TAGEDENS E M I N A R S I N P E R I N A T O L O G Y 46 (2022) 151591

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Seminars in Perinatology
www.seminperinat.com

Periventricular- intraventricular hemorrhage in the

premature infant- A historical perspective
Jeffrey M. Perlman*
Department of Pediatrics, Weill Cornell Medicine, Division Chief of Newborn Medicine, New York Presbyterian Hospital, 1283 York Avenue
15th Floor, New York, NY, 10065

AB STR ACT

The objective of this chapter is to trace the evolution of intraventricular hemorrhage in the pre-
mature infant highlighting the importance of the germinal matrix, a critical role for cerebral
blood flow changes in the genesis of hemorrhage, clinical factors that increase the bleeding risk,
and potential preventative strategies. In 1976, neuropathological studies demonstrated capillary
rupture within the germinal matrix as the precursor of hemorrhage. In 1980, introduction of cra-
nial ultrasound facilitated diagnosis of intraventricular hemorrhage. In 1979, loss of cerebral
autoregulation in sick newborn infants was demonstrated. In the 1980’s, studies demonstrated
the importance of intravascular factors in provoking hemorrhage. In 1983, the association of
cerebral blood flow velocity fluctuations and subsequent hemorrhage was demonstrated. In
1994, antenatal steroids use to accelerate lung development was recommended. This was associ-
ated with an unanticipated reduction in hemorrhage. In the mid 1990’s early indomethacin
administration was associated with a reduction of severe hemorrhage.
Ó 2022 Elsevier Inc. All rights reserved.

(31%). IVH was further categorized as Grade I (blood within the

Background
Periventricular
intraventricular PV-IVH, particular when severe,
remains the most common serious neurologic lesion of the neo-
natal period, specifically in the tiniest population, i.e. < 28 weeks.1
A landmark study by Papile et al in the 1970’s utilized computed
tomography (CT) brain scanning to define the magnitude of the
problem in 46 consecutive live-born infants < 1500g.2 The overall
incidence of IVH was 43% with hemorrhage significantly more
likely to occur in those infants who died (64%) versus survivors
germinal matrix (GM)), Grade II (some blood within the lateral
ventricles), Grade III (blood filling the lateral ventricles), and Grade
IV (IVH with adjacent parenchymal hemorrhage). The smaller
hemorrhages resolved spontaneously whereas hydrocephalus fre-
quently developed in infants with the more severe hemorrhage.
The introduction of cranial ultrasound imaging (CUS) towards the
end of the 1970’s, utilizing the anterior fontanel as the window to
the neonatal brain, further defined the magnitude of the
problem.3,4 Thus, in the largest initial reported series of premature
infants < 2250g birthweight, approximately 40% exhibited some

Abbreviations: PV-IVH, Periventricular-Intraventricular Hemorrohae; CT, computerized tomography; GM, Germinal Matrix; CUS, Cranial
Untrosound Imaging; CBF, Cerebral Blood Flow; CBFV, Cerebral Blood Flow Velocity; ANS, Antenatal Steroids; GMH, Germinal Matrix
Hemorrhage; GA, Gestational Age; ACA, Anterior cerebarl artery; GFAP, Glial Acidic Fibrillary Protein; VEGF, Vascular Endothelial Growth
Factor; PVHI, Periventricular Hemorrhage Infarction; WMI, White Matter Injury; RDS, Respiratory Distress Syndrome; NIRS, Near Infrared
Spectroscopy; ABP, Arterial Blood Pressure; HMD, Hyaline Membrane Disease; CP, Cerebral Palsy; RR, Relative Risk; CI, Confidence Inter-
val; PIH, Pregnancy Indiced Hypertension
*Corresponding author.
E-mail address: JMP2007@med.cornell.edu

https://doi.org/10.1016/j.semperi.2022.151591
0146-0005/Ó 2022 Elsevier Inc. All rights reserved.
2 S E M I N A R S I N P E R I N A T O L O G Y 46 (2022) 151591

Table 1 – Historical Perspective of Events Related to Periventricular/Intraventricular Hemorrhage

