Continuing Education Activity

Periventricular-intraventricular hemorrhage is a disease process that primarily affects the premature newborn infant born at less than 33 weeks of gestation. Hemorrhage occurs when vessels of the germinal matrix in the periventricular area rupture and extend into the intraventricular space. When bleeding extends into the intraparenchymal space adjacent to the ventricle, it is termed periventricular hemorrhage. In severe cases, bleeding occupies a significant portion of the ventricle, in which case it is described as intraventricular hemorrhage. This activity describes the evaluation, diagnosis, and management of periventricular-intraventricular hemorrhage in newborns and stresses the role of team-based interprofessional care for affected patients.

Objectives:

• Describe the infant population at risk for periventricular-intraventricular hemorrhage.
• Explain how to evaluate periventricular-intraventricular hemorrhage.
• Review management strategies for newborn periventricular-intraventricular hemorrhage.
• Identify interprofessional team actions to improve detection and management of newborn periventricular-intraventricular hemorrhage.

Introduction

Periventricular-intraventricular hemorrhage (PIVH) is a disease process that affects the premature newborn infant. Hemorrhage occurs when vessels of the germinal matrix in the periventricular area rupture, which can then extend into the ventricles as intraventricular hemorrhage (IVH). In severe cases, bleeding will occupy a significant portion of the ventricle and extend into the intraparenchymal area. Infants most at risk are those born before 33 weeks of gestational age, as after this time, the germinal matrix involutes.[1]

The second most frequent cause of death in preterm infants is PIVH and is one of the leading causes of cerebral damage in low birth-weight preterm newborns.[2] Hyaline membrane disease is the most frequent cause of death in preterm infants.

Intraventricular hemorrhage (IVH) was first discovered by Abraham Towbin in 1968.[3] In 1978 Papile et al. developed a classification for PIVH based on the head computed tomographic scan.[4] This classification was later adapted in 1984 for ultrasound as the equipment is portable and can be frequently repeated.[5] 

The degree of hemorrhage is graded I through IV:

• Grade I – hemorrhage limited to Germinal matrix
• Grade II – IVH without ventricular dilatation
• Grade III - IVH with ventricular dilatation occupying > 50% of the ventricle
• Grade IV – IVH with intraparenchymal hemorrhage

Grade III and IV are termed as “severe IVH”.

Etiology

The predominant etiology of PIVH is the fragility of the vessels in the germinal matrix and the immature cerebral autoregulation mechanism in the preterm neonate.

Blood vessel morphology in the germinal matrix of the neonate differs from that in other cortical areas, mainly due to the increased metabolic demand required by the rapid turnover of precursor cells in this region. Blood vessels supplying the germinal matrix have a higher density and area than other cortical areas. In addition to this, the vessel morphology differs, mainly in that vessels supplying the germinal matrix are more round versus flat in other cortical regions due to a level of vessel immaturity.[1][6]

Damage to the surrounding white matter tissue from PIVH has been attributed to compression from ventricular dilation and direct white matter tissue trauma from the weakened ependymal lining. Compression on the adjacent white matter from dilated ventricles has been shown in non-human models to [roduce axonal damage, white matter edema, and various reactive cellular components. A similar mechanism is present when the ependymal lining stretches and ruptures exposing blood products and other reactive cellular components directly to the white matter.[7] Neonatal transport following outside delivery is the major risk factor. Neonatal factors such as mechanical ventilation, hypercarbia, pneumothorax, respiratory distress syndrome, and frequent intubations. Fluctuation of blood pressure have also shown associated with IVH.[8] 

Epidemiology

The worldwide incidence of PIVH ranges from 3.70 to 44.68%.[2] A recent study showed an overall incidence of 36.2%, with severe grades (III, IV) being present in 7.1% of them.[9] The overall frequency of PIVH grades I, II, III, and IV in preterm infants is 17.0%, 12.1%, 3.3%, and 3.8%, respectively.[9] When PIVH occurs, about 50% occur on the first day of life, and by the third day of life, it is 90%.[10]

Generally, the incidence of PIVH has decreased since the 1980s. In Brazil, a progressive decline in incidence from 50.9% in 1991 to 11.9% in 2005 had been shown.[2] However, in the United States, preterm birth delivery rates of 10% have remained stable over the last years.[11]

