Non-traumatic intraventricular hemorrhage in the fetus and newborn: clinical guidelines

List of Abbreviations

aPTT – activated partial thromboplastin time

IVH – intraventricular hemorrhage

GA – gestational age

INR – international normalized ratio

MRI – magnetic resonance imaging

NSG – neurosonography

VLBW – very low birth weight

PT – prothrombin time

PVL – periventricular leukomalacia

PHI – periventricular hemorrhagic infarction

PIVH – peri-intraventricular hemorrhage

PET – positron emission tomography

РКИ – randomized controlled trial

FFP – fresh frozen plasma

CSF – cerebrospinal fluid

SEH – subependymal hemorrhage

US – ultrasound examination

EEG – electroencephalography

Terms and Definitions

Intraventricular hemorrhage (IVH) is bleeding into the lateral and third or fourth ventricles of the brain.

The diagnosis of "non-traumatic intraventricular hemorrhage in the fetus and newborn" defines a group of non-traumatic conditions in newborn infants associated with bleeding into the germinal matrix of the subependymal region and/or the ventricular system of the brain, which may be combined with periventricular hemorrhagic infarction.

Periventricular hemorrhagic infarction (PHI) is hemorrhagic necrosis of the periventricular white matter caused by impaired venous drainage through the terminal and medullary veins draining the cerebral white matter.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Intraventricular hemorrhage (IVH) is bleeding into the lateral and third or fourth ventricles of the brain.

Periventricular hemorrhagic infarction (PHI) is hemorrhagic necrosis of the periventricular white matter caused by impaired venous drainage through the terminal and medullary veins draining the cerebral white matter. PHI may be a complication of IVH and typically occurs from several hours to several days after the initial hemorrhage.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causes and sources of intraventricular hemorrhage in term and preterm infants differ significantly [1,2]. Intraventricular hemorrhages in preterm infants have a multifactorial genesis. Three groups of factors are distinguished: antenatal, intranatal, and postnatal [3–5].

Antenatal factors include pregnancy complicated by maternal arterial hypertension, abnormal uterine contractions accompanied by impaired uteroplacental blood flow and, accordingly, sharp fluctuations in fetal cerebral blood flow [6,7], fetoplacental or feto-fetal transfusion (creating a risk of fetal blood loss and associated hemodynamic disorders), intrauterine infection, particularly viral, causing amnionitis and placentitis [8], and the absence of antenatal prophylaxis for respiratory distress syndrome.

Intranatal factors include: placental abruption, precipitous labor, development of disseminated intravascular coagulation (DIC) in the mother, complicated delivery, etc., including the pathological nature of preterm labor and abnormal fetal presentation [9–11].

Postnatal factors include: respiratory distress syndrome, peri- and postnatal asphyxia with the development of hypoxia and hypercapnia, systemic blood pressure fluctuations, hypo- or hyperglycemia, electrolyte disturbances, patent ductus arteriosus and congenital heart defects, sepsis, coagulopathy, dehydration or massive intravenous infusions of hyperosmolar solutions, inadequate mechanical ventilation modes, pneumothorax, numerous invasive procedures, and failure to maintain thermal and protective care regimens [4,5,12].

The pathogenesis of IVH is multifactorial and includes fragility of the germinal matrix vessels, increased fibrinolytic activity of the germinal matrix, absence of autoregulation and fluctuation of cerebral blood flow, fluctuations in venous pressure, coagulation disorders, and genetic factors. The most important independent risk factor for IVH is gestational age [1,13–17]. Hemorrhage develops as a result of the combined effects of vascular, intra-, and extravascular factors, the significance of which may vary in different situations. Bleeding occurs into the germinal matrix, an embryonic tissue that serves as a source of neurons and glial cells which, starting from the 8th week of gestation, migrate from it to form the cerebral cortex and basal ganglia. Accelerated angiogenesis occurs within the germinal matrix, causing it to contain a large number of immature, wide, thin-walled vessels. The absence of pericytes and low fibronectin content in immature basement membranes contribute to the fragility of germinal matrix vessels. In addition, germinal matrix cells are rich in mitochondria and highly sensitive to oxygen deprivation, which explains the importance of germinal matrix hypoxia in the pathogenesis of IVH [13,15,18–22]. The germinal matrix is located beneath the ependyma of the brain ventricles; in early developmental stages, it lines the entire wall of the lateral and third ventricles. After 24–26 weeks, against the background of ongoing neuronal and glial migration, regression of the germinal matrix begins, and by 32–34 weeks it persists only in the region of the head of the caudate nucleus and in the caudothalamic groove, while by 36 weeks it generally ceases to exist altogether. Remnants of the germinal matrix persist the longest on the surface of the head of the caudate nucleus and in the caudothalamic groove, and it is in this region that hemorrhages form at 28–32 weeks of development [23–27].

Impairments in cerebral blood flow autoregulation play an important role in the development of perinatal brain injury. Autoregulation mechanisms ensure relative constancy of cerebral perfusion during wide fluctuations in systemic blood pressure [23,28]. Under conditions of hypoxia, autoregulation is disrupted, and cerebral blood flow passively follows changes in systemic blood pressure. Autoregulation mechanisms are formed only in the final weeks of pregnancy and are not yet established in extremely preterm infants [29,30].

Increased cerebral blood flow velocity against the background of elevated blood pressure and venous congestion can lead to the development of IVH of varying severity. The predisposition to venous plethora in the germinal matrix is due to the presence in this zone of a specialized venous network whose veins drain into a single central vein at an acute angle, which impedes venous outflow [5,31].

Blood coagulation disorders in IVH in preterm newborns remain a subject of debate. Nevertheless, prematurity is accompanied by thrombocytopenia, which is an independent factor in the development of hemorrhage. Common causes of early thrombocytopenia include alloimmunization or chronic fetal hypoxia [32–34]. The onset of late thrombocytopenia (>72 hours after birth) is primarily associated with nosocomial infection (preterm newborns have an impaired ability to upregulate thrombopoietin levels to compensate for platelet consumption during sepsis). A small size of megakaryocytes (platelet precursors) is also observed. Thus, the mechanism of neonatal thrombocytopenia combines destruction and reduced production of platelets. Coagulation disorders in preterm newborns with IVH are manifested by abnormal levels of the international normalized ratio (INR), antithrombin III, and fibrinogen [35].

The genesis and onset of neonatal IVH may also be underpinned by genetic factors. At the germinal matrix level, the COL4A1 gene, which encodes type IV procollagen, plays a key role in vascular stabilization. Alterations in this gene are associated with neonatal intraventricular hemorrhage in preterm infants [36,37]. Genetically determined collagenopathy dictates the permeability of the vascular basement membrane responsible for hemorrhage from the germinal matrix. Pathogenic variants of the NOS3 gene, which encodes endothelial nitric oxide synthase (eNOS), have been shown to be associated with an increased risk of hemorrhage and influence cerebral blood flow autoregulation in newborns [38]. Variants of anti-inflammatory interleukin genes, such as tumor necrosis factor, are associated with neonatal IVH, while variants of factor V Leiden or prothrombin G20210A are prognostic factors for neonatal IVH [39]. Thus, it cannot be denied that genetic alterations influence the onset of IVH, but the understanding of the various pathways remains unclear.

Postnatally, subependymal and intraventricular hemorrhages occur almost exclusively during the first week of life: in 50% of affected infants, the onset of hemorrhage occurs on the first day of life, and up to 90% of IVH develop by 72 hours [40]. Hemorrhage progression and transition to higher grades occur rapidly, within 1–3 days. After the first week of life, the risk of hemorrhage in premature infants decreases regardless of gestational age. This is likely due to the postnatal increase in blood and tissue oxygen concentration, suppression of vascular endothelial growth factor, and a decrease in angiopoietin-2 levels. The cessation of postnatal angiogenesis induces vascular maturation, making vessels more resistant to rupture.

