24 hours) might be due to an IVH, particularly if it occurs during the first week after birth and is not accompanied by obvious bleeding elsewhere.

Would imaging studies be helpful? If so, which ones?

Screening cranial ultrasonography should be performed on all preterm babies less than 30 weeks’ gestation at two time points: (1) between 1 and 2 weeks of age to detect initial IVH and (2) at 36-40 weeks postconceptional age or before discharge home (even if there was no IVH on initial screening) to detect periventricular white matter lesions and/or ventriculomegaly.

Magnetic resonance imaging (MRI) is better than cranial ultrasonography at detecting white matter lesions and cerebellar hemorrhage. Emerging data are providing some evidence for the use of MRI, ideally performed at term-equivalent age, in predicting neurodevelopmental outcome of extremely preterm babies, including those with IVH. However, there is not enough evidence to recommend routine MRI screening before discharge in all very low birth weight infants.

The Papile grading system, which describes the site and extent of IVH, was published in 1978 using computed tomography (CT) findings, but the same grading system has been applied to cranial ultrasonography and is widely used.

Grade 1: Subependymal hemorrhage confined to the germinal matrix (over the body of the caudate at the level of the foramen of Monro)

Grade 2: Hemorrhage within the lateral ventricle, but not enough to distend it

Grade 3: Hemorrhage fills more than 50% of the lateral ventricle, enough to distend or dilate it

Grade 4: Parenchymal hemorrhage or hemorrhagic infarction; may be with or without ventricular hemorrhage; occurs most commonly in the frontoparietal region.

If you are able to confirm that the patient has this condition, what treatment should be initiated?

There are no specific treatments for IVH. Acute management consists of (1) intensive neurologic monitoring for seizures and/or apnea (some recommend continuous electroencephalographic monitoring); (2) correction of anemia, thrombocytopenia, or coagulopathy if present; and (3) ongoing general cardiopulmonary, nutritional, and metabolic support.

Small open label interventional trials have been performed using hemostatic agents, such as recombinant activated factor VII, as an acute "rescue" treatment for IVH - the goal being to try and promote coagulation and thus prevent extension of hemorrhage. However, no randomized, placebo-controlled, clinical trials evaluating this off-label use of factor VII are currently available.

Babies with grade III IVH are at risk for the development of posthemorrhagic hydrocephalus resulting from arachnoiditis and/or blood/debris obstructing the normal CSF outflow. Daily measurement of head circumference and monitoring of cranial suture separation, as well as weekly cranial ultrasonography should be initiated in all babies with significant amounts of intraventricular blood.

What are the possible outcomes of intraventricular hemorrhage?

Babies with severe IVH are at higher risk for periventricular white matter injury (possibly due to venous infarction), which may result in periventricular leukomalacia and/or cerebral atrophy.

Grade I and grade II hemorrhages are generally followed by resolution, whereas grade III hemorrhage often evolves over a period of 1-3 weeks, resulting in posthemorrhagic hydrocephalus and ultimately the need for ventricular drainage—either temporary (external ventricular drain; subgaleal shunt) or permanent (ventriculoperitoneal shunt). Grade IV parenchymal hemorrhage may evolve into porencephalic cysts resulting from liquefaction necrosis and/or continuity of the parenchymal hemorrhage with the lateral ventricles.

Babies with IVH are at higher risk for neurologic sequelae, including cerebral palsy, developmental delay, seizures, and hearing and vision impairments. Grade I and II hemorrhages are not usually associated with significant neurologic morbidity, but these milder hemorrhages may be a biomarker of severity of illness.

One study reported that extremely low birth weight (< 1000 g) babies with even a small grade I-2 hemorrhage are at higher risk for neurodevelopmental impairment compared with similar babies without IVH. However, a more recent study, from the large NICHD Neonatal Network, found that neurodevelopmental outcomes of these tiny premature babies with low-grade hemorrhages are not different from those whithout hemorrhage. Grade III hemorrhage is associated with neurodevelopmental impairment in approximately one third of babies, and the risk increases if the baby develops posthemorrhagic hydrocephalus. Grade IV hemorrhage is associated with neurologic sequelae in at least half of affected babies.

Parents should be counseled regarding the risk for neurologic sequelae associated with each grade of IVH as well as the risk for development of posthemorrhagic hydrocephalus in babies with grade III IVH. Parents should be informed that the available follow-up data on which these risk assessments are based is necessarily outdated because follow-up studies report data on babies born many years earlier. Hopefully, general improvements in perinatal and neonatal care will improve the outcome of these babies.

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from intraventricular hemorrhage?

Posthemorrhagic hydrocephalus may develop in babies with significant amounts of ventricular blood (grade III IVH). Mechanisms include (1) impaired CSF reabsorption because of chemical arachnoiditis caused by blood and (2) acute obstruction of CSF flow through the foramen of Monro or the aqueduct of Sylvius by clot or subependymal scarring.

Periventricular leukomalacia or other white matter abnormalities may develop from venous infarction and/or low cerebral blood flow. Babies may have neurodevelopmental impairments, including developmental delay, cerebral palsy, and hearing/vision impairment

Are additional laboratory studies available; even some that are not widely available?

Follow-up brain imaging using MRI at term may help to predict neurodevelopmental outcome in preterm infants with or without IVH. Imaging sequences such as diffusion-weighted, diffusion tensor, and susceptibility weighted imaging may improve the predictive value. However, consideration should be given to potential harmful effects that the results of a term MRI scan may have for the parents.

How can intraventricular hemorrhage be prevented?

