Clinical manifestations and diagnosis of intraventricular hemorrhage in the

newborn

Clinical manifestations and diagnosis of intraventricular hemorrhage in the newborn

Author
Lisa M Adcock, MD
Section Editors
Joseph A Garcia-Prats, MD
Douglas R Nordli, Jr, MD
Deputy Editor
Melanie S Kim, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2013. | This topic last updated: Feb 26, 2013.
INTRODUCTION Intraventricular hemorrhage (IVH; also known as subependymal or germinal matrix-IVH) is an important
cause of brain injury in premature infants. Although the incidence has declined since the 1980s, IVH remains a significant
problem, since improved survival of extremely premature infants has resulted in a greater number of survivors with this
condition [ 1,2 ].
The epidemiology, pathogenesis, clinical presentation, and diagnosis of IVH are discussed in this topic review. The management,
complications, and outcome of IVH in the newborn are discussed separately. (See "Management and complications of
intraventricular hemorrhage in the newborn" .)
PATHOLOGY
Preterm infants In preterm infants, the site of origin of bleeding is generally the subependymal germinal matrix, which is
located between the caudate nucleus and thalamus at the level of the foramen of Monro [ 3 ]. Neuropathologic studies suggest
that the hemorrhage is primarily within the capillary network, which freely communicates with the venous system, although
bleeding can also occur from the arterial circulation [ 4 ]. Vessels in this region occupy border zones between cerebral arteries
and the collecting zone of the deep cerebral veins, and have increased permeability when subjected to hypoxia and/or increased
venous pressure [ 5 ]. (See 'Germinal matrix fragility' below.)
Severity and grading of IVH Severity of hemorrhage is based on whether the bleeding is confined to the germinal matrix
region or if it extends into the adjacent ventricular system or white matter (intraparenchymal). The following grading system is
used to define the extent of bleeding ( table 1 ) [ 3 ]:

Grade I Bleeding is confined to the germinal matrix ( image 1 and image 2 )

Grade II IVH occupies 50 percent or less of the lateral ventricle volume
Grade III IVH occupies more than 50 percent of the lateral ventricle volume ( image 3 )
Grade IV Hemorrhagic infarction in periventricular white matter ipsilateral to large IVH ( image 4 )

Grade I corresponds to mild, grade II moderate, and grades III and IV severe IVH. Each grade of IVH may be unilateral, or
bilateral with either symmetric, or asymmetric grades of IVH.
Term infants In contrast, the initial site of bleeding in term infants is variable based on limited data as illustrated by the
following:

In one neuropathologic study of 32 term infants, the majority of IVH arose from the choroid plexus [ 6 ].
In another study of term infants, ultrasonographic imaging showed subependymal germinal matrix and choroid plexus
hemorrhages occurred at similar rates [ 7 ].

Thalamic hemorrhage may also contribute to IVH in term infants, as described in a series of 19 cases, in which twothirds had associated thalamic hemorrhage detected by computed tomography [ 8 ]. This is likely a venous
hemorrhagic infarction caused by thrombosis in the internal cerebral vein(s), or more extensive venous
thrombosis, rather than a primary hemorrhage.
These findings suggest that the origin of intracranial bleeding in term infants differs from that seen in preterm infants with
subependymal IVH.
EPIDEMIOLOGY IVH generally occurs in preterm infants, and the incidence increases with decreasing gestational age and
birth weight.
Prematurity IVH occurs most frequently in infants born before 32 weeks gestation or less than 1500 g birth weight. Since
the late 1990s, the reported rate of IVH in the United States is about 20 percent in very low birth weight (VLBW) infants (birth
weight <1500 g) and 45 percent in extremely low birth weight (ELBW) infants (birth weight <750 g) [ 9-12 ].
As noted above, the incidence of IVH increases with decreasing gestational age as illustrated by a population-based study of
2896 premature infants (<32 weeks gestation), in which IVH rates decreased 3.5 percent with each added week of gestation
[ 13 ].
The risk of severe IVH also increases with decreasing gestational age and birth weight as noted by the following studies
(see 'Severity and grading of IVH' above):

In a study from the National Institute of Child Health and Human Development (NICHD) neonatal research network of
9575 infants with gestational age between 22 and 28 weeks and birth weight 401 to 1500 g, the overall incidence
of IVH was 36 percent for all grades of IVH, which increased with decreasing gestational age [ 12 ]. The
prevalence of severe IVH (defined as grades III and IV) also increased with decreasing gestation with rates of 38,

36, 26, 21, 14, 11, and 7 percent of survivors for infants with gestational ages 22, 23, 24, 25, 26, 27, and 28,
respectively [ 12 ].