Periventricular hemorrhagic infarction (PHI), also referred to as parenchymal hemorrhagic infarction or periventricular venous infarction, develops in 15% of children with IVH. Germinal matrix hemorrhage and intraventricular hemorrhage of any grade can be complicated by PHI, but the higher the grade of hemorrhage, the greater the likelihood of its development. The pathogenesis of periventricular hemorrhagic infarction is caused by venous obstruction of the terminal vein and its tributaries, which drain the cerebral white matter and germinal matrix. Venous stasis leads to ischemia and edema of the periventricular white matter with the rapid development of secondary hemorrhagic imbibition. High intraventricular pressure during massive hemorrhage can additionally disrupt blood flow in the subependymal veins, increasing the size of the venous infarction. The development of PHI in hemorrhage confined to the germinal matrix is likely associated with its localization in the caudothalamic groove and the peculiar venous anatomy in this zone (presence of acute venous angles and a propensity for venous stasis). Periventricular hemorrhagic infarction typically occurs from several hours to several days after the initial bleeding. Intraventricular hemorrhage also leads to non-hemorrhagic injury of the periventricular white matter in preterm infants. The accumulation of blood in the cerebral ventricles of newborns damages the adjacent white matter, destroys the periventricular germinal matrix, and damages the corpus callosum and the corona radiata of the white matter. IVH increases intracranial pressure, reduces cerebral blood flow and oxygen metabolism, and apparently disrupts the blood-brain barrier, increasing its permeability as well. Lysis of blood accumulated in the ventricles and brain parenchyma leads to the release of thrombin, complement, hemoglobin, and iron into the extracellular space, which are toxic to brain tissue. IVH causes severe inflammation around the cerebral ventricles, damages axons, induces apoptosis and maturation arrest of oligodendrocyte precursors, leading to decreased white matter myelination. Survivors may experience adverse neurological development outcomes, including cerebral palsy, cognitive impairment, and hydrocephalus [1,21,22,41–43]. Progressive posthemorrhagic ventriculomegaly (posthemorrhagic hydrocephalus) develops in approximately 25% of children with IVH, which is life-threatening and may require surgical treatment. Posthemorrhagic ventriculomegaly can complicate any IVH where blood enters the ventricular system, but is more commonly observed after severe forms of IVH and PHI. Posthemorrhagic ventriculomegaly develops as a result of obstruction of CSF pathways and due to an imbalance between CSF production, circulation, and resorption. Blood clots or fibrin debris can obstruct CSF pathways at various levels. Depending on the site of obstruction, various types of ventricular dilation may develop: unilateral ventriculomegaly following unilateral obstruction of the foramen of Monro, supratentorial (triventricular) ventriculomegaly following aqueductal obstruction, complete internal (tetratentorial/tetriventricular) hydrocephalus following obstruction of the fourth ventricle outlets (foramina of Luschka and Magendie). In some cases, the fourth ventricle becomes isolated from CSF circulation due to combined aqueductal and fourth ventricle outlet obstruction [21,41,44–46].

Intraventricular hemorrhage in term newborns occurs in 3.5–5% of cases and may be associated with various prenatal, perinatal, and postnatal risk factors. In term infants, IVH typically originates not from the germinal matrix (which is fully regressed by birth), but from the choroid plexus, where the connective tissue framework is also poorly developed.

In term newborns, IVH may be a consequence of prolonged labor combined with asphyxia and hypoxia, leading to endothelial damage, venous congestion, and pathological centralization of blood circulation. Venous congestion during prolonged difficult labor can cause rupture of small meningeal and choroid plexus vessels in term infants.

Another cause of IVH in term newborns can be coagulation disorders: disseminated intravascular coagulation (DIC), cerebral venous sinus thrombosis, and thrombocytopenia. About 30% of IVH cases in term infants develop against the background of thrombosis of the straight sinus, the vein of Galen, and deep cerebral veins. The combination of intraventricular hemorrhage with unilateral thalamic hemorrhage in term and late preterm infants is highly characteristic of cerebral venous sinus thrombosis.

Despite the complete regression of the germinal matrix by 36 weeks of gestation, subependymal hemorrhages in the stage of partial lysis or subependymal cyst formation are frequently observed in term newborns, indicating an antenatal origin of the germinal matrix hemorrhage [2,14,18,47–50].

1.3 Epidemiology of the Disease or Condition

The incidence of intraventricular hemorrhage is 20–25% among very low birth weight (VLBW) infants [4,23,51,52]. Grade 1 intraventricular hemorrhage in premature newborns occurs with a frequency of about 17.0%, grade 2 with a frequency of about 12.1%, grade 3 up to 3.3%, and periventricular hemorrhagic infarction (PHI) up to 3.8%. The risk and severity of IVH increase with decreasing gestational age and/or birth weight: among survivors born at 24 weeks of gestation, the incidence of the most severe IVH ranges from 10 to 25%, whereas among survivors born after 28 weeks it is less than 5%. In term newborns, intraventricular hemorrhages develop significantly less frequently, detected in 3.5–5% of cases [2,15,21]. Approximately 25% of children with IVH develop posthemorrhagic hydrocephalus. The vast majority of progressive posthemorrhagic hydrocephalus cases (up to 80%) occur following massive IVH and when IVH is combined with PHI. In most cases, posthemorrhagic hydrocephalus eventually resolves—approximately 40% spontaneously and another 15% after conservative treatment. However, about 35% of children with progressive posthemorrhagic hydrocephalus require surgical treatment, and 10% die. Obstruction of the cerebrospinal fluid pathways by blood clot fragments is the cause of progressive posthemorrhagic hydrocephalus in only 10% of cases. In 90% of cases, the main pathogenetic mechanism of hydrocephalus is impaired cerebrospinal fluid resorption due to the development of obliterating arachnoiditis in the posterior cranial fossa resulting from reactive inflammation associated with IVH [53–56].

Intraventricular hemorrhages often occur synchronously with pathologies of other organs and systems characteristic of this period: congenital infections, bronchopulmonary dysplasia, retinopathy of prematurity, patent ductus arteriosus, necrotizing enterocolitis, etc. Mortality in premature infants with IVH has decreased from 31–56% to 20–25%, but maintains a direct dependence on the infant's gestational age and birth weight [57]. Long-term neurological complications develop in 50–75% of IVH survivors, including cerebral palsy, learning and cognitive impairments, mental disorders, and posthemorrhagic hydrocephalus, with 25% requiring surgical shunt placement [58].

1.4 Features of Coding the Disease or Condition

P52.0 Grade 1 intraventricular (non-traumatic) hemorrhage in fetus and newborn (Subependymal hemorrhage (without extension into the cerebral ventricles))

P52.1 Grade 2 intraventricular (non-traumatic) hemorrhage in fetus and newborn (Subependymal hemorrhage with extension into the ventricles)

P52.2 Grade 3 and 4 intraventricular (non-traumatic) hemorrhage in fetus and newborn (Subependymal hemorrhage with extension into the ventricles and brain tissue)

P52.3 Unspecified intraventricular (non-traumatic) hemorrhage in fetus and newborn

P52.4 Cerebral (non-traumatic) hemorrhage in fetus and newborn

1.5 Classification of the disease or condition

IVH classification is based on neuroimaging methods. It is grounded in the volume of shed blood, which determines the severity of IVH [59–62]. (Appendix A3.2)

In international practice, the classification of intraventricular hemorrhages proposed by Papile L. et al. in 1978 was widely used for several decades. Papile's classification was based on the assumption that the progression of hemorrhage from grade I to grade IV represents a continuum, namely: subependymal hemorrhage confined to the germinal matrix (grade I), intraventricular hemorrhage extending into normal-sized ventricles and typically filling <50% of the ventricular lumen (grade II), intraventricular hemorrhage extending into dilated ventricles (grade III), and intraventricular hemorrhage extending into the parenchyma (grade IV) [62].

