Background: Intraventricular hemorrhage (IVH) is a major cause of death and the most important predictor of neurodevelopmetal disabilities in very low birth weight (VLBW) infants. Materials and Methods: Maternal, perinatal and infant data of 87 babies weighing <1500 g who had transfontanelle ultrasonography (TFU) scan were obtained to determine the prevalence, risk factors, features and outcome of IVH by multivariate analyses. Results: The prevalence of IVH was 24.1%. Gestational age <28 weeks; early onset sepsis (EOS) and severe birth asphyxia (SBA) at 5-min were associated with a greater risk of development of IVH. The use of antenatal steroids however reduced the risk. Respiratory distress, clinically identifiable seizures, temperature instability and acidosis, were more common in babies with IVH. Mortality rate was also significantly higher among them (P = 0.005). Babies with severe IVH were 23 times more likely to die than those without IVH (relative risk = 23.3, 95% confidence interval = 1.58-343.42, P = 0.010). Conclusion: The high-rate, morbidity and mortality of IVH emphasize the need for routine TFU scans among VLBW infants. Deliveries before 28 weeks, EOS, failure of antenatal steroids treatment and SBA contributed to the development of IVH. Aggressive prevention/management of these factors are necessary to reduce the burden of IVH in these high-risk neonates.
Keywords: Antenatal steroids, asphyxia, extreme prematurity, intraventricular hemorrhage, transfontanelle scan
|How to cite this article:
Adegoke SA, Olugbemiga AO, Bankole KP, Tinuade OA. Intraventricular hemorrhage in newborns weighing <1500 g: Epidemiology and short-term clinical outcome in a resource-poor setting. Ann Trop Med Public Health 2014;7:48-54
|How to cite this URL:
Adegoke SA, Olugbemiga AO, Bankole KP, Tinuade OA. Intraventricular hemorrhage in newborns weighing <1500 g: Epidemiology and short-term clinical outcome in a resource-poor setting. Ann Trop Med Public Health [serial online] 2014 [cited 2020 Nov 24];7:48-54. Available from: https://www.atmph.org/text.asp?2014/7/1/48/145013
Intraventricular hemorrhage (IVH), the most common form of intracranial bleeding in the very low and extremely low birth weight (ELBW) babies, less frequently occur in near-term and term infants.  While the latter tend to develop subarachnoid hemorrhage; about 90% of all IVHs in the newborn period occur in infants of <35 weeks’ gestation.  Although most cases of intracranial bleeding in term babies result from birth trauma, perinatal asphyxia, primary hemorrhagic disorders or congenital vascular anomalies, IVH in preterm’s usually occur spontaneously without apparent trauma. 
The clinical presentations of IVH are diverse; including asymptomatic presentation, subtle and non specific symptoms such as refusal of feeds and vomiting, bulging of the anterior fontanelle with a fixed gaze, abnormal posture and or tone, and rapid deterioration in the neurological state such as development of seizure and unconsciousness.  Although the rate of morbidities and mortality is higher among those with severe neurological disturbances; those with non specific symptoms also experience high-mortality and morbidity.
There is controversy on the timing of intraventricular bleeding and hence the most appropriate time for cranial scanning in preterm babies. Most clinicians, however, tend to believe that nearly all IVH occur within 72 h of life, about 60-80% within 48 h of birth, 40-60% within 24 h and about 30% within the first 6 h of life. ,, Routine transfontanelle ultrasonography (TFU) screening should, therefore, be performed toward the end of the 1 st week (optimally between days 5 and 7 of life). 
Studies in developed countries had found that severe IVH, especially those with intraparenchymal involvement is the most important predictor of development of cerebral palsy and other neurodevelopmental abnormalities in very low birth weight (VLBW) infants; in whom the risk of future development of cerebral palsy is about 9-22 times higher than babies with normal birth weight. , In addition, IVH is also a major contributor to mortality in this group of babies. In recent times, Qureshi et al.  reported a two-fold higher rate of mortality in African American neonates and infants with IVH.
