Prevention of Intraventricular Hemorrhages and

Periventricular Leukomalacia in the Extremely

Low Birth Weight Infant
Jackie B. Martin, DNP, RN, NNP-BC, CCNS

The purpose of this integrated review is to examine research on the prevention of intraventricular
hemorrhage/periventricular leukomalacia in premature infants. Nursing and medical research literature was
electronically searched through Pubmed, Medline, and Cinahl from 2000 to 2010. Hand searching by
reviewing bibliographies of published studies and review of conference proceedings were also used. Key
search words included the terms prevention of intraventricular hemorrhage, periventricular leukomalacia, and
premature infants. Study selection included randomized controlled trials, meta-analysis, and other comparative
studies of the prevention of intraventricular hemorrhage/periventricular leukomalacia. Reports exploring the
use of near-infrared spectroscopy measurement of cerebral oxygenation to determine risks associated with
specific nursing care interventions leading to intraventricular hemorrhage/periventricular leukomalacia were
also examined. Data synthesis revealed that prevention of intraventricular hemorrhage/periventricular
leukomalacia in the preterm infant is a collaborative effort involving resources during the antenatal,
intrapartum, and postnatal periods.
Keywords: Intraventricular hemorrhage; Periventricular leukomalacia

Background
Germinal matrix-intraventricular hemorrhage (GM-IVH) is the
most common and distinctive type of intracranial hemorrhagic
diagnosis observed in premature infants. Germinal matrix
hemorrhage is bleeding into the subependymal GM with or
without subsequent rupture into the lateral ventricle.1 It occurs
most frequently before 35 weeks' gestation and is typically seen
in very low birth weight (b1500 grams) premature infants
because they lack the ability for autoregulation of cerebral blood
flow. Although there has been a decline in the incidence of IVH
from 40% to 50% in the late 1970s to 1980s to 15% to 20% in
the mid-1990s, that does not indicate that IVH is a lessening
problem because survival rates for the smallest premature infant
continue to increase and the incidence of IVH is directly
correlated with the degree of prematurity. Currently, IVH
occurs in 20% to 25% of these very low birth weight infants and
in approximately 49% of infants weighing 500 to 749 grams.2
Infants with GM-IVH are at risk for periventricular hemorrhagic
infarction, posthemorrhagic hydrocephalus, periventricular
leukomalacia (PVL), and neurodevelopmental disability. 1

From the Carilion Clinic, Roanoke, VA 24019; and Mednax, Inc.

Address correspondence to Jackie B. Martin, DNP, RN, NNP-BC,
CCNS Carilion Clinic, 141 Hillview Dr, Roanoke, VA 24019.
E-mail: JBMartin@carilionclinic.org.
2011 Elsevier Inc. All rights reserved.
1527-3369/1103-0421$36.00/0
doi:10.1053/j.nainr.2011.07.006

Periventricular leukomalacia is the main determinant of cerebral

palsy in the preterm infant and is characterized by diffuse injury
of deep cerebral white matter accompanied by focal necrosis in
some. Several hypotheses relate the pathogenesis of PVL to
hypoxic-ischemia and reperfusion in the sick premature infant.3
The purpose of this integrated review of the literature is to
examine methods to prevent GM-IVH and PVL in the smallest
of infants. Intraventricular hemorrhage and PVL will be defined;
and the neuropathology and pathogenesis will be discussed,
providing the groundwork for the explanation of the diagnosis,
management, and prevention of the two disease processes.
Recommendations for prevention of IVH/PVL will be categorized by the antenatal, intrapartum, and postnatal periods.

Methods
The original search strategy used to generate information for
review was to perform separate searches for the prevention of
IVH and the prevention of PVL in premature infants using
nursing and medical research literature from the years 2005
2010. Results of the review led to an extended search including
the years 20002004. The electronic databases Pubmed,
Medline, and Cinahl were used. Key search words included
the terms prevention of intraventricular hemorrhage, periventricular leukomalacia, and premature infants. English-language
restrictions were imposed. Hand searching by reviewing
bibliographies of published studies and review of conference
proceedings from 2010 and 2011 were also used.

142

Table 1. Critical Review of Studies on the Prevention of IVH/PVL in the ELBW Infant
Study

Methods

Participants

Interventions

Results

Critique

Experimental design
To investigate whether
preemptive morphine
analgesia decreases the rate
of a composite, primary
outcome of neonatal death,
severe IVH, or PVL in a
preterm infant

Ventilated preterm infants

2332 wk's gestation
n = 446 morphine
n = 444 placebo

Intubated within 72 h of
birth and ventilated b8 h at
enrollment. Neonates
received a loading dose of
morphine followed by
continuous infusion. Use of
sedatives not allowed.
Intermittent morphine was
allowed for both groups.