However, modern pathomorphological studies have proven that grade IV IVH according to Papile L. represents a periventricular hemorrhagic venous infarction associated with compression of cerebral veins draining the white matter, rather than the extension of the initial intraventricular hemorrhage into the parenchyma due to rupture. PHI can occur with any grade of intraventricular hemorrhage; therefore, current international authors strongly recommend an IVH classification divided into three grades with separate designation of PHI presence, as in J. Volpe's classification (2008). According to J. Volpe, IVH is classified as: grade I – hemorrhage confined to the germinal matrix, grade II – IVH without ventricular dilation, grade III – IVH with acute ventricular dilation. Furthermore, acute ventricular dilation in grade III IVH is considered to result from the effusion of a large volume of blood into the ventricular lumen and typically develops within the first 3 days. Ventricular dilation occurring after 7–10 days should be regarded as posthemorrhagic ventriculomegaly, i.e., considered a complication of IVH. Periventricular hemorrhagic infarction (PHI) is not included in J. Volpe's IVH classification, but is described separately indicating its size and localization. J. Volpe's modern classification, based on the amount and extent of hemorrhage into the lateral ventricles and the presence of acute ventricular dilation, is a strong predictor of neurodevelopmental outcomes and is recommended for use both in clinical practice and in research contexts [13,22,41,44,45,63,64].

In all the classifications listed above, the emphasis is placed on germinal matrix hemorrhage, meaning they encompass only hemorrhages in premature infants and do not account for hemorrhages from other sources (such as the choroid plexus) characteristic of term newborns [19,65,66].

1.6 Clinical presentation of the disease or condition

During the clinical manifestation of IVH, the symptoms and their onset rate can vary. Symptoms present as varying degrees of impaired consciousness, muscular hypotonia, altered character or decreased general motor activity, oculomotor disorders (strabismus, vertical gaze palsy, limitation of horizontal eye movement, wandering eye movements, "doll's eyes" sign), and decreased hematocrit. Convulsions, apnea, tension and bulging of the fontanelle, poor tolerance of enteral nutrition, and regurgitation may develop. Meningeal signs are observed in 10% of cases. With a progressive massive hemorrhagic CNS lesion, clinical symptoms develop within several hours. The leading symptoms become depression of consciousness to coma, respiratory disorders and apnea, generalized tonic tension, convulsions, decerebrate posture, impaired pupillary light reflex (mydriasis), and roving eye movements. Bradycardia and arterial hypotension increase, thermoregulation is impaired, hematocrit decreases, acidosis and hyper- or hypoglycemia develop, and circulating blood volume decreases. With this clinical course, a fatal outcome is most frequent and occurs in 33% of cases [52, 67].

The clinical course of hemorrhage correlates with its grade. In grade 1 IVH, specific clinical symptoms are absent, and the diagnosis is established using neurosonography (NSG) and laboratory data.

In grade 2 IVH, muscular hypotonia (75%), depression of consciousness (10%), and moderate ventricular dilatation (84%) may be observed, which resolves without surgical interventions. Subependymal cysts, as a consequence of grade 1–2 IVH, resolve over the next 3–10 months without specific treatment [57].

In grade 3 IVH, depression of consciousness to stupor (64%) or coma (32%), apnea (50%), convulsions, and muscular hypotonia (62%) may be noted. For periventricular hemorrhagic infarction (PVHI), the clinical picture is more severe, and the development of life-threatening symptoms is characteristic.

The source of IVH in term infants is most often the choroid plexuses; less commonly, the cause may be cerebral venous sinus thrombosis. In term infants, the features of IVH and its clinical picture are similar to those in preterm infants. In both term and preterm infants, IVH is often combined with ischemic injury, as they share common causes and triggering factors [67, 68].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing "Intraventricular hemorrhage"

The diagnosis of "Intraventricular hemorrhage" can be established based on pathognomonic data from brain ultrasound (neurosonography) if germinal matrix hemorrhage or hemorrhage within the ventricular system is detected.

2.1 Complaints and Anamnesis

Comments: risk factors include: absence of antenatal corticosteroid therapy, chorioamnionitis, multiple pregnancy, gestational age of 32 weeks or less, birth weight of 1500 grams or less, Apgar score of 5 points or less, vaginal delivery at a gestational age of 32 weeks or less, body temperature drop to 35°C⁰ or less, transfer to another hospital, need for mechanical ventilation, need for inotropic therapy, coagulopathy, thrombocytopenia, metabolic acidosis, and the need for electrolyte solutions (ATX code B05XA) – sodium bicarbonate**.

2.2 Physical Examination

See Section 1.6 "Clinical Presentation"

Comments: head circumference is measured with a tape measure using anatomical landmarks (occipital protuberance and supraorbital ridges). A doubling of the head circumference growth rate over two weeks, separation of cranial sutures, and bulging and tension of the large fontanelle are regarded as symptoms of intracranial hypertension [86].

Implementation of this thesis recommendation for newborns with a gestational age of 35 weeks or more and diagnosed grade 1 IVH in the cyst-formation stage is optional and performed at the discretion of the attending physician.

2.3 Laboratory Diagnostics

Comments: the child may exhibit changes in the complete blood count requiring correction (anemia, thrombocytopenia).

Implementation of this thesis recommendation for newborns with a gestational age of 35 weeks or more and diagnosed grade 1 IVH in the cyst-formation stage is optional and performed at the discretion of the attending physician.

• For a newborn with IVH, it is recommended to perform a coagulogram (screening hemostasis test) – determination of blood fibrinogen level, prothrombin (thromboplastin) time in blood or plasma, activated partial thromboplastin time, and international normalized ratio (INR) to assess hemostatic disorders and determine further therapeutic management [89, 90, 92].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: The coagulogram test and the range of analyzed parameters depend on the laboratory capabilities of the medical organization.

Thromboelastometry and thromboelastography methods are used to assess the extrinsic and intrinsic pathways of coagulation, fibrinogen levels and function, and fibrinolytic activity; the obtained results allow for targeted therapy of clotting disorders [93–95].

Implementation of this thesis recommendation for newborns with a gestational age of 35 weeks or more and diagnosed grade 1 IVH in the cyst-formation stage is optional and performed at the discretion of the attending physician.

2.4 Instrumental Diagnostics

Brain ultrasound (neurosonography) can reliably detect such pathological brain changes as germinal matrix hemorrhage and intraventricular hemorrhage, periventricular hemorrhagic infarction, posthemorrhagic ventricular dilatation, cerebellar hemorrhage, and white matter injury. Thus, neurosonography remains a universal tool for screening and monitoring brain injuries in newborns (Appendix A3.3).

• For a newborn with suspected IVH, it is recommended to perform neurosonography to detect intraventricular and parenchymal hemorrhage [73, 96–108].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments. Neurosonography is recommended for all newborns with neurological symptoms and clinical deterioration allowing suspicion of IVH development, progression, or its complications.

Given the high risk of IVH development, it is advisable to routinely perform neurosonography in preterm infants with a gestational age of 32 weeks or less or a birth weight of less than 1500 g on days 1–2, 3–4, and 7 of life, and thereafter as clinically indicated.

Brain ultrasound performed on the first day of life allows the detection of antenatal brain injury; however, if antenatal IVH occurred long before birth, residual signs such as ventricular dilatation, intraventricular clots and strands, and parenchymal defects may be subtle. Neurosonography after the first week of life allows the detection of posthemorrhagic ventriculomegaly and late-onset IVH.

Ultrasonic evaluation of the brain in intraventricular hemorrhage includes:

1) detection of hemorrhage in the germinal matrix or within the ventricular system,

2) measurement of ventricular dimensions to assess their dilatation,

3) assessment of the echogenicity of periventricular white matter to identify ischemic or hemorrhagic parenchymal injury.