Sadly, in most developing nations where neonatal mortality is high and social supports for individuals with cerebral palsy and neurodevelopmental disabilities are poor; the exact contribution of IVH to mortalities involving VLBW infants, its possible risk factors and long-term outcome among these babies have not been well studied. We, therefore, determined the prevalence and the severity of IVH, associated risk factors and immediate clinical outcomes among VLBW and ELBW babies admitted in a Nigerian teaching hospital.
|Materials and Methods|
Study design, location, subjects and methods
This prospective cross-sectional study was carried out at the Special Care Baby Unit (SCBU) of the hospital Wesley Guild Hospital, Ilesa (a division of Obafemi Awolowo University Teaching Hospital), Nigeria from April, 2012 to May, 2013. The hospital which admit neonates from within the hospital and from outside provides both lying-in-care and special neonatal care services such as care for babies with perinatal asphyxia, sepsis, preterm/low birth weight, bleeding disorders and jaundice. However, intensive neonatal care services, especially mechanical ventillatory support, use of surfactants, blood gas analysis and total parenteral nutrition are not currently available. The radiology unit of the hospital provides comprehensive ultrasonographic services including routine TFU for newborns.
All preterm babies weighing < l500 g who were admitted into the SCBU of the hospital during the study period were recruited after obtaining informed consent from the mother or the caregiver. Those who did not give consent or those with obvious congenital anomalies such as neural tube defects were not included. The study protocols were in accordance with the ethical standards of the Helsinki Declaration of the World Medical Association. Preterm babies were those delivered before 37 completed weeks of gestation. Gestational age of babies was estimated in weeks counting from the 1 st day of the mother’s last menstrual period (LMP) and or using the modified Ballard scoring system done within 48 h of delivery.  Babies were also classified as small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age using Lubchencho classification of intra-uterine growth  Babies with birth weight of 1000-1499 g were VLBW babies and those whose birth weights were < 1000 g were ELBW babies. For those delivered in our hospital, the APGAR scores at 1-min and 5-min were documented. APGAR score of ≤3 was taken as severe birth asphyxia (SBA). ,
Relevant maternal data such as age, date of LMP, antenatal history, place and mode of delivery, parity, gestational age at delivery and duration of labor were recorded. The use of steroid in pregnacy was also noted. Prolonged labor was taken as labor lasting for more than 12 h in primiparous and 8 h in the multiparous woman, while precipitate labor was defined as labor lasting for < 4 h.  Furthermore, the birth weight, sex and age of the baby at presentation were documented. A detailed physical examination findings including axillary temperature, presence or absence of respiratory distress, seizures, apnea, pallor, abnormal tone or posture, coma were noted. Hypothermia was defined as axillary temperature of < 36.5°C while fever was temperature > 37.5°C. Routine standard management protocols were followed for each baby following admission. All babies had full blood count (heamatocrit, white cell count and platelet count), blood sugar, serum bicarbonate and pulse oximetry done by standard procedures at presentation,  and the results documented. Anemia and polycythaemia were defined as venous haematocrit <45% and > 65% respectively, acidosis as serum bicarbonate < 20 mmol/L, hypoglycemia as serum glucose < 2.2 mmol/L and hypoxemia as SpO 2 <92%. Those with positive blood culture were regarded as having early onset sepsis (EOS).
Each baby had TFU by the hospital consultant radiologist (second author) when clinically stable. The TFU was done only once for each baby within the 1 st week of life (from 60 h to day 7) using a real-time sector scanner DP 8500 with a high-resolution 7.5 Mhz transducer, linear probe. The anterior fontanelle which has the widest and the least variable window was used. The scanning was done for both coronal and sagittarius sections. The findings of the TFU was documented as normal or IVH. Those with IVH were further subdivided into IVH grade I, II, III and IV according to Papile et al.  In IVH grade I, hemorrhage is limited to subependymal region, that is, choroid plexus; IVH grade II there is bleeding beyond the subependymal region, but with no ventricular dilatation. In IVH grade III, there is IVH with ventricular dilatation, while, in grade IV, there is associated parenchymal involvement.
