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Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis

Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis
Literature review current through: Sep 2023.
This topic last updated: Jun 15, 2023.

INTRODUCTION — Germinal matrix and intraventricular hemorrhage (GMH-IVH; also referred to as simply IVH) is an important cause of brain injury in preterm infants. Although the incidence has declined since the 1980s, GMH-IVH remains a significant problem, as improved survival of extremely preterm infants has resulted in a greater number of survivors with this condition [1-3].

The epidemiology, pathogenesis, clinical presentation, and diagnosis of GMH-IVH are discussed in this topic review. The management, complications, and outcome of GMH-IVH in the newborn are discussed separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)

PATHOGENESIS

Preterm infants

Origin of bleeding

GMH-IVH – In preterm infants, the origin of bleeding is generally in small blood vessels in the germinal matrix (GM, also termed the ganglionic eminence), located between the caudate nucleus and the thalamus at the level of the foramen of Monro. Neuropathologic studies suggest that the hemorrhage is primarily within the capillary network that freely communicates with the venous system, although bleeding can also occur within the arterial circulation. Vessels in the GM 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 [4]. Bleeding can disrupt the ependymal lining and extend into the lateral ventricle.

Periventricular hemorrhagic infarction (PVHI) – PVHI (previously referred to as grade IV IVH) is due to infarction caused by impaired venous drainage of the medullary veins in the white matter after GMH-IVH [5-7]. The circulatory disturbance occurs in the subependymal region where the medullary veins drain into the terminal vein [8].

PVHI most often involves the parietal and frontal cerebral areas, and in 10 to 15 percent of infants, PVHIs are bilateral [7,9]. Depending on the site of the lesion, PVHI may result in the destruction of the motor and associative white matter axons and may evolve into a single or multiple white matter cysts, which may become confluent with the lateral ventricle (image 1 and image 2) [5]. Depending on the site of the lesion, affected infants are at risk of developing cerebral palsy (eg, spastic hemiparesis if there is unilateral involvement or asymmetric spastic quadriparesis if there is bilateral involvement) [10,11]. In addition, affected infants often have intellectual deficits [7,12]. (See "Cerebral palsy: Epidemiology, etiology, and prevention", section on 'Prematurity'.)

Coexisting lesions — In neuropathologic studies, severe GMH-IVH rarely is an isolated lesion. Most infants who die more than one week after GMH-IVH onset also have associated white matter injury (cystic periventricular leukomalacia [c-PVL]) or necrosis in the pons and the subiculum of the hippocampus.

GMH-IVH is an independent risk factor for white matter injury in very preterm infants born at <28 weeks' gestation [13]. (See 'White matter injury' below.)

Hemorrhages in the cerebellum also often coexist. (See "Neonatal cerebellar hemorrhage".)

Contributing physiologic factors — Physiologic factors that contribute to the pathogenesis of GMH-IVH in preterm infants include fragility of the vessels in the GM from a lack of structural support due to immaturity and instability of cerebral blood flow (CBF) [14]. CBF instability includes disturbances related to hypoxia-ischemia and reperfusion, elevated arterial blood flow, elevated venous pressure, and impaired cerebral autoregulation.

Germinal matrix fragility – In preterm infants, GMH-IVH generally originates within the GM; the highly cellular and richly vascularized layer in the subependymal and the subventricular zone that gives rise to neurons and glia during fetal development. As the fetus matures, the GM begins to involute starting at 28 weeks gestation as its cellularity and vascularity decrease, and by term, it is generally absent [15].

In preterm infants, a deficient structural support system makes the GM vulnerable to hemorrhage and injury, especially when there is hemodynamic instability. Within the GM, the capillary network consists of numerous thin-walled, large blood vessels that lack structural support and are highly metabolically active [4]. The microvasculature of the GM is particularly delicate because of the abundance of angiogenic blood vessels with a paucity of pericytes, immature basal lamina, and deficiency of tight junctions and glial fibrillary acidic protein in the astrocyte end-feet. In more immature infants, there are also fewer glial fibers, a structural component for blood vessels that normally develops with increasing maturation [4].

The 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 congestion and stasis, resulting in increased cerebral venous pressure (CVP), which contributes to GMH-IVH [4]. Magnetic resonance susceptibility-weighted imaging (SWI) venography demonstrated features of the subependymal venous system that may predispose to GMH-IVH in the preterm infant, including a narrower curvature of the veins in the thalamus compared with term infants [16].

