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.
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. Hyaline membrane disease is the most frequent cause of death in preterm infants.
In 1978 Papile et al. developed a classification for PIVH based on the head computed tomographic scan. This classification was later adapted in 1984 for ultrasound as the equipment is portable and can be frequently repeated.
The degree of hemorrhage is graded I through IV:
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.
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.
The worldwide incidence of PIVH ranges from 3.70% to 44.68%. A recent study showed an overall incidence of 36.2% with severe grades (III, IV) being affected in 7.1% of them. 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. PIVH occurs about 50% on the first day of life, and by the third day of life, it is 90%.
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. In the United States, however, preterm birth delivery rates of 10% have remained stable over the last years.
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%. There is a 3.5% decrease in disease for each week of additional gestation age up to 32 weeks. The overall incidence for all neonates of 22 to 28 weeks of gestational age is 32%.
Based on weight, PIVH occurs in 25-30% of neonates less than 1500 g and occurs in up to 45% of neonates less than 1000g.
Most patients with grade III or IV weight less than 1000 g or have a gestational age of 22-27 weeks; gestational age >31 weeks or weight > 1500g rarely produces a grade III or IV (2.7%).
The germinal matrix is an immature thin-walled capillary network located on the head of the caudate nucleus and underneath ventricular ependyma. It is present in 24-32 weeks fetus 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. 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.
Spontaneous rupture of the germinal matrix vessels may occur from hypoxia as a consequence of fluctuation in cerebral blood flow. The germinal matrix is more prone to hemorrhage in premature infants during the first 48-72 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. 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 are 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.
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.
Specific details from the birth of the infant may also increase the likelihood of PIVH in the preterm infant.
Preterm infants with grade IV weighed less at birth and have less gestational age when compared with those with grade III. 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. Grade IV and III are more common in infants born after placental abruption.
The use of antenatal steroid treatments and cesarean section are factors which reduce the occurrence of PIVH.
Diagnosis of PIVH is via the use of 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.
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. Fetal MRI does not have added value to a standard ultrasound or neurosonography (axial, coronal, and sagittal) for the fetus at risk.
Daily measurement of head circumference is useful to monitor the development of hydrocephalus.
The primary treatment strategy should be aimed at the prevention of preterm birth, if possible. This should include the routine administration of antenatal steroids 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.
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.
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.
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 the 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. 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).
The care bundle has been used in Brazil with promising results and is summarized below:
1. Keep the infant in prone 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 of 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)
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.
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.
Preterm infants with severe PIVH are at increased risk for cerebral palsy, especially those whose weight is below 1000 grams.
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. There are multiple proposed treatment strategies for hydrocephalus, including subgaleal shunt placement, ventricular reservoir placement, or ventriculoperitoneal shunt placement. The only statistically significant associated risk factor for posthemorrhagic hydrocephalus is the severity of the IVH. Gender, age, weight are not significant.
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.
Cerebral palsy incidence is increased in premature children with severe PIVH, especially those weighing below 1000 grams.
Seizures and neurodevelopmental impairment are a long-life sequelae after PIVH, especially in severe cases.
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 are asymptomatic, and those grades I and II had a good or excellent prognosis with very few complications.
The care of the preterm infant requires highly specialized facilities that employ an interprofessional team (pediatrician, neonatologist, intensivist, radiologist, neurosurgeon, obstetrician, and intensive care nurses). Born outside a perinatal tertiary center is a risk factor for PIVH. 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%). 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).
|||Novak CM,Ozen M,Burd I, Perinatal Brain Injury: Mechanisms, Prevention, and Outcomes. Clinics in perinatology. 2018 Jun; [PubMed PMID: 29747893]|
|||Marba ST,Caldas JP,Vinagre LE,Pessoto MA, Incidence of periventricular/intraventricular hemorrhage in very low birth weight infants: a 15-year cohort study. Jornal de pediatria. 2011 Nov-Dec [PubMed PMID: 22015432]|
|||Papile LA,Burstein J,Burstein R,Koffler H, Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. The Journal of pediatrics. 1978 Apr [PubMed PMID: 305471]|
|||Bowerman RA,Donn SM,Silver TM,Jaffe MH, Natural history of neonatal periventricular/intraventricular hemorrhage and its complications: sonographic observations. AJR. American journal of roentgenology. 1984 Nov [PubMed PMID: 6385669]|
|||Ballabh P, Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatric research. 2010 Jan; [PubMed PMID: 19816235]|
|||Adler I,Batton D,Betz B,Bezinque S,Ecklund K,Junewick J,McCauley R,Miller C,Seibert J,Specter B,Westra S,Leviton A, Mechanisms of injury to white matter adjacent to a large intraventricular hemorrhage in the preterm brain. Journal of clinical ultrasound : JCU. 2010 Jun; [PubMed PMID: 20232402]|
|||[PubMed PMID: 28104401]|
|||[PubMed PMID: 32332449]|
|||Gotardo JW,Volkmer NFV,Stangler GP,Dornelles AD,Bohrer BBA,Carvalho CG, Impact of peri-intraventricular haemorrhage and periventricular leukomalacia in the neurodevelopment of preterms: A systematic review and meta-analysis. PloS one. 2019 [PubMed PMID: 31600248]|
|||Kaiser JR,Gauss CH,Pont MM,Williams DK, Hypercapnia during the first 3 days of life is associated with severe intraventricular hemorrhage in very low birth weight infants. Journal of perinatology : official journal of the California Perinatal Association. 2006 May [PubMed PMID: 16554847]|
|||Mukerji A,Shah V,Shah PS, Periventricular/Intraventricular Hemorrhage and Neurodevelopmental Outcomes: A Meta-analysis. Pediatrics. 2015 Dec; [PubMed PMID: 26598455]|
|||[PubMed PMID: 26131081]|
|||Perlman JM,Goodman S,Kreusser KL,Volpe JJ, Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood-flow velocity in preterm infants with respiratory distress syndrome. The New England journal of medicine. 1985 May 23 [PubMed PMID: 3887165]|
|||[PubMed PMID: 30361892]|
|||[PubMed PMID: 28856015]|
|||McCrea HJ,Ment LR, The diagnosis, management, and postnatal prevention of intraventricular hemorrhage in the preterm neonate. Clinics in perinatology. 2008 Dec; [PubMed PMID: 19026340]|
|||Sarkar S,Bhagat I,Dechert R,Schumacher RE,Donn SM, Severe intraventricular hemorrhage in preterm infants: comparison of risk factors and short-term neonatal morbidities between grade 3 and grade 4 intraventricular hemorrhage. American journal of perinatology. 2009 Jun [PubMed PMID: 19267317]|
|||Badiee Z, Intraventricular hemorrhage in very low birth weight infants. Associated risk factors in Isfahan, Iran. Saudi medical journal. 2007 Sep [PubMed PMID: 17768461]|
|||[PubMed PMID: 28626857]|
|||van der Knoop B,Zonnenberg I,Verbeke J,de Vries L,Pistorius L,van Weissenbruch MM,Vermeulen RJ,de Vries J, Additional value of advanced neurosonography and magnetic resonance imaging in fetuses at risk for brain damage. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2019 Dec 11 [PubMed PMID: 31828836]|
|||[PubMed PMID: 32383569]|
|||[PubMed PMID: 26938917]|