Analysis for all patients

showed no significant
difference in the combined
outcomes or its
components death, severe
IVH, PVL. For infants not
receiving intermittent
morphine, rates of the
outcomes were lower than
those given intermittent
morphine. Placebo group
had worse rates than those
not receiving open label

Study done in 12 American

centers and 4 European
centers. Strength: large
sample size. Limitation: all
infants could receive
intermittent boluses

Blickstein et al10
2006

Meta-analysis
To compare the effect of
antenatal corticosteroid
therapy on the risk for
severe IVH (grades III/IV)
in preterm singleton and
multiple VLBW infants.

From 28 neonatal units

N = 5022 single infants
N = 1016 twin pairs
N = 194 triple sets
2432 wk's gestation

Antenatal corticosteroid
therapy was provided and
was defined as:
Complete: delivery
occurred N24 h and b7 d
after treatment.
Partial: if delivery b24 h
after 1st dose or N1 wk
after last dose
None: no treatment.

Incidence of IVH grades

IIIIV ranged from 6.8% in
single infants receiving a
complete course to 29.3%
in triplets without any
treatment. A complete
course of antenatal steroids
was associated with
decreased risk of severe
IVH in single or
multiple infants.

Study done in Rehovot.

Strength: data collected
prospectively on a
prestructured form,
patterned after the
Vermont Oxford in the
United States.
Limitation: specific
corticosteroid used at each
facility was
not documented.

Chawla et al12
2010

Retrospective review
To compare outcomes of
ELBW infants exposed to
no ANS, incomplete ANS,
and complete course of
ANS at varying intervals
before delivery.

N = 169 ELBW infants

with ANS at varied dose
intervals.

Group 1: no ANS exposure

Group 2: born after 1 dose
Group 3: born after 2 doses
Group 4: born after 2 doses
N7 d before delivery.

Mortality and IVH were

significantly lower in
groups 3 and 4 compared
with groups 1 and 2.
Infants with 1 dose of ANS
had a significantly lower
incidence of severe IVH
than infants without ANS
exposure.

Study done in the United

States (Detroit, MI)
Strength: large sample size,
more than required to
provide a power of 80%.
Limitation: retrospective
study.

Anand et al
2004

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143

Dani et al26
2009

Retrospective review
Prospective review
To demonstrate the
hypothesis that a
coagulopathy screening
and the early treatment
with FFP of proven
coagulopathy may
contribute to decrease the
occurrence of IVH in
infants b29 wk's gestation.

n = 127 infants in
screening group
n = 91 infants in
no-screening group
b29 wk gestational age

19992002: infants
received FFP as rescue
after a bleed
20032006: infants
sampled for coagulation
tests; if abnormal,
given FFP.

Coagulopathy screening
decreases the risk of
developing IVH in preterm
infants of 2326 wk's
gestation only.

Study done in Florence,

Italy.
Strength: daily care by
physicians with common
practices.
Limitation: part of study
was prospective and part
retrospective. Care can
change drastically over a
7-y period.

Di Renzo et al13
2005

Experimental
To determine whether the
adjunctive administration
of aminophylline and
magnesium sulfate to
mothers at risk for preterm
birth can reduce the rate of
IVH in neonates born at
b30 wk's gestation.

n = 78 newborns in
group A
n = 68 newborns in
group B
b30 wk gestational age

Group A received ritodrine,

magnesium sulfate,
aminophylline, and
corticosteroids.
Group B received ritodrine
and corticosteroids only.

A highly significant
decrease in the incidence of
IVH was observed in group
A compared with B.

Study in Perugia, Italy.

Strength: first evidence
that combined
aminophylline and
magnesium sulfate
reduce the rate of IVH in
very preterm infants.
Limitation: each
medication was not trialed
individually; difficult to
know contribution of
each drug.

Fowlie et al20
2010

Meta-analysis
To determine the effect of
prophylactic indomethacin
on mortality and morbidity
in preterm infants.

19 Trials
2872 Infants
Most were VLBW
b1500 grams, one study
b1000 grams.

Comparison of
prophylactic indomethacin
vs placebo or no drug in
preterm infants.

The incidence of
symptomatic PDA and
surgical ligation was
significantly lower in the
treated infants.

Strength: large number of

infants participating.
Limitation: 19 centers
involved; not all infants in
same weight range: some
VLBW, others ELBW.

Gagnon et al33
1999

Quasi-experimental
To investigate the
frequency of events that
cause cerebral oxygenation
disturbances in ventilatordependent neonates.

n = 10 neonates
2833 wk gestational age.
7151665 grams
body weight.

Near-infrared spectroscopy
measurements were made
at 1/2-s intervals on 10
ventilator-dependent
neonates during nursery
events (opening incubator
doors, handling, heel stabs,
and conversation).

Results: open incubator =

40% increase in
blood volume
Staffing heel = 20%
increase in blood volume
60 s.
Conversation = 35%
decrease to 15% increase in
blood volume

Study done in Canada.

Strength: study conducted
using daily occurring
events.
Limitation: only 10
subjects with large weight
variation.

(continued on next page)

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Table 1 (continued)
Study

Participants

Interventions

Quasi-experimental
To assess the impact of
sampling volume and
velocity from umbilical
venous catheters

n = 20 neonates
Birth weight = 4101900
grams
2731 wk gestational age.