In a population-based prospective study of all preterm infants with gestational age below 27 weeks born in Sweden
from 2004 to 2007, the incidence of IVH increased from 5.2 percent of survivors born at 26 weeks gestation to 19
and 20 percent of survivors born between 22 and 23 weeks gestation [ 14 ].
Although older literature has suggested that VLBW infants who were small for gestational age (SGA) were less likely to have IVH
[ 15 ], subsequent data have shown no difference in the incidence of IVH between SGA and appropriate size for gestational age
premature infants [ 16,17 ].
Term infants Severe IVH occurs infrequently in term infants, although minor hemorrhages are not uncommon. In a study of
505 healthy asymptomatic term infants who underwent head ultrasonography within 72 hours of life, the incidence of IVH was 4
percent [ 18 ]. In the term infant, IVH may be associated with trauma (eg, abdominal compression), alloimmune
thrombocytopenia, rupture of a vascular malformation, sinovenous thrombosis (particularly in infants with thalamic
involvement), and a diagnosis of hemophilia and other coagulation abnormalities [ 19-21 ]. In some cases, it is unclear whether
the coagulation abnormality is causal or is a result of IVH [ 21 ].
PATHOGENESIS The pathogenesis of IVH in premature infants is due to [ 22 ]:

Germinal matrix fragility from the lack of structural support of rete of immature blood vessels due to immaturity.
Disturbances of cerebral blood flow, particularly ischemia-reperfusion, increased arterial flow, or increased venous
pressure.
Germinal matrix fragility In preterm infants, IVH generally originates within the germinal matrix, the highly cellular and
richly vascularized layer in the subependymal, subventricular zone that gives rise to neurons and glia during fetal development
[ 23 ]. As the fetus matures, the germinal matrix begins to involute starting at 28 weeks as its cellularity and vascularity
decrease, and by term it is generally absent [ 24 ].
In the germinal matrix, the capillary network consists of numerous thin-walled, large blood vessels that lack structural support,
which contributes to the increased risk of hemorrhage in this area of the brain compared to other regions [ 3,22,25-27 ]. The
microvasculature of the germinal matrix is particularly fragile because of the abundance of angiogenic blood vessels that have a
paucity of pericytes; and have immature basal lamina, and deficiency of tight junctions and glial fibrillary acidic protein (GFAP) in
the astrocyte endfeet (which are components of a competent blood-brain barrier) [ 22 ]. Glial fibers normally develop with
increasing maturation as demonstrated in a study showing minimal immunocytochemical staining of GFAP at 27 weeks gestation,
which became more prominent with increasing gestational age, especially after 31 weeks gestation [ 28 ]. The deficient
structural support makes the germinal matrix vulnerable to injury primarily due to hemodynamic instability in preterm infants,
related to altered cerebral blood flow caused by a variety of perinatal/neonatal events or disorders (eg, hypoxia/ischemia).
This fragile capillary network drains into a well-developed deep venous system that forms the terminal vein, which changes
direction in a U-turn fashion as it empties into the internal cerebral vein. It is postulated that the venous system is prone to
venous congestion and stasis, resulting in increased cerebral venous pressure, which contributes to germinal matrix IVH [ 21 ].
Cerebral blood flow instability Fluctuations of cerebral blood flow (CBF) in preterm infants are associated with IVH [ 2932 ]. Preterm infants are particularly vulnerable to alterations in CBF because they have impaired autoregulation of CBF
compared to term infants. This impairment results in a pressure-passive circulation, in which the infant cannot sustain constant
CBF with changes in systemic blood pressure [ 33 ]. As a result, increases or decreases in blood pressure are reflected by similar
changes in CBF, leading to injury of the fragile blood vessels of the germinal matrix.
The association of impaired autoregulation and IVH were demonstrated in studies of preterm infants that monitored mean
arterial blood pressure (MAP), and CBF using near-infrared spectroscopy (NIRS).

