Intraventricular Hemorrhage in Premature Infants: A Review of Risk

Factors, Pathology, Treatment, and Prognosis.

Geta Mitrea ¹·², Mirela Matasaru¹, Madalina Alexandru¹·²
“St. Ap. Andrei” Emergency County Clinical Hospital, Galati,
“Dunarea de Jos” University Galati - Faculty of Medicine and Pharmacy

General:
Hemoragia intraventriculară (IVH) represents a frequent and severe complication of prematurity,
having the potential to impact the neurological development of newborns. This review aims to
synthesize current information about IVH in preterm infants, focusing on risk factors, pathology,
and major long-term consequences of the condition.

Abstract:

Intraventricular hemorrhage (IVH) in newborns is defined as bleeding within the ventricles,

surrounded by the brain. This condition is most commonly observed in premature newborns
and is directly proportional to gestational age; the smaller the gestational age, the higher the
risk of IVH. It typically occurs in the subependymal germinal matrix, a highly vascularized area
undergoing significant development in newborns and regression in full-term infants.

The etiology is multifactorial and primarily attributed to the intrinsic fragility of the
vascularization of the germinal matrix. Risk factors for IVH in premature infants include the
immaturity of the cerebral vascular system, fluctuations in blood pressure, hypoxia, and
oxidative stress. Furthermore, clinical factors such as respiratory distress syndrome, mechanical
ventilation, and coagulation disorders contribute to the vulnerability of preterm infants to this
complication.

Regarding treatment, interventions can range from careful monitoring and medical support to
surgical procedures such as cerebrospinal fluid drainage or ventriculoperitoneal shunting in
severe cases. Pharmacological therapy, including the use of anti-inflammatory drugs, may be
implemented to minimize brain injuries.

Complications of IVH include obstructive hydrocephalus, non-obstructive hydrocephalus, post-

hemorrhagic hydrocephalus, developmental disorders, cerebral palsy, and seizures.

In conclusion, IVH in premature infants remains a complex and delicate issue in neonatology. An
integrated approach covering both prevention and treatment is essential to minimize the
negative impact of this complication on the neurological development of premature infants.
Continuous research is necessary to develop innovative and effective strategies for managing
this critical problem in neonatal medicine.

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Transfontanelar ultrasound remains the election method for diagnosis. Mild and moderate forms
have shown favorable progression, while severe IVH has led to the development of post-
hemorrhagic obstructive hydrocephalus.

Objectives:

A comprehensive and clear understanding of IVH in preterm infants, explaining risk factors,
pathogenesis, classification, and the impact of this complication on neonatal health, as well as
prevention strategies and interventions that can minimize the incidence and impact of IVH in
this vulnerable population.

Keywords: premature, intraventricular hemorrhage, transfontanelle ultrasound, hypoxia, germinal

matrix

Materials and methods:

At the latest update as of January 2022,
specific figures regarding the exact
percentage of intraventricular hemorrhage
(IVH) in premature infants worldwide are
not available due to variations based on
regions, healthcare resources, and other
factors. Accurate statistics might also
depend on the quality of medical care
provided to preterm infants in different
countries.
However, it is known that approximately
12,000 premature infants develop
intraventricular hemorrhage (IVH) each year
in the United States alone. The incidence of
IVH in very low birth weight infants (<1500
g) decreased from 40 to 50% in the early
1980s to 20% by the late 1980s. In 50% of
cases, hemorrhage occurs on the first day of
life, and in 90% of cases, it occurs within the
first 4 days of life.
In the last two decades, the occurrence of
IVH has remained stable. In extremely
premature infants weighing 500–750 g, IVH
occurs in approximately 45% of newborns.
Consequently, IVH continues to be a
significant issue for premature infants in
modern Neonatal Intensive Care Units
(NICUs) worldwide.
The study is retrospective and made over a
period of 2 years (January 2021 to
December 2022) in the Neonatology
Department of the Emergency Clinical
Hospital 'St. Ap. Andrei' Galati. It included all
preterm infants with a gestational age
between 29 and 36 weeks admitted to our
department (381), among whom 29
presented specific ultrasound signs of
intraventricular hemorrhage. Diagnosis was
established through ultrasound, the
preferred method for both symptomatic and
asymptomatic cases. A sectorial transducer
with a 5MHz wavelength was used for serial
ultrasounds.