CBF instability – Fluctuations in CBF in preterm infants are associated with GMH-IVH [4,17,18]. Preterm infants are particularly vulnerable to alterations in CBF because they have impaired autoregulation of CBF compared with term infants. This impairment results in a pressure-passive circulation, in which the infant cannot sustain constant CBF during changes in systemic blood pressure [19,20]. As a result, increases or decreases in systemic blood pressure are reflected by similar changes in CBF, leading to injury of the fragile blood vessels of the GM.

Other factors that have been implicated in CBF fluctuations that can lead to GMH-IVH include anemia, hypercarbia, acidemia, hypoglycemia, asphyxia, and abrupt elevations in systemic blood pressure (due to noxious stimuli, rapid volume expansion with fluid boluses, and seizures).

The association of impaired autoregulation with GMH-IVH was demonstrated in studies of preterm infants that monitored mean arterial pressure (MAP) and CBF using near-infrared spectroscopy (NIRS) [17,18,21]. In these studies, cerebral hyperperfusion and loss of autoregulation (based on concordant changes in CBF and MAP) correlated with increased risk of severe GMH-IVH. The risk of GMH-IVH in these studies correlated more strongly with impaired cerebral autoregulation as measured by both NIRS and MAP compared with MAP variations alone.

Another novel technique for assessing impaired CBF regulation is diffuse correlation spectroscopy (DSC), which can monitor CBF continuously. Using this technique, loss of cerebral autoregulation was noted in preterm infants who developed early-onset severe IVH [22].

Term infants

Causes — Causes of IVH in term infants include [23]:

Trauma during delivery. (See "Neonatal birth injuries", section on 'Intraventricular hemorrhage'.)

Hypoxic-ischemic encephalopathy (HIE). In a study of 157 term infants with HIE, brain magnetic resonance imaging (MRI) performed in 138 infants demonstrated subdural hemorrhage in almost half of the cohort (47 percent) and intraparenchymal hemorrhage in approximately one-quarter (22 percent) [24]. The risk of intraparenchymal hemorrhage was highest in infants receiving inotropes. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Neuroimaging'.)

Coagulation or platelet abnormalities (alloimmune thrombocytopenia, hemophilia [25], genetic mutations of other hemostatic genes). (See 'Genetic factors' below and "Clinical manifestations and diagnosis of hemophilia", section on 'Initial presentation' and "Neonatal thrombocytopenia: Etiology".)

Therapeutic hypothermia during extracorporeal membrane oxygenation (ECMO) [26].

Sinovenous thrombosis (particularly in infants with thalamic involvement) [27].

Rare causes include:

Gene mutations of the collagen genes (COL4A1 and COL4A2), tight junction protein (JAM3), or genes related to coagulopathy. (See 'Genetic factors' below.)

Rupture of a vascular malformation [28-30].

Sites of bleeding — The origin and location of IVH in term infants differs from that of preterm infants. The following are the relative frequency of the location and origin of IVH in term infants [23,27]:

35 percent choroid plexus

24 percent thalamus

17 percent GM

14 percent periventricular cerebral parenchyma

10 percent no origin determined

EPIDEMIOLOGY — GMH-IVH occurs predominantly in very low birth weight (VLBW; <1500 g) infants and/or very preterm infants (gestational age [GA] <32 weeks). The incidence increases with decreasing gestational GA and birth weight. Although prematurity is the predominant risk factor, there are additional factors that impact the risk of GMH-IVH, such as antenatal glucocorticoid therapy (which has a protective effect) and neonatal transport (which increases the risk).

Incidence

Prenatal hemorrhage — Prenatal GMH-IVH is rare [31,32]. A systematic review of the literature identified 240 cases of prenatal GMH-IVH in the published literature from 1980 to 2019 [32]. Approximately 10 percent were mild (grade I/II), 40 percent were grade III, and 44 percent were PVHI (grade IV IVH); the remaining cases were not classified.

Term newborns — Intracranial hemorrhages (including epidural, subdural, subarachnoid, intraventricular, and intraparenchymal) are uncommon in term neonates, with reported incidence rates ranging from 2.7 to 4.9 per 10,000 live births [33-35].