 1976 - Neuropathological studies demonstrating rupture of capillaries within the germinal matrix as a precursor of intraventricular hemor-
rhage (IVH)5
 1976 - Computerized Tomography (CT) diagnosis of Intraventricular Hemorrhage (IVH)2
 1979 - 1980 - Cranial Ultrasound Imaging introduction facilitated the diagnosis of IVH3
 1979 - Initial Study demonstrating loss of Cerebral Autoregulation in sick newborn infants55
 1980 - 1983 - Studies demonstrating the importance of intravascular factors in genesis of IVH22-25
 1980
Studies involving Phenobarbital, Vitamin E, and Ethamsylate to prevent IVH37-41
 1983 - Association of Fluctuations in Cerebral blood flow Velocity (CBFV) and subsequent IVH17
 1985 - Elimination of Fluctuations in CBFV associated with a reduction in IVH32
 1994 - NIH consensus recommending Antenatal Steroids (ANS) use to accelerate lung development was subsequently associated with the
unanticipated reduction in IVH.
 1994 - Study showing the benefits of Indomethacin in the prevention of IVH44
 2000 - Studies demonstrating the association of chorioamnionitis/funisitis and IVH51
 2002 - Second Study demonstrating a reduction in severe IVH in infants receiving Indomethacin but with no effect on long term neurocog-
nitive outcome45
 2004 - Impact of full course of ANS on a reduction of IVH48
 2005 - Study demonstrating loss of autoregulation with increasing pCO2 levels (Hypercarbia)35

form of hemorrhage.3 Moreover, it became evident that most
cases occurred in the first 72 hours of life, and were most likely to
evolve in the sick intubated premature infant with respiratory dis-
tress syndrome (RDS).
This review will trace the evolution of understanding of IVH
in the premature infant in terms of the importance of the ger-
minal matrix (GM), a critical role for cerebral blood flow
changes (CBF) in the genesis of the lesion, clinical factors that
increase the risk of bleeding and potential preventative strat-
egies (Table 1).
The Germinal Matrix (GM) and the relationship to
IVH
The primary lesion in PV-IVH is bleeding from vessels within
the periventricular subependymal GM located between the
caudate nucleus and thalamus at the level of the foramen of
Monro5,6 (Fig. 1). The site of origin of GM hemorrhage (GMH)
varies with gestational age (GA) with most lesions in larger
infants originating over the head, whereas for infants < 28
weeks it originates over the body of the caudate nucleus. The
GM is a transitional gelatinous region that provides poor sup-
port for a large, immature network of blood vessels primarily
supplied by Heubner’s artery, a branch of the anterior cere-
bral artery (ACA).5-7 The microvasculature of the germinal
matrix is fragile in part because of an abundance of angio-
genic blood vessels, which exhibit immaturity of basal lam-
ina, the latter lacking pericytes and fibronectin as well as a
lack of glial fibrillary acidic protein (GFAP) in the covering
astrocytes end feet.7 The associated elevation of vascular
endothelial growth factor (VEGF) and angiopoietin-2 levels
may be related to a relative hypoxia within the germinal
matrix. Venous drainage involves the terminal, choroidal,
and thalamostriate veins that lead to the internal cerebral
vein. The blood flow then makes a U-turn in the subependy-
mal region at the level of the foramen of Monro, the location
of origin of most hemorrhages. This unique venous anatomy
suggests that elevated venous pressure secondary to obstruc-
tion of venous drainage (as might occur with a large GMH)
may lead to venous distention with obstruction of the termi-
nal and medullary veins, and hemorrhagic rupture.5,6 Recent
data suggest that anatomic variants within subependymal
veins may predispose to IVH.8
The GM is site of active cellular proliferation and is a source
of neuronal precursors early in gestation as well as the source
of glial elements that become oligodendroglia and astrocytes
in the third trimester.7 It involutes after approximately 32
weeks and by term gestation, this region is essentially absent.
Its destruction may result in impairment of myelination,
brain growth, and subsequent cortical development.7

