Final Master thesis DEPARTMENT OF NEONATOLOGY Sara Bergstrom Medical Faculty

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Final Master thesis

DEPARTMENT OF NEONATOLOGY

Sara Bergstrom

Medical Faculty

Risk factors of intraventricular hemorrhage in extremely

premature neonates

Supervisor: Prof. Dr. Rasa Tamelienė

Lithuanian University of Health Sciences

KAUNAS 2019

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SUMMARY

Author’s name and surname: Sara Bergstrom

Research title: Risk factors of intraventricular hemorrhage in extremely premature neonates. Aim: To determine the incidence and analyze neonatal and maternal risk factors of intraventricular

hemorrhage (IVH) in extremely premature neonates (gestational age (GA) <28 weeks). Since no absolute treatment is available, identifying risk factors is important in the development of effective prevention strategies of IVH.

Objectives:

1. To determine the incidence of IVH among the collected infants.

2. To collect neonatal and maternal factors of all extremely premature neonates born during 2016-2017 in Kaunas Clinics of Lithuanian University of Health Sciences (LUHS). To state the significance of the investigated factors.

3. To evaluate and draw conclusion of the collected data.

Methodology and study participants: This study is a retrospective case-control of 60 preterm infants

(22-27 weeks of gestation) born between Jan 2016-Dec 2017 in Kaunas Clinics (LUHS). The study was performed in the department of Neonatology in Kaunas Clinics (LUHS). Infants were divided into 2 groups: case group with IVH (n=37) and control group without IVH (n=23). Diagnosis of IVH was made by cranial ultrasonography during the first days of life and graded according to Papile criteria.

Results: Incidence of IVH was 62%. It is a significant difference of lower GA and birth weight (BW)

between the case and control group (p= 0,002 and p= 0,01 respectively). Presence of IVH was linked to infection of the infant (p=0,001), anemia of the infant (p=0,001), vaginal delivery (p=0,002), male gender (p=0,034), maternal infection (p=0,05) and lumbar puncture (p=0,02). Low Apgar score and maternal age >35 were not significant risk factors. C-section was a protective factor for IVH (OR= 0,18, CI=0,05-0,59, p=0,157).

Conclusions: The lower the birth weight increases the risk of IVH. Infection of the infant, maternal

infection, lumbar puncture, vaginal delivery, male gender, lower BW and low GA are significant risk factors for IVH in extremely preterm neonates. Cesarean section can be advantageous for infants <28 weeks’ GA, although it is associated with its own risk factors and should not be recommended without other indication. Anemia of the infant is significantly associated with IVH although, based on this study, it cannot be defined whether it contributes to or is a result of the bleeding itself.

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ACKNOWLEDGEMENTS

I would like to thank my supervisor for the support and guidance along the writing of this final master thesis. I would also like to thank the staff of the neonatology and gynecology department for taking their time to help me use the database programs. And finally, I would like to thank Fredrik Lundin, Dr in statistics, for helping me with my final statistical calculations.

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CONFLICTS OF INTEREST

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PERMISSION ISSUED BY THE ETHICS COMMITTEE

The study “Risk factors of intraventricular hemorrhage in extremely premature neonates” was approved by the Ethics committee of Lithuanian University of Health Sciences on 2018-11-12 with the verification number: BEC-MF-83.

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LIST OF ABBREVIATIONS

IVH Intraventricular hemorrhage GA Gestational age

LUHS Lithuanian University of Health Sciences BW Birth weight

VPT Very preterm EPT Extremely preterm LBW Low birth weight VLBW Very low birth weight ELBW Extremely low birth weight SGA Small for gestational age LGA Large for gestational age CBF Cerebral blood flow

PVHI Periventricular hemorrhagic infarction PVL Periventricular leukomalacia

NDI Neurodevelopmental impairment GMH Germinal matrix hemorrhage

GM-IVH Germinal matrix intraventricular hemorrhage CSF Cerebrospinal fluid

PHVD Post hemorrhagic ventricular dilatation PHH Post hemorrhagic hydrocephalus WMI White matter injury

PMA Post menstrual age

ICP Increased intracranial pressure CT Computed tomography

rEPO Recombinant erythropoietin NICU Neonatal intensive care unit

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INTRODUCTION

During the last decades the survival of preterm infants has increased markedly. This is mainly due to improvements of perinatal medicine and neonatal intensive care. Nonetheless, the incidence of CNS lesions remains high among the preterm survivors [1, 2]. Intraventricular hemorrhage (IVH) is a known major cause of morbidity and mortality among these infants. Neurological manifestations of IVH can be both cognitive and motor disabilities. It is one of the major causes of cerebral palsy and mental retardation, with the incidence mainly ranging between 15-40% depending on the center [2]. Some studies have even reported as high incidences as 50-80% when considering all grades of IVH [28]. Furthermore, the treatment of an infant with IVH constrains a great economic burden on health services [1].

More than 50% of bleedings occur during the first 24 hours of life [3, 4], with <5% occurring after day 4/5 [4]. This makes the first week of life the highest risk period for bleeding and by the end of this week, 90% of hemorrhages can be detected at their full extent. This risk period is independent of gestational age (GA). When aiming to prevent injury, knowledge of the risk period is critical for success [5]. Intraventricular hemorrhage (IVH) is the most common form of bleeding into the central nervous system in infants and, although the incidence of IVH is

decreasing, it remains a serious problem in the preterm neonate [6-8].

Identifying the risk factors for IVH has the potential to allow for the development of effective prevention strategies of many neurodevelopmental problems of prematurely born infants. Several risk factors have been proposed for the development of IVH: low birth weight and

gestational age, maternal smoking, male gender, low Apgar score, intrauterine infection, vaginal delivery, prolonged labor, postnatal resuscitation and intubation, early onset sepsis [2], respiratory distress syndrome or pneumothorax, metabolic acidosis and rapid bicarbonate infusion and high-frequency ventilation. Pregnancy-induced hypertension is associated with a lower rate of IVH. For reducing the incidence of IVH, several pharmacological interventions have been proposed,

including antenatal steroids, prenatal tocolytic therapy, postnatal administration of low-dose indomethacin and surfactant [4].

In this investigation, I have assessed some associated risk factors of IVH in premature neonates to constitute a base for the development of prevention strategies.

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AIM AND OBJECTIVES

The aim of this study is to determine the incidence and analyze neonatal and maternal risk factors of intraventricular hemorrhage (IVH) in extremely premature neonates (gestational age (GA) <28 weeks). Since no absolute treatment of IVH is available, identifying risk factors is important for the development of effective prevention strategies of IVH.

Objectives:

1. To determine the incidence of IVH among the collected infants.

2. To collect neonatal and maternal factors of all extremely premature neonates born during 2016-2017 in Kaunas Clinics of LUHS. To state the significance of the investigated risk factors. 3. To evaluate and draw conclusion of the collected data.

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1. REVIEW OF LITERATURE

1.1 Terminology of neonatal maturity

There are several definitions that are important when discussing time of birth.