Near-infrared spectroscopy
measure of tissue
oxygenation index and
changes in concentrations
of cerebral oxygenated and
deoxygenated hemoglobin
were measured. Changes in
cerebral oxygenation and
cerebral blood volume
were calculated.

Blood sampling from

umbilical artery reduces
cerebral oxygenation and
cerebral blood volume.

Study done in Essen,

Germany.
Strength: compares
cerebral oxygenation/
peripheral arterial
oxygenation.
Limitation: small sample
size with large birth weight
variation.

Limperopoulos
et al32 2008

Prospective study
To examine the circulatory
changes experienced by the
immature systemic and
cerebral circulations during
routine events in the
critical care of preterm
infants and to identify
clinical factors that are
associated with greater
hemodynamicoxygenation changes
during these events.

N = 82 infants weight
b1500 grams
2330 wk's gestation
requiring intensive care
nursing and continuous
blood pressure monitoring
by an umbilical artery
catheter.

Continuous recording of
cerebral and systemic
hemodynamic and
oxygenation changes
was performed.
Studied 6 events:
1. Quiet baseline
2. Minor manipulation
3. Diaper changes
4. Endotracheal tube
suctioning
5. Endotracheal tube
repositioning
6. Complex Events

Routine caregiving
procedures produce major
circulatory fluctuations
that are clinically
underappreciated and
underdetected with current
monitoring.
Cerebral hemodynamic
changes were associated
with early parenchymal
ultrasound abnormalities.

Study done in Quebec,

Canada.
Strength: large number of
patients matched with
quiet baseline period.
Limitation: BP only
monitored centrally; so if
catheter out, unable to
monitor.
U/S timing and frequency
inconsistent.

Liu et al14 2006

Randomized controlled
trial

n = 280 pregnant women

with premature newborns
b35 wk's gestation

Group A: received
antenatal IM/IV vitamin K1
for 27 d.
Group B: received antenatal
IM/IV dexamethasone
1 d.
Group C: received
dexamethasone 2 d.
Group D: received vitamin
K1 and dexamethasone.

Results showed PIVH in:

Group A = 42.5%
Group B = 54%
Group C = 51.4%
Group D = 31.8%
More control group infants
had grades III/IV IVH.
IVH was decreased with
steroids and vitamin K

Study done in Beijing, China.

Strength: first study to
review the use of antenatal
steroids and vitamin K1
combined in the
prevention of IVH.
Limitation: overall large
number of participants, but
divided into 4 groups,
which tremendously
decreased number in
each intervention.

Hning et al
2007

Methods
31

Results

Critique

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Experimental
To evaluate the effects of
prenatal corticosteroid
treatment on the incidence
of IVH-PVL in premature
infants.

n = 163 premature infants

between 26 and 34 wk's
gestation.

Experimental group
received single course of
corticosteroids.
Control group received no
steroids.

Significantly less IVH/PVL

in experimental group vs
control group.
Percentage of severe IVH/
PVL significantly higher in
control than experimental
group.

Study done in Sarajevo,

Bosnia and Herzegovina.
Strength: large sample size
Limitation: experimental
infants received better
perinatal care than control
infants. Apgar scores b5
min were higher in
experimental vs control.

Ment et al21
2004

Randomized controlled
To test the hypothesis that
indomethacin would have
sex-mediated effects on the
incidence of IVH and longterm neurodevelopmental
outcome in the VLBW
population.

n = 431 infants, birth

weight 6001250 grams,
and no IVH at the 6th
postnatal hour.

222 Infants received

indomethacin
209 Infants received saline.
Ultrasound at day 5.
Neurodevelopmental status
at age 3, 5, 6, & 8 y.

15% of girls and 15% of

boys had IVH at day 5.
Boys assigned to
indomethacin had less IVH
(9%); no difference in girls.

Study done in the United

States.
Strength: nice, large sample
size, randomized to group.
Limitation: trial over 3 y in
multiple centers.

Mercer et al15
2006

Randomized controlled
To compare the effects of
immediate and delayed
cord clamping on VLBW
infants on 2 variables:
bronchopulmonary
dysplasia and suspected
necrotizing enterocolitis;
also late-onset sepsis
and IVH.

n = 72 mother/infant pairs
b32 wk gestational age

Assigned to immediate and

delayed cord
clamping groups.
Immediate clamp at 510 s.
Delayed clamp at 3045 s.

No difference in incidence
of BPD and suspected
NEC. Delayed cord
clamping may protect
VLBW infants from IVH
and late-onset sepsis for
male infants.

Study done in the United

States (Rhode Island).
Strength: groups had
almost identical
demographics;
randomized well.
Limitation: protocol
violations in 10%. Also,
some infants received
prophylactic indomethacin;
others did not.