Preterm infants — The risk of GMH-IVH increases with decreasing GA. Reported incidence rates among all infants <32 weeks GA range from 15 to 25 percent [36-38]. Most of these represent mild GMH-IVH (ie, grade I-II). Reported incidence rates of severe GMH-IVH (ie, grade III or greater) according to GA are as follows [36-42]:

GA 22 to 23 weeks – 30 to 45 percent

GA 24 to 25 weeks – 18 to 26 percent

GA 26 to 27 weeks – 7 to 14 percent

GA 28 to 29 weeks – 3 to 6 percent

GA 30 to 32 weeks – 0.5 to 2 percent

Trends over time — Rates of severe GMH-IVH have declined over time [36-38]. For example, in a study from the California Perinatal Collaborative, rates of severe GMH-IVH among infants <32 weeks GA declined from 9.7 percent in 2005 to 5.9 percent in 2015 [37]. Similar findings were reported in a study from the Australian and New Zealand Neonatal Network [38]. The factor most strongly associated with the reduction in severe GMH-IVH in these studies was maternal antenatal glucocorticoid administration. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

Risk factors other than GA — In addition to decreasing GA, the following prenatal, perinatal, postnatal, and genetic factors may impact the risk of GMH-IVH.

Prenatal factors

Protective role of antenatal glucocorticoid therapy – Antenatal steroid therapy for mothers at high risk of preterm delivery has repeatedly been shown to decrease the risk of GMH-IVH [43-47]. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery", section on 'Evidence of efficacy'.)

Maternal chorioamnionitis – Data are conflicting regarding whether chorioamnionitis increases the risk of GMH-IVH. Some studies have found an association [48-53], while others have not [54,55]. A contributory role for maternal inflammation is supported by several studies that have shown an association between GMH-IVH and increased cytokine production and release (used as a biomarker for inflammation), and/or histologic evidence of inflammation [50-52,56,57]. (See "Clinical chorioamnionitis", section on 'Perinatal outcome'.)

Maternal hypertensive disorders of pregnancy – Data are conflicting regarding the risk of GMH-IVH in preterm infants born to mothers with preeclampsia or HELLP syndrome (hemolysis with a microangiopathic blood smear, elevated liver enzymes, and a low platelet count) [58-61]. (See "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)

Several retrospective studies have reported that GMH-IVH is increased in newborns of mothers with severe preeclampsia and HELLP syndrome compared with mothers with normal blood pressure [59-61].

In contrast, multicenter studies reported a significant decreased risk of GMH-IVH if preeclampsia was present prior to birth [58] and if there was maternal hypertension during pregnancy [62].

In utero exposure to maternal medications

Indomethacin – In a meta-analysis of observational studies, maternal indomethacin use was associated with increased risk of severe IVH but not the overall risk of GMH-IVH [63].

No effect of low-dose aspirin – In a meta-analysis of clinical trials evaluating antiplatelet agents (primarily low-dose aspirin) for prevention of preeclampsia, the rate of GMH-IVH was not different between the treatment and control group (relative risk [RR] 0.88, 95% CI 0.63-1.22) [64].

Perinatal factors

Mode of delivery – During labor and vaginal delivery, compression of the infant's head by the uterus increases central venous pressure (CVP), which theoretically could promote GMH-IVH [4]. However, most of the available data suggest that the risk of GMH-IVH is not impacted by active labor or mode of delivery [65-72], with only a few studies reporting increased risk of GMH-IVH with vaginal birth [73,74].

Delayed cord clamping – Delayed cord clamping does not appear to reduce the risk of GMH-IVH [75-78]. Nevertheless, delayed cord clamping in stable preterm infants is recommended for its potential associated benefits. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Early versus delayed cord clamping'.)

Cord milking – Cord milking or stripping the umbilical cord is associated with an increased risk of severe GMH-IVH in preterm infants (GA 23 to 27 weeks) [79,80]. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Cord milking'.)

Postnatal factors

Neonatal transport – Infants who require transport to receive appropriate neonatal care are more likely to develop GMH-IVH [81-84].

Hemodynamic instability – Hypotension, rapid increases in blood pressure, receiving inotropic medications, and receiving cardiopulmonary resuscitation are associated with increased risk of GMH-IVH and of severe IVH in preterm infants [39,85-91]. (See "Assessment and management of low blood pressure in extremely preterm infants".)

Respiratory distress, mechanical ventilation, and pneumothorax – Respiratory distress with episodes of hypocapnia, hypercapnia, hypoxia, and/or acidemia are associated with increased risk of GMH-IVH [92-96]. These factors are thought to be associated with fluctuations in cerebral blood flow (CBF), elevated CVP and severe hypoxemia [96,97]. Intubation and mechanical ventilation may also contribute to fluctuations in CBF and increased CVP and are associated with increased risk of GMH-IVH [39,98-101]. The risk is increased if multiple intubation attempts are required, high tidal volumes are used, or if there are large fluctuations in end-tidal carbon dioxide. Several reports have shown an association between pneumothorax and GMH-IVH, postulated to be related to increased CVP [102,103].