Gestational age is defined as the age of the fetus in terms of pregnancy duration in weeks and is measured from the first day of the last menstrual period. Gestation is recorded as completed weeks and never rounded up. For example, an infant who is born at 26 weeks and 5 days is defined as being 26 weeks. “Term” birth is classically defined as 37 to 42 weeks [9]. “Preterm birth” is defined as a birth that occurs before 37 completed weeks (less than 259 days) of gestation [9, 10]. Preterm birth is often further subdivided into a classification based on GA as follows: “Late

preterm” infants are those with a GA between 34 and <37 weeks, “moderate preterm” infants has a GA between 32 and less than 34 weeks, “very preterm” (VPT) infants has a GA between 28 and less than 32 weeks, and “extremely preterm” (EPT) which is the primary focus of this discussion, is less than 28 weeks gestational age [9-11]. Infants who are extremely preterm have the highest mortality rate (approximately 50 percent) and if they survive, also have the greatest risk for severe impairment [10]. Worldwide, most preterm births are late preterm [9].

Another classification is according to birth weight (BW), often associated with

prematurity, is as follows: “low birth weight” (LBW) infants has a BW less than 2500 g, “very low birth weight” (VLBW) infants has a BW less than 1500 g and, “extremely low birth weight”

(ELBW) infants has a BW of less than 1000 g [10, 11]. Classification of maturity according to time and BW are listed in Table 1.

Label Definition (week’s completed gestation)

Extremely preterm <28 Very preterm 28 to <32 Moderate preterm 32 to <34 Late preterm 34 to <37 Early-Term 37 to <39 Term 38 to <41 Late-Term 41 to <42 Post-Term >42

SGA Weight less than 10th_{percentile for}

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LGA Weight greater than 90th_{percentile for}

gestational age

VLBW Less than 1500 grams

ELBW Less than 1000 grams

Table 1 List of definitions ofterms related to maturity and time of birth.

Another central definition includes “small for gestational age” (SGA), which is defined as weight less than 10th percentile at a given fetal gestational age. Viability is defined as the GA where there is a 50 percent chance of survival with or without medical care. The viability in developed, high income countries is somewhere between 22-24 weeks. In low -and middle-income countries the viability is closer to 34 weeks GA [9].

1.1.1 Apgar score

The Apgar score provide an established and convenient method for reporting status of the newborn infant immediately after birth and the response to resuscitation if needed. The Apgar score comprises 5 components: (1) color; (2) heart rate; (3) reflexes; (4) muscle tone; and (5) respiration. Each of the components gives a score of 0, 1, or 2. Thus, the Apgar score provides a standardized assessment that measures the clinical signs of neonatal depression, such as cyanosis or pallor, bradycardia, hypotonia, depressed reflex response to stimulation, apnea or gasping respirations. The score is described at 1 minute and 5 minutes after birth for all infants. For infants with a 5-minute score less than 7, the points are reevaluated every 5th minute until 20 minutes [12]. An infant who scores 7 or above is generally considered in good health.

1.2 Incidence and epidemiology of IVH

Intraventricular hemorrhage (IVH) is a major complication of prematurity, and the incidence increases with decreasing gestational age (GA) and birth weight (BW). The highest incidence of IVH is seen in very low birth weight (VLBW; BW<1500 g) and/or very preterm infants (GA<32 weeks). However, the incidence of IVH has decreased over the last decades including in extremely preterm infants (GA <28 weeks) who are the most susceptible population [2].

Preterm birth rate varies throughout the world. The highest rate of premature birth (close to 18%) is noted in Southeastern Asia. Preliminary data for 2012 show a preterm birthrate of 11,5%, compared to a maximum of 12,5% in 2009. The subgroup of extremely preterm births

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comprises approximately 6% of all preterm births and are less than 1% of all births [9]. As well as the incidence of preterm births, the incidence of infants with IVH have had a decreasing trend over the last decades. Among very low birth weight infants (infants birth weight [BW] <1500 g) IVH appears in approx. 20-25% [3].

1.3 Pathogenesis of IVH

The first postnatal week make up the highest risk period for IVH. IVH characteristically initiates in the periventricular germinal matrix and blood may then rupture into the ventricular system [5, 13]. There are three main mechanisms of IVH in the preterm: disturbances of the cerebral blood flow, inherent fragility of the germinal vasculature, and platelet/coagulation disturbances [1, 14]. The germinal matrix is a highly vascular collection of future neuronal and glial cells in the immature brain. In preterm infants, these micro vessels are immature which means that they are lacking a sufficient basement membrane deposition, tight junctions, and glial endfoot investiture. Thus, all components of a competent blood brain barrier [5, 13]. Preterm infants are also particularly vulnerable to alterations in cerebral blood flow (CBF) because they have impaired autoregulation of CBF compared with term infants. The preterm infant has a pressure-passive circulation causing the infant not being able to sustain a constant CBF during changes of systemic blood pressure. The deficient structural support system makes the germinal matrix vulnerable to hemorrhage and injury especially when there is hemodynamic instability [15]. Factors that often are associated with prematurity and have been implicated in CBF fluctuations are anemia, hypotension, hypoxemia, hypercapnia, acidosis, [5, 13, 15] and abrupt elevations of systemic blood pressure (due to noxious stimuli, rapid volume expansion with fluid boluses, and seizures) [15]. The periventricular region is especially vulnerable to hemorrhage in premature infants during the first 48 hours of life [5]. When the hemorrhage in the germinal matrix is significant, the ependyma breaks and blood may rupture into the ventricular system [13, 15].

Summarized, IVH is typically a progression of germinal matrix hemorrhage and the etiology of IVH is multifactorial and is primarily attributed to the intrinsic fragility of the germinal matrix vasculature and the disturbance in cerebral blood flow. Hence, the rapid stabilization of the angiogenic vessels and the restoration of normal cerebral blood flow on the first day of life are potential strategies to prevent IVH in premature neonates [5].

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1.4 Risk factors and prevention

Knowledge about the etiology plays a central role in the identification and assessment of risk factors of IVH of the premature infants. As seen, IVH is a multifactorial disorder, of which the most important risk factors are prematurity and low birth weight [15]. Risk factors that appears to induce IVH primarily by disturbing the cerebral blood flow includes: vaginal delivery, prolonged delivery, low Apgar score (below 4 in the first minute or below 7 in the fifth minute), severe respiratory distress syndrome, hypoxia, pneumothorax, hypercapnia, early sepsis, seizures,

metabolic acidosis, patent ductus arteriosus, low GA, low BW, hypotension in the first 24 hours of life requiring therapeutic intervention, maternal chorioamnionitis/infection, antenatal maternal hemorrhage, absence of antenatal steroid exposure, treatment with pressors, or delayed surfactant administration. Platelet and coagulation disorders such as thrombocytopenia and low hematocrit contributes to IVH by causing hemostatic failure [3, 5, 13, 15-17]. Limited data also suggests that there is a genetic predisposition by hemostatic gene mutations in both preterm and term infants [15].

To address the massive societal and financial burden of IVH, both pharmacologic and care-oriented prevention strategies have been implemented, including antenatal steroids, prenatal tocolytic therapy, postnatal administration of low-dose indomethacin and surfactant [3, 13]. Antenatal steroid therapy for mothers of high risk of preterm delivery has repeatedly been shown to decrease the risk of IVH, even in pregnancies complicated by chorioamnionitis. Infants who require transport are more likely to develop IVH, thus maternal transport should strongly be

considered. Off-peak delivery (delivery between midnight and seven o’clock am) is an independent reported risk factor which may reflect a poorer quality of resuscitation efforts during this time period resulting in an increased risk of IVH [15].