• In newborns with grade 2–3 IVH and/or parenchymal hemorrhage, it is recommended to perform brain magnetic resonance imaging (MRI) if necessary to adjust management tactics in order to clarify the extent and nature of brain lesions [97, 109–114].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: The execution of this neuroimaging method depends on the capabilities of the specific medical organization. MRI determines the degree and extent of hemorrhage, the nature of brain parenchyma damage, impaired cerebrospinal fluid circulation, and the formation of posthemorrhagic hydrocephalus. Brain magnetic resonance imaging offers higher diagnostic sensitivity and specificity, as well as an expanded characterization of the lesion.

2.5 Other Procedures

• For a newborn infant with IVH, it is recommended to have an initial/follow-up appointment (examination, consultation) with a neurologist to diagnose neurological disorders [115–118].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: The implementation of this thesis recommendation for newborns with a gestational age of 35 weeks or more and diagnosed grade 1 IVH in the cyst-formation stage without abnormal neurological symptoms is optional and performed at the discretion of the attending physician.

• A newborn infant with IVH and increasing lateral ventricle dimensions is recommended to undergo an initial/follow-up evaluation (examination, consultation) by a pediatric neurosurgeon to determine the indications for neurosurgical intervention [119–121].

LoE BGoE 2Level of evidence B (grade of recommendation – 2)

• A preterm infant with IVH is recommended to undergo an initial/follow-up evaluation (examination, consultation) by an ophthalmologist for the detection and monitoring of retinopathy of prematurity [122,123].

LoE AGoE 2Level of evidence A (grade of recommendation – 2)

Comments: The initial ophthalmological examination of preterm infants born at a gestational age of less than 27 weeks is performed at 31 weeks of gestation, and for those born at 27 weeks or more, at 4 weeks of chronological age¹.

¹ Order of the Ministry of Health of the Russian Federation No. 442n dated October 25, 2012, "On approval of the Procedure for providing medical care to children with diseases of the eye, its adnexa and orbit" (as amended)

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

There are no specific treatments for intraventricular hemorrhage. Management of IVH involves treating concurrent pathology and developed complications of IVH.

3.1 Concomitant Symptomatic Therapy

• A newborn with IVH and detected seizure syndrome is recommended to receive anticonvulsant therapy [124–128].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: Indications for anticonvulsant therapy include clinical seizures or signs of seizure activity detected by amplitude-integrated electroencephalography (aEEG). Anticonvulsant medications include: benzodiazepine derivatives (ATX code N05CD), barbiturates and their derivatives (ATX code N03AA), other antiepileptic drugs (ATX code N03AX), and fatty acid derivatives.

The list of drugs used for anticonvulsant therapy may be modified in accordance with local protocols and formularies.

• A newborn with IVH and persistent coagulopathy abnormalities following prophylaxis for hemorrhagic disease of the newborn, characteristic of vitamin K-dependent factor deficiency, is recommended to receive vitamin K (ATX code B02BA) – phytomenadione [129,130].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: Phytomenadione (ATX code B02BA) is administered intramuscularly or intravenously at a dose of: 1 mg (0.1 ml) for term newborns and preterm infants with a birth weight of 2500 g or more; 0.4 mg/kg (0.04 ml/kg) for preterm newborns with a birth weight of less than 2500 g.

In the absence of phytomenadione (ATX code B02BA), menadione sodium bisulfite** (ATX code B02BA) may be used at a dose of 1 mg/kg/day (0.1 ml/kg/day) intramuscularly, not exceeding 4 mg per day [131].

• A newborn with IVH is recommended to receive other systemic hemostatic agents (ATX code B02BX) – etamsylate** [132].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Etamsylate** (ATX code B02BX) is administered intravenously at 12.5 mg/kg (0.1 ml/kg) every 6 hours for 4 days [132].

This thesis-recommendation does not apply to newborn infants with a gestational age of 35 weeks or more diagnosed with grade 1 IVH in the cyst formation stage.

• A newborn with newly diagnosed IVH or progressing IVH combined with coagulopathy is recommended to undergo correction of blood clotting factors [133–137].

GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)

Comments: Coagulation profile testing (screening hemostasis assay) and the range of analyzed parameters depend on the laboratory capabilities of the medical organization (MO). Definitions of coagulopathy in preterm and term newborns at birth, depending on gestational age (GA) and postnatal age, are presented in Table 1 [134].

Table 1. Prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen levels in newborns and infants in the first 3 months of life with coagulopathy [114] (modified from Andrew M. et al., 1988, Christensen RD. et al., 2014)

The dose of fresh frozen plasma (FFP) is 10–20 ml/kg [138]. The duration of transfusion must not exceed 4 hours [139].

Cryoprecipitate may be prescribed if plasma fibrinogen concentration remains <1.0 g/l despite FFP transfusions. Cryoprecipitate may be administered before FFP or in combination with FFP in cases of very low plasma fibrinogen concentration (less than 0.5 g/l), its rapid decrease, or massive bleeding. For newborns, the volume of cryoprecipitate is 5–10 ml/kg of body weight [140].

• A newborn with IVH and identified anemia requiring correction is recommended to receive a transfusion of red blood cell components [141].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: Transfusion of red blood cell components is carried out in accordance with the clinical guidelines "Early Anemia of Prematurity" 2021²

• A newborn with IVH and identified thrombocytopenia requiring correction is recommended to receive a platelet concentrate transfusion [142–145].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: Indications for platelet concentrate transfusion are presented in Table 2 [146].

Table 2. Indications for platelet concentrate transfusion in newborns, modified (Sparger K. et al. 2015, Girelli G. et al. 2015, Curley A. et al., 2019) [147–149].

² Russian Association of Neonatologists. Clinical guidelines "Early Anemia of Prematurity", 2021.

3.2 Surgical Treatment

• A newborn with IVH and posthemorrhagic ventricular dilation is recommended to undergo neurosurgical intervention [150].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The goal of neurosurgical intervention is to normalize cerebrospinal fluid dynamics and evacuate blood and its breakdown products from the CSF spaces. The main methods used to achieve this goal include: brain ventricle puncture and evacuation of cerebral hematoma; lumbar puncture; external drainage of the lateral ventricles of the brain or placement of an external ventricular drain; ventriculoperitoneal shunting; a set of examinations for diagnosing brain formations [150]. The decision regarding the necessity and method of neurosurgical intervention is made by a neurosurgeon.

Criteria for an initial evaluation (examination, consultation) by a neurosurgeon are signs of intracranial hypertension manifested on neurosonography by a progressive increase in lateral ventricle dimensions exceeding the 97th percentile for a given gestational age and/or accelerated head growth (more than 14 mm per week).

Table 3. Normal ventricular system parameters in term newborns (Naumova E.Kh., 2003) [151].

Table 4. Dimensions of the anterior horn of the lateral ventricle in preterm infants (Whitelow A., 2007) [151].

3.3 Other Treatment

The therapeutic and protective regimen involves creating optimal conditions for nursing premature newborns.

An important component in the management of preterm infants is an adequate intake of enteral nutrition (breast milk fortified with a human milk fortifier, or a specialized dry/liquid formula for feeding preterm and low birth weight infants) or, in cases of enteral feeding intolerance, the prescription of parenteral nutrition [152].