Bicarbonate therapy – Bicarbonate may theoretically increase the risk of GMH-IVH, due to hyperosmolarity that may alter CBF [104].

Hypothermia – Hypothermia following birth has been linked to increased risk of GMH-IVH in some studies [105], but not others [106]. Different definitions of hypothermia, size of study groups, and study design may explain conflicting results.

Coagulation and platelet abnormalities – Thrombocytopenia and coagulation disorders are common in preterm infants, especially critically ill neonates with other risk factors for GMH-IVH. While severe coagulation abnormalities may contribute to worsening GMH-IVH once it has occurred, milder abnormalities are likely not causal in most cases [107-114]. In particular, failure of prophylactic plasma transfusions to prevent GMH-IVH raises questions about a causal relationship [6,115]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Supportive care' and "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management".)

Other potential risk factors

Off-peak delivery (delivery between midnight and 7 AM) has been reported to be an independent risk factor for severe IVH in some studies [116]. This may reflect a poorer quality of resuscitation efforts during this time period resulting in an increased risk of GMH-IVH. Other studies were unable to confirm this difference [117,118], provided that there was a dedicated neonatal team present at birth.  

Low initial hematocrit (<45 percent) has been reported to be associated with increased risk of periventricular hemorrhage and IVH in extremely low birth weight infants (birth weight <1000 grams) [119]. The proposed mechanism is that early anemia is associated with lower intravascular volume which contributes to cerebral hypoperfusion.

Genetic factors — There are conflicting reports on whether mutations of hemostatic genes (factor V Leiden, prothrombin G20210A, factors VII and XIII) predispose preterm infants to GMH-IVH [120-122]. If there is an association, these are likely to be of lesser importance than the clinical risk factors discussed above. Other genetic variants that have been reported to be associated with risk of neonatal GMH-IVH include mutations in collagen genes (COL4A1 and COL4A2), inflammatory genes (eg, interleukin IL-6), and tight junction protein (JAM3) [28,30,56,123-126].

CLINICAL FEATURES

Timing — Virtually all GMH-IVHs in preterm infants occur within the first few days after birth; most occur within 24 hours after birth [127-130].

In approximately 20 to 40 percent of cases, there is further progression of the hemorrhage over the next three to five days [4].

Presentation — GMH-IVH in the preterm neonate has three distinct presentations [4]:

Silent presentation – A clinically silent GMH-IVH without clinical symptoms occurs in 25 to 50 percent of cases and is detected by routine cranial ultrasound screening. (See 'Screening' below.)

Saltatory or stuttering course is the most common presentation and evolves over hours to several days. It is characterized by nonspecific findings including:

Altered level of consciousness

Hypotonia

Decreased spontaneous and elicited movements

Subtle changes in eye position and movement

Alterations in the respiratory pattern, though this finding may be absent

Catastrophic deterioration is the least common presentation and evolves over minutes to hours. Signs may include:

Stupor or coma

Irregular respirations, hypoventilation, or apnea

Decerebrate posturing

Generalized seizures

Flaccid weakness

Cranial nerve abnormalities, including nonreactive pupils

Bulging anterior fontanelle

Other findings may include hypotension, bradycardia, a falling hematocrit/hemoglobin, metabolic acidosis, and inappropriate antidiuretic hormone secretion.

Cerebrospinal fluid findings — Lumbar puncture (LP) is not a routine part of the evaluation for GMH-IVH, though LP may be performed in the management of the complications of GMH-IVH (ie, posthemorrhagic ventricular dilation), as discussed separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Interventions for CSF drainage'.)

In some cases, LP may be performed earlier in the newborn period for other reasons (eg, sepsis evaluation) and the cerebrospinal fluid (CSF) findings may suggest IVH. The following CSF findings are suggestive of IVH:

Elevated CSF red blood cells (RBC) count

High CSF protein concentration

Several hours after the hemorrhage, the CSF becomes xanthochromic and the glucose concentration may be reduced

These findings are not sufficient to make the diagnosis since high CSF RBC count and protein can also occur in the setting of central nervous system infection or traumatic LP. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Interpretation of cerebrospinal fluid'.)

Ultimately, cranial ultrasonography is required to make the diagnosis of GMH-IVH, as discussed below. (See 'Cranial ultrasound' below.)

Of note, in neonates with findings that are concerning for elevated intracranial pressure (eg, asymmetric pupils, bulging fontanelle, markedly depressed mental status), cranial ultrasonography should generally be obtained before performing LP. In some cases, there may be findings on ultrasound that would make it unsafe to perform LP (eg, significant ventricular dilatation with a large third and small fourth ventricle, which suggests aqueductal stenosis). (See "Hydrocephalus in children: Physiology, pathogenesis, and etiology", section on 'Isolated hydrocephalus'.)