The most effective strategy for prevention of IVH is prevention of preterm birth, a goal that has not yet been met. Considering that IVH has a perinatal onset and can progress until the end of the first postnatal week, prevention should start from the antenatal period and continue. Among antenatal pharmacologic interventions, corticosteroids are confirmed to reduce both severity and incidence of IVH. Other medications, such as phenobarbital, magnesium sulfate, vitamin K, and indomethacin prophylaxis have not seemed to reduce the risk of IVH and, is therefore not used as routine prophylaxis [15, 18]. Prevention guidelines for IVH in the neonatal period still remain an issue of strong controversial debate [1].

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1.5 Severity and grading of IVH

The most commonly used system is the grading system proposed by Burstein, Papile et al. based on sonography. The severity of the IVH in the preterm infants is based on the presence and extent of blood in the germinal matrix and lateral ventricles, evidence of white matter injury, and the presence of ventricular distension, demonstrated by the cranial ultrasound. IVH is

accordingly described in four grades: Grade I- Bleeding is confined to the germinal matrix. Grade II- The hemorrhage occupies less than 50 percent of the ventricle volume and without distension of the ventricular system. Grade III- The hemorrhage occupies more than 50 percent of the lateral ventricle volume and is associated with acute ventricular distension. Periventricular hemorrhagic infarction (PVHI; previously referred to as Grade IV IVH)- Hemorrhagic infarction in the

periventricular white matter ipsilateral to large IVH. The most common forms are Grade I and II, which are referred as mild IVH and are often with no further complications. Grade III and grade IV (PVHI) are defined as severe and have a poorer long-term neurodevelopmental outcome than patients with mild IVH [3, 6, 13, 15]. Each grade of IVH may be unilateral or bilateral, with either symmetric or asymmetric grades of IVH [15].

In the newborn period, 5-10% of preterm infants with severe IVH suffer seizures and as many as 50% develop post hemorrhagic hydrocephalus [3, 6, 15].

Studies have shown that mortality is higher in infants with grade III-IV IVH than in GA-matched subjects without grade III-IV IVH. Grade III-IV IVH are considered major determinants of poor later neurodevelopmental outcomes, including cerebral palsy and subnormal cognitive function. Post-hemorrhagic hydrocephalus and periventricular leukomalacia are two significant sequelae of severe IVH. The white matter injury, which accompanies IVH, is believed to represents the major cause of the neurodevelopmental impairments (NDIs) suffered by these infants [3].

1.6 The diagnosis and screening for IVH

1.6.1 Ultrasonography

Ultrasound uses sound waves to create a picture of internal structures. An ultrasound scan is the most commonly used modality for the diagnosis of cerebral lesions in preterm infants. A cranial ultrasound can view the internal cerebral structures through the fontanelles of the infant. It is the preferred imaging modality because of its high sensitivity for detecting acute IVH, its ease of portability (bedside imaging), and lack of ionizing radiation [6, 15, 17, 19]. IVH is the most commonly recognized cerebral lesion on ultrasound in extremely preterm infants [19]. But, the reliability in grading mild hemorrhage by cranial ultrasound is low [28]. Because the germinal

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matrix hemorrhage (GMH) is usually diagnosed during the first 72 postnatal hours, that is the optimal time to perform ultrasound scans [19]. Coronal and parasagittal ultrasound views are obtained to identify blood in the germinal matrix, ventricles, or cerebral parenchyma, and any other echogenic abnormalities. With the ultrasonography, the amount of bleeding can be graded (Papile’s grading) according to its severity based on the location and extent of the GMH-IVH and its

presence of ventricular dilation. A higher grade of IVH represents an increased severity [15]. Picture 1-4 illustrates grade I-IV IVH as seen with the ultrasound in coronal and parasagittal view.

Picture 1 Cranial ultrasound images of a preterm infant (GA 27 weeks), with bilateral grade I

GMH. Coronal view (A) and parasagittal view (B) showing the GMH as an area of increased echogenicity (arrows) [15].

Picture 2 Cranial ultrasound images of a preterm infant (28 weeks gestation) with a grade II

GMH-IVH on the left side (arrows). Coronal view (A) showing that the left ventricle is larger than the right one. Parasagittal view (B) showing that the GMH and blood in the occipital horn [15].

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17 Picture 3 Cranial ultrasound images of a preterm infant (29 weeks gestation) with a bilateral

grade III GMH-IVH (arrows) with acute dilatation due to a large clot in both ventricles. Coronal view angling backwards (A) and parasagittal view (B) [15].

Picture 4 Cranial ultrasound images of a preterm infant (26 weeks gestation), with a left-sided

periventricular hemorrhagic infarction (PVHI; arrows). Coronal (A) and parasagittal (B) views. Magnetic resonance image at 30 weeks postmenstrual age of the same infant, showing the left-sided PVHI with cystic evolution (arrows). Axial (C) and parasagittal (D) views [15].

Because of that up to one-half of GMH-IVH cases are clinically silent, routine ultrasound screening should be performed in preterm infants. It is the method of choice for diagnosis and

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follow-up, since its low cost and is easily performed [17]. The Practice Committee of the Child Neurology Society and the Quality Standards Subcommittee of the American Academy of Neurology published the following recommendations:

• Routine ultrasound screening should be performed on all infants with a GA less than 30 weeks.

• Screening should be made at 7 to 14 days of age and repeated at 36 to 40 weeks postmenstrual age (PMA) (estimated GA based upon completed weeks from the mother’s last menstrual period).

• Ultrasound screening should be considered in all infants with abnormal clinical signs, high severity of illness, or other major risk factors.

A delay of the initial ultrasound screening and limited number of subsequent imaging can stand in the way of an early detection of GM-IVH and its associated complications. Optimal management is dependent on early detection prior to the onset of clinical symptoms of increased intracranial pressure (ICP) [6, 13].

1.6.2 Other modalities

Other possible radiographic studies include: Magnetic resonance imaging (MRI) which is better than ultrasound at detecting white matter lesions, hemorrhagic lesions, and peripheral areas of infarction. But because of that many infants are not stable enough to be taken to the MR as well as the requirement of nonmetallic monitoring etc. MRI is not the initial preferred diagnostic imaging modality. Computed tomography (CT) is not recommended especially in view of the exposure to ionizing radiation and is thus generally avoided. Only in the case of emergencies (eg. neurosurgical emergency) a CT should be considered, or when other imaging modality is not available [6, 13].

1.7 Management and treatment of IVH

Although the care of the sick and premature infants has advanced greatly, there is no specific therapy to limit the extent of IVH after it has occurred. Management of IVH is mainly supportive and directed towards the preservation of cerebral perfusion and minimization of any further brain injury. General measures include maintenance of arterial perfusion to avoid hypotension or hypertension to preserve the cerebral blood flow, adequate oxygenation and ventilation to avoid hypercarbia, hypocarbia, and acidosis and the provision of appropriate fluid,

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metabolic, and nutritional support. Seizures should be treated to avoid any associated impairment of cerebral oxygenation and cerebral perfusion, or elevations of systemic blood pressure [15]. Early detection of complications including the major one, posthemorrhagic ventricular dilation (PHVD), is of great importance. Cranial ultrasound should be performed twice per week and is the most important monitoring since serial studies can detect early and asymptomatic PHVD. Late manifestations of PHVD are signs and symptoms of increased intracranial pressure (ICP) and head circumference. Although it is relatively uncommon [15].

Recombinant erythropoietin (rEPO) has appeared to decrease the incidence of severe GM-IVH, and a limited data suggests that the use of rEPO improves neurodevelopmental outcome in preterm infants. But still, clinical trials confirming the long-term benefit are needed before rEPO can be recommended as routine therapy for patients with GM-IVH [10]. Occasionally surgery is necessary to stabilize the condition of the infant which most commonly involves placing a shunt from the skull of the infant [6].

