Cerebellar Hemorrhage in the Preterm Infant: Ultrasonographic Findings and Risk Factors
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《小儿科》
Fetal-Neonatal Neurology Program, Department of Neurology Clinical Research Program, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
Department of Radiology Department of Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
ABSTRACT
Cerebellar hemorrhage (CBH) in premature infants is increasingly diagnosed secondary to improved neuroimaging techniques and survival of very small preterm infants. Information is limited, however, on the incidence, topography, and risk factors for CBH in the preterm infant.
Objectives. To define the incidence of CBH in preterm infants diagnosed by neonatal cranial ultrasound (US), describe the sonographic features of CBH, and identify maternal and perinatal risk factors associated with this lesion.
Methods. A systematic electronic database search identified preterm infants born 1998–2002 with US diagnosis of CBH. For 35 cases of CBH we double-matched (according to gestational age, gender, and year of birth) 70 preterm controls with normal cranial USs and performed detailed medical-record reviews for both patients and controls.
Results. Unilateral CBH was seen in 25 patients (71%), vermian hemorrhage was seen in 7 (20%), and combined bihemispheric and vermian hemorrhage was seen in 3 (9%). Isolated CBH occurred in 8 patients (23%); the remaining infants had associated supratentorial lesions. The incidence of CBH in preterm infants weighing <750 g at birth showed significant increase over the study period. Univariate analyses identified maternal, intrapartum, and early postnatal hemodynamic risk factors; multivariate regressions indicated that emergent caesarian section, patent ductus arteriosus, and lower 5-day minimum pH independently increased the odds of CBH. Neonatal mortality and morbidity were significantly higher among patients with CBH compared with preterm controls.
Conclusions. CBH is an important complication of extreme preterm birth and has been underrecognized in surviving preterm infants. Predictors of CBH seem to be multifactorial and include combined maternal, intrapartum, and early postnatal factors.
Key Words: cerebellar hemorrhage premature infants cranial ultrasound incidence risk factors
Abbreviations: CBH, cerebellar hemorrhage US, ultrasound/ultrasonographic GM-IVH, germinal matrix-intraventricular hemorrhage PVHI, periventricular hemorrhagic infarction PDA, patent ductus arteriosus BPD, bronchopulmonary dysplasia OR, odds ratio CI, confidence interval
Hemorrhage into the immature cerebellum is an underrecognized complication of premature birth. However, improved survival of very preterm infants and advanced neonatal neuroimaging techniques have made possible the early and accurate diagnosis of this lesion.1–3 Previous reports suggest that in preterm infants cerebellar hemorrhage (CBH) often occurs concomitantly with supratentorial hemorrhage and is associated with high mortality.3,4 More recently, CBH in preterm infants (birth weight of <1500 g) has been reported to be clinically silent in presentation (ie, diagnosed on routine cranial ultrasound [US]) and not associated with significant supratentorial bleeding.2
The exact incidence of CBH is unknown, although existing neuropathologic studies suggest that CBH is more common than clinically appreciated. In fact, CBH is reported to occur in 15% to 25% of low birth weight infants postmortem.5,6 To date, there are few clinical studies defining the nature and frequency of CBH in the premature infant.2
Identification of CBH by conventional US through the anterior fontanelle is complicated by the highly echogenic tentorium and cerebellar vermis.7,8 Recent use of the mastoid fontanelle, the thinnest region of the temporal bone at the junction of the squamosal, lambdoidal, and occipital sutures,9 has vastly improved visualization of the posterior fossa.9 Use of this mastoid-window approach has increased the detection of CBH1,10,11 and has become part of the neonatal US protocol at many centers, including our own. However, to date, the topographic characteristics of CBH by US in the preterm infant remain poorly defined. In addition, no study has systematically characterized the incidence of and risk factors for CBH in the preterm infant. Given these gaps in our understanding of CBH, the objectives of this study were to define (by neonatal US) the incidence of CBH in preterm infants, to describe its sonographic features, and to identify maternal and perinatal risk factors associated with this lesion.