Each baby was followed up till they were either discharged or till death, and the outcome documented.
Simple descriptive statistics were used to analyze the clinical characteristics of the neonates and their mothers. Risk factors for IVH were classified into antepartum, intrapartum and postpartum events. These factors, as well as clinico-laboratory variables of the babies, were compared between groups with IVH and those with no IVH; using Chi-squared test or Fisher’s exact test for categorical variables and independent sample t-test for continuous data. For each potential risk factor, relative risk (RR), 95% confidence interval (95% CI) and P values were determined. Variables that were associated with IVH with a P < 0.05 were further tested in the multivariate models.
One thousand and thirty-five babies were admitted into the SCBU of the hospital during the 14-month study period. Ninety-six (9.3%) comprising of 71 VLBW and 25 ELBW had birth weight of < 1500 g. Nine babies were however excluded from the study. These included five who died before TFU could be done, two ELBW babies whose caregivers did not give consent, and two babies with undefined TFU results. Hence, the remaining 87 preterm with birth weight < 1500 g (68 VLBW and 19 ELBW) formed the basis for further analysis.
Characteristics of the 87 babies
The birth weight of these babies ranged from 750 to 1490 g, with a mean of 1193 ± 344 g. Nineteen (21.8%) had birth weight between 750 and 999 g, 27 (31.0%) had birth weight between 1000 and 1249 g, and the remaining 41 (47.2%) had birth weight between 1250 and 1490 g. Forty-eight (55.2%) were females with male to female ratio of 1: 1.2. Majority, 70 (80.5%) were AGA, and the remaining 17 (19.5%) were SGA. Fifteen (17.3%) were delivered before 28 weeks of gestation, 35 (40.2%) between 28 and 32 weeks gestation and 37 (42.5%) after 32 weeks of gestation.
Prevalence of intraventricular hemorrhage
Sixty-six (75.9%) of the babies had a normal TFU result while 21 (24.1%) had IVH. This comprised of 11 (52.4%) with a grade I IVH, 5 (23.8%) with grade II IVH, 3 (14.3%) with grade III IVH and 2 (9.5%) with grade IV IVH, hence 16 (76.2%) had mild IVH (grades I and II) while 5 (23.8%) had severe IVH (grades III and IV).
Prevalence of IVH decreased with gestational age. Twelve (80.0%) of the 15 babies delivered before 28 weeks of gestation, five (16.7%) of the 35 delivered between 28 and 32 weeks and four (12.1%) of the 37 delivered after 32 weeks had IVH.
Socio-demographic characteristics of the babies with intraventricular hemorrhage and their mothers
As shown in [Table 1], there was no association between gender of the babies, maternal age, maternal education and presence of IVH. However, gestational age, birth weight and maternal parity influenced the development of IVH. The mean gestational age and birth weight of the babies with IVH were significantly lower than those without IVH, P = 0.001. Similarly, more women whose babies had IVH were primipara, P = 0.003, RR (95% CI) = 4.92 (1.63, 14.88).
|Table 1: Socio-demographic characteristics of the babies with IVH and their mothers
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Pre/perinatal risk factors for intraventricular hemorrhage
Among the risk factors considered in [Table 2], EOS, use of antenatal steroids, APGAR score at 1 and 5 min and estimated duration of oxygen use were significantly associated with IVH. Babies with EOS were more likely to have IVH than those without, χ = 4.869, P = 0.027, RR = 3.24, 95% CI = (1.14, 9.24). Significantly more babies with IVH had SBA, that is, APGAR score ≤3 at both 1 and 5-min of life. The APGAR score of the 42 babies who were delivered in our hospital, comprising of eight with IVH and 34 without IVH were analyzed. Six (75.0%) of the 8 with IVH as against 7 (20.6%) of 34 without IVH had SBA at 1-min (χ =6.606, P = 0.010, RR = 11.57, 95% CI = (2.00, 67.10). Similarly, 7 (87.5%) of those with IVH compared to 3 (8.8%) of those without had SBA at 5-min of life (χ = 17.974, P = 0.001, RR = 72.3, 95% CI = (6.95, 75.29). Babies whose mothers used corticosteroids in pregnancy tended to be protected from developing IVH, χ = 6.816, RR = 0.1, 95% CI = (0.01, 0.47), P = 0.009.