1.8 IVH importance of adverse neurodevelopmental outcome

GM-IVH remains a common problem of preterm infant and is commonly associated with significant neurodevelopmental disability as the neonatal period is a critical window for brain development [18, 20]. Approximately 35-40% of infants will suffer from neurodegenerative delays, seizures, hydrocephalus, increased intracranial pressure, periventricular leukomalacia, and cerebral palsy. Mortality ranges from 30-60% [18]. Along with the dramatic improvement in survival rate of extremely preterm infants, there is great interest in their long-term prognosis [21-22]. The neurodevelopmental outcomes in neonates with GM-IVH are determined by the maturity of the brain, the specific underlying etiology, the location and extent of the hemorrhage and the presence of other concomitant disorders [20]. Several earlier studies have reported that cognitive outcome may be directly related to gestational age at birth, recent data also suggest that medical risk factors may be equally important predictors of neurologic outcome [1].

The lifetime costs of children with severe IVH are significant. Extended efforts to prevent severe IVH in preterm infants are needed [3, 13]. Data from the U.S. Census Bureau, the NICHD Neonatal Network and the Centers for Disease Control, there are over 3600 new cases of mental retardation attributable to IVH in the United States each year, and the lifetime care costs for these children exceeds 3,6 billion dollars [13].

Outcomes of IVH can be divided into short-term and long-term sequelae. The two most significant among short-term sequelae of IVH are post-hemorrhagic hydrocephalus (PHH) and periventricular leukomalacia (PVL) [13, 15]. Patients with PHH usually present with rapidly

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increasing head circumferences, enlarging ventricles on radiologic examination and signs of increased intracranial pressure. Because of the compliance of the neonatal brain the signs and symptoms of hydrocephalus may not be evident until several weeks post-hemorrhage. Most of the PHH are thought to be secondary to the impaired CSF reabsorption after blood is introduced into the CSF [13].

Infants with severe IVH (grades III and IV) are at risk of having white matter injury (WMI). The most common form of WMI is diffuse gliotic damage, PVL is a less common manifestation of WMI. PVL is typically defined as multiple cystic foci in the periventricular cerebral white matter, and on histology demonstrate coagulation necrosis and loss of cellular architecture, which may be long lasting. When PVL follows IVH, it is related to the decrease in blood flow that occasionally come with the introduction of blood into the CSF. The clinical

presentation of PVL lesions depends on its severity and location, it may range from spastic diplegia to decreased visual fields and cognitive impairment. Many investigators believe that it is the white matter injury which may accompany severe IVH that represents the major cause of the

neurodevelopmental impairments suffered by these infants [13].

Finally, grade IV IVH can also result in porencephaly independent of PVL and/or PHH. They are hemispheric cavitary lesions that generally communicate with the ventricular system, even though porencephaly rarely may present as a fluid-filled cyst that obstructs the ventricular system and may present with symptoms of increased intracranial pressure [13].

Increased severity of GM-IVH and decreasing GA increases the mortality and worsens the long-term outcome of infants who survive with GM-IVH. In a study from the Netherlands the mortality was almost 30% for neonates with grade III and 20% for those with PVHI. It remains controversial whether infants with mild GM-IVH are at increased risk for long-term NDI [15].

Because of the high risk of adverse outcomes in preterm infants and the economic burden, the discussion about resuscitation of these extremely premature infants is controversial. The recommendations for resuscitation of the extremely premature infants varies widely amongst the highly developed countries, but there is a general agreement for comfort care at 22 weeks’ GA and active care at 25 weeks’ GA [23]. In Lithuania active treatment is given from 22 weeks’ GA [24].

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2. RESEARCH METHODS AND MATERIALS

2.1 Ethical perspective of collection

The study protocol was reviewed and approved by the LUHS Kaunas Clinics ethics committee. The identification of infants and their respective mother have been protected by not collecting any sensitive data, such as names or date of birth.

2.2 Sample collection

2.2.1 Inclusion criteria

All extremely premature infants (GA <28 weeks) born at Kaunas Clinics (LUHS) between January 2016 to December 2017 were included in the study. All the included infants have been hospitalized at the Neonatal Intensive Care Unit (NICU) and underwent at least one cranial ultrasound.

2.2.2 Exclusion criteria

Initially 82 infants were collected from Kaunas Clinics (LUHS) NICU database. 14 infants were thereafter excluded from the study because of that they were born in other hospital, a fact that made it not possible to identify the mothers of the infants, thus maternal risk factors could not be assessed. Another 6 infants were excluded since cranial ultrasound not had been performed, in most cases this was due to early postnatal death. Another 2 infants, twins, had to be excluded from the study since the mother could not be found in the database. This left the study with a total number of 60 included infants as illustrated in Figure 1.

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22 Figure 1 The collection of the study population according to the criteria.

2.2.3 Study population

I identified the infants using the Kaunas Clinics (LUHS) NICU clinical database. 7 variables of the infants were assessed: gender, gestational age, birth weight, Apgar score, IVH status, infections and anemia. Maternal factors include the age of the mother, way of delivery, the presence of infection, hypertension, preeclampsia and diabetes. Birth weight of the infant were divided into three classes: <500 g, <1000 g and <1500 g. Low Apgar score was defined as a score of <7 at 5 minutes of life [8, 25]. Infections of the infants include sepsis, meningitis and/or

pneumonia, the diagnosis was based on clinical suspicion supported by fever or laboratory tests (increased CRP or leukocytes), bacterial growth on culture (blood, nasopharyngeal or CSF) or CSF analysis (pressure, appearance, protein, PMN, white cell count, gram stain etc.). Age of the mother was divided into two groups: age >35 or age ≤35. Way of delivery was either vaginal or by c-section. Chorioamnionitis was the most frequent occurring infection of the mother, diagnosis was primarily clinical, supported by fever >38C and/or increased CRP or leukocytes on blood tests.

Total of 82 extremely preterm infants hospitalized

in the NICU 2016 - 2017

14 infants excluded due to being born in other hospitals

6 infants excluded due to no cranial ultrasoundperformed

2 infants excluded due to mother not found indatabase

60 infants remaining

37 infants with IVH on cranial ultrasound: the case group

23 infants without signs of IVH on cranial ultrasound:

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Hypertension was defined as a blood pressure that exceeds 140/90 mmHg on two or more occasions without the presence of protein in the urine or other signs of pre-eclampsia.

Preeclampsia is defined as hypertension and one of the following complications after the 20th week of pregnancy: proteinuria, thrombocytopenia, increased level of liver enzymes, pulmonary edema, new-onset headaches or visual disturbances [26].

A total of 60 infants were included in the study. The infants were then divided into two groups; infants with IVH (n=37) the “case group” and infants without IVH (n=23), the “control group”. All infants that were born between January 2016 to December 2017 before 28 weeks of gestation and that had no signs of IVH after cranial ultrasound/s were included in the control group.

To identify the mothers of the infants, date of birth, surnames, birth weight and Apgar score of the infant were used to find the mothers in the Book of births 2016-2017 of the Kaunas Clinics (LUHS) maternity ward. The Book of births were assessed from the Kaunas Clinics central archive, in these the personal data (identification number and name) of the mothers could be collected. By the help of the maternal identification number, I used the database of the Kaunas Clinics (LUHS) Gynecology department to assess further information about the maternal factors of interest – maternal age, infections, hypertension, preeclampsia, anemia and diabetes. To ensure the confidentiality of the patients they were named “infant one”, “infant two” etc., and mothers in the same way respectively “mother one”, “mother two” etc. The characteristics of the included infants in the study are presented in Table 2.

