Intraventricular hemorrhage in premature infants with respiratory distress syndrome treated with surfactant: Incidence and risk factors in the prospective cohort study

Intraventricular hemorrhage (IVH) is the most frequent form of early brain injury in preterm newborns. A significant clinical and prognostic importance can be attributed to both extensive grade 3 hemorrhage, in which blood fills more than 50% of the lumen of the lateral ventricle causing it to enlarge, and periventricular hemorrhagic infarction (PVHI), also known as grade 4 IVH [1].

The main cause of the occurrence of IVH is immaturity and lack of autoregulation of cerebral vessels, observed in infants born before 32 gestational weeks. In this population, the highest risk applies to infants with respiratory and circulatory failure in the course of neonatal Respiratory Distress Syndrome (RDS). Hypotension, disturbance in the cerebral blood flow, and secondary reperfusion are the causative factors [2, 3].

Since most bleedings occur in the first three days of life, it is important to identify factors that are already working in the prenatal and early neonatal periods, which could reduce the risk of this complication [4]. This is particularly important in the prevention of extensive bleedings (grade 3/PVHI), because they increase the risk of abnormal neurological development, such as cerebral palsy, cognitive, and behavioral abnormalities.

To determine the incidence of IVH in neonates with RDS treated with surfactant, and the identification of risk factors for IVH in this population.

The study was prospective and carried out within the framework of a wider project, the NeoPro study.

The investigation was carried out in 936 premature newborns, with 652 survivors. The study population consisted of 55.3% males, while regarding the place of delivery − the majority of the infants were inborn (88.9%). The median gestational age was 28 weeks (IQR: 26.3-30.0 weeks), the median body weight was 1050 g (IQR: 800-1346 g). Preterm newborns with extremely low body weight (<1000 g) comprised 47% of the group. Detailed clinical characteristics of the study subjects are shown in table I.

Data were collected using a paper-based questionnaire in tertiary (n=42) and secondary reference neonatal intensive care units (n=5), between November 2014 and December 2015.

Inclusion criteria were: (1) gestational age ≤ 32 weeks; (2) diagnosis of RDS regardless of the degree of radiological findings in the lungs; and, (3) need for exogenous surfactant. The exclusion criterion was the presence of a clinically significant congenital defect. The study protocol was approved by the Bioethics Committee of the Medical University of Warsaw.

The following factors were considered as potentially influencing the incidence of IVH: antenatal steroids, method of delivery, time elapsed prior to umbilical cord clamping, umbilical cord milking, time of initiation of caffeine citrate, use of invasive ventilation, and duration of invasive ventilation.

Treatment with caffeine citrate was not explicitly defined in the study protocol and the time of its initiation depended upon the practice at the specific site. The group of patients receiving “early” caffeine treatment was defined as those infants in whom caffeine citrate was initiated within the first 24 hours of life; patients receiving “late” caffeine were those who initiated this treatment on the second day of life or later.

IVH was diagnosed using trans-fontanel ultrasonography performed according to the approved standards and further classified using Papile’s grading system [5, 6].

Two-tailed Student’s t-test (in the case of normal distribution) or U-Mann-Whitney test (non-normal distribution) were used, as appropriate, to compare the means between independent variables. For comparisons of percentages, chi-square test or Fisher’s exact probability test were employed. The significance level (alpha) was set at 0.05, with p-values less than alpha considered to be statistically significant.

The aim of this study was to estimate the incidence rate of intraventricular hemorrhage in newborns with respiratory distress syndrome treated with surfactant, and to identify the factors that might be in&uential in lowering the risk of intracranial hemorrhage in a prospective study of infants born before 32 gestational weeks.

Despite the fact that treatment of extremely preterm infants has evolved in the last 20 years, the problem of IVH is still present. Based on the data obtained from EU countries, the incidence rate of severe hemorrhage (measured as the sum of grade 3 IVH and PVHI) ranges from 2% do 25% in the population at risk consisting of preterm infants born before 32 weeks’ gestation (7).

The main protective factor during the fetal period, which reduces the incidence of intraventricular hemorrhage, is the antenatal administration of steroids.The administration of a full course of corticosteroids reduces the incidence rate of postnatal hemorrhage into the brain ventricles by two to three times, compared to infants whose mothers did not receive this treatment, or mothers who were not administered the full course [8, 9, 10, 11, 12]. Corticosteroids are beneficial, as they facilitate lung development, which makes it possible to achieve cardiorespiratory stabilization after birth, and also helps the maturation of cerebral blood vessels, in which damage could potentially lead to IVH.The refers mainly to an extensive vascular network that nourishes the stem substance located underneath the lateral ventricles. Our study showed that in the absence of antenatal corticosteroids there was a statistically significant increase in the incidence rate of severe hemorrhage from 14.2% to 22.1%. This emphasizes the importance of this treatment and should encourage promoting the treatment among obstetric and neonatal professionals, according to the established standards.

Data concerning the risk of IVH based on the method of delivery is contradictory, and many studies reporting such data were written during a period when the use of antenatal corticosteroids was still limited. Prolonged labor and breech births may lead to negative hemodynamic effects, while a cesarean section performed before the start of uterine contractions seems to act as a protective factor [13, 14]. However, studies concerning the development of infants born with extremely low birth weight (ELBW) indicate that the labor method is not a significant factor that generates IVH [15]. Obstetricians’ experience shows that in case of extreme prematurity (23-25 gestational weeks) performing a cesarean section on a uterus that is not yet prepared for labor may cause the uterus to constrict on the fetus, thus making it hard to extract the baby, which, in turn, raises the risk of intracranial hemorrhage in the newborn.

Recent studies show that additional transfusion of blood from the placenta to the infant born prematurely using delayed umbilical cord clamping, or by removing blood from the umbilical cord reduces the risk of IVH (41% fewer cases of IVH). This is beneficial from the hemodynamic point of view and enables better filling of the placenta with blood [16, 17]. In our study, we failed to confirm this effect. However, the lack of observable effect may result from the fact that in the study patients the delayed umbilical cord clamping was performed only in a small group of newborns (14.9%).

caffeine is one of the basic medications used in neonatology and is considered the ‘gold standard’ in the prevention and treatment of apnea of prematurity. It has been noted that caffeine reduces the incidence rate of bronchopulmonary dysplasia (BPD), patent ductus arteriosus, and also contributes to better development of these newborns in future [18]. Recently, a study by Taha et al. proved that when the medication is administered ‘early’ (no later than in the third day of life), the incidence rate of severe IVH is significantly lower [19].

In our study caffeine administration during the first 24 hours of life very often meant that the medication was given during the first few hours after birth and even directly after birth, which significantly reduced the risk of IVH.The indicates the need to continue the population-based studies in this area. Most intracranial hemorrhage (more than 90%) occur in the first week after birth, thus mechanical ventilation of the infant that takes longer than seven days should not raise the risk of IVH. Higher incidence rates of intraventricular hemorrhage in infants who were ventilated for a longer time period may indicate that in newborns whose condition was more severe and harder to quickly stabilize, IVH occurs more often, and the condition of their lungs does not allow to cease the ventilation earlier.

The results of our study confirmed that the pharmacological treatment of a fetus with corticosteroids administered to mothers at risk of preterm labor has a protective effect on the risk of severe manifestations of IVH. In addition, the method of delivery was important in newborns exposed to corticosteroids; natural birth was associated with an elevated risk of IVH. Mechanical ventilation was a major risk factor. Finally, early (from the first 24 hours of life) caffeine treatment reduced the risk of bleeding into the central nervous system.