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Results:

The incidence of the disease varied directly (9), anemia (14), severe respiratory distress
proportional to the gestational age: 34-36 syndrome (20), moderate RDS (5),
weeks – 6 cases (5 alive and 1 deceased), hemorrhages (16), mode of delivery:
30-33 weeks – 6 newborns alive, ≤29 weeks cesarean section (18) vs. vaginal birth (11),
– 17 newborns, among whom 10 deceased cranial presentation (18), pelvic (9), and
and 7 alive (Fig1). transverse (1), ventilation mode and the
need for administering Curosurf (20),
Fig.1 Varsta de gestatie infections, thrombocytopenia (1).
20 As for complications, the most common
15 were: HTPP (4), seizures (2), pneumothorax
10 (2), NEC (1) (Fig. 3).
5
Fig.3 Complicatii
0
VG 34-36 EUN
VG 30-33 vii
VG <=29 1

vii decedati PTX

2
Convulsii
The incidence was higher among VLBW - 13 2
newborns and ELBW - 6 newborns (Fig. 2), HTPP
4
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
fIG.2
The need for Curosurf administration plus
NBW LBW VLBW ELBW ventilator support was initiated in 21
7% preterm infants, among whom 6 required
21% HFOV, 16 - IPPV, 1 - NIPPV, 4 - CPAP, and 2
- free-flow O2 (Fig.4).
28%
Fig.4

45%

with a higher incidence in males compared

to females and a tendency towards rural
areas compared to urban areas. The main
incriminated risk factors were hypoxia (29), VM-HFVO VM-IPPV NIPPV
complex resuscitation in the delivery room CPAP O2 flux liber

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The distribution of cases by severity grades
was as follows: grade I - 5 cases, grade II - 6
Among 29 premature newborns with IVH
cases, grade III - 7 cases, and grade IV - 11
pathology, 6 were in the 34-36 weeks
cases (Fig.5). Most cases were
gestational age group (1 deceased), 6 in the
asymptomatic, diagnosed through TF
30-33 weeks group, and 17 in the ≤ 29
ultrasound. Among confirmed IVH cases,
weeks group (10 deceased). Eleven preterm
75.86% had a fulminant progression with
infants developed IVH within the first week
progressively deteriorating neurological
of life, while others showed IVH after one
status, altered muscle tone, and respiratory
week involving multiple risk factors
frequency disturbances. 37.9% presented
(mechanical ventilation, suspected or
catastrophic progression leading to death,
documented infection, blood pressure
with bulging anterior fontanelle, cranial
fluctuations, thermal instability, lack of
suture dehiscence, seizures, decerebrate
antenatal corticosteroids, anemia,
posture, and apnea periods.
hypercapnia, hypertension, excessive
Fig.5
fibrinolytic activity, coagulation disorders).

7
6
5
4 7
6
3 5 4.5
2
1
0
GRAD I GRAD II GRAD III GRAD IV

______________________________________________________________________________________________________

Pathogenesis:

The pathogenesis of intraventricular hemorrhage (IVH) in premature infants involves a complex

series of events that are often associated with the immaturity of the cerebral vascular system
and stress factors that can occur in the first days and weeks of a premature infant's life. Here are
some key aspects of IVH pathogenesis in premature infants:

Immaturity of the Vascular System: The premature brain has a vascular system that is still
developing and fragile. Blood vessels are thin and sensitive to pressure fluctuations,
predisposing them to injuries and bleeding. Premature infants predominantly bleed in the
germinal matrix rather than in the cortical mantle or white matter, indicating intrinsic sensitivity
of the germinal matrix vasculature compared to other brain regions.

Fluctuations in Blood Pressure: Premature infants may experience significant blood pressure
fluctuations, especially in the early days of life. These fluctuations can lead to the rupture of
fragile blood vessels in the brain, including those in the germinal matrix area. Abnormal blood
pressure, cerebral venous pressure, and other prematurity complications are common.

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Unstable Hemodynamics: Cardiovascular immaturity in premature infants can contribute to
unstable hemodynamics, meaning that blood supply to the brain may vary. This instability can
increase the risk of ischemia and bleeding.

Oxidative Stress: Premature infants are more susceptible to oxidative stress, where levels of free
radicals are increased. This stress can contribute to blood vessel damage and play a role in IVH
pathogenesis.

Mechanical Ventilation: The use of mechanical ventilation to treat respiratory distress syndrome
can affect intrathoracic pressure and may influence blood flow to the brain, thereby contributing
to the development of intraventricular hemorrhage.

Coagulation Disorders: Immaturity of the coagulation system can increase the risk of bleeding.
Coagulation disorders may be more frequent in premature infants and can contribute to IVH
pathogenesis.

Infections: Infections can trigger an inflammatory response that, combined with the immaturity
of the vascular system, may increase the risk of brain bleeding.