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24 Infant IVH GA (weeks) BW (g) Gender Congenital infection Acquired infection Low Apgar Anemia Lumbar puncture Mother's age Delivery Maternal

infection Hypertension Preeclampsia Diabetes

1 IVH IV 26 1010 boy no yes no yes yes 25 vaginal yes no no no

2 no 26 900 girl no no no yes no 35 vaginal no no no no

3 no 27 910 boy yes no yes no no 24 vaginal no no no no

4 IVH IV 27 900 girl no no no no no 32 vaginal yes no no no

5 no 26 975 girl no no no no no 30 c-section no no no no

6 no 27 1250 girl no no no no no 26 c-section no no no no

7 no 25 690 boy no no yes yes no 37 c-section no no yes no

8 IVH I 27 800 girl yes no no no no 32 vaginal yes no no no

9 IVH III 25 645 boy no no yes yes yes 28 vaginal no no no no

10 IVH I 25 790 boy yes yes no yes no 30 vaginal no no no no

11 no 25 700 girl yes yes no yes no 30 vaginal no no no no

12 no 27 750 girl yes yes no yes yes 25 c-section no yes yes no

13 IVH III 26 862 boy yes yes no yes yes 27 vaginal no no no no

14 no 26 1085 boy yes no yes no no 39 c-section no no no no

15 IVH I 27 725 girl yes no no yes no 26 c-section no no yes no

16 IVH I 27 1060 girl yes no no no no 41 vaginal no no no no

17 no 27 1035 girl yes yes no no yes 27 vaginal yes yes yes no

18 no 23 600 boy no yes no yes yes 33 vaginal no yes yes no

19 no 27 1200 boy no no no no no 23 c-section no no no no

20 no 27 1005 girl yes no no yes no 38 vaginal no yes yes no

21 IVH III 27 970 boy no yes yes yes yes 23 vaginal no no no no

22 IVH III 26 860 girl no yes no no yes 35 c-section no no yes no

23 IVH I 27 1455 boy yes no no no no 39 vaginal yes no no no

24 IVH I 24 547 girl yes yes yes yes yes 28 vaginal yes no no no

25 no 26 835 girl no no no yes no 26 vaginal yes no no no

26 IVH II 23 700 boy yes yes yes yes yes 24 vaginal no yes yes no

27 IVH IV 24 730 boy no yes yes yes no 20 vaginal no no no no

28 no 27 1085 girl no no no no no 30 vaginal yes no no no

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25

30 no 25 495 girl yes yes yes yes yes 28 c-section no no yes no

31 IVH IV 22 420 boy yes no yes yes no 33 vaginal yes no no no

32 IVH IV 23 575 girl no yes yes yes yes 40 vaginal yes no no no

33 IVH II 25 780 girl yes yes yes yes yes 23 vaginal no no no no

34 no 26 965 boy no no no no no 23 vaginal yes no no no

35 IVH IV 24 688 girl yes yes yes yes yes 29 vaginal no no no no

36 IVH II 24 700 girl yes yes yes yes yes 29 vaginal no no no no

37 IVH III 27 778 boy yes no yes yes yes 33 c-section yes no yes no

38 no 26 775 boy no no yes no no 31 c-section no no no no

39 IVH II 22 630 boy yes yes no yes no 33 vaginal yes no no no

40 IVH II 23 600 boy no no yes yes no 24 vaginal no no no no

41 IVH IV 22 476 boy yes no yes yes no 35 vaginal yes no no no

42 IVH I 27 698 boy no no no no no 38 c-section no no yes no

43 IVH IV 23 562 girl no yes yes yes yes 28 c-section yes no no no

44 no 26 800 girl no no yes no no 35 c-section no no no no

45 IVH IV 23 599 boy no yes no yes yes 32 vaginal no no no no

46 no 26 1305 boy yes no yes no yes 34 vaginal no no no no

47 IVH II 24 605 boy yes yes yes yes yes 38 vaginal no yes yes no

48 IVH III 24 480 girl yes yes no yes yes 28 vaginal yes no no no

49 no 23 580 boy yes no yes no no 17 vaginal no no no no

50 IVH IV 25 875 girl yes yes yes yes yes 34 vaginal no no no no

51 IVH I 23 500 boy no yes yes yes yes 23 vaginal yes no no no

52 no 27 675 girl no no no no no 40 c-section no no yes no

53 IVH IV 27 1160 boy yes no no yes yes 34 vaginal no no no yes

54 IVH III 27 915 boy yes no no no no 34 vaginal no no no yes

55 IVH IV 24 676 girl yes yes no yes yes 24 vaginal yes no no no

56 no 27 1130 boy no yes no no no 24 c-section yes no no no

57 IVH II 24 715 boy no yes no yes yes 37 vaginal no no no no

58 IVH II 27 685 boy yes yes no yes no 24 c-section no no yes no

59 IVH IV 23 546 boy no yes yes yes yes 29 vaginal yes no no no

60 IVH II 25 755 girl yes no no no yes 44 vaginal no no no no

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26

2.3 Diagnosis of IVH

Intraventricular hemorrhage was diagnosed with the use of a cranial ultrasonographic scan. Cranial ultrasonography was performed accordingly in Kaunas Clinics (LUHS): For the premature babies <32 weeks of gestation, cranial ultrasound is recommended in the first, second, third and, fourth week of life and in 36 weeks of GA. In premature infants of bad condition, the scheme follows the guidelines of the American Academy of Neurology (AAN) ultrasound examination is recommended between day 1-3 of life, 8-10 day of life, second, third and, fourth week of life and at 36th_{week of life}

or when going home. The classification of intraventricular hemorrhage was based on the Papile grading IVH grading system [27]. Infants who had undergone several ultrasounds, the most severe grade of IVH were considered and included in the study.

2.4 Investigated risk factors

I have explored the relationship between IVH and the following prenatal and perinatal variables: gestational age (GA, weeks), birth weight (BW, grams), gender, infection of the infant (congenital and acquired), maternal infection, way of delivery (vaginal birth vs. cesarean section), low 5-min(defined as <7 points at five minutes) [8, 25], anemia (low hematocrit). Maternal factors: age >35, hypertension, preeclampsia, diabetes and infection. The selection of which risk factors to

investigate was based on investigated factors in other previous studies and also in regard to assessable data of the infants and mothers in the Kaunas Clinics (LUHS) databases.

2.5 Statistical analysis

The statistical analysis was performed using Microsoft Excel 2011 and IBM SPSS Statistics. The continuous data (GA and BW) were described as mean and standard deviation (SD). T-test was used for comparison of quantitative sizes of 2 independent samples. From the collected data the, maximum, minimum and average values of GA and BW were calculated. A relative risk with 95% confidence interval (CI) was used to quantify the association between the investigated factor and IVH diagnosis. A P-value less than 0.05 was considered significant. The values were used to evaluate the significance of selected risk factors between the groups. Pearson’s chi-square test for correlation was used to calculate the relationship between the remaining risk factors and IVH. The correlation of IVH given certain risk factor was calculated using odds ratio (OR) with a 95% CI and significance= p<0,05.