Nutrition for term newborns involves feeding with breast milk or an adapted infant formula for feeding from birth in the absence or insufficiency of lactation, or if there are maternal contraindications to breastfeeding.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

To achieve the highest effectiveness in reducing the incidence of disabling conditions in children with consequences of perinatal CNS lesions (including IVH), the following general principles of rehabilitation/habilitation are distinguished:

1) early initiation of rehabilitation in the intensive care unit, including extremely low birth weight preterm infants;

2) an individualized approach from the perspective of the child as a whole organism, taking into account age, degree of maturity, severity of the underlying pathology, comorbid conditions, and individual constitutional and genetic characteristics;

3) a comprehensive combination of various methods – drug therapy, surgery, physical therapy, psycho-pedagogical, immunoprophylactic, and nutritional methods;

4) continuity between various stages of rehabilitation, ensuring a logical sequence of applied methods and evaluating rehabilitation effectiveness through dynamic patient monitoring.³

• Newborns with IVH who are at high risk for cerebral palsy are recommended to undergo a complex of physical rehabilitation/habilitation methods depending on the leading pathological symptom at the age of 0 months to 2 years. The principle of a comprehensive approach involves the use of physical, psychological, medicinal, and other methods. General massage and gymnastics in early childhood, and massage for nervous system disorders in early childhood (general classical massage, trophic, point, segmental massage, positioning therapy, corrective gymnastics) [153].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: The effectiveness of comprehensive rehabilitation is much higher if initiated early (before 6 months of life). Patients who begin treatment in the first 6 months show significant improvement in motor activity [154]. The main methods of comprehensive physical rehabilitation aimed at reducing spasticity and motor disorders include: basic exercise therapy, therapeutic gymnastics, various types of massage, positioning, Bobath positioning, and medical rehabilitation services for children with neurological diseases using applied kinesotherapy methods (Vojta therapy, hydrokinesitherapy) [155–159].

³ Government Decree of the Russian Federation No. 1839-r dated August 31, 2016, "On Approval of the Concept for the Development of Early Intervention in the Russian Federation for the Period up to 2020"

5. Prevention and Dispensary Observation

• In threatened preterm labor, antenatal prevention of fetal respiratory distress syndrome is recommended to reduce the incidence of IVH [160,161].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• Delivery at a gestational age of less than 32 weeks is recommended by Caesarean section to reduce the risk of IVH [162–164].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

• During delivery, delayed cord clamping for 60-120 seconds or more is recommended to reduce the incidence and severity of IVH [165–168].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

• During delivery, umbilical cord milking at a gestational age of less than 32 weeks is not recommended [169].

GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)

Comments: etamsylate** (ATX code B02BX) is administered intravenously at 12.5 mg/kg (0.1 ml/kg) every 6 hours for 4 days [132].

• Extremely preterm infants in the first 72 hours after birth are recommended neonatal neuroprotective comprehensive care to reduce the incidence of IVH [178–184]:

  1) maintaining the head in the midline position, an elevated head position of the standard neonatal incubator by 15–30 degrees, avoiding sudden and excessive elevation of the pelvis and lower limbs [178–183,185];

  Level of recommendation validity B (evidence level – 3)

  2) minimizing contact with the patient – adherence to a protective regimen [184];

  Level of recommendation validity B (evidence level – 3)

  3) elimination of light and sound stimuli [186];

  Level of recommendation validity B (evidence level – 3)

  4) blood sampling from a central vein or artery for analysis followed by catheter flushing is recommended to be performed slowly, no more than 1.5 ml per 30 sec [186];

  Level of recommendation validity B (evidence level – 3)

  5) minimizing respiratory tract care under mechanical ventilation; if necessary, care should be performed using a closed tracheal suction system [184,187];

  Level of recommendation validity B (evidence level – 3)

  6) administering non-pharmacological and/or pharmacological pain relief before invasive procedures [188–191].

  Level of recommendation validity B (evidence level – 2)

Comments: The set of examinations during mechanical ventilation includes: tidal volume, inspiratory pressure, respiratory rate, inspiratory and expiratory time, and PCO₂ levels. Hypocapnia (35 mm Hg or less) and hypercapnia (60 mm Hg or more) are risk factors for the development of IVH [193–195].

• Extremely preterm infants in the first 72 hours of life are recommended to maintain mean arterial pressure equal to GA to reduce the incidence and severity of IVH [199–204].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: Blood pressure values after 72 hours of life depending on postmenstrual age are presented in Appendix A3.4 [204,205]. Performing targeted echocardiography (EchoCG) with assessment of the main pathogenetic links of hemodynamic disorders allows for targeted prescription of vasoactive therapy (inotropic and/or vasopressor therapy, hormonal therapy, changing infusion volume, or volume expander therapy). Performing EchoCG with afterload assessment as an important pathogenetic link in hemodynamic disorders leads to a reduction in the incidence of severe disabling hemorrhages, severe pulmonary hemorrhages, and mortality in the most immature preterm patients [185,206–208]. A differentiated approach to prescribing inotropic and cardiotonic therapy using targeted EchoCG helps reduce excessive prescription of vasoactive therapy, which carries the risk of severe IVH [209,210]. Monitoring the hemodynamic significance of patent ductus arteriosus signs in extremely preterm newborns with a gestational age of 26 weeks is associated with a reduction in severe IVH [211,212].

6. Organization of Medical Care

Indications for hospitalization in a medical organization:

For timely diagnosis and selection of further management tactics for a newborn with suspected IVH, medical care is recommended to be provided in a level 3-A or 3-B medical facility with the capability of providing resuscitation and intensive care, consultations by specialists (neurologist, neurosurgeon, ophthalmologist), examinations (neurosonography, MRI), and therapy.

Indications for discharging a patient with IVH from a medical organization:

- stabilization of the patient with the ability to independently support vital functions; absence of symptoms of intracranial hypertension and progressive hydrocephalic syndrome (neuroimaging evidence);

- absence of seizure syndrome;

- absence of symptoms of hemostatic disorders.

After discharge from the hospital, children are subject to outpatient follow-up by a neurologist and other specialists depending on the identified etiology of IVH [90].

The frequency of consultations by a neurologist is determined individually, depending on the developed complications and neurological deficit.

Neuroimaging (choice of research method and frequency) is determined by the neurologist for each case individually.

The decision on the need for re-hospitalization is made by the physician in each case individually.

Suspicion of occlusive hydrocephalus development (increasing symptoms of intracranial hypertension, neurosonographic signs of progressive hydrocephalus) and symptoms of cerebral insufficiency (agitation/depression, seizures, impaired sucking/swallowing) are indications for re-hospitalization of a child with a history of IVH.

Issues related to the rehabilitation of neurological deficits are addressed by a neurologist on an individual basis.

7. Additional Information

The prognosis of the disease depends on the severity of IVH, etiological factors, and the presence of complications. With a small volume of IVH and the absence of perinatal asphyxia, the prognosis is favorable [42,90]. In newborns with grade III and IV hemorrhages, the probability of developing psychomotor retardation and cerebral palsy is more than 75%. Thus, in the group of children with grade 3-4 IVH (according to L. Papile's classification), monoparesis was detected in 27% of cases, hemiparesis in 67%, paraparesis in 35%, tetraparesis in 50%, and the hypotonic form of cerebral palsy in 39%. Only 14% of children had no significant motor disorders verified [213–215].

Psychomotor retardation, seizures, periventricular leukomalacia, increased intracranial pressure, hydrocephalus, and cerebral palsy are detected in 35–40% of children with IVH [216,217]. The combination of perinatal intraventricular hemorrhages with lesions of the subcortical nuclei and cerebral cortex leads to the most severe consequences; the combination of lesions in these areas and the brainstem, as well as the periventricular region, leads to more severe sensorimotor deficits [218].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Ekaterina N. Balashova – Candidate of Medical Sciences, Leading Researcher, Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor of the Department of Neonatology; Member of the Council of the Russian Society of Neonatologists

2. Yulia K. Bykova – Candidate of Medical Sciences, Ultrasound Diagnostics Physician, Department of Ultrasound Diagnostics, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor of the Department of Pediatric Diagnostic Radiology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

3. Nikolay N. Volodin – Doctor of Medical Sciences, Academician of the Russian Academy of Sciences, Professor, President of the Russian Association of Specialists in Perinatal Medicine (RASPM), Head of the Department of Pediatrics, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev of the Russian Ministry of Health.