Risk Factors:

The most significant risk factor for intraventricular/germinal matrix hemorrhage is extremely low
gestational age. Infants with a gestational age below 32 weeks constitute the high-risk
population. IVH is less common in females, the Black race, and with prenatal steroid use, but it is
more frequently observed in the presence of mechanical ventilation, respiratory distress,
pulmonary hemorrhage, pneumothorax, chorioamnionitis, asphyxia, sepsis, and persistent
ductus arteriosus (PDA). A close relationship has been demonstrated between fluctuations in
cerebral blood flow, increased blood pressure, and the occurrence of IVH. The main causes of
increased cerebral blood flow include disruption of cerebral autoregulation, rapid volume
replacement, hypercarbia, low hematocrit levels, and hypoglycemia. Dalton et al. (13) also
reported that hypernatremia was an independent risk factor for IVH in very low birth weight
premature infants.

Diagnosis:

Ultrasound remains the standard diagnostic method, its main advantage being that it doesn’t
involve ionizing radiation, can be performed at the patient's bedside, while its disadvantage is
the inability to detect cerebellar hemorrhages or small lesions in the white matter.

Classification:

IVH can be classified into four grades of severity, useful for prognostic reasons when counseling
parents and for clinicians. This classification is more based on radiological appearance rather
than a pathophysiological description of the events leading to IVH. The IVH grading system,
established by Papile in 1978 based on computed tomography (CT) findings, was adapted to

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ultrasound findings by Volpe in 2008. In this grading system, the grades were classified as
follows:

Grade I - hemorrhage in the germinal matrix region, very small hemorrhage, or no hemorrhage
in the ventricle;

Grade II - hemorrhage filling 10–50% of the ventricle;

Grade III - hemorrhage filling more than 50% of the ventricle;

Grade IV - periventricular echodensity.

This hemorrhage, previously classified as Grade IV, is now categorized as periventricular

hemorrhagic infarction (PVHI). Grades I and II are defined as mild grades, while grades III and
PVHI are defined as severe grades.

Grade I

Grade I - Minimal hemorrhage or periventricular hemorrhage of grade I (PVH). Subependymal

region and/or germinal matrix. (From the Neonatology Clinic archive of the Emergency County Hospital
'Saint Apostle Andrew' in Galați.).

Grade II

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 Grade II - Moderate hemorrhage (subependymal, without ventricular enlargement, or small)..
Subependymal hemorrhage extending into the lateral ventricles without ventricular enlargement
(From the Neonatology Clinic archive of the Emergency County Hospital 'Saint Apostle Andrew' in Galați).

Grade III/IV

Severe hemorrhage or Grade III (subependymal, with significant ventricular enlargement). Grade
III/IV - Subependymal hemorrhage extending into the lateral ventricles with ventricular
enlargement. (From the Neonatology Clinic archive of the Emergency County Hospital 'Saint Apostle
Andrew' in Galați)

Transfontanelar ultrasound is recommended as a screening tool for premature newborns with a

gestational age up to 32 weeks and for all newborns with a gestational age of 32 weeks or

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higher at increased risk, who are clinically unstable and show neurological signs.

Screening protocols vary from one center to another. In our unit, screening is conducted for
high-risk newborns on days 1, 3, 7, and 15-30, and before discharge. Depending on risks, the
number of screenings in the first week might be reduced under certain conditions. Some
protocols repeat the screening on the 7th and 14th day and during the 35-40 post-menstrual
weeks.

Sequels:

Major sequelae of IVH refer to the destruction of brain parenchyma and the development of
post-hemorrhagic hydrocephalus. Additionally, the sequels of ventriculoperitoneal shunt
placement (primarily infection) may contribute to poor neurological developmental outcomes.
Following parenchymal hemorrhages, necrotic areas form cysts that may become contiguous
with the ventricles (porencephalic cysts). Cerebral palsy is the primary neurological condition
observed post-IVH, although mental retardation and seizures can also occur. The long-term
effects of losing glial cell precursors are unknown. Two disorders that may arise with IVH are
global hypoxic-ischemic injury and periventricular leukomalacia (PVL).

Treatment:

There isn't a specific treatment for IVH. Regulating hemodynamics, ensuring optimal
oxygenation and ventilation, fluid and nutritional support, seizure control, and management for
each complication separately constitute treatment.

Conclusion:

Intraventricular hemorrhage is a severe and common pathology in premature newborns, directly

proportional to gestational age, causing severe neurological sequelae in advanced stages of the
disease.

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Conflict of interest: No conflict of interest has been declared by the authors.

Financial support: The authors have stated that this study received no financial support

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