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3. RESULT

3.1 Incidence of IVH and frequency of risk factors

Out of the 60 extremely premature infants born during 2016-2017 in Kaunas Clinics, the prevalence of any grade of IVH was 62% (n=37), furthermore 38% (n=23) of infants constitutes the control group without IVH. The most frequently occurring risk factor in this study was infection in the infant (sepsis, pneumonia and/or meningitis that were either congenital and/or acquired) which makes up 73% (n=44). Second most frequently occurring is vaginal delivery 70% (n=42) followed by anemia 63% (n=38), lumbar puncture 48% (n=29), boys 47% (n=28), 5-min Apgar score <7 45% (n=27), maternal infection (most frequently chorioamnionitis) 35% (n=21), c-section 30% (n=18), maternal age >35 22% (n=13), preeclampsia 15% (n=9), hypertension 8% (n=5) and diabetes 3% (n=2). Frequency of investigated risk factors are presented in Figure 2, gestational age and birth weight are not included but is presented later.

Figure 2 Overview of the frequency of investigated risk factors.

The most frequent occurring grade of IVH in this study is grade IV which constitutes 35% (n=13) of the total number of included infants diagnosed with IVH (n=37). Followed by grade II IVH of 24% (n=9), grade I IVH of 22% (n=8), grade III IVH of 19% (n=7). The gestational age of the collected infants had a range of 22-27 weeks. Mean GA=25,4 weeks. BW of the included infant range between 420-1305g, mean BW=822,2 g. The distribution of the birthweight in included infants are shown in Figure 3. 0 5 10 15 20 25 30 35 40 45 50 N r o f in fan ts Risk factor

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28 Figure 3 The distribution of birthweight (g).

There is a marked difference between the included years in the study, year 2016 and 2017, where 2016 77% (n=20) of the extremely premature infants were diagnosed with IVH. 2017 instead, had a prevalence of 50% (n=17). The years will not further be investigated separately.

The results and the significance of investigates risk factors are summarized in Table 3 where the infants (%) according to group of each investigated factor is presented. The P-value indicates their significance. Each investigated factor will thereafter that be discussed separately.

Characteristic Control group (SD) Infants with IVH (SD) p-value Neonatal

factors

Mean gestational age

(weeks) 26,09 (1,14) 24,84 (1,72) 0,002

Mean birth weight (g) 896,74 (216,77) 742,49 (204,96) 0,01

Female gender (%/n) 46/13 54/15 0,705

Male gender (%/n) 31/10 69/22 0,034

Low Apgar score (%/n) 33/9 67/18 0,083

Neonatal infection (%/n) 27/12 73/33 0,001 Anemia (%/n) 24/9 76/29 0,001 Lumbar puncture (%/n) 21/6 79/23 0,002 Vaginal delivery (%/n) 26/11 74/31 0,002 Cesarean section (%/n) 67/12 33/6 0,157 Maternal factors Age >35 (%/n) 38/5 62/8 0,225 Infection (%/n) 29/6 71/15 0,05 Hypertension (%/n) 20/1 80/4 0,18 Preeclampsia (%/n) 33/3 67/6 0,317

Table 3 Summary of the study results and their significance.

0 200 400 600 800 1000 1200 1400 1600 0 10 20 30 40 50 60 70 Bir th w ei gh t (g rams ) Infant

Distribution of BW

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3.2 Incidence of IVH according to the investigated factors

3.2.1 Birth weight (BW)

According to the collected data for the included infants the birthweight range between 420 g to 1305 g with a total average of 801,6 g. The case group had an average of 742,5 g, while the control group had an average of 896,7 g. The birthweight of the case group is statistically significantly lower than that of the control group (p=0,01).

Of infants with a birthweight ≤500 g (n=5) 80% were diagnosed with IVH. The grade of IVH of these infants were distributed as follows: 20% (n=1) grade I, 0% (n=0) grade II, 20% (n=1) grade III and 40% (n=2) grade IV. The control group of this BW consists of one infant, 20% (n=1). Among infants with a birthweight between 501-1000 g (n=44) 66% were diagnosed with IVH, distributed as follows: 11% (n=5) grade I, 20% (n=9) grade II, 14% (n=6) grade III and 20% (n=9) grade IV, the control group of this BW establishes 34% (n=15). Infants with a BW between 1001-1500 g (n=11), 36% (n=4) were diagnosed with IVH and distributed as follows: 18% (n=2) with grade 2, 0% (n=0) with grade II, 0% (n=0) with grade III and 18% (n=2) with grade IV IVH, the control group of this BW establish 64% (n=7). The prevalence of IVH grade I-IV according to birth weight is illustrated in Figure 4.

Figure 4 Distribution of grade I-IV IVH according to birthweight.

4.2.2 Gestational age (GA)

The gestational age of the included infants is according to the inclusion criteria of 22-27 weeks. The mean gestational age of the case group is statistically significantly lower than that of the control group (24,8 vs. 26,1, p=0,02). 0% 10% 20% 30% 40% 50% 60% 70% ≤500 500-1000 1001-1500 In fan ts (% ) Birthweight (g)

Grade of IVH according to BW

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The most frequent GA is 27 weeks, which constitutes 33% (n=20). Listing from the highest to the lowest prevalence of GA are 20% 26th week of gestation (n=12), 15% 23rd week of gestation (n=9), 13% 25th week of gestation (n=8), 13% 24th week of gestation (n=8) and 5% 22th week of gestation (n=3). Number of infants diagnosed with IVH according to gestational age are presented in Figure 5.

Figure 5 The number of infants with and without IVH according to gestational age.

The distribution of IVH grade I-IV over the included gestational weeks (week 22-26) are presented in Figure 6. Infants of 22 weeks GA (n=3): 66% (n=2) were diagnosed with grade IV IVH followed by 33% (n=1) with grade II IVH, there are no infants diagnosed with grade I or III IVH and no infants in the control group of this GA. In 23 weeks of GA (n=9): The most frequent was grade IV IVH of 44% (n=4) followed by grade II IVH with 22% (n=2) and grade I IVH with 11% (n=1), the control group constitutes 22% (n=2). 24 weeks of GA (n=8): grade IV of 38% (n=3) and grade II IVH also of 38% (n=3) are the most commonly diagnosed degrees of IVH followed by grade III of 13% (n=1) together with grade I of 13% (n=1), there are no infants in the control group of this GA. 25 weeks of GA (n=8): Most frequently diagnosed grade of IVH is grade II of 25% (n=2), followed by grade I of 13% (n=1), grade III of 13% (n=1) and grade IV also of 13% (n=1), infants of the control group of this GA is 38% (n=3). 26 weeks of GA (n=12): Most frequently diagnosed is grade III IVH of 17% (n=2) followed by grade IV of 8% (n=1), the control group of this GA constitutes 75% (n=9). 27 weeks of GA (n=20): The most frequently diagnosed degree of IVH was grade I of 25% (n=5),

followed by grade III of 15% (n=3), grade IV of 10% (n=2) and lastly grade II of 5% (n=1), in this GA infants of the control group constitutes 45% (n=9).

0 2 0 3 9 9 3 7 8 5 3 11 2 2 2 3 2 4 2 5 2 6 2 7 N R O F IN FA N TS

GESTATIONAL AGE (GA) (WEEKS)

INCIDENCE OF IVH ACCORDING TO

GESTATIONAL AGE

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31 Figure 6 The distribution of IVH grade I-IV according to gestational age.