SCREENING — Because up to one-half of GMH-IVH cases are clinically silent, we suggest routine screening with cranial ultrasound for all preterm infants <32 weeks gestational age (GA).

The optimal timing for the initial ultrasound and frequency of follow-up scans is uncertain, and published guidelines vary [131,132].

The authors' practice is to use the following schedule for performing screening ultrasounds, which is based upon the infant's GA, clinical course, and other comorbidities:

<28 weeks GA – For infants born at <28 weeks GA, we suggest performing routine screening at the following intervals:

Once on the day of admission

Then two to three times during the first week

Then weekly until 34 weeks postmenstrual age (PMA)

Then every two weeks

One scan is performed at discharge or at term-equivalent age (TEA)

28 to <32 weeks GA – For infants born at 28 to 32 weeks GA, the schedule is as follows:

Once on the day of admission

Once on day 4 to 7

Then weekly until 34 weeks PMA

Then one scan at discharge or at TEA

≥32 weeks GA – GMH-IVH is far less common in preterm infants born at GA ≥32 weeks compared with more premature infants and thus routine screening is generally not necessary for these infants [133,134]. However, GMH-IVH can occur in these patients and cranial ultrasound should be performed if there is clinical suspicion for GMH-IVH or if there are clinical circumstances that place the neonate at high risk for GMH-IVH (eg, following cardiopulmonary resuscitation).

Reasons for more frequent surveillance – Follow-up ultrasounds should be performed in the following circumstances:

If severe GMH-IVH (ie, grade III or periventricular hemorrhagic infarction [PVHI]) is detected on screening ultrasonography, we suggest performing serial ultrasounds at least twice weekly to monitor for posthemorrhagic ventricular dilation (PHVD). (See 'Serial monitoring' below.)

After any acute clinical deterioration (eg, sepsis, necrotizing enterocolitis, surgery, significant increase in apneas, sudden drop in hemoglobin/hematocrit).

If the infant has abnormal clinical findings suggestive of GMH-IVH. (See 'Presentation' above.)

Infants with other congenital or acquired brain lesions may warrant more frequent ultrasound monitoring.

Other institutions may use different schedules for performing cranial ultrasound screening. For example, few North American centers use the approach outlined above.

The rationale for routine screening is that it allows early detection and, if needed, early intervention for treatment of complications such as PHVD. Screening also facilitates diagnosis of white matter injury. (See 'Posthemorrhagic ventricular dilatation (PHVD)' below and 'White matter injury' below.)

Guidelines from various pediatric societies, including the American Academy of Pediatrics (AAP) and the Canadian Paediatric Society (CPS), support the practice of routine ultrasound screening in preterm neonates [131,132]. However, the schedule of screening in these guidelines is later and less frequent than the approach outlined above. The approaches endorsed by the AAP and CPS are less likely to facilitate early detection of PHVD [135]. We favor earlier and more frequent screening because optimal management of PHVD depends on early detection prior to the onset of clinical symptoms of increased intracranial pressure (ICP). (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Management of PHVD'.)

DIAGNOSIS

Cranial ultrasound — The diagnosis of GMH-IVH is confirmed with cranial ultrasonography. Ultrasound is the preferred imaging modality because of its high sensitivity for detecting acute GMH-IVH, its ease of use and portability (bedside imaging), and lack of ionizing radiation [4,136].

Standard cranial ultrasonographic screening should include views from the anterior and mastoid fontanelles [131]. Additional posterior fontanelle and vascular imaging can be performed for additional information. Coronal and parasagittal ultrasound views can identify blood in the germinal matrix (GM), ventricles, or cerebral parenchyma, and any other moderate to severe periventricular white matter abnormalities.

However, cranial ultrasound is less sensitive than MRI in identifying low-grade GMH-IVH and subtle lesions in the white matter and cerebellum [137]. (See 'Other radiographic studies' below.)

Grading of severity — The severity of hemorrhage on ultrasonography is graded based upon the location and extent of the GMH-IVH and presence of lateral ventricular dilatation (table 1):

Grade I – Either:

Bleeding is confined to the germinal matrix (ie, GMH only) (image 3), or

GMH plus IVH occupying <10 percent of the lateral ventricular area

Grade II – IVH that occupies 10 to 50 percent of the lateral ventricle area (image 4)

Grade III – IVH that occupies >50 percent of the lateral ventricle area and is associated with acute ventricular dilatation (image 5)

Periventricular hemorrhagic infarction (PVHI; previously referred to as Grade IV IVH) – Hemorrhagic infarction in periventricular white matter ipsilateral to large IVH (image 1 and image 2)

Each grade of GMH-IVH may be unilateral or bilateral, with either symmetric or asymmetric grades of GMH-IVH. "Low-grade" or "mild" GMH-IVH refers to grades I and II and "severe" refers to grades III and PVHI (grade IV). Infants with severe GMH-IVH are at considerably higher risk of neurodevelopmental disabilities than infants with milder GMH-IVH. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Outcome'.)