The incidence of PIVH varies based on gestational age and birth weight. Each additional week increase in gestational age of preterm infants with a weight of 1000 g or less decreased the probability of severe PIVH by 19%.[12] There is a 3.5% decrease in disease for each week of additional gestation age up to 32 weeks.[13] The overall incidence for all neonates of 22 to 28 weeks of gestational age is 32%.[13]

Based on weight, PIVH occurs in 25 to 30% of neonates less than 1500 g and occurs in up to 45% of neonates less than 1000 g.[2]

Most patients with grade III or IV weight less than 1000 g or have a gestational age of 22 to 27 weeks; gestational age greater than 31 weeks or weight greater than 1500g rarely results in a grade III or IV (2.7%).[10]

Pathophysiology

The germinal matrix is an immature thin-walled capillary network located on the head of the caudate nucleus and underneath the ventricular ependyma.[6][14] It is present in 24 to 32 weeks fetuses and contains a highly vascular collection of glial and neuronal precursor cells. The germinal matrix encircles the lateral ventricle but is more prominent on the head of the caudate nucleus. PIVH results from the rupture of capillaries at the germinal matrix due to the fragility of the vasculature, disturbed cerebral blood flow, or coagulation disorders.[6][9] If the germinal matrix hemorrhage is severe, the weak ependymal layer is compromised, and the hemorrhage extends into the ventricle or other intraparenchymal adjacent locations.[1][6]

Spontaneous rupture of the germinal matrix vessels may occur from hypoxia as a consequence of fluctuation in cerebral blood flow.[6][15] The germinal matrix is more prone to hemorrhage in premature infants during the first 48 to 72 hours of life. The structural fragility of the germinal matrix is what leads to PIVH. Due to immaturity, endothelial tight junctions, basement membrane, pericytes, fibronectin, and astrocyte end-feet may be defective.[6] The parenchyma of basal lamina is relatively soft and fragile because of deficient fibronectin and collagen. Intracranial vasculature of preterm neonates has the same innate immaturity as the vessels in other organs, which means that the walls are much weaker than in adults and are more prone to rupture. The cross-sectional area of the blood vessels is the largest in the human germinal matrix. Decreased expression of glial fibrillary acidic protein in the germinal matrix is very likely to reduce the strength of the cytoskeletal structure. The structural variants of subependymal veins are also confirmed to bring about the brittleness of the germinal matrix, as well as the inclination of thrombosis. The high vascularization adds to the fragility of the germinal matrix as well, especially when the neonate encounters hypoxia. Furthermore, the premature vasculature lacks the autoregulation to modulate the lumen under fluctuant hemodynamics.[6][16]

Periventricular Hemorrhagic Infarction (PHI)

Commonly and mistakenly, the parenchymal hemorrhagic infarction was termed as an extension of IVH. The incidence of hemorrhagic infarction increases with low gestational age. The PHI seemed to be associated with IVH as 1) it was observed in association with large IVH, 2) it occurred on the same side of the large IVH, and 3) it was detected after the occurrence of the IVH. The IVH leads to obstruction of the terminal veins and ultimately causes periventricular venous congestion with the development of hemorrhagic venous infarction.[17] The most common result of the PHI is a large porencephalic cyst.[18]

History and Physical

In the majority of the patients, PIVH is found incidentally during ultrasound screening for low-weight or preterm infants. Those with symptoms may show clinical neurological deterioration, respiratory distress, apnea, bulging fontanelle, seizures, hypoactivity, decreased responsiveness, or stupor.

Historical features that will predispose an infant to PIVH primarily result from the course of the pregnancy of the mother.[6][12][19][20][21][22]

• Gestational age ≤32 weeks
• The absence of antenatal steroids
• Antenatal maternal hemorrhage
• Maternal chorioamnionitis
• Vaginal delivery

Specific details from the birth of the infant may also increase the likelihood of PIVH in the preterm infant.