Pellicer et al28
2003

Prospective study
To assess changes in
cerebral blood volume and
cerebral blood flow with
positioning of the head in
ventilated patients using a
noninvasive method.
The influence of the type of
ventilation and of birth
weight was evaluated.

n = 13 conventional
ventilator
n = 8 high-frequency
oscillating ventilator
Birth weight = 5603000
grams
2438 wk gestational age

Near-infrared spectroscopy
measure of cerebral blood
volume and cerebral blood
flow with head supine
midline position and
rotated 90 to one side.
Other vital signs were
collected.

Mean cerebral blood

volume was lower in
supine with head midline
than with the head rotated
to one side. Changes in
cerebral blood volume not
associated with ventilator
type or birth weight.

Study was done in

Madrid, Spain.
Strength: the same
investigator did all
ultrasounds and
near-infrared spectroscopy.
Limitation: only 21 infants
in study; with full data only
on 12; with 2 types of
ventilation.

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2008

& INFANT NURSING REVIEWS, SEPTEMBER 2011

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146

Table 1 (continued)
Study

Participants

Interventions

Quasi-experimental
To assess the impact of
sampling volume and
velocity from umbilical
artery catheters.

n = 48 infants
Birth weights = 4801500
grams
2334 wk gestational age

Near-infrared spectroscopy
was used to measure
changes in concentrations
of cerebral oxygenated and
deoxygenated hemoglobin
during routine blood
sampling from umbilical
arterial catheters.

A significant drop in
cerebral oxygenation and
cerebral blood volume
during umbilical artery
blood sampling was
documented.

Study was done in Essen,

Germany.
Strength: use of a specific
strict protocol for the
blood sampling.
Limitation: no. of
sequential variations for
each infant.

Simons et al25
2003

Randomized,
double-blinded,
placebo-controlled trial

N = 150 newborns
receiving ventilator
support

IV morphine or placebo
infusion were given for 7 d

Routine morphine infusion

decreased the incidence of
IVH (23% vs 40%) but did
not influence poor
neurological outcome.

Study done in 2 Level III

NICUs in the Netherlands.
Strength: blinding of
physicians, parents, and
investigators.
Limitation: both control
and experimental infants
could receive extra doses
of morphine.

Slncheva
et al19 20006

Randomized controlled trial

To compare the use of
indomethacin alone,
indomethacin; and
phenobarbital together;
and indomethacin,
phenobarbital, and
surfactant for the
prevention of IVH.

n = 130 preterm infants

b32 wk gestational age
VLBW or ELBW

Group I: indomethacin
Group II: indomethacin
and phenobarbital
Group III: indomethacin,
phenobarbital, &
surfactant
Group IV: control group

IVH/PVL percentage was

lowest in group III,
followed by group II, and
then group I.

Study done in Bulgaria.

Strength: use of a
reference group.
Limitation: different
combinations of meds
were trialed, but not each
medication individually.

Veldman
et al27 2006

Quasi-experimental
To evaluate the use of a
general hemostatic agent
such as recombinant
activated factor VII in
reducing the extent of
severe IVH.

n = 10 infants
2328 wk gestational age.

Cerebral ultrasound done

in first 2 h of life. Infants
given injection of
recombinant activated
factor VII in first 2 h of life
and every 4 h 72 h.

Activated factor VII did not

accumulate and did not
cause disseminated
intravascular coagulation.
No embolic events. Could
not assess incidence of IVH.
20% of infants had grades
IIIIV hemorrhage similar
to rate in infants not
receiving activated factor VII.

Study done in Frankfort,

Germany.
Strength: cerebral U/S done
before enrolling.
Limitation: small sample
size.
Lack of a control group.

Roll et al
2006

Methods
30

Results

Critique

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Walti et al18
2002

Meta-analysis
To evaluate prophylactic vs
rescue treatment with
porcine-modified lung
surfactant in reducing the
rate of PIVH.

n = 345 infants given

prophylactic
n = 326 infants given
rescue
2431 wk gestational age

Prophylactic: intubated at
birth and treated within
10-15 min. Retreatment
allowed.
Rescue infants were
electively intubated only if
significant respiratory
distress present.
Retreatment allowed in
some centers.

Combined incidence of
overall IVHs was:
Grades IIV = 49.2%
Grades IIIIV = 13.3%
Comparison:
Prophylactic
Grades IIV = 43.2%
Grades IIIIV = 9.9%
Rescue:
Grades IIV = 52.8%
Grades IIIIV = 16.3%

Study done in 4 countries:

the Netherlands, Sweden,
France, and Italy.
Strength: large sample size.
Limitation: each trial
developed independently,
and some aspects were
slightly different.

Whitelaw and
Odd23 2008

Meta-analysis
To determine the effects of
postnatal administration of
phenobarbital on the risk
of IVH,
neurodevelopmental
outcome, or death in
premature infants.

10 Controlled trials
n = 740 infants
b24 h old
b34 wk gestational age
Birth weight b1500 grams
If on ventilator could be:
3336 wk or up to birth
weight 1750 grams.

Phenobarbital was given IV

or IM starting within 24 h
of birth, with or without
maintenance therapy, for
up to 7 d.

No difference noted
between phenobarbitaltreated group and control
group in IVH, severe IVH,
death, or
neurodevelopmental
impairment. Trend for
increased ventilator use
with phenobarbital.