Additional ischemic lesions in the white matter and hemorrhages in the cerebellum, which are not always visible with ultrasound, should be mentioned separately as they are not covered in this grading system and can have consequences for neurodevelopmental outcomes. (See "Neonatal cerebellar hemorrhage" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Long-term neurodevelopmental outcomes'.)

Other radiographic studies

MRI can identify small GMH-IVH in the temporal and occipital GM, which ultrasound may not identify [138]. MRI can also identify additional white matter lesions, cerebellar hemorrhages, subdural or posterior fossa hemorrhages, and peripheral areas of infarction [136,139]. However, many critically ill preterm infants are not stable enough to travel to the MRI suite during the first few days after birth. In addition, nonmetallic monitoring and support equipment appropriate for newborn infants is required. As a result, MRI is not the initial preferred diagnostic imaging modality.

Computed tomography does not play a role in the evaluation of GMH-IVH and is rarely used in neonatal care in general. This is because it requires transport out of the neonatal intensive care unit and it exposes the neonate to ionizing radiation.

ACUTE COMPLICATIONS

Posthemorrhagic ventricular dilatation (PHVD) — Posthemorrhagic ventricular dilatation (PHVD), also referred to as posthemorrhagic hydrocephalus (PHH), is the major acute complication of severe GMH-IVH (ie, grade III or periventricular hemorrhagic infarction [PVHI]) (image 6A-C). Of note, it is important to differentiate PHVD from the acute ventricular distension that is seen in grade III IVH related to the volume of blood in the ventricle (image 5). (See 'Grading of severity' above.)

PHVD is associated with increased risk of mortality and neurodevelopmental impairment (NDI) [7,140,141]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Long-term neurodevelopmental outcomes'.)

PHVD is thought to be caused by impaired reabsorption of the cerebrospinal fluid (CSF) due to inflammation of the subarachnoid villi by blood [4,141,142]. Transforming growth factor beta one (TGF-B1), one of the inflammatory factors, stimulates the production of extracellular matrix, which causes scarring and obstruction of arachnoid villi [143-145]. This results in communicating hydrocephalus, in which the entire ventricular system is dilated. Less frequently, infants can have noncommunicating hydrocephalus due to obstruction by a clot or scarring within the ventricular system, most often at the level of the aqueduct. (See "Hydrocephalus in children: Physiology, pathogenesis, and etiology", section on 'Pathogenesis'.)

Risk factors for PHVD — The risk of PHVD increases with the severity of GMH-IVH, decreasing gestational age (GA), and greater severity of illness [4,146,147]. It most commonly occurs in infants with grade III IVH or PVHI (previously called grade IV IVH) [7,147-150]. In a study that included nearly 150,000 preterm infants with GMH-IVH, the risk of PHVD within each severity category was as follows [149]:

Grade I – 1 percent

Grade II – 4 percent

Grade III – 25 percent

PVHI (grade IV) – 28 percent

Clinical presentation and course — PHVD usually begins within one to three weeks after the onset of severe IVH. The early stages of PHVD can be detected by routine screening followed by serial ultrasound monitoring if IVH is detected. (See 'Screening' above and 'Serial monitoring' below.)

The clinical presentation of increasing head circumference and signs of increased intracranial pressure (ICP) occurs late in the course of PHVD development and usually presents several weeks after ventricular dilatation is detected by brain imaging studies (image 6A and image 6B and image 6C) [151].

PHVD can follow three distinct clinical courses [4,146]:

Spontaneous arrest without a need for intervention (40 percent)

Rapid progression (10 percent)

Persistent slow progression (50 percent)

Among the third category (those who slowly progress), approximately 40 percent can be managed successfully with temporizing CSF drainage and 60 percent eventually require permanent shunting. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Management of PHVD'.)

A small subset of infants for whom the PHVD initially appears to have arrested (either spontaneously or in response to treatment) develop late progression of ventricular dilatation. This usually occurs during the neonatal period, but rarely can occur after discharge from the neonatal intensive care unit (NICU) in the first year of life.