METHODS
Using a retrospective case-control design and a detailed and systematic electronic database search of all neonatal cranial US reports, we identified all preterm infants (<37 weeks' gestational age) with an US diagnosis of CBH admitted to the Brigham and Women's Hospital neonatal intensive care unit (NICU) from January 1998 through December 2002. Clinically indicated cranial US studies at our center have incorporated a mastoid view as part of the routine cranial US protocol since the mid-1990s. All cranial US studies were reviewed by 2 experienced radiologists (C.B.B. and D.N.D.) who were blinded to the clinical course and outcome of these infants and to each other's findings. For 2 cases in which there was disagreement regarding the diagnosis, these investigators reviewed the US studies together and reached a consensus.
We included all preterm infants (<37 weeks' gestational age) admitted to the Brigham and Women's Hospital NICU over the 5-year study period (1998–2002) with a sonographic diagnosis of CBH. We specifically excluded term infants or preterm infants with known or suspected brain malformation, dysmorphic features or congenital anomaly suggestive of a genetic syndrome, metabolic disorder, chromosomal abnormality, or central nervous system infection.
For each preterm infant with a diagnosis of CBH, we matched 2 control infants on the basis of gestational age, gender, and year of birth. We defined our control group as preterm infants with normal cranial US studies throughout their NICU stay. Detailed medical-record reviews were performed for all infants for pertinent demographic, maternal, and neonatal data. Our institution's Committee on Clinical Investigation approved this study.
US Criteria
The routine clinical US protocol in our NICU includes 2 cranial US studies performed during the first week of life and a third US study at 30 days of age, with additional studies performed when clinically indicated. Posterior fossa views have been part of the routine protocol since 1995. All cranial USs were reviewed blindly to confirm the diagnosis of CBH and distinguish between parenchymal and extra-axial hemorrhage. We defined CBH as a unilateral or bilateral echodense lesion in the cerebellar hemispheres or vermis. The cerebellar parenchyma was also examined for the presence of architectural distortion (eg, central hypoechoic foci, peripheral echogenic foci, folia disruption). By examining all serial US studies, we carefully distinguished posterior fossa subarachnoid hemorrhage (in which the echodense areas were outside and surrounding the cerebellum) from CBH (in which the echodense areas were within the confines of the cerebellar parenchyma).
We defined supratentorial lesions by cranial US using previously published criteria.12 We graded the severity of germinal matrix-intraventricular hemorrhage (GM-IVH) as follows: grade I, the hemorrhage was confined to the germinal matrix with no or minimal intraventricular hemorrhage; grade II, echogenic blood filled <50% of the ventricular area; and grade III, a large blood clot filled >50% of the ventricular area, often distending the lateral ventricles. Periventricular hemorrhagic infarction (PVHI) was defined as a unilateral globular or fan-shaped echogenic lesion located most commonly in the frontal and/or parietal region. Periventricular leukomalacia was defined as bilateral echodensity in the white matter dorsal and lateral to the lateral ventricles with evolution into echolucent cysts.
Clinical Data Collection
We performed medical-record reviews and collected demographic, prenatal, intrapartum, and acute postnatal and short-term outcome data on all identified infants. Demographic data included gestational age at birth, birth weight, head circumference, and gender. Maternal data included mode of conception, single versus multiple gestation, pregnancy-induced hypertension, prenatal infection, and use of tocolysis and antenatal steroids. Intrapartum factors included fetal heart rate abnormalities (sustained fetal bradycardia with <100 beats per minutes, decreased variability, and late decelerations), vaginal versus cesarean birth, emergent cesarean section, meconium-stained amniotic fluid, maternal fever (temperature of >38°C within 72 hours of delivery), vaginal bleeding, Apgar score at 1 and 5 minutes, and need for respiratory and cardiovascular resuscitation (with or without medications). We also collected data from placental pathology reports for the presence of chorioamnionitis, placental abruption, or infarction.