Strength: large sample size,

10 trials.
Limitation: some trials
randomized and some
quasi-randomized.

Yanowitz et al22
2003

Retrospective
To determine the relative
risk of severe IVH between
2 early indomethacin
treatment strategies.

n = 102 infants received

prophylactic
indomethacin.
n = 117 infants received
echocardiogram and if PDA
present received
indomethacin.
b29 wk gestational age

Medical record review.

Included infants admitted
within 12 h of birth and
survived 24 h and had at
least 1 cranial ultrasound.
If received prophylactic
indomethacin or evaluated
for a PDA by echo before
36 h, they were included.

Grades III/IV IVH less

frequent in infants
receiving prophylactic
indomethacin than among
infants in the echo group.
Grades I and II IVH rates
did not differ between
treatment groups.

Study done in
Pittsburg, PA.
Strength: adequate
sample size.
Limitation: study was a
retrospective record
review.

BP indicates blood pressure; BPD, bronchopulmonary dysplasia; ELBW, extremely low birth weight; NEC, Necrotizing Enterocolitis; NICU, neonatal intensive care unit; PDA, patent ductous arteriosus; U/S,
ultrasound; VLBW, very low birth weight.

147

Studies involving research during the antenatal, intrapartum,

and postnatal periods were reviewed. Study selection included
randomized controlled trials, meta-analysis, and other comparative studies of the prevention of IVH/PVL. Reports exploring
the use of near-infrared spectroscopy measurement of cerebral
oxygenation to determine risks associated with specific nursing
care interventions leading to IVH/PVL were also examined.
Table 1 summarizes the research reviewed for both prevention
of IVH and prevention of PVL.

Neuropathology
The GM includes tissue in the developing brain, which is
located above the caudate nucleus, in the ependymal wall of the
lateral ventricles.4 Before 32 weeks' gestation, this area of the
brain receives a significant portion of the cerebral blood flow to
support the development, proliferation, differentiation, and
migration of cells that serve as precursors for neurons and glial
cells. The GM is bathed by a rich network of fragile thin-walled
capillaries that are extremely sensitive to hypoxia and changes
in perfusion pressure. An increase in arterial blood pressure in
these vessels can lead to rupture and bleeding into the GM.1,4
In some infants, the GM hemorrhage is confined to the
subependymal area; and in others, the original hemorrhage
ruptures into the lateral ventricles and then into the third and
fourth ventricles.1 Blood may collect in the subarachnoid space
of the posterior fossa, often extending into the basal cistern. The
rupture of the hemorrhage from the GM into the ventricles may
be a protective function that decompresses the hemorrhagic
area and reduces further tissue damage. Obstruction of cerebral
spinal fluid (CSF) due to an obliterative arachnoiditis or blood
clots at the level of the aqueduct of Sylvius or the foramen of
Monroe may cause progressive ventricular dilatation. Blood
may also be found in the periventricular white matter with
severe hemorrhage.4

Pathogenesis
The pathogenesis of GM-IVH is multifactorial, including
intravascular, vascular, and extravascular factors.2 Intravascular
factors relate to the regulation of blood flow, pressure, and
volume in the microvasculature of the GM bed. In some infants,
factors relating to platelet-capillary function and to blood
clotting capability may also play a role. Intravascular factors
include rapid volume expansion, hypercarbia, decreased
hematocrit or decreased blood glucose, a fluctuating cerebral
blood flow as seen in the ventilated preterm infant with
respiratory distress syndrome, or an increase in cerebral blood
flow as seen with systemic hypertension. Other intravascular
factors include an increase in cerebral venous pressure seen with
a pneumothorax or with endotracheal suctioning, a decrease in
cerebral blood flow followed by reperfusion such as with
systemic hypotension, and platelet and coagulation disturbance
seen in sick infants.2
Vascular factors are those due to the blood vessels of the GM
and are grouped into two categories: intravascular and

148

extravascular. Intravascular factors are related to the poor

integrity of the small matrix vessels, making these vessels
particularly vulnerable to hypoxic-ischemic injury.2 Extravascular factors are those found in the space surrounding the GM
capillaries and are grouped into three categories: deficient in
vascular support, fibrinolytic activity, and postnatal decrease in
extravascular tissue pressure.2 The GM is a gelatinous, friable
structure and provides poor support for the large capillaries that
course through it and are the site of the hemorrhage; therefore,
it is deficient in vascular support. An excessive amount of
fibrinolytic activity has been noted in the periventricular GM
region, and it is reasonable to suspect that this activity is
required for the remodeling of the GM and may contribute to
how the small capillary hemorrhages of the matrix become
the large lesions of an IVH. It has been hypothesized that
postnatal decrease in extravascular tissue pressure may cause an
increase in intravascular-extravascular pressure gradient sufficient to provoke hemorrhage; however, the timing of this event
is unclear.2