The risk of mortality and impaired neurodevelopmental outcome are greater in preterm infants who develop PHVD compared with those without PHVD, especially among extremely preterm infants [7,140]. The adverse effects on neurodevelopment from PHVD are thought to be caused by injury to the periventricular white matter [6]. In one small study, MRI at term-equivalent age (TEA) showed decreased volumes of deep gray matter and cerebellum in infants with PHVD compared with controls without PHVD, implying a greater amount brain tissue injury in infants with PHVD [152]. Diffusion tensor imaging (DTI) studies also showed injury and developmental disruptions of the periventricular white matter in preterm infants related to PHVD [153-155]. (See 'White matter injury' below and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Outcome'.)

Serial monitoring — The early stages of PHVD can be detected by serial cranial ultrasound monitoring demonstrating progressive ventricular dilatation. In our center, infants with severe IVH (grade III and PVHI) have ultrasounds performed at least twice weekly for four weeks after onset of the IVH (algorithm 1). Frequent monitoring allows for earlier detection of PHVD prior to the development of signs and symptoms of increased ICP. This facilitates earlier intervention, if warranted, which may improve outcome. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Management of PHVD'.)

Indices to measure — Serial measurements of the following indices are recorded and plotted to determine if there is progressive ventricular dilatation, the rate of change, and if and when intervention should be performed (image 7) [156-160].

The ventricular index (VI) is defined as the distance between the falx and the lateral wall of the anterior horn based on imaging through the coronal plane at the level of the foramen of Monro. It is the main determinant for intervention for infants with PHVD.

Anterior horn width (AHW) is defined as the diagonal width of the anterior horn measured at its widest point in the coronal plane at the level of the foramen of Monro.

Thalamo-occipital distance (TOD) is defined as the distance between the outermost point of the thalamus at its junction with the choroid plexus and the outermost part of the occipital horn in the parasagittal plane.

Frontal temporal horn ratio (FTHR) and frontal occipital horn ratio (FOHR) are obtained by measuring the widest distance of the frontal and occipital horns, respectively, and temporal horns and dividing the average of these measurements by twice the largest biparietal distance.

Resistance index of cerebral artery blood flow is defined as the difference between peak systolic flow velocity and end diastolic flow velocity/peak systolic flow velocity.

The VI and AHW are the main determinants for intervention in infants with PHVD, as discussed separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Management of PHVD'.)f

Tools for plotting ventricular measurements are available based on postmenstrual age 24 to 42 weeks and for postmenstrual age between 24 and 29 weeks, and used to categorize PHVD risk [141,158].

Interpretation — Based on serial ultrasonography findings, infants with PHVD can be classified into one of the following categories [141,156,157,161,162]:

No PHVD – Infants who are monitored for four weeks and have no signs of ventricular dilatation on serial ultrasonography generally do not require treatment or further ultrasound monitoring. They should undergo neuroimaging at term-equivalent age, as discussed separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention", section on 'Selective MRI imaging'.)

Moderate risk – Infants with moderate ventricular dilation (ie, VI >97th percentile to ≤4 mm above the 97th percentile and AHW 6 to 10 mm) are categorized as having moderate risk of developing symptomatic PHVD. Management of moderate-risk patients is detailed separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Moderate-risk infants'.)

High risk – Infants with more severe ventricular dilatation (ie, VI >4 mm above the 97th percentile and AHW >10 mm or TOD >25 mm) are categorized as having high risk of developing symptomatic PHVD. Management of high-risk patients is detailed separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'High-risk infants'.)

Differentiating PHVD from ex-vacuo hydrocephalus — PHVD is distinguished from ex-vacuo hydrocephalus (also called nonprogressive or stable ventriculomegaly) by the progressive dilatation seen on serial cranial ultrasounds. Ex-vacuo hydrocephalus occurs in 25 percent of preterm infants with GMH-IVH and is caused by cerebral atrophy and impaired brain growth. Some degree of cerebral atrophy may also be present in infants with PHVD [146]. It is important to distinguish between the two conditions as the approach to management differs. In those with ex-vacuo dilatation, the ventricular shape may be irregular and dilatation is especially pronounced posteriorly. The subarachnoid space and interhemispheric fissure are widened as well.

White matter injury — Infants with severe IVH (grade III and PVHI) are also at risk for having WMI [163-165]. This may be initially recognized with cranial ultrasound as increased echogenicity in the periventricular white matter. More commonly, WMI is detected on MRI. The most common findings are areas of increased signal intensity on a T2-weighted sequence and punctate lesions in the white matter, which can be hemorrhagic or more often ischemic in nature. On a repeat MRI later in infancy, sequelae in the white matter can be seen as abnormal signal in the periventricular white matter suggestive of gliosis.