3.2.3 Gender

Among the total number of included infants (n=60) there were 53% boys (n=32) and 47% girls (n=28). 37% (n=22) of all included infants were boys diagnosed with IVH and 25% (n=15) were girls are diagnosed with IVH. The distribution of IVH between the gender among the included infants are shown in Figure 7. Of the included boys 69% (n=22) were diagnosed with some degree IVH while 54% of the included girls (n=15) were diagnosed with IVH. The results show that extremely premature boys (OR= 1,91, CI= 0,66-5,47, p= 0,034) have a clinically and statistically significant increased risk of IVH than girls (OR= 0,52, CI= 0,18-1,5, p=0,705).

Figure 7 Distribution of IVH according to gender.

0% 10% 20% 30% 40% 50% 60% 70% 80% 22 23 24 25 26 27 In fan ts ( % ) GA (weeks)

Grade of IVH according to GA

I II III IV Control

37%

17% 25%

21%

IVH DISTRIBUTION AMONG GENDER

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3.2.4 Infections

At least one type of infection (congenital, acquired or maternal) were found in 75% (n=45) of all included infants (n=60). The same number, 75% (n=45) is seen when only neonatal infections (congenital or acquired) are considered. The distribution of infections among the infants (n=60) were as follows: 30% (n=18) inhibit both a congenital and acquired infection, 25% (n=15) inhibit only a congenital infection, 20% (n=12) inhibit only an acquired infection, and 25% (n=15) does not have any form of infection. The distribution of infection of all infants (n=60) is illustrated in Figure 8.

Figure 8 The distribution of congenital and acquired infections.

3.2.4.1 Infections of the infant

Congenital neonatal infections were identified in 55% (n=33) and acquired neonatal

infections were identified in 50% (n=30) of the sample proportion (n=60). Most of these infants (n=18) were diagnosed with both congenital and acquired infections. Of infants only diagnosed with

congenital infection (n=15), 67% (n=10) were diagnosed with IVH. In neonates with only an acquired infection (n=12), 83% (n=10) were diagnosed with IVH. In this study the two types of infections are frequently coexisting. To evaluate the significance of infections of the infants, the results have been put together since the numbers otherwise becomes too small to be able to draw any conclusions. The result is therefor based on infants with infection and infants without infection. 45 infants established an infection, and 73% (n=33) of them were diagnosed with IVH. 15 infants did not have any infection and, of them 27% (n=4) were diagnosed with IVH. The calculations show that there are a statistically

30%

25% 20%

25%

PREVALENCE OF INFECTION

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and clinically significant difference between infants with an infection and without for the development of IVH (OR= 7,6, CI 2,4-33,74, p= 0,001).

3.2.4.2 Maternal infections

35% (n=21) of all included mothers in the study had an infection. Among infants to mothers with an infection, 71% (n=15) established IVH. Of infants to mothers without an infection 56% (n=22) established IVH. Most often an infection in the mother resulted in a congenital infection of the infant. Only in 7% (n=4) of mothers that had an infection, the infant did not establish an infection. Of infants that had not established a congenital or acquired infection but had mothers with infection 25% (n=1) was diagnosed with IVH. Infants to mothers with an infection are clinically and statistically significantly more frequently affected with IVH (71% vs. 56%, OR= 1,93, CI= 0,62-6,03, p=0,05).

3.2.5 Apgar score

Of infants included in this study, 45% (n=27) had a low Apgar score, meaning <7 points after 5 minutes. 67% (n=18) of infants with a low Apgar score were diagnosed with IVH. Of infants with an Apgar score >7 (n=33), 56% (n=19) were diagnosed with IVH. Infants with a low Apgar score were not statistically significantly more frequently affected by IVH than infants with a higher score (67% vs. 56%, p=0,083, although OR= 1,47, CI= 0,51-4,24).

3.2.6 Anemia of the infant

In this study, 63% (n=38) of all included infants were diagnosed with anemia. Of infants with anemia 76% (n=29) were diagnosed with IVH. Of infants without anemia, 36% (n=8) were diagnosed with IVH. All infants that were diagnosed with anemia received blood transfusion, of different number of occasions. Anemia of the infant is clinically and statistically significantly associated with IVH (76% vs. 36%, OR= 5,64, CI= 1,79-17,74, p=0,001).

3.2.7 Early lumbar puncture

48% (n=29) of included infants (n=60) underwent lumbar puncture. 79% (n=23) of these infants were diagnosed with IVH. Of infants without lumbar puncture, 45% (n=14) were diagnosed with IVH. Lumbar puncture is clinically and statistically significantly associated with IVH of the infant (79% vs. 45%, OR= 4,65, CI= 1,48-14,61, p=0,002).

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3.2.7 Vaginal delivery and c-section

Among all infants in the study, 30% (n=18) were delivered by c-section. The majority of infants delivered by c-section did not develop IVH, only 33% (n=6) of infants delivered by c-section were diagnosed with IVH. Of infants delivered by vaginal delivery (n=42), 74% (n=31) developed IVH. The incidence of IVH in the two different ways of delivery is presented in Figure 9. Vaginal delivery is a clinically and statistically significant risk factor for IVH (OR= 5,64, CI= 1,7-18,66, p=0,002). C-section is a clinically suspected significant protective factor although not statistically significant (OR= 0,18, CI= 0,05-0,59, p=0,157).

Figure 9 The incidence of IVH according to way of delivery.

3.2.8 Advanced age of the mother

Mothers with an age >35 years represents 22% (n=13) of mothers in this study. The ages vary between 36-46 years old, mean 39,5 years. 62% (n=8) of infants to mothers of an age >35 were diagnosed with IVH. Of mothers ≤35 years old, the age range between 17-35 years, mean 28,2 years old. Also in this group of mothers (n=47), 62% (n=29) of infants were diagnosed with IVH. Infants with a mother aged >35 years does not have a statistically significant higher risk of developing IVH (62% vs. 62%, OR= 0,99, CI= 0,28-3,51, p= 0,225).

3.2.9 Maternal hypertension and preeclampsia

In total 15% (n=9) of the mothers were diagnosed with preeclampsia and in 67% (n=6) of cases IVH of the infants were diagnosed. Of infants to mothers without preeclampsia (n=51), 61%

0% 10% 20% 30% 40% 50% 60% 70% 80% Vaginal C-section In fan ts (% ) Way of delivery

Incidence of IVH according to way of delivery

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(n=31) were diagnosed with IVH. Only 7% (n=5) of the mothers were diagnosed with hypertension. Maternal hypertension resulted in IVH in one infant (20%). Of infants to mothers without hypertension (n=55), 65% (n=36) were diagnosed with IVH. Figure 10 illustrates the incidence of IVH divided into

three groups: maternal hypertension, preeclampsia and none of these diagnoses. Nor maternal

hypertension or preeclampsia were statistically significantly related with IVH (OR= 13, CI= 0,01-1,27, p= 0,18 and OR= 1,29, CI= 0,29-5,76, p= 0,317, respectively). Additionally, the small number of mothers diagnosed with preeclampsia and hypertension makes it not possible to make any conclusions that can be trusted. Hypertension can only clinically be suspected as a protective factor.

Figure 10 The incidence of IVH in case -and control groups of: maternal hypertension,

preeclampsia or none of the diagnoses.

3.2.10 Maternal diabetes as risk factor of IVH

The study includes only one mother (1,7%) with diabetes, although she gave birth to twins, both with IVH. The sample is too small to evaluate if there is a statistically significant or clinically significant higher risk of IVH of this group.