|Table 2: Bivariate analysis of the pre/perinatal risk factors for IVH
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Multivariate logistic regression analysis [Table 3] included all the parameters with P < 0.05 and 95% CI exclusion of unity in the bivariate analysis of socio-demographic characteristics of the babies and mothers as well as risk factors for IVH from [Table 1] and [Table 2]. The analysis identified that gestational age < 28 weeks (RR = 2.2, 95% CI = 0.13-0.84, P = 0.018); EOS (RR = 3.4, 95% CI = (0.10, 0.65), P = 0.003) and SBA at 5-min (RR = 6.3, 95% CI = [0.39, 0.88], P = 0.001) were associated with a greater risk of development of IVH in our babies with birth weight of < 1500 g. Conversely, with the use of antenatal steroids, there was a lower risk of IVH, RR = 0.7, 95% CI = (0.31, 0.84), P = 0.032.
|Table 3: Multivariate logistic regression analysis of risk factors for IVH
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Clinical and laboratory features of intraventricular hemorrhage
Respiratory distress including apnea, clinically identifiable seizures, temperature instability (fever or hypothermia) and acidosis were more common in babies with IVH as shown in [Table 4].
|Table 4: Clinical and laboratory features of babies with IVH
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The overall mortality of babies with birth weight of < 1500 g during the study period was 42.7%, as 41 of the 96 babies died. This comprised of 14 of the 21 babies with IVH, 21 of the 66 babies without IVH, five babies who died before TFU could be done and one of the two babies with undefined TFU result. The 14 babies with IVH included nine (56.3%) of the 16 babies with mild IVH (grades I and II) and all the five (100%) babies with severe IVH (grades III and IV). Mortality rate among babies with IVH was therefore 66.7%, significantly higher than 31.8% (i.e. 21 deaths) of the 66 babies without IVH (χ =8.046, P = 0.005, RR = 4.3, 95% CI = [1.54, 11.93].
Babies with severe IVH (grades III and IV) were about 23 times more likely to die than those without IVH, RR = 23.3, 95% CI = (1.58, 343.42), P = 0.010. Although, there was no significant difference in the likelihood of death between babies with mild IVH (grades I and II) and those without IVH (P = 0.069, 95% CI = [0.93, 8.16], the only baby identified with posthaemorrhagic hydrocephalus had grade II IVH. The remaining survivor with grade II IVH and three survivors with grade I IVH had multiple clinically identifiable seizures while on admission. They were subsequently lost to follow-up. Two other babies with grade I IVH were discharged in stable conditions.
In this study, we identified prenatal and perinatal risk factors to IVH in VLBW and ELBW babies as well as defined its prevalence and clinical features. These findings may potentially be applied to other developing nations with a high-neonatal mortality rates contributed majorly by low-birth weight/preterm, perinatal asphyxia and sepsis. 
The 9.3% prevalence of preterm VLBW/ELBW babies in our hospital was comparable to 7.9-15.5% in many developing nations, ,, but much higher than what is obtainable in most developed countries with better economy, medical technologies and infrastructures.  Similarly, the prevalence of IVH during the 1 st week of life of 24.1% among our patients agrees with findings from a report in the Northern part of Nigeria  and also in Tanzania.  It is, however, possible for this rate to be indeed higher giving the fact that five other VLBW/ELBW babies died within 60 h of admission before cranial ultrasonography could be done. Furthermore, since TFU scans were done only once within the 1 st week of life, few other babies who might have developed IVH after scanning would have been missed.