4. Lyubov D. Vorona – Candidate of Medical Sciences, Leading Researcher, Neonatologist, Pediatrician, Scientific and Practical Center for Specialized Medical Care for Children named after V.F. Voyno-Yasenetsky of the Moscow Healthcare Department; Assistant Professor of the Department of Hospital Pediatrics named after Academician V.A. Tabolin, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Member of RASPM.

5. Dmitry N. Degtyarev – Doctor of Medical Sciences, Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Head of the Department of Neonatology, Pediatric Faculty, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Council of the Russian Society of Neonatologists

6. Maria G. Degtyareva – Doctor of Medical Sciences, Professor of the Russian Academy of Sciences, Professor of the Department of Neonatology, Faculty of Continuous Professional Education, Pirogov Russian National Research Medical University of the Russian Ministry of Health

7. Maria V. Duminskaya – Neurologist, Department of Neonatal and Pediatric Neurology, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health

8. Viktor V. Zubkov – Doctor of Medical Sciences, Director of the Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor of the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Council of the Russian Society of Neonatologists

9. Aleksey E. Ermilin – Clinical Pharmacologist, Scientific and Practical Center for Specialized Medical Care for Children named after V.F. Voyno-Yasenetsky of the Moscow Healthcare Department; Assistant Professor of the Department of Clinical Pharmacology, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

10. Oleg V. Ionov – Doctor of Medical Sciences, Head of the Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor of the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Chairman of the Russian Society of Neonatologists

11. Anna R. Kirtbaya – Doctor of Medical Sciences, Head of Clinical Work, Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor of the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Council of the Russian Society of Neonatologists

12. Anna A. Lenyushkina – Candidate of Medical Sciences, Head of Neonatal Intensive Care Unit No. 2, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Member of the Council of the Russian Society of Neonatologists

13. Marina V. Narogan – Doctor of Medical Sciences, Leading Researcher, Department of Pathology of Newborns and Premature Infants, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Professor of the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Council of the Russian Society of Neonatologists

14. Andrey G. Prityko – Doctor of Medical Sciences, Professor, Neurosurgeon, Scientific and Practical Center for Specialized Medical Care for Children named after V.F. Voyno-Yasenetsky of the Moscow Healthcare Department.

15. Alesya A. Rudakova – Senior Researcher, Anesthesiologist-Intensivist, Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Member of the Russian Society of Neonatologists

16. Olga I. Sapun – Head of Neonatal Intensive Care Unit No. 2, Children's Regional Clinical Hospital, Krasnodar; Chief freelance Neonatologist of the Ministry of Health of Krasnodar Krai; Member of the Council of the Russian Society of Neonatologists

17. Yanina S. Solovyova – Neonatologist, Scientific and Practical Center for Specialized Medical Care for Children named after V.F. Voyno-Yasenetsky of the Moscow Healthcare Department.

18. Lyubov V. Ushakova – Candidate of Medical Sciences, Neurologist, Head of the Department of Neonatal and Pediatric Neurology, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

19. Elena A. Filippova – Candidate of Medical Sciences, Head of the Department of Ultrasound Diagnostics, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.

20. Diyana R. Sharafutdinova – Candidate of Medical Sciences, Senior Researcher, Anesthesiologist-Intensivist, Prof. A.G. Antonov Neonatal Intensive Care Unit, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health; Associate Professor of the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University); Member of the Russian Society of Neonatologists

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the guidelines included publications from the Cochrane Library, PubMed, EMBASE and MEDLINE, Scopus, Web of Science, eLibrary, ClinicalTrials.gov, electronic libraries, and clinical guidelines published by The National Institute for Health and Care Excellence, The European Association of Perinatal Medicine, The European Society for Pediatric Research, The European Foundation for the Care of Newborn Infants, and The European Society for Neonatology. The search depth was 45 years.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with the rating scheme.

Scales for assessing levels of evidence (LoE) (Table P1) for diagnostic, preventive, therapeutic, and rehabilitation methods (diagnostic, preventive, therapeutic, and rehabilitation interventions) with definitions, and the scale for assessing grades of recommendation (GoR) (Table P2) for preventive, diagnostic, therapeutic, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions).

Methods used for analyzing evidence:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

When selecting publications as potential sources of evidence, the methodology used in each study was reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not evaluated.

Method of guidelines validation:

• external expert review;

• internal expert review.

Description of the guidelines validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

Recent changes in these guidelines are presented for discussion in a draft version. The updated version for broad discussion was posted on the websites of the Russian Society of Neonatologists (RSN) and the Russian Association of Perinatal Medicine (RAPM) www.neonatology.pro and www.raspm.ru so that all interested parties could take part in discussing and improving the guidelines.

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience for these clinical guidelines:

1. neonatologists

2. anesthesiologists-resuscitators

3. pediatricians

4. obstetricians and gynecologists;

5. neurologists

6. neurosurgeons

7. medical students

8. residents and interns

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Related Documents

1. Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

2. Order of the Russian Ministry of Health No. 203n of May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

3. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (World Health Organization), 2019 version.

4. Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on September 24, 2020, with rev. of October 26, 2022) "On Approval of the Nomenclature of Medical Services."

5. Decree of the Government of the Russian Federation No. 3053-r dated December 31, 2018 (as amended on February 20, 2024) "On Approval of the List of Medical Devices Implanted into the Human Body When Providing Medical Care Within the Framework of the State Guarantee Program for Free Medical Care to Citizens, as well as the List of Medical Devices Dispensed by Prescription for Medical Devices Upon Provision of a Set of Social Services."

6. Order of the Russian Ministry of Health No. 222n dated April 17, 2025 "On Approval of the Procedure for Providing Medical Care in the Field of Neonatology" (Registered with the Ministry of Justice of Russia on June 2, 2025, No. 82516).

7. On approval of the list of vital and essential drugs, as well as lists of medicinal products for medical use and the minimum range of medicinal products required for the provision of medical care (Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019).

Appendix A3.2. Classification of Intraventricular Hemorrhage

Classification of intraventricular hemorrhage [59–62]

Periventricular hemorrhagic infarction (PHI) – hemorrhagic necrosis of the periventricular white matter caused by impaired venous outflow through the terminal and medullary veins draining the cerebral white matter. PHI can be a complication of IVH, typically occurring from several hours to several days after the initial hemorrhage

Appendix A3.3 Cranial Ultrasound (Neurosonography)

When intraventricular hemorrhage is suspected, cranial ultrasound is performed using the standard technique [14, 47, 219–223].

Through the anterior fontanelle, by changing the position and tilt angle of the ultrasound transducer, the brain is examined in frontal (coronal), median (sagittal), and parasagittal sections. These sections clearly visualize the lateral and third ventricles of the brain, the periventricular and central regions of the frontal and parietal lobes, the thalami, and the basal ganglia. The germinal matrix region (the source of IVH in preterm neonates), located in the upper part of the caudotaminal groove, is targeted in the coronal section at the level of the interventricular foramina (Monro) and in the parasagittal section through the medial regions of the heads of the caudate nucleus and through the lateral ventricle.

Visualization of the occipital lobes and posterior cranial fossa structures through the anterior fontanelle is generally difficult due to the large depth of location and anatomical features of these regions. For a detailed assessment of these regions, brain scanning is performed via alternative acoustic windows. Through the posterolateral (mastoid) fontanelle, a more accurate image of the fourth ventricle, cerebellum, cisterna magna, as well as the lumen of the transverse and sigmoid sinuses can be obtained. The parenchyma of the occipital lobes and the posterior horns of the lateral ventricles are best visualized through the posterior (small) fontanelle. Through the anterolateral (sphenoid) fontanelle, the lumen of the third ventricle, cerebral aqueduct, thalami, midbrain, and temporal lobes of the hemispheres can be assessed in axial sections.

Ultrasound diagnostics of intracranial hemorrhage is based on identifying hyperechoic thrombi within the lumen of the CSF system or hyperechoic foci in the brain parenchyma. In ultrasound, structures or foci whose brightness exceeds or equals that of the choroid plexuses are referred to as hyperechoic.