In a study of 445 extremely preterm infants (<28 weeks gestation) who underwent MRI at TEA, 59 percent had evidence of mild WMI, 15 percent had moderate WMI, and 4 percent had severe WMI [164]. Many of the infants with MRI evidence of WMI, particularly those with mild findings, did not have severe IVH on cranial ultrasound during the newborn period.  

Cystic periventricular leukomalacia (c-PVL) characterized by periventricular focal necrosis with subsequent cystic formation has become a less common manifestation of WMI [166,167]. The observed decline may reflect over-diagnosis of c-PVL in earlier studies, as cases of PVHI that remain separate from the lateral ventricles and evolve into multiple cysts may have been misclassified as c-PVL. However, it is more likely to be due to a real decline in c-PVL [166]. c-PVL presents two to three weeks after injury with a typical distribution dorsolateral to the external angles of the lateral ventricles and involves the region adjacent to the trigones and to the frontal horn and body of the lateral ventricles. There are data to suggest that GMH-IVH may exacerbate c-PVL, due to the presence of non-protein-bound iron in the CSF [6].

The criteria for performing MRI at TEA to detect WMI injury and types of brain injury in high-risk preterm neonates are discussed separately. (See "Long-term neurodevelopmental impairment in infants born preterm: Risk assessment, follow-up care, and early intervention", section on 'Selective MRI imaging'.)

LONG-TERM COMPLICATIONS — Long-term complications of GMH-IVH, including risk of cerebral palsy and need for permanent CSF shunting, are discussed in detail separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Long-term neurodevelopmental outcomes'.)

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 5th to 6th 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 10th to 12th 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" and the keyword(s) of interest.)

Basics topics (see "Patient education: Intraventricular hemorrhage in newborns (The Basics)")

SUMMARY AND RECOMMENDATIONS

Epidemiology and risk factors – Germinal matrix-intraventricular hemorrhage (GMH-IVH) is an important cause of brain injury in preterm infants. Severe GMH-IVH (ie, grade III or periventricular hemorrhagic infarction [PVHI]) occurs in approximately 5 to 10 percent of infants born at <32 weeks' gestational age (GA); the risk increases with decreasing GA. Additional risk factors include maternal chorioamnionitis, lack of maternal antenatal glucocorticoid therapy, neonatal transport, prolonged neonatal resuscitation, and respiratory distress requiring mechanical ventilation. (See 'Epidemiology' above and 'Risk factors other than GA' above.)

Pathogenesis – In preterm infants, GMH-IVH generally originates from the germinal matrix (GM). Preterm neonates are at increased risk of GMH-IVH compared with term infants due to fragility of the vessels in the GM and instability of cerebral blood flow (CBF). (See 'Pathogenesis' above.)

Clinical presentation – The presentation of GMH-IVH can be clinically silent, saltatory, or catastrophic. Approximately 25 to 50 percent of cases are asymptomatic and only detected through routine cranial ultrasonography screening. In symptomatic neonates, signs may include (see 'Clinical features' above):

Altered level of consciousness

Hypotonia or decreased spontaneous movements

Apnea, hypoventilation, or irregular respirations

Seizures

Cranial nerve abnormalities, including gaze and pupillary abnormalities

Bulging anterior fontanelle

Screening – We suggest routine screening for GMH-IVH with cranial ultrasound for all preterm infants <32 weeks (Grade 2C). In our practice, we perform the initial ultrasound on the day of admission. The schedule for follow-up scans depends on GA and other risk factors. If severe GMH-IVH (ie, grade III or PVHI) is detected on screening ultrasonography, we perform serial ultrasounds at least twice weekly for four weeks to monitor for development of posthemorrhagic ventricular dilation (PHVD). (See 'Screening' above and 'Serial monitoring' above.)

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

Complications – Acute complications of severe IVH (ie, grade III or PVHI) include PHVD (image 6A-C) and white matter injury. These complications are associated with increased risk of mortality and neurodevelopmental impairment (NDI). (See 'Posthemorrhagic ventricular dilatation (PHVD)' above and 'White matter injury' above.)

Long-term complications of GMH-IVH, including risk of cerebral palsy and need for permanent cerebrospinal fluid (CSF) shunting, are discussed in detail separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome", section on 'Long-term neurodevelopmental outcomes'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lisa M Adcock, MD, who contributed to an earlier version of this topic review.

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Topic 5051 Version 35.0

References

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