Early postnatal data were collected in the first 5 days of life and included blood gases (pH, PCO2, PO2, plasma bicarbonate concentration), blood cell counts and platelets, need for cardiopulmonary support (use of inotropic agents and/or volume expanders), highest level of mechanical ventilation, presence of a patent ductus arteriosus (PDA), pulmonary hemorrhage, and infection (confirmed by positive blood, urine, or mucosal culture or clinical suspicion resulting in a full course of antibiotic treatment). The diagnosis of PDA was based on confirmatory echocardiogram before day of life 5 or on a clinical diagnosis before day of life 5 with subsequent confirmation by echocardiogram.
Short-term outcome data included neonatal mortality, duration of mechanical ventilation, supplemental oxygen requirement, length of hospitalization, neonatal seizures, necrotizing enterocolitis, operative procedures (eg, PDA ligation, bowel surgery), retinopathy of prematurity (stage III or higher), and radiologic evidence of bronchopulmonary dysplasia (BPD).
Statistical Analysis
To examine the incidence of CBH over time by birth weight, we categorized infants into 3 birth weight categories: <750, 750 to 999, and 1000 to 1499 g. In each birth weight category, we used an exact trend test and exact logistic regression to assess trends over time (StatXact 5.0; Cytel Software Corporation, Cambridge, MA).
US characteristics of CBH were analyzed by using means and standard deviations (SDs) for continuous data and proportions for categorical data.
Potentially clinically important risk factors were grouped into 3 domains: prenatal, intrapartum, and early postnatal factors. Univariate analyses with conditional logistic regression were used to determine the effects of these factors on the odds of CBH. All variables significant at the 5% level were considered in our multiple conditional logistic-regression model. After arriving at an initial main-effects model through stepwise selection, clinically important variables were entered individually into the model to test for statistical significance at the 5% level and to assess confounding. In our assessment of the initial main-effects model and potential additional terms, we preferred to include conditions rather than treatments to avoid confounding by indication. Potential nonlinear effects of continuous variables were tested by adding a set of design variables identifying the quartile of the distribution of the variable to the regression containing the linear term and examining whether the joint effect of the design variables was statistically significant at the 5% level by using the likelihood ratio test. Clinically plausible interactions were tested for significance at the 5% level by using the Wald test.
Early clinical outcomes were then compared between infants having CBH and controls by using linear regression with a fixed effect to adjust for matching for continuous variables and conditional logistic regression for dichotomous variables. These statistical analyses were completed by using Stata 8.2 (StataCorp, College Station, TX).
RESULTS
Incidence of CBH in Preterm Infants
A total of 1242 preterm infants weighing <1500 g were born at the Brigham and Women's Hospital from January 1998 through December 2002 (Table 1). The overall proportion of infants diagnosed with CBH showed a significant positive trend across the 5-year study period, with the odds of CBH increasing 44% per year (P = .005). When CBH was analyzed by birth weight category over the 5-year period, the only significant positive trend in the proportion of infants with CBH was for preterm infants weighing <750 g at birth, for whom the odds of CBH increased 88% per year (P < .001). It is interesting to note that among all 259 live births of <750 g over the study period, mortality within the first 5 days of life decreased across the study period. Specifically, for preterm infants at <750 g birth weight, the mortality rate in the first 5 days of life decreased from 48% (n = 49) between 1998 and 1999 to 30% (n = 35) between 2000 and 2002.
US Findings
We identified 35 preterm infants born between the years 1998 and 2002 who met our diagnostic criteria for CBH. Table 2 summarizes the US findings in this study population. Unilateral focal CBH was seen in 25 infants (71%), with a twofold predominance in the right cerebellar hemisphere (64% right versus 36% left). The hemorrhages were either circular or lentiform in shape and located primarily inferior and toward the dorsal periphery of the cerebellar hemisphere (Fig 1). CBH that involved the vermis occurred in 7 patients (20%), and concomitant infratentorial extra-axial hemorrhage was observed in 20 patients (57%). Extensive CBH (ie, diffuse hemorrhage involving both cerebellar hemispheres and the vermis) was seen in 3 patients (9%) (Fig 2). CBH resulted in cerebellar atrophy in 13 patients (37%) by follow-up US at 73.4 ± 4.9 days (range: 61–96 days) (Fig 3).