Fig. 1 – Pathological specimen from the brain of a premature
infant who died from intraventricular hemorrhage. Note
blood in the germinal matrix (A), blood extending into the
lateral ventricle which is distended (B), blood in the third
ventricle (C) and fourth ventricle (D).
Origin of the hemorrhage
The vasculature of the GM has been difficult to categorize,
because the small capillaries, venules, and arterioles are hard
to distinguish from one another histologically, in part
 TAGEDENS E M I N A R S I N P E R I N A T O L O G Y 46 (2022) 151591 3

because of their relatively simple endothelial wall

structure.5,9 The primary vascular source of PV-IVH has not
been clearly established. Indeed, the initial descriptions sug-
gested a venous origin10 while others described it as emanat-
ing from capillary or arterial vessels.5 From studies
conducted over the years, it is most likely that PV-IVH is a
consequence of both arterial and venous perturbations.6,11
The hemorrhage, when it evolves, may be confined to the GM
region (Grade I) or it may extend and rupture into the adja-
cent ventricular system (defined as Grade II or III) depending
on the degree of blood, or it may extend into the white matter
(previously termed a Grade IV IVH or intraparenchymal echo-
genicity (IPE) but is more appropriately termed periventricu-
lar hemorrhagic infarction (PVHI))6,11,13 (Fig. 2 a). The latter
lesion, which is invariably unilateral, represents an area of
hemorrhagic necrosis of varying size within periventricular
white matter, dorsal and lateral to the external angle of the
lateral ventricle.3,6,12

Periventricular White Matter Injury (WMI)