From this study, gestational age was inversely related to IVH and it was one of the four factors that independently determined the development of IVH. Babies delivered before 28 weeks of gestation are more likely to have IVH because the germinal matrix is largely unsupported at this time. In addition, spontaneous involution of the germinal matrix is usually completed after 28 weeks of gestation, during which the risk of hemorrhaging is largely reduced. 
Early onset sepsis was also found to be an independent risk factor to the development of IVH in this group of babies. This increased risk of IVH is perhaps due to coagulopathies commonly seen with sepsis.  The use of appropriate antibiotics and fresh plasma transfusion in preterm low birth weight babies will, therefore, not only manage sepsis, but also will reduce the incidence of IVH in them. Fresh frozen plasma transfusion as a form of hyperalimentation or immunotherapy is known to improve survival of babies with sepsis especially those with neonatal tetanus. 
Preterms with SBA, especially at 5-min of life were about six times more likely to have IVH in this cohort of babies (RR = 6.3, P = 0.001). From this study, APGAR scoring is a good measure of ante and intrapartum events culminating in IVH. This agrees with data from many developing nations. ,, In perinatal asphyxia, presence of hypoxemia, acidosis and hypercapnia tend to reduce platelet survival and aggregatory functions.  Asphyxia also alter the balance between bleeding and clotting cascades.  These ultimately lead to impair homeostasis among babies with birth asphyxia.
We did not find any association between the development of IVH and other maternal and perinatal factors such as the gender of the baby, maternal age or education, pregnancy induced hypertension, eclampsia or diabetes mellitus, place and mode of delivery and duration of labor. The role of hypotension and mechanical ventillation also could not be determined in this study because the requisite facilities to do them are not available in our hospital. Some researchers have however shown that hypotension and high-pressure of mechanical ventilation in preterm babies significantly predispose them to IVH. 
The use of steroid in pregnancy in this study was observed to confer some protection against the development of IVH in both bivariate and regression analyses [[Table 2] and [Table 3], RR < 1.0]. The use of steroids antenatally especially by mothers with prelabor rupture of membrane, therefore will in addition to improving lung maturity, protect against the development of IVH in high-risk population.
Respiratory distress including apnea, clinically identifiable seizures, temperature instability (fever or hypothermia) and acidosis were more commonly observed features of IVH in this study. Respiratory distress in VLBW/ELBW babies resulting from hyaline membrane disease (HMD), pneumothorax and bronchopulmonary dysplasia is a known accompaniment of IVH.  The use of mechanical ventillation, presence of HMD and acidosis promote sudden dilatation and constriction of germinal matrix leading to damage of its vascular walls. 
The high-mortality rate of IVH among our patients is comparable to findings in other developing countries. ,,, The severity of IVH also significantly predicted death, with 100% of babies with severe IVH (grades III and IV) dying. This is because grades III and IV IVH are commonly associated with significant concealed hemorrhage and shock. Intraparenchymal extension also compromise cardiorespiratory functions. The only patient with posthaemorrhagic hydrocephalus was referred for ventriculoperitoneal shunting.
This study is limited by non-availability of computerized tomography scan or magnetic resonance imaging which could have demonstrated IVH with better resolution. However, the high-rate of IVH and its attendant morbidity and mortality among VLBW/ELBW babies emphasizes the need to routinely do TFU scans even in resource-poor settings. This will ultimately improve prompt identification and management of IVH among these high-risk neonates. Furthermore, our data highlight the influence of gestational age, EOS, antenatal use of corticosteroids and SBA on the development of IVH; thus calling for aggressive prevention and management of these factors.
We sincerely appreciate the resident doctors and nurses in the SCBU of the hospital for their dedication, cooperation and support during the study period.
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Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4]