• Birth weight less than 1500 g 
• Early sepsis
• Hypotension requiring intervention
• Hypoxemia
• Hypercapnia
• Respiratory distress syndrome
• Positive pressure ventilation at birth
• Longer duration of assisted ventilation
• Pneumothorax
• Low Apgar score at 1 and 5 minutes
• Seizure
• Patent ductus arteriosus
• Higher frequency of endotracheal suctioning
• Surfactant use
• Thrombocytopenia

Preterm infants with grade IV weighed less at birth and have less gestational age when compared with those with grade III.[12][21] Other factors that have been commonly cited for PIVH do not influence the appearance of a grade III vs. a grade IV, including hypotension, early-onset sepsis, patent ductus arteriosus, surfactant therapy, prenatal steroid administration, maternal bleeding, maternal fever, mode of delivery, Apgar scores, and premature rupture of membranes.[21] Grade IV and III are more common in infants born after placental abruption.

The use of antenatal steroid treatments and cesarean section are factors that reduce the occurrence of PIVH.[22]

Evaluation

The majority of IVH in preterm infants occurs within the first three days of life.[23] Of these 70% of the IVH occurs within first 24 hours after birth and 95% occurred within 7 days of life.[24]

Current American Academy of Pediatrics recommendation for ultrasonographic IVH screening[25]

• All infants born at ≤ 30 weeks’ gestational age should be screened by 7 to 10 days of age.
• Repeat screening is recommended at 4 to 6 weeks of age and 36 weeks gestational age or before hospital discharge.
• Serial and more frequent cranial ultrasonography is recommended for infants with abnormal cranial ultrasonography findings.
• CT scan is not recommended for IVH screening.
• Routine MRI before discharge is also not recommended.

Diagnosis of PIVH is via transcranial ultrasound doppler screening in all neonates less than 30 weeks gestational age. This is the recommendation established by the American Academy of Neurology and suggests that the initial ultrasound should take place between 7 and 14 days of life with a repeat ultrasound at between 36 and 40 weeks of maturity.[1][20]

Although not routinely employed in the initial evaluation, brain magnetic resonance imaging (MRI) has been demonstrated to be useful in identifying cerebellar hemorrhages and white matter injury. It is used to investigate suspected cerebral anomalies found on ultrasound.[26] Fetal MRI does not have added value to a standard ultrasound or neurosonography (axial, coronal, and sagittal) for the fetus at risk.[27]

Daily measurement of head circumference is useful to monitor the development of hydrocephalus.

Treatment / Management

The primary treatment strategy should be aimed at the prevention of preterm birth, if possible. This should include the routine administration of antenatal corticosteroids if preterm birth is expected and the transfer of the mother to a facility that has advanced capabilities of caring for very low birth weight infants before delivery. Maternal corticosteroid administration for fetal lung maturation showed a protective effect against PIVH in preterm newborns.[19]

In the delivery of the preterm infant, delayed cord clamping should be the routine practice. This method has support from the American College of Obstetricians and Gynecologists, and a delay of between 30 and 180 seconds has demonstrated a reduced risk of PIVH compared to the immediate clamping group.[1]

Postnatal management should be targeted to limit hypoxia and fluctuations in cerebral blood flow. Several pharmacologic agents have been utilized to achieve those goals, such as phenobarbital and indomethacin. The meta-analysis of 10 trials showed a reduction in the incidence of severe IVH (grade III and IV) with use of prophylactic indomethacin.[28]

After the PIVH is established, no specific treatment exists to limit the hemorrhage. However, PIVH can be prevented by implementing early interventions to maintain stability and avoid fluctuations in cerebral blood flow and blood pressure. These interventions include head position along the midline, adequate respiratory support, avoidance of physical therapy maneuvers, constant blood pressure maintenance, and interventions to minimize pain.[10] These interventions should be used at least for the first 72 hours of life when PIVH has the highest incidence (50% on the first day and 90% on the third day).[10]

The care bundle has been used in Brazil with promising results and is summarized below:[10]

1. Keep the infant in supine position and head along the midline (Improper positioning may affect jugular venous return)
2. Do not perform physical therapy maneuvers (Can cause changes in intracranial pressure and cerebral blood flow)
3. Orotracheal tube suctioning only if necessary (Can alter blood pressure, cerebral blood flow, and intracranial pressure)
4. Do not collect cerebrospinal fluid (Lumbar puncture will alter heart rate and oxygen saturation)
5. Do not weigh the infant (Manipulation can trigger changes in the heart rate, oxygen saturation, and blood pressure)

Differential Diagnosis

The differential diagnosis for this condition is limited as the diagnosis is based on screening of the preterm neonate for this specific condition. Sepsis has to be recognized as treatment needs to be started as soon as possible. Hypoglycemia can decrease the level of consciousness quickly.