In one study of 32 preterm infants (gestational age between 23 and 31 weeks) who were receiving mechanical
ventilation, 8 of 17 patients with impaired autoregulation (based on concordant changes in CBF and MAP)
developed severe germinal matrix-intraventricular hemorrhage, periventricular leukomalacia (PVL), or both. In
contrast, only 2 of 15 infants with apparently intact autoregulation developed severe lesions.

In another study of 88 preterm infants <32 weeks, the risk of IVH was associated with greater cerebral pressure
passivity (based on MAP and NIRS measurements) but not with MAP variations alone [ 30 ].

Observational studies that did not monitor CBF have shown that changes in blood pressure are associated with IVH [ 34,35 ].
The assumption is affected infants were more likely to have impaired autoregulation. Causes of abrupt elevation of MAP that may
contribute to IVH include noxious stimuli, rapid volume expansion with fluid boluses, tracheal suctioning, and seizures. (See 'Risk
factors' below.)
Other factors that have been implicated with fluctuations of CBF and IVH include hypercarbia, hypoglycemia, and asphyxia.
RISK FACTORS IVH risk factors include prenatal conditions, complications of labor and delivery, and postnatal conditions.
They can often be related to underlying pathogenetic processes, such as fluctuations in cerebral blood flow (CBF) during rapid
fluid boluses, or increases in cerebral venous pressure (CVP) with fetal head compression during labor and delivery.

Prenatal factors Maternal chorioamnionitis, lack of antenatal steroid therapy, and prenatal asphyxia
Neonatal and postnatal factors Prematurity, coagulation abnormalities, respiratory distress, hypotension, hypoxia,
and hypercapnia

Labor and delivery factors Mode of delivery, breech presentation, and intrapartum asphyxia

Prenatal factors
Chorioamnionitis Maternal intrauterine infection and/or amniotic sac inflammation are associated with increased risk of IVH
[ 36-42 ]. The severity of IVH also increases with chorioamnionitis as illustrated by a large multicenter Canadian prospective
study of 3094 preterm infants (gestational age less than 33 weeks) born between 2005 and 2006 [ 37 ]. Patients with
chorioamnionitis (15 percent of the cohort) were more likely to have severe IVH (defined as grades III and IV) compared to
those without chorioamnionitis (22 versus 11 percent). In a multivariate logistic regression, which included adjustments for
gestational age, birthweight, treatment with antenatal corticosteroids, and presence of maternal hypertension, infants with
chorioamnionitis had a 1.6-fold increased risk of severe IVH compared to those without chorioamnionitis.
Indirect evidence linking maternal intrauterine infection to IVH is provided in a meta-analysis that showed prenatal antibiotic use
for prolonged rupture of membranes reduced the incidence of all grades of IVH [ 43 ]. In addition, a low neonatal neutrophil
count (less than 1000 neutrophils/microL) within 2.5 hours of birth was associated with IVH and its severity [ 44 ]. For infants
born at 28 through 36 weeks of gestation, the lower limits of normal for neutrophil counts at birth and at six to eight hours after
birth were 1000/microL and 1500/microL. This degree of neutropenia is associated with infection or preeclampsia. (See "Clinical
features and diagnosis of sepsis in term and late preterm infants", section on 'Total neutrophil count' .)
A contributory role for maternal inflammation is supported by several studies that have shown the association between IVH and
increased cytokine production and release (used as a biomarker for inflammation) and/or histologic evidence of inflammation
[ 39,41,42,45,46 ].
Maternal drug therapy Antenatal steroid therapy has been shown to decrease the risk of IVH [13,47-49 ], even in
pregnancies complicated by chorioamnionitis [ 36 ].
It is unclear whether the use of maternal aspirin is associated with IVH. In one series of 108 infants (gestational age 34
weeks), the incidence of IVH was greater in preterm infants whose mothers used aspirin in the last week of pregnancy compared
to controls [ 50 ]. However, in a systematic review of trials of antiplatelet agents (primarily low-dose aspirin) to prevent
preeclampsia, the rate of IVH was not different between treatment and control groups (RR 0.88, 95% CI 0.63-1.22) [ 51 ].
Neonatal and postnatal factors
Prematurity As noted above, prematurity is the most important neonatal risk factor for IVH because of preterm infants
germinal matrix fragility and inability to autoregulate CBF. (See'Pathogenesis' above.)
Other risk factors Other neonatal and postnatal factors include:

Respiratory distress with episodes of hypocapnia, hypercapnia, and/or hypoxia. These factors are associated with
fluctuations in CBF and elevated CVP [ 52 ].