Clinical Presentation
Clinical manifestations seen with GM-IVH vary in individual
infants from silent to subtle to catastrophic.2 Clinically silent,
subependymal hemorrhages have minimal or no signs and are
usually discovered with routine ultrasound screening. Infants
with subtle hemorrhages may show an unexplained fall in
hematocrit or failure of the hematocrit to rise with transfusion.
Other signs include alterations in level of consciousness,
hypotonia, abnormal eye movements or positions, and altered
mobility. These infants survive with variable developmental
outcomes. Major hemorrhages that develop rapidly over several
minutes or hours usually cause catastrophic deterioration.
Clinically, the infant with a catastrophic bleed will have stupor
progressing to coma, respiratory distress progressing to apnea,
seizures, decerebrate posturing, fixation of pupils to light, and
flaccid quadriparesis. Other clinical findings include a declining
hematocrit, bulging fontanelle, hypotension, bradycardia,
hypoglycemia, and syndrome of inappropriate antidiuretic
hormone. The mortality rate is high for the infant with a
catastrophic hemorrhage, and survivors have a poor prognosis
for later neurodevelopment.4

Diagnosis
An ultrasound scan of the neonatal head is recommended for
diagnosis of a GM-IVH because it is effective in identification
of all classifications of hemorrhage.2 Intraventricular hemorrhages are classified according to the site and extent of the bleed.
Two classifications of IVH are available. The more severe grades
of hemorrhage are associated with high degrees of morbidity
and mortality.5
The first classification is by Papile et al6 developed in 1978:
Grade
Grade
Grade
Grade

I = GM hemorrhage
II = IVH with no dilation
III = intraventricular, with dilation
IV = intraparenchymal

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The second classification is by Volpe 2 (2008) using

ultrasound scan:
Grade I = GM hemorrhage with no or minimal IVH (b10%
of ventricular area on parasagittal view)
Grade II = IVH (10%50% of ventricular area on parasagittal
view)
Grade III = IVH (N50% of ventricular area on parasagittal
view; usually distends lateral ventricle)
A lumbar puncture, usually obtained for evaluation of sepsis,
can also provide useful information about IVH. In an infant with
IVH, the CSF initially consists of many red blood cells and an
elevated protein content, followed by xanthochromia and
depressed glucose content. The degree of elevation of the CSF
protein correlates with the severity of the hemorrhage.2

Management
Management of GM-IVH/PVL involves prevention in infants
who are at risk and acute care of infants who are currently
experiencing an illness. Prevention is a collaborative effort
beginning prenatally and continuing intrapartum and upon
admission to the neonatal intensive care unit. The review of the
literature will begin with antenatal interventions.

Antenatal Interventions

Timing of the Hemorrhage

Ultrasound screening has assisted in providing information
about the timing of the occurrence of the GM-IVH. About 50%
of the infants have onset of hemorrhage on the first postnatal
day, 25% more on the second postnatal day, and an additional
15% on the third postnatal day; therefore, by day three, 90% of
the bleeds have occurred. The remaining 10% occur at or after
day four. Progression or extension of the hemorrhage occurs in
20% to 40% by day three to five.2

Periventricular Leukomalacia
Periventricular leukomalacia is the main type of brain injury
in premature infants and is the leading known cause of
cerebral palsy in preterm infants. Periventricular leukomalacia
is damage to the immature cerebral white matter of the brain.
The pathology is characterized by two components: the first
component is a focal ischemic necrosis in the periventricular
region, and the second component is a diffuse reactive gliosis
in the surrounding white matter. These components may
occur together or separately. The necrotic foci may involve all
tissue components (axons, glial cells) and become cysts or
focal glial scars. Diffuse reactive gliosis results in an overall
delay in myelination.4,7 Periventricular leukomalacia most
often occurs in the absence of hemorrhage and usually occurs
bilaterally.8 Necrotic lesions have been correlated with the
motor deficits of cerebral palsy, and the diffuse white matter
lesions are broader and may include cognitive and behavioral
abnormalities. Infants are most at risk during postconceptional
weeks 24 to 32.4,7
Ultrasonography of the head is most often used in the
diagnosis of PVL and demonstrates increased periventricular
white matter echogenicity with or without cystic abnormalities.
Magnetic resonance imaging can be useful with diffuse white
matter injury. Periventricular leukomalacia is detectable in utero
or after birth; however, cystic abnormalities do not become
visible until 1 week or longer after birth. Most cases (90%)
evolve within the first 72 hours of life.8 A diagnosis of PVL can
be excluded if results of head ultrasounds obtained at 1 week

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and 1 month after birth are normal.9 The incidence of PVL is

highly correlated with prematurity and less strongly with
chorioamnionitis. Other conditions increasing the incidence of
PVL include hypocarbia, hypotension, apnea, bradycardia, and
prolonged cardiac surgery.8