Hemorrhage was isolated to the cerebellum in 8 patients (23%), whereas combined CBH and supratentorial extraparenchymal or parenchymal hemorrhage occurred in 27 patients (77%). Specifically, CBH was associated with a maximal grade I GM-IVH hemorrhage in 7 patients (26%), grade II GM-IVH in 5 patients (19%), and grade III GM-IVH in 7 patients (26%). PVHI accompanied CBH in 7 patients (26%) and periventricular leukomalacia in 1 patient (4%). Table 2 summarizes the US characteristics of CBH in our cohort.
CBH was identified on cranial US studies later than were GM-IVH and PVHI. Specifically, CBH was first identified at a mean age of 5.2 ± 1.8 days (range: 1–12), whereas GM-IVH and PVHI were diagnosed at mean ages of 1.7 ± 1.9 days (range: 1–6) and 2.3 ± 1.9 days (range: 1–7), respectively (P < .01). There was no difference in the timing of identification of CBH in preterm infants with isolated CBH compared with those with combined CBH and supratentorial lesions (5.1 ± 1.8 vs. 5.2 ± 1.6 days, respectively).
Demographic Characteristics of the Patients and Controls
We double-matched our 35 preterm infants with CBH to 70 control infants with normal neonatal cranial US throughout the neonatal period according to gestational age, gender, and year of birth. Mean gestational age was comparable between the 2 study groups (CBH cases versus controls: 26.2 ± 2.2 weeks [range: 24–32] vs. 26.1 ± 1.8 weeks [range: 23.6–32]), as were birth weight (CBH cases versus controls: 787.7 ± 262.4 g [range: 460–1450] vs. 817.1 ± 228.0 g [range: 460–1490]) and head circumference at birth (CBH cases versus controls: 24.2 ± 2.5 vs. 24.0 ± 2.1 cm). There were no differences between the 2 groups in gender distribution (male patients versus male controls: 18 [51%] vs. 36 [51%]) and singleton births (patients versus controls: 21 [60%] vs. 43 [61%]).
Risk Factors Associated With CBH (Univariate Analyses)
Maternal Factors
The odds of CBH were nearly 5 times higher in infants after assisted conception (P = .006) (Table 3). Pregnancy-induced hypertension, antenatal infection and medications, prenatal abnormal fetal heart rate, and the presence of chorioamnionitis and placental abruption were not associated with CBH (Table 3).
Intrapartum Factors
Abnormal fetal heart rate, delivery by emergent cesarean section, and lower Apgar scores at 1 and 5 minutes all significantly increased the odds of CBH (P .03 for each) (Table 4). Maternal fever, vaginal bleeding and vaginal delivery, the need for respiratory resuscitation, cardiac compressions, and medication for resuscitation were not associated with CBH.
Early Postnatal Factors (First 5 Days of Life)
The need for high-frequency ventilation, pressor support and volume expanders, and the presence of PDA and pulmonary hemorrhage significantly increased the odds of CBH (P .04 for each) (Table 5). Lower 5-day minimum pH and plasma bicarbonate concentration, as well as lower 5-day minimum platelets and hematocrit were also significant risk factors for CBH (P .01; Table 5).
Risk Factors Independently Associated With CBH (Multiple-Regression Analysis)
Stepwise selection led to an initial main-effects model including emergent caesarian section, PDA, and 5-day minimum pH. No other clinically important variables individually entered into the model were statistically significant, and all confounding was either deemed minor or resulted from confounding by indication. The test for nonlinearity in the effect of 5-day minimum pH was not statistically significant (P = .93). Although it was thought clinically plausible to assess a potential interaction between 5-day minimum pH and emergent caesarian section, this interaction was not statistically significant (P = .12). Thus, emergent caesarian section independently increased the odds of CBH eightfold (odds ratio [OR]: 8.14; 95% confidence interval [CI]: 1.67–39.73; P = .01), and PDA increased the odds of CBH nearly sevenfold (OR: 6.91; 95% CI: 1.51–31.63; P = .01). Adjusting for these factors, the odds of CBH decreased by 10% for each 0.01 unit increase in 5-day minimum pH (OR: 0.90; 95% CI: 0.85–0.96; P = .002).