Increases in arterial blood pressure [ 34 ], which may be caused by noxious stimuli (eg, manual ventilation) [ 53 ]
and rapid fluid boluses [ 54 ], are associated with increased CBF.

Mechanical ventilation, likely by contributing to fluctuations in CBF and increased CVP [ 55,56 ].
Inter-hospital transport [ 57 ].
Bicarbonate therapy may be associated with an increased risk of IVH, potentially due to hyperosmolarity [ 58 ]. In
one report, the increased risk of IVH appeared to be related to the rapidity of infusion of sodium bicarbonate ,
which may alter CBF [ 59 ].
Data are conflicting on whether or not hypothermia, pneumothorax, and coagulation and platelet defects are associated with
IVH:

Hypothermia following birth has been linked to increased risk of IVH in some studies [ 60 ] but not others [ 61 ];
differing definitions of hypothermia, variations in size of study groups, and differing study design may explain
conflicting results.

Several reports have shown an association between pneumothorax and IVH, postulated to be related to increased CVP
[ 56,62,63 ]. In contrast, in a study of 675 premature infants (28 weeks), there was no increase in IVH
occurrence in the 62 neonates with pneumothorax compared with those without this complication [ 64 ].

Coagulation and platelet abnormalities Thrombocytopenia and coagulation defects are common in premature
infants, especially those with other risk factors for IVH. Although several observational studies have shown an
association between these two conditions and IVH [ 65-68 ], it remains uncertain whether coagulopathy and
thrombocytopenia have a causal role in the pathogenesis of IVH. In particular, the failure of procoagulant therapy
to reduce IVH raises questions about a causal relationship [ 69,70 ].
Genetic factors Limited data suggest that genetic factors contribute to IVH. A study of premature twin pairs reported IVH
occurred in 9 of 63 monozygotic twins (26 percent) and 39 of 185 dizygotic twins (21 percent), and logistic regression analysis
suggested that there were familial factors that contributed to IVH susceptibility [ 71 ].
Proposed genetic factors include:

Hemostatic genes There are conflicting reports on whether mutations of hemostasis genes predispose preterm
infants to IVH, but these are likely to be of lesser importance than other risk factors described above.

 In a prospective study, DNA testing for factor V Leiden, prothrombin G20210A, and mutations of factor VII and XIII
were performed in a cohort of 1008 VLBW infants [ 72 ]. There was no difference in the rate of IVH in the 178
infants with a mutation of one of the hemostatic genes compared to 830 infants without a mutation. As an
example, the rates of IVH in the 74 infants with mutations of factor V Leiden compared to those without were 19
versus 17.5 percent.

In contrast, two smaller case-control studies reported an increased risk of IVH in preterm infants with factor V Leiden
mutations [ 73,74 ]. In the first study, 5 of 22 infants with grades II to IV IVH compared to 1 of 29 control infants
without IVH had a factor V Leiden mutation [ 73 ]. In the second study of 130 preterm infants with birth weight
<2500 g, those with grade I IVH were more likely to have a mutation of factor V Leiden compared to control
infants without IVH (frequency of mutated allele, 10 versus 4.8 percent) [ 74 ].

Collagen gene In several case reports, a mutation in the collagen gene Col4a1 has been associated with severe
prenatal intracranial hemorrhage, but there are no reported studies with large cohorts [ 75,76 ].

Inflammatory genes Although data are conflicting, polymorphisms in the proinflammatory cytokine IL-6 have been
proposed as genetic modifiers for the risk of IVH [ 46,77 ]
Labor and delivery It remains uncertain whether labor and route of birth affect the risk of IVH. During labor and vaginal
delivery, compression of the fetal head by the uterus increases CVP [ 78 ], which theoretically could promote IVH. However, data
are inconsistent on whether or not vaginal delivery increases the risk of IVH when compared with caesarean delivery.