There have been many prevention strategies investigated, both antenatal and postnatal, but none has been shown to be clearly effective. This is primarily because the pathogenesis of IVH is likely so multifactorial with many overlapping and/or interactive pathways. Preventive strategies have generally focused on (1) stabilizing CBF (eliminating fluctuations), (2) enhancing the stability of the germinal matrix, and most recently (3) targeting specific genetic factors that may increase the risk for IVH (hemostatic, inflammatory, male/female factors)

Antenatal prevention strategies have included the following:

Maternal steroids are beneficial in reducing risk for IVH, but this may be an indirect effect of decreasing severity of illness (by decreased respiratory distress syndrome). Steroids may also provide some brain protection from higher neonatal blood pressure (which may reduce the need for blood pressure support with its attendant CBF fluctuations), and/or by upregulating glial fibrillary associated protein, which may lessen the fragility of germinal matrix vessels.

Maternal phenobarbital, vitamin K, magnesium sulfate have been tried, but there is not consistent evidence that these are effective prevention strategies for neonatal IVH.

Postnatal prevention strategies have included the following:

Indomethacin: This drug has been started immediately after birth. The rationale for this therapy is twofold: (1) stabilization of CBF, especially the increases in CBF associated with hypoxia and hypercapnia and (2) acceleration of microvessel maturation in the germinal matrix.

Two large clinical trials have shown that this preventive treatment approach does decrease the incidence and severity of IVH in very preterm infants, but despite less IVH, there was limited or no beneficial effect on neurodevelopmental outcome. Both trials noted differential effects of indomethacin prophylaxis on girls versus boys, suggesting that sex may play an important role in susceptibility to brain injury and response to treatment.

Phenobarbital: The rationale for the use of this drug includes stabilization of blood pressure (by sedating the baby) and decreased free radical production. No consistent beneficial effect has been found.

Vitamin E: The rationale for using vitamin E is decreased free radical production. No consistent beneficial effect has been found.

Ethamsylate: This agent promotes platelet adhesion and may increase capillary basement membrane stability. Clinical trials have shown decreased rates of IVH but no beneficial effect on severe IVH or neurodevelopmental impairment.

Platelet transfusion: Correction of thrombocytopenia by platelet transfusion has not been shown to be an effective IVH prevention strategy.

Volume-targeted ventilation: Compared with pressure-limited ventilation, volume-targeted ventilation may reduce the risk for IVH.

Neutral head positioning: The rationale for keeping the preterm baby’s head midline is to avoid head tilting, which may cause occlusion of the jugular venous drainage system and consequent cerebral venous blood leakage as well as potentially impair cerebral autoregulation. Current evidence supports a plan of care that includes midline head positioning for very preterm infants.

Delayed umbilical cord clamping: The optimal timing for clamping the umbilical cord after preterm birth is not known. A Cochrane review in 2012 evaluated studies of delayed cord clamping (for 30 to 120 seconds) and noted less IVH (all grades) in 10 of 15 clinical trials. However, there were insufficient data regarding the long-term effects of this strategy.

What is the evidence?

Ballabh, P. "Intraventricular hemorrhage in premature infants: mechanism of disease". Pediatr Res. vol. 67. 2010. pp. 1-8.

(Nice review of possible causes of IVH.)

Brouwer, A, Groenendaal, F, vanHaastert, IL. "Neurodevelopmental outcome of preterm infants with severe IVH and therapy for post-hemorrhagic ventricular dilatation". J Pediatr. vol. 152. 2008. pp. 648.

(Discusses the outcomes of babies with posthemorrhagic hydrocephalus after severe IVH.)

Inder, TE, Wells, SJ, Mogridge, NB. "Defining the nature of the cerebral abnormalities in the premature infant: A qualitative MRI study". J Pediatr. vol. 143. 2003. pp. 171.

(A very nice introduction to MRI findings in preterm infants.)

McCrea, HJ, Ment, LR. "The diagnosis, management and postnatal prevention of IVH in the preterm neonate". Clin Perinatol. vol. 35. 2008. pp. 777-92.

(Another nice review.)

Papile, LA, Burstein, J, Burstein, R. "Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 grams". J Pediatr. vol. 92. 1978. pp. 529-34.

(The original imaging [CT scan] classification schema for degrees of IVH [grade I, II, and so on].)

Schmidt, B, Asztalos, EV, Roberts, RS. "Trial of indomethacin prophylaxis in preterms. Long-term effects of indomethacin prophylaxis in ELBW infants". N Engl J Med. vol. 344. 2001. pp. 1966-72.

(The long-term follow-up of babies in whom there were fewer cases of IVH after receiving prophylaxis with Indomethacin.)

Davis, AS, Hintz, SR, Goldstein, RF. "Outcomes of extremely preterm infants following severe intracranial hemorrhage". J Perinatol. vol. 34. 2014. pp. 203.

(Retrospective review from the NICHD Neonatal Research Network of imaging and clinical variables that predict outcomes in extremely preterm infants with severe ICH.)

Volpe, JJ, Volpe, JJ. "Neurology of the newborn". Saunders. 2008. pp. 517-88.

(A lovely review of this "disease" by an acknowledged expert in the field.)

Whitelaw, A. "Core concepts: intraventricular hemorrhage". NeoReviews. vol. 12. 2011. pp. e94-101.

(Another nice review of this condition.)

Ongoing controversies regarding etiology, diagnosis, treatment

The overall strategy regarding neonatal IVH pathogenesis, prevention, and treatment has broadened to include all manner of preterm neonatal brain injury, not specifically IVH. Future neuroprotective strategies for this vulnerable patient population must address genetic (including sex) and neonatal intensive care unit environmental factors that increase risk for brain injury. Treatment and prevention strategies will likely become increasingly individualized and/or targeted at specific high-risk patient populations.

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