Clinical manifestations and diagnosis of intraventricular hemorrhage in the newborn

Clinical manifestations and diagnosis of intraventricular hemorrhage in the newbornAuthor   Lisa M Adcock, MD   Section Editors   Joseph A Garcia-Prats, MD   Douglas R Nordli, Jr, MD   Deputy Editor   Melanie S Kim, MD   DisclosuresAll 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 two-thirds 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 [ 29-

32   ]. 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"   .)

INFORMATION FOR PATIENTS  — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the

Basics.” The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer

the four or five key questions a parent might have about a given condition. These articles are best for parents who want a

general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more

sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for parents who

want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to the

parents of your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info”

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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.)

REFERENCES

1. Owens R. Intraventricular hemorrhage in the premature neonate. Neonatal Netw 2005; 24:55. 2. Kenet G, Kuperman AA, Strauss T, Brenner B. Neonatal IVH--mechanisms and management. Thromb Res 2011; 127

Suppl 3:S120.

3. Volpe JJ. Intracranial hemorrhage: Germinal matrix-intraventricular hemorrhage. In: Neurology of the Newborn, 4th ed, WB Saunders, Philadelphia 2001. p.428.

4. Ghazi-Birry HS, Brown WR, Moody DM, et al. Human germinal matrix: venous origin of hemorrhage and vascular characteristics. AJNR Am J Neuroradiol 1997; 18:219.

5. Takashima S, Tanaka K. Microangiography and vascular permeability of the subependymal matrix in the premature infant. Can J Neurol Sci 1978; 5:45.

6. Lacey DJ, Terplan K. Intraventricular hemorrhage in full-term neonates. Dev Med Child Neurol 1982; 24:332.

7. Heibel M, Heber R, Bechinger D, Kornhuber HH. Early diagnosis of perinatal cerebral lesions in apparently normal full-term newborns by ultrasound of the brain. Neuroradiology 1993; 35:85.

8. Roland EH, Flodmark O, Hill A. Thalamic hemorrhage with intraventricular hemorrhage in the full-term newborn. Pediatrics 1990; 85:737.

9. Jain NJ, Kruse LK, Demissie K, Khandelwal M. Impact of mode of delivery on neonatal complications: trends between 1997 and 2005. J Matern Fetal Neonatal Med 2009; 22:491.

10. Philip AG, Allan WC, Tito AM, Wheeler LR. Intraventricular hemorrhage in preterm infants: declining incidence in the 1980s. Pediatrics 1989; 84:797.

11. Wilson-Costello D, Friedman H, Minich N, et al. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pediatrics 2005; 115:997.

12. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010; 126:443.

13. Bajwa NM, Berner M, Worley S, et al. Population based age stratified morbidities of premature infants in Switzerland. Swiss Med Wkly 2011; 141:w13212.

14. EXPRESS Group, Fellman V, Hellström-Westas L, et al. One-year survival of extremely preterm infants after active perinatal care in Sweden. JAMA 2009; 301:2225.

15. Amato M, Konrad D, Hüppi P, Donati F. Impact of prematurity and intrauterine growth retardation on neonatal hemorrhagic and ischemic brain damage. Eur Neurol 1993; 33:299.

16. Bartels DB, Kreienbrock L, Dammann O, et al. Population based study on the outcome of small for gestational age newborns. Arch Dis Child Fetal Neonatal Ed 2005; 90:F53.

17. Giapros V, Drougia A, Krallis N, et al. Morbidity and mortality patterns in small-for-gestational age infants born preterm. J Matern Fetal Neonatal Med 2012; 25:153.

18. Hayden CK Jr, Shattuck KE, Richardson CJ, et al. Subependymal germinal matrix hemorrhage in full-term neonates. Pediatrics 1985; 75:714.

19. Wu YW, Hamrick SE, Miller SP, et al. Intraventricular hemorrhage in term neonates caused by sinovenous thrombosis. Ann Neurol 2003; 54:123.

20. Tarantino MD, Gupta SL, Brusky RM. The incidence and outcome of intracranial haemorrhage in newborns with haemophilia: analysis of the Nationwide Inpatient Sample database. Haemophilia 2007; 13:380.

21. Volpe JJ. Intracranial hemorrhage: subdural, primary subarachnoid, cerebellar, intraventricular (term infant), and miscellaneous. In: Neurology of the Newborn, 5th ed, Saunders, Philadelphia 2008. p.483.

22. Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 2010; 67:1.