Two single-center retrospective studies reported an increased risk of IVH in preterm infants delivered vaginally than
those delivered by caesarean birth [ 79,80 ].

Other single center observational studies report no difference in the risk of IVH between the two modes of delivery
[ 81-83 ]. A similar finding that the mode of delivery did not affect the incidence of IVH was reported in a review
of the Israeli National VLBW Infant Database of all very low birth weight (VLBW) infants born between 1995 and
2004 [ 84 ].

Systematic review of randomized controlled trials found that data were insufficient to determine whether or not
caesarean delivery reduces the risk of IVH in preterm infants [ 85,86 ].
CLINICAL PRESENTATION
Prenatal hemorrhage Prenatal IVH appears to be rare. In a report from Italy, six cases of intracranial hemorrhage were
detected among 6641 prenatal ultrasound examinations [ 87 ]. In a review of the literature, 35 additional case reports were
identified. These 41 cases were divided into three groups: isolated IVH (n = 20), parenchymal hemorrhage alone (n = 13), and
subdural or subarachnoid hemorrhage (n = 8). Overall outcome was poor.
Postnatal IVH
Manifestations IVH has three different presentations:

Silent presentation A clinically silent IVH without symptoms occurs in 25 to 50 percent of cases, with detection of
the hemorrhage by routine ultrasonographic screening [ 88 ]. (See 'Ultrasound screening' below.)

Saltatory or stuttering course is the most common presentation and evolves over hours to several days [ 89 ]. It is
characterized by nonspecific findings, including an altered level of consciousness, hypotonia, decreased
spontaneous and elicited movements, and subtle changes in eye position and movement. Respiratory function
sometimes is disturbed.

Catastrophic deterioration is the least common presentation and evolves over minutes to hours [89 ]. Signs include:
Stupor or coma
Irregular respirations, hypoventilation, or apnea
Decerebrate posturing
Generalized tonic seizures
Flaccid weakness
Cranial nerve abnormalities, including pupils fixed to light
Other features of the catastrophic presentation include a bulging anterior fontanelle, hypotension, bradycardia, a
falling hematocrit, metabolic acidosis, and inappropriate antidiuretic hormone secretion.
Timing Virtually all IVH in premature infants takes place within the first five postnatal days, with 50, 25, 15, and 10 percent
of cases occurring on the first, second, third, fourth, and fifth days of life, respectively [ 90 ]. In one series in which serial
ultrasound examinations were performed beginning shortly after birth in infants with birth weight <1750 g, IVH was detected

before one hour of age in 20 percent of patients [ 91 ]. IVH progressed over three to five days in approximately 20 to 40 percent
of cases [ 90 ]. Late IVH is associated with low cerebral blood flow, which may be due to low superior vena caval flow seen in
infants with large ductal shunts or hypotension [ 92-94 ].
Coexisting lesions In neuropathologic studies, IVH rarely is an isolated lesion [ 95 ]. The majority of infants who die more
than one week after IVH also have periventricular leukomalacia (PVL) or necrosis in the pons and the subiculum of the
hippocampus. (See "Periventricular leukomalacia" .)
DIAGNOSIS Cranial ultrasonography is generally used to diagnosis IVH. It is the preferred imaging modality because of its
high sensitivity for detecting acute hemorrhage, portability, and lack of ionizing radiation [ 90 ]. Coronal and parasagittal views
are obtained routinely to identify blood in the germinal matrix, ventricles, or cerebral parenchyma, and any other echogenic
abnormalities. Ultrasonography is able to accurately grade the severity of IVH based upon the location and extent of the IVH
( table 1 ) [3 ]. Grade I ( image 1 and image 2 ), grade II, and grades III ( image 3 ) and IV ( image 4 ) correspond to mild,
moderate, and severe IVH, respectively.
Ultrasound screening Because up to one-half of IVH cases are clinically silent, routine ultrasound screening should be
performed in premature infants. (See 'Manifestations' above.)
In our center, we follow the following recommendations published by the Quality Standards Subcommittee of the American
Academy of Neurology and the Practice Committee of the Child Neurology Society [ 96 ]:

Routine ultrasound screening should be performed on all infants with a gestational age less than 30 weeks.
Screening should be performed at 7 to 14 days of age and repeated at 36 to 40 weeks postmenstrual age (estimated
gestational age based upon completed weeks from the mother's last menstrual period).