Perinatal medicine today is characterized by an approach

aimed at reducing the incidence of prematurity and therefore
reducing GM-IVH. Measures include special obstetric care for
high-risk pregnancy, treatment of bacterial vaginosis that
reduces premature delivery and prevents fetal-maternal
inflammatory reactions, and prevention of preterm labor
using tocolytic agents. 1 Several antenatal medications
have been proposed for the prevention of GM-IVH. Three
studies 10-12 examined the use of antenatal steroids in
prevention of IVHs or severe IVH. Blickstein et al (2006)
found that the incidence of IVH grades III to IV ranged from
6.8% in singleton infants receiving a complete steroid course
to 29.3% in triplets without any treatment. Blickstein et al
(2006) and Maksic et al (2008) revealed that a complete course
of antenatal corticosteroid therapy was associated with
decreased risk for severe IVH. In a retrospective review,
Chawla et al (2010) found that mortality and IVH were
significantly reduced in infants born after two doses of
antenatal steroid exposure (ANS) given in 1 week and in
infants born after two doses of ANS given more than 7 days
before delivery compared with infants born without ANS and
infants born after one dose of ANS. Chawla et al12 (2010) also
found that infants receiving one dose of ANS had a
significantly lower incidence of severe IVH than infants
without ANS exposure. All three researchers found benefit
with the use of antenatal steroids in the prevention/reduction
of GM-IVH.
Two other researchers13,14 found benefit with the use of
antenatal steroids in combination with other pharmacologic
agents. In the first study, mothers in one group received
ritodrine, magnesium sulfate, aminophylline, and corticosteroids; and mothers in the second group received only ritodrine
and corticosteroids.13 DiRenzo et al (2005) found a highly
significant decrease in the incidence of IVH in the group
receiving ritodrine, magnesium sulfate, and aminophylline
compared with the group receiving only ritodrine and
corticosteroids. The second researchers14 randomized mothers
to one of four groups. Group A received antenatal intramuscular
(IM) or intravenous (IV) vitamin K for 2 to 7 days, group B

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149

received antenatal IM or IV injection of dexamethasone for 1

day, group C received antenatal IM or IV injection of
dexamethasone for 2 days, and group D received dexamethasone for 1 day and vitamin K for 2 to 7 days. The frequency of
severe IVH was decreased significantly in mothers who received
combined antenatal corticosteroid and vitamin K vs corticosteroid or vitamin K when used alone.14 In summary, antenatal
steroids alone or antenatal steroids combined with other
pharmacologic agents such as ritodrine, magnesium sulfate,
or vitamin K used during the antenatal period have been
associated with a decrease in severe IVH.10-14 Although
antenatal interventions have been found to be effective,
measures within the intrapartum period have also decreased
the incidence of GM-IVH.

Intrapartum Interventions
One intrapartum measure to reduce the risk of GM-IVH is in
utero transfer to the tertiary center and cesarean delivery in
selected cases. Interuterine transfer is important because staff at
the tertiary center are trained in providing specialized care for
the mother and preterm infant. Cesarean deliveries prevent
increased cerebral venous pressure during vaginal labor and
therefore prevent GM-IVH.1 Another intrapartum intervention
that is known to decrease GM-IVH is delayed cord clamping at
the time of delivery. Mercer et al (2006) studied 72 infants born
at less than 32 weeks' gestation who were randomly assigned to
one of two groups. The first group was the immediate cord
clamping group where the cord was clamped at 5 to 10 seconds
after birth, and the second group was the delayed cord clamping
group where the cord was clamped at 30 to 45 seconds
after birth. Significant differences were found between immediate and delayed cord clamping demonstrating that delayed
cord clamping may protect very low birth weight infants from
IVH, especially the male infants.15 However, it is important to
note that only one study on delayed cord clamping was
available for review. Although intrapartum interventions for the
prevention of GM-IVH/PVL are limited, many postnatal
interventions are available.

Postnatal Interventions
The first postnatal intervention to be discussed is
resuscitation of the preterm infant by a neonatologist and a
trained team. Providing an open airway, head midline, and
avoiding hyperextension of the head; establishing ventilation;
preventing hypoxemia, hypercarbia, and hypocarbia; and
maintaining the infant's temperature at greater than or equal
to 36C are interventions that the trained neonatal team may
provide and that have been previously documented as
preventing IVHs.4,16,17 This is why intrapartum transport to
a tertiary center is so important. A second postnatal
intervention is the use of surfactant. Two studies of surfactant
use were reviewed.18,19 One used porcine-modified lung
surfactant prophylactically vs rescue and found fewer IVHs
and less severe IVHs in infants treated prophylactically than