Finally, there were no differences between the effects on the odds of having isolated CBH and the effects on the odds of having combined CBH and supratentorial lesions of PDA (P = .05) and 5-day minimum pH (P = .17).
Short-Term Outcome
Neonatal mortality was significantly higher among infants who developed CBH (14%) compared with the control group (1%) (P = .04) (Table 6). Median postnatal age at death in infants with CBH was 6 days (range: 4–15 days) versus the age at death of the 1 infant in the control group, which was 18 days. Survivors of CBH were far more likely to require longer assisted ventilation than control infants (P = .001) and to have extended oxygen requirements (P = .004). Subacute complications such as necrotizing enterocolitis, PDA ligation, BPD, and retinopathy of prematurity (stage III or higher) were significantly more frequent in infants with CBH, and length of hospitalization was greater (P .04 for each).
DISCUSSION
In this study, we describe the sonographic characteristics of CBH in infants born prematurely. Our results indicate that the incidence of CBH in the preterm infant is inversely related to birth weight. In fact, we show a significant increase in the incidence of CBH in the extremely low birth weight infants (<750 g) across the 5-year study period. We then demonstrate that risk factors associated with the development of CBH are multifactorial and include combined maternal and intrapartum factors as well as acute early postnatal cardiorespiratory derangements. Taken together, these factors point to a greater degree of fetal–early-neonatal illness preceding the CBH, as well as a greater risk for subsequent neonatal morbidity and mortality.
The incidence of CBH in the premature infant has not been well defined. Although neuropathologic studies5,6 have reported CBH in up to 25% of low birth weight infants and suggest that CBH is more common than clinically appreciated at present, very few clinical studies have addressed this issue. Of these, the reports addressed the incidence of CBH in combined preterm and term populations, and in this population the incidence has been estimated at 2.5% to 3.6%.1,2 Although the overall incidence of CBH in our cohort of preterm infants was 2.8%, the incidence of this lesion increased to 8.7% in infants born at <750 g. In fact, in the latter 3 years of this study period, the incidence of CBH was 15.0% in these extremely low birth weight infants. This trend likely reflects the decrease in mortality among the sickest and most immature infants, a decrease evident in our population over the course of our study period. In addition, increasing expertise with the mastoid-view approach might have increased detection of CBH. Our data suggest that CBH is an important and increasingly diagnosed complication in infants surviving extreme preterm birth.
The topography of CBH in our cohort was primarily focal, and unilateral, within the peripheral parenchyma of the cerebellar hemisphere. The vermis was involved in slightly less than one third of patients. Subpial germinal matrix bleeding within the external granular cell layer may account for the intrahemispheric CBHs identified along the peripheral parenchyma of the cerebellum. The subpial external granular cell layer is thickest at 24 weeks' gestation and begins to involute by 30 weeks' gestation.12,13 Cases of vermian hemorrhage likely represent hemorrhages within the germinal matrix located in the subependymal layer of the roof of the fourth ventricle.12,14
The exact pathogenesis of CBH is unknown, but undoubtedly multifactorial, and likely includes intrapartum factors and circulatory events related to prematurity. In the context of our study, we sought to characterize the risk profile associated with the development of CBH in preterm infants. A number of prenatal, intrapartum, and early postnatal risk factors were found to be associated with CBH. Recent studies have shown an association between the development of GM-IVH and assisted methods of conception.15,16 Although we found assisted conception to be associated with the development of CBH in our univariate analyses, this association was not supported in our multiple-regression analyses when controlling for other risk factors. It is notable that inflammatory markers were implicated recently in the genesis of fetal and neonatal brain injury.16,17 However, we found no relationship between CBH and maternal fever, documented maternal infection, chorioamnionitis confirmed by placental pathology, or postnatal infection.