Ultrasound screening should also be considered in infants with abnormal clinical signs, high severity of illness, or other
major risk factors.
This strategy is designed to detect clinically unsuspected IVH that may influence monitoring and management, as well as
periventricular leukomalacia (PVL) and/or ventriculomegaly, which provides prognostic information about neurodevelopmental
outcome. (See "Periventricular leukomalacia", section on 'Ultrasound' .)
IVH also occurs in preterm infants with birth gestation 30 to 34 weeks; for example, a study described IVH incidences between
3.3 and 6.3 percent in a group of 463 infants in this gestational range [ 97 ]. However, there is currently no specific guideline for
cranial ultrasound screening in these older preterm infants. As a result, clinical suspicion for IVH should be high for any preterm
infants with a gestational age 30 weeks who exhibit any subtle changes in neurologic or respiratory status, or who have
conditions associated with IVH, and a cranial ultrasound should be performed.
Other radiographic studies Computed tomography (CT) or magnetic resonance imaging (MRI) scans offer no significant
advantage as a routine screening tool to detect IVH or document ventricular size in comparison with cranial ultrasound. In
addition, the need to transport infants to the scanner, exposure to ionizing radiation (CT), and the requirement for nonmetallic
monitoring and support equipment and a long examination time (MRI) limit their usefulness in the neonatal setting. These
modalities are helpful, however, to document additional complicating lesions, including subdural or posterior fossa hemorrhages,
peripheral areas of infarction, or other parenchymal abnormalities. CT scanning is generally avoided now in newborns except for
emergencies (eg, neurosurgical emergency) when ultrasound or MRI is available.
Lumbar puncture If cranial ultrasonography is not available, lumbar puncture can assist in the diagnosis [ 3 ]. In IVH, the
cerebrospinal fluid (CSF) typically contains numerous red blood cells and a high protein concentration. The CSF becomes
xanthochromic several hours after the hemorrhage, and the glucose concentration may be reduced. (See "Lumbar puncture:
Indications, contraindications, technique, and complications in children" .)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to the
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Basics topics (see "Patient information: Intraventricular hemorrhage in newborns (The Basics)" )
SUMMARY AND RECOMMENDATIONS Intraventricular hemorrhage (IVH; also known
assubependymal/intraventricular hemorrhage) is an important cause of brain injury in premature infants.

IVH occurs most frequently in infants born <32 weeks gestation or with a birth weight <1500 g. The risk of IVH
increases with decreasing gestational age. Additional risk factors include chorioamnionitis, lack of prenatal
glucocorticoid therapy, prolonged neonatal resuscitation, and respiratory distress syndrome.
(See 'Epidemiology' above and 'Risk factors' above.)

In preterm infants, IVH generally originates from the germinal matrix, because of its structural fragility, which makes
it vulnerable to disturbances in cerebral blood flow (CBF). Preterm infants are particularly vulnerable to alterations
in CBF because of impaired cerebrovascular autoregulation, so that they are unable to sustain constant CBF with
changes in systemic blood. (See 'Pathogenesis' above.)

 The presentation of IVH can be clinically silent, saltatory, or catastrophic. A clinically silent syndrome occurs in 25 to
50 percent of cases but can be detected by routine ultrasonographic screening. Most IVH occurs within the first
five postnatal days. (See 'Clinical presentation' above.)

The diagnosis of IVH is made by cranial ultrasonography. The grading of the severity of IVH is based upon the location
and extent of the IVH ( table 1 ). (See 'Diagnosis' above.)

Because approximately one-half of IVH is clinically silent, we recommend ultrasound screening in premature infants
( Grade 1B ). All infants with gestational age <30 weeks or <1500 g birth weight should be initially screened with
ultrasound at 7 to 14 days with a repeat ultrasound at 36 to 40 weeks postmenstrual age. Clinical suspicion for
IVH should be high for any preterm infants with a gestational age 30 weeks who exhibit any subtle changes in
neurologic or respiratory status, or who have conditions associated with IVH, and a cranial ultrasound should be
performed. (See 'Diagnosis' above.)

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