associated with IVH

The etiology of the Grade IV IVH was unclear in the early 1980’s.
The initial hypothesis was that the intraparenchymal lesion rep-
resented an “extension” of hemorrhage from the GM or lateral
ventricle into previously normal periventricular white matter.2
However, subsequent neuropathological data indicated that the
intraparenchymal lesion represents regions of hemorrhagic
necrosis, due to impaired venous drainage.12-14 Furthermore, a
CBF study utilizing positron emission tomography indicated
extensive impairment involving the entire hemisphere in excess
of the hemorrhage visualized on CUS15 (Fig. 2b). We prefer the
term PVHI because, depending on the extent of involvement, it
more closely related to outcome. 12 The pathogenesis of the
white matter injury (WMI) associated with hemorrhage remains
unclear, but appears to be closely linked to the adjacent bleed.
Two potential pathways have been proposed. The first suggests
a direct relationship to the PV-IVH based on several clinical
observations: a) The WM lesion is always noted concurrent with
or following a large GM and /or IVH, b) The WMI is always
observed ipsilateral to the side of the larger hemorrhage when
there is bilateral involvement of the ventricular system.6,12,14
Fig. 2 – A Cranial ultrasound scan coronal view (top). Note
This consistent relationship between the GM and the WMI may
the large left-sided germinal matrix hemorrhage with some
in part be explained by the venous drainage of the deep white
blood in the lateral ventricle. Note the adjacent fan-shaped
matter (see above). A second explanation is a de novo evolution
intraparenchymal echodensity in the distribution of the
of WMI. Since both the GM and the periventricular white matter
medullary veins. B Positron Emission Tomography scan
represent border zone regions, the risk for ischemic injury is
(bottom). This scan is from the patient with the hemorrage
increased during periods of systemic hypotension, particularly in
noted above. The activity scan reflects actual cerebral blood
the face of a pressure passive cerebral circulation.16 Indeed, ele-
flow (CBF) measurements. Note that white-red- reflects
vated hypoxanthine and uric acid levels (perhaps as markers of
highest cerebral flow. Note the marked reduction in CBF on
reperfusion injury) have been observed on the first postnatal day
the left versus right hemisphere. Note the blood flow reduc-
in infants who subsequently developed white matter injury.18,19
tion involves the entire left hemisphere in excess of what
was observed on the cranial ultrasound scan.
Cerebral autoregulation and pressure-passive
circulation of systemic blood pressures. It was unknown in the late
1970’s whether autoregulation was intact or not in sick new-
Cerebral autoregulation is the intrinsic ability of the cerebral born infants. The seminal data of Lou and colleagues16
blood vessels to maintain relatively constant CBF over a range derived from 19 newborn infants with varying degrees of
4 S E M I N A R S I N P E R I N A T O L O G Y
Fig. 3 – Factors important in the pathogenesis of intraventricular hemorrhage. These are considered boadly as intravascular,
vascular, and extravascular factors. Intravascular factors appear to predominant (see text for details). CBF = cerebral blood
flow. IVH = intraventricular hemorrhage.
respiratory distress syndrom (RDS), studied in the first hours
of life, were the first to indicate that CBF varied considerably
with spontaneous variations in blood pressure, suggesting
that autoregulation was lacking. Subsequent studies utilizing
different methods to assess CBF or cerebral blood flow veloc-
ity (CBFV) including Xenon, Near Infrared Spectroscopy
(NIRS), and Doppler have supported the concept of a pressure
passive cerebral circulation in the sick infant, i.e. CBF varying
directly with changes in systemic blood pressure.17,20-22This
state places the developing brain at great risk for injury dur-
ing times of hypotension and or elevated blood pressures. By
contrast, the circulation appears to be intact in the “stable”
human preterm infant17 as well as in fetal and neonatal ani-
mals.23 Notably, in fetal lambs, resting blood pressure has
been shown to be slightly above the lower limit of the autore-
gulatory curve.23 This is highly relevant because if a similar
situation exists in newborn infants, moderate hypotension
will result in reduced CBF and the potential for ischemic cere-
bral ischemic brain injury.
Evaluation of the cerebral circulation using
Doppler
Application of the Doppler technique in the early 1980’s to
measure CBFV through the anterior fontanel facilitated the
ability to link systemic events to the pathogenesis of PV-
IVH.24 Measurements were obtained from the pericallosal
artery (terminal branch of the ACA) as it courses around the
genu of the corpus callosum, as well as from the right or left
middle cerebral artery through the coronal sutures. Although
Doppler does not measure CBF, it has certain advantages;
specifically, it is noninvasive and readily available at the bed-
side and facilitates repeated measurements. When coupled
with frequent sonographic assessments, it provides an
46 (2022) 151591
opportunity for linkage of simultaneous systemic and cere-
bral circulation perturbations to the subsequent development
of IVH.24
Pathogenesis of PV-IVH
The genesis of PV-IVH is complex with predisposing factors
including a combination of vascular, intravascular, and extravas-
cular influences1,2 (Fig. 3). Several reasons pointed to a critical
role for intravascular factors and specifically perturbations in
arterial blood pressure (ABP) as a major factor in capillary rup-
ture and hemorrhage. First, the cerebral circulation of the sick
infant was shown to be pressure passive (see above).16,17,20-22
Second, in a beagle puppy model, GMH could be produced by
induced systemic hypertension with or without prior
hypotension.25,26 Third, infants with lower mean ABP in the first
postnatal days as well infants who received rapid volume expan-
sion to correct hypotension were more likely to develop IVH.27,28
Conversely, elevations in venous pressure were also considered
to be an important mechanism of hemorrhage, in part based on
the peculiarity of the anatomy of the venous drainage of white
matter and germinal matrix (see above).6,8,29 In this regard,
simultaneous increases in venous pressure were observed in
infants who exhibited variability in ABP, such as with RDS and
associated complications, e.g. pneumothorax.20,29,30 Subsequent
evidence suggested that these intravascular responses may be
modulated by additional factors, i.e. inflammation associated
with chorioamnionitis.31
Additional contributing factors include vascular and extra-
vascular influences, i.e. the poorly supported blood vessels,
fragility of the germinal matrix vasculature, excessive fibrino-
lytic activity noted within the matrix region, and a prominent
postnatal decrease in tissue pressure.7,32
 TAGEDENS E M I N A R S I N P E R I N A T O L O G Y 46 (2022) 151591 5