Prognosis

The prognosis and mortality are directly related to the extent of the injury, with the rate of mortality for grades I through IV at 4%, 10%, 18%, and 40%, respectively. Any degree of PIVH predisposes to later neurocognitive developments, with rates of cerebral palsy for grades I through IV at 8%, 11%, 19%, and 50%. Infants less than 27 weeks with a grade I or II PIVH are not associated with developmental delay.[1][13]

Preterm infants with severe PIVH are at increased risk for cerebral palsy, especially those whose weight is below 1000 grams.[11]

The neurodevelopmental outcomes of infants with IVH vary based on the parenchymal injury. EPIPAGE study demonstrated a relationship between IVH and adverse neurological outcomes.[29] Cerebral palsy rates were as high as 33% in infants born at 24-26 weeks GA as compared to 5% in infants born at 31-32 weeks GA.

Complications

One of the primary complications following PIVH is posthemorrhagic hydrocephalus; this can be a communicating or non-communicating type that occurs as a result of impaired cerebrospinal fluid reabsorption or by obstruction of the foramen of Monroe. Posthemorrhagic hydrocephalus should be suspected in any preterm infant with IVH that presents with rapidly increasing head circumference. Clinically infants should be monitored by daily head circumference measurement and examining anterior fontanel. Hydrocephalus can be monitored by measuring either the Evans ratio (the ratio of bifrontal horn diameter to the biparietal bone diameter) or the frontal and occipital horn ratio (FOHR), which is the average of the frontal and occipital horn dimensions divided by the biparietal diameter.[30][31] Although both measurements can have interobserver variation, serial measurement on ultrasound is more meaningful. Neurosurgical consultation and intervention are required when FOHR > 0.55 and significant clinical criteria such as split sutures, bulging fontanel, and bradycardia.[32] There are multiple proposed treatment strategies for hydrocephalus, including subgaleal shunt placement, ventricular reservoir placement, or ventriculoperitoneal shunt placement.[1][20] The only statistically significant associated risk factor for posthemorrhagic hydrocephalus is the severity of the IVH.[33][34] Gender, age, weight are not significant.[33]

Periventricular leukomalacia (PVL): It is an ischemic white matter injury, frequently diagnosed by ultrasound or MRI. IVH may contribute to the development of PVL. There is a correlation of impaired cognitive function in infants with PVL. Production of free radicles following IVH, ischemic insult after large IVH, and release of iron from ventricular blood contributes to white matter injury and occurrence of PVL. Although not specific, cranial ultrasound before discharge or at 36 weeks PMA is important to screen for PVL.

PIVH may also lead to periventricular leukomalacia, which is composed of multiple cystic foci in the periventricular space produced by coagulation necrosis. Periventricular leukomalacia may be the primary cause of neurodevelopmental delay following PIVH.[20]

Cerebral palsy incidence is increased in premature children with severe PIVH, especially those weighing below 1000 grams.[11]

Seizures and neurodevelopmental impairment are long-life sequelae after PIVH, especially in severe cases.

Deterrence and Patient Education

Patient education should target risk factor avoidance during pregnancy that would predispose to preterm delivery, including smoking cessation and routine prenatal care.

Mothers should be encouraged that most PIVH is asymptomatic, and those grades I and II had a good or excellent prognosis with very few complications.

Enhancing Healthcare Team Outcomes

The care of the preterm infant requires highly specialized facilities that employ an interprofessional team including a pediatrician, neonatologist, intensivist, radiologist, neurosurgeon, obstetrician, and neonatal nurses). Born outside a perinatal tertiary center is a risk factor for PIVH.[10] When caring for the infant, there has been a demonstrated benefit that reduces the risk of PIVH in the preterm infant when delivery is in a facility that specializes in the care of very low birth weight children (13.2% vs. 27.4%).[1] The implementation of a care bundle for the management of premature infants reduced the incidence of PIVH from 34.8% to 26.3% in all grades, but the reduction is most noted in its most severe forms (grades III and IV).[10]