23. Sidman RL, Rakic P. Development of the human central nervous system. In: Histology and histopathology of the nervous system, Haymaker W, Adams RD (Eds), CC Thomas, Springfield, IL 1982. p.1.

24. Perlman JM. The relationship between systemic hemodynamic perturbations and periventricular-intraventricular hemorrhage--a historical perspective. Semin Pediatr Neurol 2009; 16:191.

25. Gould SJ, Howard S. Glial differentiation in the germinal layer of fetal and preterm infant brain: an immunocytochemical study. Pediatr Pathol 1988; 8:25.

26. Grunnet ML. Morphometry of blood vessels in the cortex and germinal plate of premature neonates. Pediatr Neurol 1989; 5:12.

27. Volpe JJ. Neuronal proliferation, migration, organization, and myelination. In: Neurology of the Newborn, 5th ed, Saunders, Philadelphia 2008. p.51.

28. Gould SJ, Howard S. An immunohistochemical study of the germinal layer in the late gestation human fetal brain. Neuropathol Appl Neurobiol 1987; 13:421.

29. Tsuji M, Saul JP, du Plessis A, et al. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 2000; 106:625.

30. O'Leary H, Gregas MC, Limperopoulos C, et al. Elevated cerebral pressure passivity is associated with prematurity- related intracranial hemorrhage. Pediatrics 2009; 124:302.

31. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood-flow velocity in respiratory-distress syndrome. Relation to the development of intraventricular hemorrhage. N Engl J Med 1983; 309:204.

32. Perlman JM, Goodman S, Kreusser KL, Volpe JJ. Reduction in intraventricular hemorrhage by elimination of fluctuating cerebral blood-flow velocity in preterm infants with respiratory distress syndrome. N Engl J Med 1985; 312:1353.

33. Soul JS, Hammer PE, Tsuji M, et al. Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants. Pediatr Res 2007; 61:467.

34. Bada HS, Korones SB, Perry EH, et al. Mean arterial blood pressure changes in premature infants and those at risk for intraventricular hemorrhage. J Pediatr 1990; 117:607.

35. Fanaroff AA, Fanaroff JM. Short- and long-term consequences of hypotension in ELBW infants. Semin Perinatol 2006; 30:151.

36. Been JV, Degraeuwe PL, Kramer BW, Zimmermann LJ. Antenatal steroids and neonatal outcome after chorioamnionitis: a meta-analysis. BJOG 2011; 118:113.

37. Soraisham AS, Singhal N, McMillan DD, et al. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 2009; 200:372.e1.

38. Kasper DC, Mechtler TP, Böhm J, et al. In utero exposure to Ureaplasma spp. is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants. J Perinat Med 2011; 39:331.

39. Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997; 42:1.

40. Verma U, Tejani N, Klein S, et al. Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 1997; 176:275.

41. Zanardo V, Vedovato S, Suppiej A, et al. Histological inflammatory responses in the placenta and early neonatal brain injury. Pediatr Dev Pathol 2008; 11:350.

42. Furukawa S, Sameshima H, Ikenoue T. Circulatory disturbances during the first postnatal 24 hours in extremely premature infants 25 weeks or less of gestation with histological fetal inflammation. J Obstet Gynaecol Res 2008; 34:27.

43. Hutzal CE, Boyle EM, Kenyon SL, et al. Use of antibiotics for the treatment of preterm parturition and prevention of neonatal morbidity: a metaanalysis. Am J Obstet Gynecol 2008; 199:620.e1.

44. Palta M, Sadek-Badawi M, Carlton DP. Association of BPD and IVH with early neutrophil and white counts in VLBW neonates with gestational age <32 weeks. J Perinatol 2008; 28:604.

45. Kassal R, Anwar M, Kashlan F, et al. Umbilical vein interleukin-6 levels in very low birth weight infants developing intraventricular hemorrhage. Brain Dev 2005; 27:483.

46. Harding DR, Dhamrait S, Whitelaw A, et al. Does interleukin-6 genotype influence cerebral injury or developmental progress after preterm birth? Pediatrics 2004; 114:941.

47. Lee BH, Stoll BJ, McDonald SA, et al. Adverse neonatal outcomes associated with antenatal dexamethasone versus antenatal betamethasone. Pediatrics 2006; 117:1503.

48. Elimian A, Garry D, Figueroa R, et al. Antenatal betamethasone compared with dexamethasone (betacode trial): a randomized controlled trial. Obstet Gynecol 2007; 110:26.