Hyperechoic blood clots appear brightest in the acute stage of hemorrhage, i.e., between 4–6 hours and 3 days after the onset of bleeding. Later, as a result of lysis, the echogenicity (density) of the blood clots gradually decreases. In the subacute phase of hemorrhage, the thrombi become isoechoic and later hypoechoic (having a hypoechoic central part and hyperechoic margins). In the earliest, hyperacute phase of hemorrhage, uncoagulated blood mixed with CSF appears hypo- or isoechoic. The hyperacute phase of IVH can only be suspected when visualizing the movement of CSF particles in the ventricles and upon their acute dilation.

Thus, the ultrasound pattern of IVH changes over time and goes through the following stages: 1) anechoic stage (0–6 hours); 2) hyperechoic thrombus stage (up to 10 days); 3) isoechoic thrombus stage (11–20 days); 4) hypoechoic thrombus stage (up to 30–40 days); and 5) residual changes stage with the development of ventriculomegaly, intraventricular adhesions, etc., within 2–3 months.

The ultrasound characteristics of a blood clot make it possible to roughly determine the timing of hemorrhage development, which is especially important in antenatal IVH detected after the child's birth. Retrospectively diagnosing and suggesting an antenatal origin of IVH is possible upon detecting hyperechoic walls of the brain ventricles. Compaction of the ependymal layer occurs as a result of reactive (aseptic) ventriculitis 10–14 days after the development of IVH, and if it is detected in the first days after birth, one can conclude that its origin is antenatal. However, it should be borne in mind that a hyperechoic ependyma can also be a manifestation of septic ventriculitis in meningitis and meningoencephalitis.

The results of brain ultrasound make it possible to assess the severity of IVH, but concurrently existing different classifications define the grade of hemorrhage differently. The most modern and scientifically grounded classification by J. Volpe (2008) distinguishes 3 grades of germinal matrix hemorrhage: hemorrhage restricted to the germinal matrix is Grade I IVH, intraventricular hemorrhage without ventricular dilation is Grade II IVH, and hemorrhage with acute ventricular dilation is Grade III IVH.

Hyperechoic hemorrhagic foci in the periventricular zone in IVH were previously classified as Grade IV hemorrhage (Papille L. et al.). However, since these hemorrhagic foci are periventricular hemorrhagic infarction (PHI) associated with cerebral vein compression rather than a consequence of blood breakthrough from the ventricles into the parenchyma, they are not included in the modern IVH classification and are noted as a separate lesion.

Grade I IVH – hemorrhage limited to the germinal matrix (subependymal hemorrhage). There is no blood in the ventricular lumen or on the choroid plexus. On ultrasound, a subependymal hematoma is most frequently detected in the coronal section at the level of the foramina of Monro and in the parasagittal section passing through the medial parts of the head of the caudate nucleus as an oval hyperechoic focus located in the upper part of the caudothalamic groove. Much less frequently, in extremely preterm infants born before 27 weeks, a subependymal hematoma may be located posterior to the caudothalamic notch. The sizes of subependymal hematomas are variable; when large, they can compress the foramen of Monro and cause partial obstruction of the lateral ventricle. As a result of subependymal hemorrhage lysis, clot retraction and progressive decrease in its echogenicity occur. Large subependymal hematomas frequently liquefy with the formation of a subependymal cyst. Post-hemorrhagic subependymal cysts can be difficult to differentiate from congenital germinolytic cysts.

Grade II IVH – this is hemorrhage into the ventricular lumen without its acute dilation. Ultrasound of the non-dilated ventricle reveals a hyperechoic thrombus occupying less than 50% of the volume of the lateral ventricle. Grade II IVH is typically indicated by small thrombi located in the anterior horn of the lateral ventricle anterior to the foramen of Monro or in the occipital horn. In dubious situations, to improve visualization of the occipital horns and detect thrombi within their lumen, additional scanning should be performed through the posterior and posterolateral fontanelles. Identifying a small amount of blood in Grade II IVH can be challenging, as small thrombotic deposits can be difficult to reliably differentiate from the choroid plexus. An enlarged, asymmetrically hyperechoic, or "knobby" choroid plexus is suspicious for IVH. The use of power Doppler imaging (PDI) can help distinguish the vascularized choroid plexus from avascular thrombotic deposits.

In dubious cases, the diagnosis of IVH can be confirmed by detecting thickening of the walls of the lateral ventricles, which appears 10–14 days after the development of IVH. Grade II IVH usually resolves completely within a few weeks and rarely causes ventriculomegaly.

Grade III IVH is a massive hemorrhage into the ventricle that causes its acute dilation. Grade III IVH is diagnosed easier than Grade II IVH, since blood clots are easier to detect in dilated ventricles. Ventricular dilation in Grade III IVH occurs due to acute stretching of the ventricle by the extravasated blood; the volume of intraventricular hemorrhage reaches its maximum size within a few days. Thrombi in Grade III IVH are clearly visible, filling more than 50% of the lumen of one or both lateral ventricles (although measuring the volume of a blood clot by ultrasound is impossible). IVH is classified as Grade III if the ventricle has dilated within the first 3 days from the onset of bleeding and the anterior horn width (AHW) exceeds 6 mm. Acute ventricular dilation in Grade III IVH should be distinguished from post-hemorrhagic ventriculomegaly, which occurs later—7–10 days later due to obstruction of the CSF pathways or several weeks later due to hypersecretion and impaired CSF resorption.

Periventricular hemorrhagic infarction

Periventricular hemorrhagic infarction (PHI) is considered part of the IVH spectrum and typically develops within a few days of its onset. The development of PHI is caused by impaired venous outflow through the terminal veins, which leads to venous stasis and ischemia in the periventricular white matter followed by hemorrhagic imbibition. A characteristic ultrasound pattern of PHI is a hyperechoic zone with clear, uneven contours of a spherical or triangular ("fan-shaped") form in the periventricular white matter. PHI may present as a large or small hyperechoic focus in the white matter or as multiple small foci located along the course of the cerebral veins. PHI may or may not communicate with the lateral ventricle. The size and location of PHI depend on which vein is occluded. When a large number of veins are obstructed, extensive unilateral or bilateral PHI may develop.

Foci of hemorrhagic imbibition in PHI gradually lyse with cyst formation in the periventricular white matter. Spherical PHI more frequently transform into porencephalic cysts. Triangular PHI and microfocal infarctions usually turn into multiple cysts, non-communicating or partially communicating with the lateral ventricle, which can be mistaken for cysts in periventricular leukomalacia. Cysts resulting from PHI persist for a long time, often single and asymmetric. In contrast, cysts in periventricular leukomalacia (PVL) are usually symmetric, located predominantly in the posterior regions of the periventricular area, and typically disappear by 4-5 months of age.

Intraventricular hemorrhage in term and late preterm neonates is not included in the aforementioned classification of germinal matrix hemorrhage, as it has a completely different nature and source. It develops due to the rupture of choroid plexus veins, i.e., it is a hemorrhage from the choroid plexus. The cause of IVH in term neonates is most often birth trauma or cerebral sinovenous thrombosis, as well as severe coagulopathies. Ultrasound examination reveals hyperechoic blood clots within the ventricular lumen as thrombotic deposits on the choroid plexus or as separate thrombi. Dilation of the lateral ventricles in choroid plexus hemorrhage may vary, but is most often mild.

IVH associated with birth trauma is detected by brain ultrasound performed in the first days of the child's life, and is often combined with signs of subarachnoid hemorrhage (in the form of hyperechoic blood overflows deep into the sulci along the convexital and medial surfaces of the hemispheres). In severe birth trauma, IVH may also be combined with epidural and parenchymal hemorrhage.