Linking Systemic and Cerebral Vascular

Perturbations in Infants with Respiratory Distress
Syndrome (RDS) to PV-IVH

Perturbations on the Arterial Side

Numerous studies had established an association between

RDS and IVH by the early 1980’s.11,33 However, the mecha-
nism(s) that linked these two co-morbidities were unclear.
Utilizing Doppler, we described an association between CBFV
fluctuations and subsequent PV-IVH in preterm infants with
RDS.20 In a study of preterm infants weighing < 1500 grams
requiring mechanical ventilation for RDS, 21 of 23 infants
(91%), with continuous beat to beat fluctuations in CBFV,
measured from around 12 hours of life, subsequently devel-
oped IVH, typically within the following 24-hours, versus 7 of
27 infants (26%) with stable CBFV patterns (Fig. 4 a, b). The
fluctuations in CBFV directly reflected similar fluctuations in
ABP in a pressure passive manner. We subsequently demon-
strated that the fluctuations were related to the respiratory
effort of the infant.34 Specifically, as work of breathing
increases, concomitant with progressive RDS, wide beat-to-
beat swings in arterial as well as venous pressures are
observed. To test the hypothesis that there was a relationship
between the systemic and cerebral fluctuations, the infant’s
respiratory effort, and development of PV-IVH, we conducted
a randomized study and eliminated the CBFV fluctuations
with muscle paralysis (Fig. 4c). All 10-control infants with
CBFV fluctuations subsequently developed IVH versus only 5
of 14 infants treated with muscle paralysis. In 4 of these 5
cases, the hemorrhage developed after cessation of the paral-
ysis.35 Importantly over time, the advent of newer ventilators
that work in tandem with the infants own respiratory efforts
coupled with the antenatal use of steroids (ANS), has made Fig. 4 – a. Stable pattern of Cerebral Blood Flow Velocity (top
this association less prominent. However, in susceptible panel) and Arterial Blood Pressure (bottom panel.). Note
infants (partial or no ANS) the same risk as described above minimal beat to beat cerebral and systemic wave form vari-
may still be apparent (see below). ability b. Beat to beat fluctuations in CBFV (top panel) and
simultaneous beat to beat fluctuations in Arterial Blood
Pressure wave form (bottom panel)in a pressure passive
Perturbations in Venous Pressure
manner. c. Note the elimination of the beat to beat fluctua-
tions in the CBFV pattern (top panel) following muscle
In subsequent studies, we observed fluctuations in venous
paralysis (bottom panel)
pressure simultaneously with ABP perturbations in preterm
infants with RDS who developed PV-IVH.29 The fluctuations
was that it had been shown that surfactant administration
can be exacerbated by higher mean airway pressures such as
acutely affects cerebral and systemic hemodynamics.37
may occur with high-frequency oscillatory ventilation, or
pneumothorax. The potential importance of these venous
fluctuations in the genesis of hemorrhage is intertwined with Hypercarbia and intraventricular hemorrhage
the venous drainage of the deep white matter (see above).
Based on experimental studies, an important role for hyper-
carbia in the genesis of IVH had been presumed. The associ-
Surfactant administration and PV-IVH ated was delineated in several neonatal studies. Thus in a
study undertaken in the first week of life in VLBW infants,
The introduction of surfactant administration to reduce the increasing PaCO2 values resulted in an increase in CBF and
severity of RDS in the late 1980’s was the most important devel- progressive impairment of cerebral autoregulation.38 Hyper-
opment in the management of sick premature infants. Surfac- capnia defined by a maximum PaCO2 recorded during the first
tant reduced mortality, severity of RDS as well as the rates of 3 days of life was associated with severe IVH. Moreover, in a
pneumothorax.36 However, in the many subsequent surfactant retrospective cohort study of 574 VLBW infants born between
trials irrespective of design, i.e. prophylactic versus rescue, syn- 1999 and mid-2004, as the maximum PaCO2 increased from
thetic versus natural, IVH persisted.36 One potential explanation 40 to 100 mm Hg, the probability of severe IVH increased from
6 S E M I N A R S
8% to 21%.39 These cumulative observations indicate that
extremes in PaCO2 should be avoided during the period in
which infants are at high risk of IVH.
Strategies to prevent severe IVH
historical
perspective (Table 1)