49. Shankaran S, Bauer CR, Bain R, et al. Prenatal and perinatal risk and protective factors for neonatal intracranial hemorrhage. National Institute of Child Health and Human Development Neonatal Research Network. Arch Pediatr Adolesc Med 1996; 150:491.

50. Rumack CM, Guggenheim MA, Rumack BH, et al. Neonatal intracranial hemorrhage and maternal use of aspirin. Obstet Gynecol 1981; 58:52S.

51. Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2004; :CD004659.

52. Fabres J, Carlo WA, Phillips V, et al. Both extremes of arterial carbon dioxide pressure and the magnitude of fluctuations in arterial carbon dioxide pressure are associated with severe intraventricular hemorrhage in preterm infants. Pediatrics 2007; 119:299.

53. Funato M, Tamai H, Noma K, et al. Clinical events in association with timing of intraventricular hemorrhage in preterm infants. J Pediatr 1992; 121:614.

54. Goldberg RN, Chung D, Goldman SL, Bancalari E. The association of rapid volume expansion and intraventricular hemorrhage in the preterm infant. J Pediatr 1980; 96:1060.

55. Aly H, Hammad TA, Essers J, Wung JT. Is mechanical ventilation associated with intraventricular hemorrhage in preterm infants? Brain Dev 2012; 34:201.

56. Wallin LA, Rosenfeld CR, Laptook AR, et al. Neonatal intracranial hemorrhage: II. Risk factor analysis in an inborn population. Early Hum Dev 1990; 23:129.

57. Mohamed MA, Aly H. Transport of premature infants is associated with increased risk for intraventricular haemorrhage. Arch Dis Child Fetal Neonatal Ed 2010; 95:F403.

58. Goddard-Finegold J. Pharmacologic prevention of intraventricular hemorrhage. In: Current Topics in Neonatology, Hansen TN, McIntosh N (Eds), WB Saunders, Philadelphia 1997. p.170.

59. Papile LA, Burstein J, Burstein R, et al. Relationship of intravenous sodium bicarbonate infusions and cerebral intraventricular hemorrhage. J Pediatr 1978; 93:834.

60. Miller SS, Lee HC, Gould JB. Hypothermia in very low birth weight infants: distribution, risk factors and outcomes. J Perinatol 2011; 31 Suppl 1:S49.

61. Audeh S, Smolkin T, Bental Y, et al. Does admission hypothermia predispose to intraventricular hemorrhage in very-low-birth-weight infants? Neonatology 2011; 100:373.

62. Hill A, Perlman JM, Volpe JJ. Relationship of pneumothorax to occurrence of intraventricular hemorrhage in the premature newborn. Pediatrics 1982; 69:144.

63. Mehrabani D, Gowen CW Jr, Kopelman AE. Association of pneumothorax and hypotension with intraventricular haemorrhage. Arch Dis Child 1991; 66:48.

64. Bhatia R, Davis PG, Doyle LW, et al. Identification of pneumothorax in very preterm infants. J Pediatr 2011; 159:115.

65. von Lindern JS, van den Bruele T, Lopriore E, Walther FJ. Thrombocytopenia in neonates and the risk of intraventricular hemorrhage: a retrospective cohort study. BMC Pediatr 2011; 11:16.

66. Setzer ES, Webb IB, Wassenaar JW, et al. Platelet dysfunction and coagulopathy in intraventricular hemorrhage in the premature infant. J Pediatr 1982; 100:599.

67. Salonvaara M, Riikonen P, Kekomäki R, et al. Intraventricular haemorrhage in very-low-birthweight preterm infants: association with low prothrombin activity at birth. Acta Paediatr 2005; 94:807.

68. Lupton BA, Hill A, Whitfield MF, et al. Reduced platelet count as a risk factor for intraventricular hemorrhage. Am J Dis Child 1988; 142:1222.

69. Shirahata A, Nakamura T, Shimono M, et al. Blood coagulation findings and the efficacy of factor XIII concentrate in premature infants with intracranial hemorrhages. Thromb Res 1990; 57:755.

70. Bassan H. Intracranial hemorrhage in the preterm infant: understanding it, preventing it. Clin Perinatol 2009; 36:737.

71. Bhandari V, Bizzarro MJ, Shetty A, et al. Familial and genetic susceptibility to major neonatal morbidities in preterm twins. Pediatrics 2006; 117:1901.

72. Härtel C, König I, Köster S, et al. Genetic polymorphisms of hemostasis genes and primary outcome of very low birth weight infants. Pediatrics 2006; 118:683.