Later development of IVH in term and late preterm neonates may be associated with cerebral sinovenous thrombosis. Ultrasound examination performed with a high-frequency linear transducer can detect thrombi in the lumen of the superior sagittal sinus or the transverse sinus (when examined through the posterolateral fontanelle). Thrombosis of the straight sinus and deep cerebral veins cannot be seen on ultrasound, but it can be suspected when IVH is combined with thalamic hemorrhage or hemorrhagic infarction in the deep white matter.

IVH in both preterm and term neonates can lead to the development of posthemorrhagic ventriculomegaly. Its formation and progression can be detected by serial measurements of the lateral ventricles. The most reliable parameters for assessing lateral ventricle size are the ventricular index (VI) and the anterior horn width (AHW), measured during a scan through the anterior (large) fontanelle in the coronal plane passing through the foramina of Monro.

The ventricular index (VI) is measured as the horizontal distance between the falx cerebri (the midline of the interhemispheric fissure) and the most lateral wall of the anterior horn in the coronal scanning plane at the level of the foramen of Monro. The ventricular index VI is usually measured separately for the left and right lateral ventricles, but a summation ventricular index can also be measured. The ventricular index increases with age (both gestational and postnatal). Enlargement of the lateral ventricles is diagnosed when the ventricular index value exceeds the 97th percentile.

The anterior horn width (AHW) is measured in the coronal plane at the level of the foramen of Monro as the maximum diagonal width of the anterior horn at its widest point. The anterior horn width is measured for both lateral ventricles; it does not change with age and in most healthy newborns does not exceed 3 mm. An anterior horn width of 6 mm or more is regarded as ventriculomegaly. During hydrocephalus development, the lateral ventricles become rounded, so the anterior horn width increases earlier than the ventricular index.

The absence of significant dilation of the anterior horns of the lateral ventricles sometimes leads to an underestimation of the severity of posthemorrhagic ventriculomegaly, since in hydrocephalus, the posterior horn and the atrium of the lateral ventricle dilate first. To assess the posterior regions of the lateral ventricles in the parasagittal plane, the thalamo-occipital distance (TOD) is measured.

General signs of severe posthemorrhagic ventriculomegaly include rounding of the upper border of the frontal horns of the lateral ventricles in coronal planes ("ballooning") and rounding of the anterior contour of the third ventricle in the sagittal plane.

Transcranial duplex scanning of arteries and veins (ultrasound Dopplerography) in infants allows the assessment of blood flow status in the anterior, middle, and posterior cerebral arteries, deep cerebral veins, superior sagittal, straight, and transverse sinuses. Severe grades of IVH and periventricular hemorrhagic infarction are accompanied by changes in cerebral blood flow and Doppler parameters, but the nature and severity of these changes depend on many factors. Against the background of an unformed autoregulation system in preterm infants, Doppler parameters are affected, in addition to IVH, by the presence of a hemodynamically significant patent ductus arteriosus, pulmonary hypertension, decreased myocardial contractility, changes in blood gas composition and pH, intracranial hypertension, concomitant somatic diseases, medications used, and many other factors. Therefore, routine determination of cerebral artery blood flow Doppler parameters for predicting brain injury and long-term neurological developmental outcomes in preterm infants has low informational value. Most frequently, in the hyperacute phase of massive IVH, vasodilation and decreased peripheral resistance indices in the cerebral arteries are noted. On days 2-3 after the development of IVH, vasoparesis is replaced by vasospasm, and peripheral resistance indices increase. The severity and duration of vasospasm in IVH are variable. The most persistent and severe vasospasm develops against the background of progressive posthemorrhagic hydrocephalus.

Appendix A3.4 Blood Pressure (mmHg)

Blood pressure parameters (Zubrow AB. et al. 1995)

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Intraventricular hemorrhage (IVH) is bleeding into the cerebral ventricles. The brain ventricles (there are 4 of them) are filled with cerebrospinal fluid (CSF). CSF is a unique biological fluid, different from all other body fluids, necessary for the proper functioning of brain tissue. CSF is produced in the brain ventricles, then flows into the subarachnoid spaces of the brain and spinal cord, where it is absorbed into the circulatory system.

Due to immaturity, preterm infants are at risk of rupture of fragile brain blood vessels and the development of cerebral hemorrhage, most commonly occurring in the brain ventricles. The lower the gestational age of the infant, the higher the incidence of IVH. The occurrence of IVH is especially high in infants born before 28 weeks of gestation. As a rule, IVH develops within the first 3 days after the child's birth.

IVH is diagnosed using brain ultrasound (neurosonography - NSG). Diagnosis and treatment of IVH are carried out in a hospital setting. There are three grades of IVH.

Grade 1 IVH is a small hemorrhage that does not lead to complications and does not require treatment. However, repeat neurosonography is necessary to ensure that the hemorrhage does not progress and subsequently enters the resolution stage. Grade 1 IVH has no adverse effect on the child's development. After discharge from the hospital, routine follow-up by a local pediatric neurologist is required.

Grade 2 and especially Grade 3 IVH are more significant hemorrhages that can both affect the child's condition and lead to complications. In Grade 2 IVH, blood is poured into the ventricle, which may cause an increase in ventricular size (ventriculomegaly). In Grade 3 IVH, hemorrhage occurs into both the ventricle and the surrounding brain tissue (periventricular region). The development of Grade 2 and 3 IVH can worsen the child's general condition, lead to apnea and cardiac dysfunction. Seizures may also develop. Treatment is carried out in a hospital, in specialized departments, taking into all developing symptoms.

With massive bleeding into the brain ventricles, the risk of the main complication—obstructive hydrocephalus—increases. Unfortunately, there are currently no means available to prevent this complication.

Obstructive hydrocephalus (water on the brain) is characterized by progressive ventricular dilation resulting from impaired cerebrospinal fluid (CSF) outflow. Blockage of the CSF pathways occurs due to the proliferation of certain cells in the ventricular walls under the irritating influence of blood and its breakdown products. Thus, CSF continues to be produced in the cerebral ventricles, but because the outflow pathways are blocked, CSF accumulates increasingly within the ventricles, leading to their progressive enlargement and elevated intracranial pressure. In such cases, neurosurgical intervention is required. Initially, ventricular punctures (tapping the brain ventricles) may be performed to remove excess CSF, and temporary drains (tubes for CSF diversion) may also be placed in the ventricle. Once the infant's condition permits, the main stage of neurosurgical treatment is performed to ensure permanent CSF diversion from the ventricles.

The neurodevelopmental prognosis for a child with grade 2 and 3 IVH is determined by the extent of brain tissue damage and the presence of obstructive hydrocephalus. With grade 2 IVH without hydrocephalus, the probability of subsequent favorable development is high. With grade 3 IVH, as well as in the event of developing obstructive hydrocephalus, the risk of psychomotor developmental delay, cerebral palsy, and epilepsy increases.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Apgar scoring of the newborn

Russian title: Newborn evaluation using the Apgar score ⁴

Original title: The Apgar Score

Source (official developer website, validated publication): Apgar V, Holaday DA, James LS, Weisbrot IM, Berrien C. Evaluation of the newborn infant-second report. JAMA. 1958; 168 (15): 1985–1988. doi:10.1001/jama.1958.03000150027007 [224]

Type: rating scale

Purpose: assessment of the newborn's condition after birth

Content (template):

Apgar score interpretation key

A score of 4–7 points at 1 minute after birth corresponds to mild to moderate birth asphyxia (P21.1), and 0–3 points at 1 minute corresponds to severe asphyxia (P21.0). Despite the fact that according to ICD-10 a total of 7 points at 1 minute after birth corresponds to mild to moderate asphyxia, it is inadvisable to assign this diagnosis, since an Apgar score of 7 points by the end of the 1st minute is not clinically and/or prognostically significant.

⁴ Methodological letter "Resuscitation and stabilization of newborn infants in the delivery room". Edited by E.N. Baybarina. Moscow: Russian Ministry of Health; 2020.