In the early 1980’s postnatal medications used to prevent
hemorrhage included phenobarbital,40,41, Vitamin E,42,43 and
ethamyslate.44 While there was initial enthusiasm for the use
of these medications, this was not borne out over time.
Importantly, in one large, randomized study, infants who
received phenobarbital exhibited a higher incidence of any
IVH when compared to controls, i.e. 51/145 versus 26/135
(p=0.003) respectively.41 Another intervention that seemed
promising was indomethacin. This was based on plausible
experimental studies in the beagle puppy.45,46 When applied
clinically, the early postnatal administration of indomethacin
was associated with a significant reduction in severe IVH, i.e.
1/209 versus 10/222 in the placebo (p=0.03).47 In a subsequent
randomized study, Schmidt et al48 demonstrated a significant
reduction in severe IVH (9 vs 13%) (p=0.02) in the indometha-
cin versus placebo groups respectively. However, at 18-month
follow-up there were no differences in the incidence of cere-
bral palsy or severe cognitive delay in the two groups.48 One
hypothesis for this unanticipated observation is while indo-
methacin reduced IVH, it had no impact on the larger under-
lying ischemic lesion12,15 (see above) (Fig. 2b).
Antenatal steroids and IVH
The single most important “intervention” shown to signifi-
cantly reduce the development of IVH has been a short course
of antenatal glucocorticoid steroid (ANS) administered to aug-
ment pulmonary maturation.49,50 In a recent Cochrane
review, a reduction in IVH was observed (average Risk Ratio
was 0.55, 95% Confidence Interval (CI) 0.40-0.76) following any
ANS exposure.49 Importantly, this was a serendipitous obser-
vation, i.e. there has not been a prospective randomized
study that has evaluated the impact of ANS on reducing
severe IVH. In a more recent population-based study
(n=28252), as ANS exposure increased from 80% in 2005 to
90% in 2016, there was a concomitant decrease in severe IVH
Table 2 – Association of ANS Dosing in Very Low Birthweight Infants and Clinical Outcome
Outcome None n (%)
HMD 37 (79)
Surfactant 34 (72)
Total IVH 27 (64)
IVH (3 or 4) 18 (43)
Death 18 (38)
y p<0.05 for complete versus none.
z p<0.05 for complete versus partial.
Adapted from Reference 48
I N P E R I N A T O L O G Y 46 (2022) 151591
from 14.5% to 9.0%.50 Both reports did not account for the
number of doses of ANS administered to the mother.49,50 This
is important since we demonstrated a dose dependent
decrease in IVH following a full course of ANS versus partial
or no ANS51 (Table 2). The mechanism(s) whereby glucocorti-
coids reduce severe IVH remain unclear, but may relate to
less severe RDS, higher resting ABP or via accelerated matura-
tion of the germinal matrix region.52,53
Magnesium sulfate
Initial studies suggested that magnesium sulfate used to treat
women with pregnancy induced hypertension (PIH) was asso-
ciated with a reduction in IVH.54 Subsequent studies failed to
show a reduction in IVH.55,56 Although a neuroprotective
effect on IVH is unclear, when magnesium sulfate is given to
mothers at risk for preterm birth, it has been shown to reduce
the risk of cerebral palsy (CP) in the child in two meta-analy-
sis. In the first report there was a reduction in CP, i.e. relative
risk (RR): 0.68, (95% CI: 0.54-0.87); this comprised 5 trials total-
ing 6145 infants. In the second analysis, there was an almost
identical result, i.e. RR 0.68, 95% CI 0.54 to 0.87, 4,601 babies, 5
trials, NNT to benefit 46.57,58
Pregnancy Induced Hypertension (uced
Hypertension (PIH)
PIH has been associated with a lower incidence of IVH. Thus
we reported less severe PV-IVH in infants born to mothers with
PIH than in those without PIH, i.e., 8.2% vs. 14% with an odds
ratio estimate of 0.43 (95% CI 0.30-0.61).59 Since all mothers in
this report received magnesium sulfate, it was unclear whether
the reduction in IVH was related to the PIH or magnesium.
However, in another study involving mothers with PIH who did
not receive magnesium, severe IVH was reduced almost 60% in
newborns born to mothers with PIH versus those without PIH.60
Route of delivery
There is conflicting data regarding the route of delivery and
subsequent IVH. Interpretation of the data is difficult since
most studies are retrospective and undertaken before the use
Antenatal Steroid Doses
Partial n (%) Complete n (%)
18 (58) 18 (39) y
20 (64) 16 (35) yz
16 (52) 11 (25) yz
8 (26) 5 (11) y
5 (16) 6 (13) y
 TAGEDENS E M I N A R S I N P E R I N A T O L O G Y 46 (2022) 151591 7