73. Petäjä J, Hiltunen L, Fellman V. Increased risk of intraventricular hemorrhage in preterm infants with thrombophilia. Pediatr Res 2001; 49:643.

74. Komlósi K, Havasi V, Bene J, et al. Increased prevalence of factor V Leiden mutation in premature but not in full- term infants with grade I intracranial haemorrhage. Biol Neonate 2005; 87:56.

75. Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 2005; 308:1167.

76. de Vries LS, Koopman C, Groenendaal F, et al. COL4A1 mutation in two preterm siblings with antenatal onset of parenchymal hemorrhage. Ann Neurol 2009; 65:12.

77. Göpel W, Härtel C, Ahrens P, et al. Interleukin-6-174-genotype, sepsis and cerebral injury in very low birth weight infants. Genes Immun 2006; 7:65.

78. Svenningsen L, Lindemann R, Eidal K. Measurements of fetal head compression pressure during bearing down and their relationship to the condition of the newborn. Acta Obstet Gynecol Scand 1988; 67:129.

79. Deulofeut R, Sola A, Lee B, et al. The impact of vaginal delivery in premature infants weighing less than 1,251 grams. Obstet Gynecol 2005; 105:525.

80. Dani C, Poggi C, Bertini G, et al. Method of delivery and intraventricular haemorrhage in extremely preterm infants. J Matern Fetal Neonatal Med 2010; 23:1419.

81. Paul DA, Sciscione A, Leef KH, Stefano JL. Caesarean delivery and outcome in very low birthweight infants. Aust N Z J Obstet Gynaecol 2002; 42:41.

82. Haque KN, Hayes AM, Ahmed Z, et al. Caesarean or vaginal delivery for preterm very-low-birth weight (< or =1,250 g) infant: experience from a district general hospital in UK. Arch Gynecol Obstet 2008; 277:207.

83. Durie DE, Sciscione AC, Hoffman MK, et al. Mode of delivery and outcomes in very low-birth-weight infants in the vertex presentation. Am J Perinatol 2011; 28:195.

84. Riskin A, Riskin-Mashiah S, Bader D, et al. Delivery mode and severe intraventricular hemorrhage in single, very low birth weight, vertex infants. Obstet Gynecol 2008; 112:21.

85. Alfirevic Z, Milan SJ, Livio S. Caesarean section versus vaginal delivery for preterm birth in singletons. Cochrane Database Syst Rev 2012; 6:CD000078.

86. Alfirevic Z, Milan SJ, Livio S. Caesarean section versus vaginal delivery for preterm birth in singletons. Cochrane Database Syst Rev 2012; 6:CD000078.

87. Vergani P, Strobelt N, Locatelli A, et al. Clinical significance of fetal intracranial hemorrhage. Am J Obstet Gynecol 1996; 175:536.

88. Lazzara A, Ahmann P, Dykes F, et al. Clinical predictability of intraventricular hemorrhage in preterm infants. Pediatrics 1980; 65:30.

89. Tarby TJ, Volpe JJ. Intraventricular hemorrhage in the premature infant. Pediatr Clin North Am 1982; 29:1077.

90. Volpe JJ. Intracranial hemorrhage: Germinal matrix-intraventricular hemorrhage. In: Neurology of the Newborn, 5th ed, Saunders, Philadelphia 2008. p.517.

91. Shaver DC, Bada HS, Korones SB, et al. Early and late intraventricular hemorrhage: the role of obstetric factors. Obstet Gynecol 1992; 80:831.

92. Kluckow M, Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000; 82:F188.

93. Evans N, Kluckow M. Early ductal shunting and intraventricular haemorrhage in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed 1996; 75:F183.

94. Ment LR, Ehrenkranz RA, Duncan CC, Lange RC. Delayed hemorrhagic infarction. A cause of late neonatal germinal matrix and intraventricular hemorrhage. Arch Neurol 1984; 41:1036.

95. Armstrong DL, Sauls CD, Goddard-Finegold J. Neuropathologic findings in short-term survivors of intraventricular hemorrhage. Am J Dis Child 1987; 141:617.

96. Ment LR, Bada HS, Barnes P, et al. Practice parameter: neuroimaging of the neonate: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002; 58:1726.

97. Bhat V, Karam M, Saslow J, et al. Utility of performing routine head ultrasounds in preterm infants with gestational age 30-34 weeks. J Matern Fetal Neonatal Med 2012; 25:116.

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