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

Control Case Control Case Control Case

Hypertension Preeclampsia None

In

fan

ts

(%

)

State of the mother

Incidence of IVH in maternal hypertension and

preeclampsia

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36

4. DISCUSSION OF RESULTS

I have investigated risk factors for the development of IVH in infants born before 28 weeks’ gestation at Kaunas Clinics (LUHS) during 2016-2017. The main goal of this study was to determine the perinatal risk factors associated with the development of IVH. The incidence of IVH in infants of my study was 62%. This falls within the range of 20-80% which previously have been documented in other studies of IVH in extremely preterm infants [9, 28], although many previous studies report an incidence between 20-50% [2, 9]. In many previous studies in the field, only high grade (severe) IVH are considered. This can mainly be due to that it is the high grades of IVH that have been associated with significant neurodevelopmental disorders and thus, often are of greatest interest. In my study the incidence of severe IVH (grade III and IV) is 33% compared to previous studies mainly being between 20-30% [7-8]. As earlier mentioned in the study, it was noticed a big difference in incidence of IVH between the investigated years: 77% 2016 vs 50% 2017. A large part of this difference can probably be explained by the fact that there was a renovation of the Kaunas Clinics (LUHS) NICU during 2016 which caused the department to be overcrowded and thus leading to more complications among the infants. The high incidence of 2016 leads to an increase of the overall incidence of IVH of this study. An increased incidence of IVH can also be related to perinatal treatment routines of the extremely premature infants at the selected hospital, factors that in previous studies have been investigated as potential risk factors and includes time of cord clamping, ventilation therapy, maternal antenatal corticosteroid administration as well as other medicaments and procedures [3, 5, 13, 15-17]. Although, no conclusions regarding treatment routines can be made only made on this study. Another factor that can contribute to the increased incidence can be the skill of the physician performing the ultrasound. The production of a high-quality image has a major role especially in the diagnosis of low-grade IVH and the IVH investigation process.

Statistically, p-values and standard deviation (SD) were established for factors of continuous data such as GA and BW. For other factors odds ratio (OR) and confidence interval were additionally established. Confidence level was set to 95%,

The results of this study are compatible with previously made studies regarding that low birth weight and gestational age are major risk factors for IVH occurrence [1, 29-30]. As previous studies in the field, my study shows an inverse correlation between the risk of IVH and birth weight of the infant [4, 8, 30-31]. It is an increased incidence of severe IVH (grade III and IV) the lower the birth weight. The severity of IVH is not correlated to GA in the same way in my study. This is most probably due to other factors that influences the outcome. The incidence of IVH is clinically higher in infants of GA 27 weeks than of 26 weeks (55% to 25%, respectively). When investigating the frequency of the risk

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factors between the groups I noticed that in the group of infants of 27 weeks GA- neonatal infections, vaginal delivery, male gender and preeclampsia are more frequent which can have affected the result.

Previous studies have identified c-section as a protective factor of IVH [8]. By the result of my study c-section is a clinically significant protective factor, the conclusion is strengthened by the narrow confidence interval. Although, the factor is not statistically significant (p= 0,157). Even if cesarean section is associated with lower incidence of IVH, it is a surgically invasive procedure with its own risks and should not be recommended without other indication [32]. Previous studies have also identified maternal hypertension as a protective factor for the development of IVH [4, 33]. That maternal hypertension serves as a protective factor for IVH can clinically be suspected in my study (1 out of 5 infants had IVH) but because of a minimal number of occurrences the calculation of

significance will be with insignificant values, no trusted conclusions can thus be made. It is the same situation regarding diabetes where only one mother had been diagnosed with diabetes, which made the factor excluded from this study.

The results of my study show that extremely preterm boys are at a significant higher risk of developing IVH than extremely preterm girls, although the factor has not been studied independently. Male gender is a previously identified risk factor of IVH [1, 34]. Contributing factors of this finding could be hormonal, physiological, genetic and molecular alteration factors. Gender can influence pathogenesis of brain injuries [1]. Additionally, studies of gender as a risk factor for IVH is less frequent than investigation of other known factors. This can probably be explained by that it is a non-modifiable factor and therefor of less clinical interest when developing prevention strategies.

Anemia with a low hematocrit level is correlated with a higher incidence of IVH, a finding consistent with previous reports [1, 31]. Even though a low hematocrit level might contribute to the hemorrhage by accelerate the cerebral blood flow, it is difficult to determine whether the low

hematocrit levels contributed to the development of IVH or were a consequence of the bleeding itself. The blood loss into the brain in case of IVH in an extremely premature infant is enough to cause anemia in the infant [35]. Anemia can therefore not be determined as a risk factor for IVH but, is statistically significant related with IVH in my study. Anemia frequently correlates with prematurity because of an untimely birth that occurs before placental iron transport and fetal erythropoiesis are complete, by blood losses taken for laboratory testing, by low levels of plasma erythropoietin due to both diminished production and accelerated catabolism, by rapid body growth, and by disorders causing RBC losses due to bleeding and/or hemolysis. Infants of this study have all been treated with RBC transfusions which is the key treatment modality for the anemia of prematurity. Vigorous attempts must be made to limit volumes of blood drawn for laboratory testing [35].

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The results of my study is compatible with other studies regarding maternal and neonatal infections as risk factors for IVH in extremely preterm infants [36]. By the results of this study a strong correlation between maternal infection and infection of the neonate can be seen. This is an important observation since infection in the infant is the most prevalent risk factor in the sample proportion. A low 5-min Apgar score (<7 points) have in previous studies been identified as a risk factor for IVH [8, 25]. By the results of my study, a low 5-min score can clinically be suspected as a risk factor for IVH based on the odds ratio and the relatively narrow confidence interval, although the factor is not statistically significant in my study.

In my study, lumbar puncture of the infant is a significant risk factor, this observation is limited by that the factor has not been investigated independently and is likely to coexist with infection of the infant. A lumbar puncture is mainly performed when there is a suspicion of infection that involves the central nervous system, the suspicion can be clinical or due to laboratory tests [37].

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CONCLUSION

1. The incidence of IVH in the studied population is within the upper range of interval of previous studies.

2. Low gestational age and birth weight, infection of the infant, vaginal delivery, lumbar

puncture, male gender, and infection of the mother are statistically significant risk factors for IVH. Low 5 min Apgar score and a maternal age over 35 years were not significant risk

factors. Anemia of the infant is significantly associated with IVH although, based on this study, it cannot be defined whether it contributes to, or is a result of the bleeding itself.

3. Neonatal infection is the most commonly observed factor in extremely preterm neonates. It is also one of the factors that is most frequently associated with IVH. Cesarean section can be advantageous for infants <28 weeks’ GA, although it is associated with its own risk factors and should not be recommended without other indication.

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RECOMMENDATIONS

This study is limited by its retrospective nature and the relatively small sample size. A matched case-control matched study by GA and BW would diminish the roles of these two relatively

established risk factors while assessing the other factors. Although, by using matching in this study the sample size would decrease markedly, by such degree that results would not be trustful. It was therefor chosen to keep the whole sample proportion while performing this study.

To further improve the perinatal care of preterm infants in Kaunas Clinics (LUHS) NICU, a study investigating the perinatal treatment routines should be performed.

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Final Master thesis DEPARTMENT OF NEONATOLOGY Sara Bergstrom Medical Faculty