Table 3 – Identification of Infants Who Are At Highest

Risk for the Development of Severe Intraventricular Preventing IVH in 2021
Hemorrhage
From the above it should be apparent that a great deal has
Perinatal Factors -Minimal intrapartum care
been learned regarding the pathogenesis and as a result,
-No glucocorticoid exposure
strategies to prevent or reduce IVH, and in particular severe
-Chorioamnionitis/funisitis
IVH. Infants with severe IVH are at greatest risk for marked
Postnatal Factors -Decreasing Gestational Age neurodevelopmental deficits.12 The risk factors for severe IVH
-Decreasing Birth Weight include perinatal factors such as late arrival to the delivery
-RDS- particularly in the absence of a full room particularly during off peak hours,63 no or minimal ANS
course of glucocorticoid exposure exposure and evidence of chorioamnionitis/funisitis. Postna-
-Respiratory morbidity, i.e. pneumothorax
tal factors include very low birth weight infants < 1000 grams
-Fluctuations or rapid elevations in systemic BP
and/or GA < 28 weeks, intubated infants, and in the absence
and/or cerebral blood flow particularly in the
absence of a full course of glucocorticoid of ANS exposure, RDS, and complications, i.e. pneumotho-
exposure rax.64 (Tables 3)
-Sudden and repeated increases in venous For such infants, the risk for IVH is even greater when there
pressure are associated perturbations in arterial and venous
pressures20,29 (Fig. 3). By contrast, the risk for severe IVH in
the non-intubated infant is low, i.e., <10%.64
Our specific approach to the prevention of IVH takes into
of antenatal steroids.11 However, this does not exclude the pos-
account the exposure to ANS. Thus for infants < 1000g or <
sibility that under certain circumstances, intrapartum events
28 weeks with no or minimal ANS exposure, we administer
may contribute to the pathogenesis of severe IVH. Thus, evi-
indomethacin within six hours. The initial results of this
dence of inflammation and in particular fetal vasculitis,
approach is shown in Table 4, which shows a significant
increases the risk of IVH which may supersede the influence of
reduction in IVH with this approach.
the route of delivery.61 In one study, while vaginal delivery was
associated with an increased risk of IVH by univariate analysis,
the risks attributable to vaginal delivery were no longer ele-
vated when adjustments were made in multivariate analysis Conclusions
for fetal vasculitis and other potential confounders.61
The overall incidence of IVH including severe IVH has been
reduced over time. The most important factor contributing to
this finding has been the perinatal administration of a com-
plete course of ANS. Future strategies should target those
infants at highest risk for IVH including the severe lesion
Timing of cord clamping (Tables 3, 4). One potential strategy is the early postnatal use
of Indomethacin as described above. Additional strategies
Many reports have evaluated the potential benefit of early should be explored. Importantly, although the incidence of
versus delayed cord clamping and the impact on the develop- severe IVH has been reduced, the long-term neurodevelop-
ment of severe IVH. In the most recent and extensive review mental outcome ofinfants with lesser hemorrhage remains
on the topic involving 14 trials and totally 2972 subjects, it unclear but important to delineate.
was not possible to exclude benefit or harm from delayed
compared to early cord clamping on the occurrence of severe
IVH (RR 0.98, 95% CI 0.67 to 1.42).62 Disclosure

Table 4 – Impact of Prophylactic Indomethacin on Devel- The author report no proprietary or commercial interest in
opment of Severe IVH in Infants not Exposed to ANS at any product mentioned or concept discussed in this article.
Cornell, NYC There are no competing interests to disclose. There are no
personal or financial relationships to disclose.
Intervention # of Infants Severe IVH

Optimal ANS 55 0
R E F E R E N CE S
Suboptimal/No ANS, 9 6*
No INDO
Suboptimal/No 13 2
ANS, + INDO 1. Stoll BJ, Hansen NI, Bell EF, et al. Eunice Kennedy Shriver
National Institute of Child Health and Human Development
Neonatal Research Network. Trends in Care Practices, Mor-
Comparison of Suboptimal Antenatal Steroids (ANS)/No Indometh-
bidity, and Mortality of Extremely Preterm Neonates, 1993-
acin versus Suboptimal ANS, + Indomethacin (p=0.03)
2012. JAMA. 2015;8(10):1039–1051. https://doi.org/10.1001/
Infants who received Indomethacin vs no treatment were of # GA
jama.2015.10244: 314PMID26348753PMCIDPMC4787615.
23.8 §0.83 vs 27 §1.8 weeks (p<0.05) and BW 652 §104 grams vs
2. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evo-
972 §259 grams (p<0.05).
lution of subependymal and intraventricular hemorrhage: a
study of infants with birth weights less than 1,500 gm. J
8 S E M I N A R S I N P E R I N A T O L O G Y
Pediatr. 1978;92(4):529–534. https://doi.org/10.1016/s0022-3476
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