150

rescued.18 The second study researched indomethacin and

phenobarbital in addition to surfactant and found that
infants receiving all three medications (indomethacin,
phenobarbital, and surfactant) had a lower percentage of
IVH/PVH than the group receiving indomethacin and
phenobarbital, than the group that just received indomethacin, or than the control group.19
Three studies of indomethacin use in the prevention of IVH
were reviewed.20-22 Two studies20,21 found that prophylactic
indomethacin decreases the incidence of severe IVH, but
Yanowitz et al (2003) did not find a decrease in the incidence of
grades I and II IVH. The third researcher found that male infants
receiving indomethacin instead of an isotonic sodium chloride
solution placebo had significantly less IVHs, but that there was
no significant difference in female infants who received
indomethacin vs an isotonic sodium chloride solution
placebo.22 Another pharmacologic agent proposed for the
prevention of GM-IVH was phenobarbital. Results of the
Cochrane Collaborative meta-analysis of 10 controlled trials
were reviewed and showed no difference between the
phenobarbital-treated infants and the control group in
incidence of IVH or severe IVH, posthemorrhagic ventricular
dilatation, neurodevelopmental impairment, or death. However, a trend toward increased use of mechanical ventilation in the
phenobarbital-treated group was noted.23
The use of morphine for prevention of IVH in preterm
infants requiring ventilation was reviewed. Two studies24,25
trialed the use of morphine vs a placebo. Anand et al (2004)
found that the analysis for all randomized patients showed no
significant differences in severe IVH, PVL, or death. All infants
in the study could receive intermittent doses of morphine if
needed, but no sedation was provided.24 Simons et al25 (2003)
found that routine morphine infusion decreased the incidence
of IVH, but did not influence poor neurologic outcome. Mixed
results from the two studies complicate decisions for providing
IVH/PVL preventative care.
Procoagulant and anticoagulant therapies have been studied
for the prevention of GM-IVH. In a research by Dani et al
(2009), two interventions were studied; one group of infants
received fresh frozen plasma (FFP) after developing a bleed, and
the second group was screened for coagulation studies and
given FFP if results were abnormal. Coagulopathy screening
decreased the risk of developing IVH in the 23- to 26-weeks'
gestation infant only.26 Veldman et al (2006) studied the use of
recombinant activated factor VII in prevention of IVH. They
demonstrated that factor VII did not accumulate and did not
cause disseminated intravascular coagulation or embolic events;
however, a small sample size limited assessment as a prevention
for IVH.27
One final, but large, area of interventions for the prevention
of IVH/PVL is the actual neonatal bedside care. Many care
factors may contribute to or prevent IVHs, the first being head
positioning of the neonate. Near-infrared spectroscopy measure
of cerebral blood volume and cerebral blood flow has
documented that the supine position with a midline head
position promotes lower cerebral blood volume than supine
with the head rotated to one side or the other.28 Turning the

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head sharply to the side can cause obstruction of the ipsilateral

jugular vein and may increase intracranial pressure4; therefore,
midline head position for the tiny preterm infant is a preferred
position. Schrod and Walter (2002) demonstrated that skin-toskin holding of small preterm infants is safe by again using nearinfrared spectroscopy to measure cerebral oxygenation with
infants in a head-elevated, body-tilt position and then in supine
repositioning. There was no change in cerebral oxygenation
with positioning or repositioning, thus supporting the safety of
skin-to-skin care in the preterm infant.29
Rapid fluid infusions for volume expansion4 may increase
the intravascular volume and can rupture the capillaries in the
GM. Roll et al (2006) and Huning et al (2007) researched infant
responses to blood sampling or withdrawing blood from
umbilical artery and umbilical vein catheters using near-infrared
spectroscopy. A significant drop in cerebral oxygenation and
cerebral blood volume was documented during umbilical artery
and vein sampling. Both studies demonstrated that the drop in
cerebral oxygenation and cerebral blood volume was due to the
amount of blood or volume withdrawn or injected and not the
speed with which it was performed.30,31
Routine caregiving procedures such as diaper changes,
endotracheal tube suctioning, and endotracheal tube repositioning were investigated by Limperopoulos et al (2008) and
were determined to produce major circulatory fluctuations that
are not always clinically apparent or appreciated. The cerebral
hemodynamic changes were associated with early parenchymal
ultrasound abnormalities.32 Gagnon et al (1999) used nearinfrared spectroscopy to review several other caregiving
procedures: opening the incubator door produced a 40%
increase in blood volume, stabbing the heel once caused a 20%
increase in blood volume, and staff conversations and a
caregiver inadvertently knocking the incubator caused a loss
of blood volume.33 Practically every aspect of neonatal care can
effect the cerebral circulation of the tiny preterm infant.
In summary, the friable cerebral vasculature of the
extremely low birth weight infant is at risk for rupture.
Hemorrhage into this GM/intraventricular area of the brain
causes mortality and morbidity to a degree based on the extent
and severity of the hemorrhage. Hypoxic ischemic events
that produce PVL also contribute to mortality and morbidity.
Several interventions for the prevention of GM-IVH have
been demonstrated:
In the antenatal period, a complete course of corticosteroids has been shown to reduce the incidence of IVH.10-14
In the intrapartum period, delayed cord clamping for 30 to
45 seconds has been shown to decrease incidence of IVH.15
In the postnatal period, surfactant use for respiratory distress,18,19 resuscitation by a trained team,
thermoregulation,16 prophylactic indomethacin,20-22 and
gentle careful neonatal care 32,33 may decrease the
incidence of IVH.
Further research is needed in all aspects of careantenatal,
intrapartum, and postnatalto provide further interventions
for the prevention of GM/IVHs and PVL.

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