We also identified several intrapartum risk factors associated with CBH, including abnormalities in fetal heart rate tracings, the need for emergent cesarean section, and low Apgar scores at 1 and 5 minutes. Previous studies have demonstrated a strong correlation between fetal distress and the development of other forms of hemorrhagic brain injury including GM-IVH and PVHI.18–23 Our findings demonstrate that fetal distress is also an important risk factor for CBH. Specifically, emergent cesarean section was a significant independent risk factor, suggesting that it may be an important marker for CBH.
Early postnatal factors for CBH identified in the first 5 days of life in our study strongly suggest that hemodynamic compromise is a significant mediator for CBH. We identified PDA as an independent risk factor for CBH. Cerebellar perfusion, particularly during diastole, may be compromised by a large PDA24 and has been associated with border-zone infarcts of the cerebellum.25 In addition, acidosis is known to impair cerebral pressure autoregulation,26,27 rendering the brain more vulnerable to hemodynamic perturbations. It is important that the need for high-frequency ventilation and for both inotropic pressor support and intravascular volume expanders were significantly associated with CBH on univariate analyses, but their effects became insignificant in the multivariate model. Collectively, these data suggest that several hemodynamic indices with potential impact on cerebral perfusion pressure may play a role in the genesis of CBH.
Our short-term outcome data suggest that mortality and morbidity are higher among premature infants who develop CBH. Although previous studies have suggested that CBH is a catastrophic complication for high-risk infants,4,8,28–31 our data suggest that currently the majority (86%) of premature infants with CBH survive the neonatal period, albeit with more frequent and severe neonatal morbidity. The neonatal complications in premature infants with CBH included, not surprisingly, prolonged ventilatory and oxygen requirements, a higher frequency of PDA ligation, necrotizing enterocolitis, and bowel surgery, BPD, severe retinopathy of prematurity (stage III or higher), and longer NICU stays.
Historically, the perceived role of the cerebellum has been limited to the domain of motor control. Recent experimental and clinical findings as well as neuroimaging studies in older children and adults have provided parallel evidence that the cerebellum controls not only movement but also aspects of social function and cognition.32–34 Survivors of extremely low birth weight demonstrate a high prevalence of long-term neuromotor, social, behavioral, and cognitive impairments,35,36 part of which may be attributable to underrecognized early-life cerebellar injury.37,38
Although we identified a number of risk factors associated with CBH, given the retrospective nature of our study design, causality-related inferences could not be examined. Also, the timing of cranial US was defined by our routine NICU clinical protocol and clinical decision-making; as a result, the exact timing of the injury and the distinction between early- and late-onset CBH are difficult to determine systematically, and our insights into the nature of the pathology are limited. Additionally, the mastoid view was incorporated into the cranial US protocol of our center in the mid-1990s. Therefore, the lower incidence of CBH in the first 2 years of our study period may relate to an initial lack of expertise with this approach, and hence the overall incidence of CBH may be underestimated in our study, particularly in the early study years. Finally, our study was not adequately powered to detect differences between the effects of risk factors and neonatal morbidity in infants having isolated CBH compared with those with combined CBH and supratentorial lesions.
CONCLUSIONS
We have demonstrated that CBH is an important complication of extreme premature birth. Determinants of CBH seem to be multifactorial and include hemodynamic derangements operating during different phases of the perinatal period that collectively seem to be associated with the development of CBH. At present, CBH seems to be underappreciated in the clinical setting but is likely to account for an appreciable portion of subsequent long-term neurodevelopmental disabilities in extremely preterm infants. A systematic and comprehensive neuroimaging and developmental follow-up study of this cohort is currently underway to determine the long-term consequences of early-life CBH in the premature infant.
ACKNOWLEDGMENTS
Dr Limperopoulos is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research. We acknowledge support from the Hearst Foundation and LifeBridge Fund.
We thank Erica Briones for assistance with data entry and David Wypij for statistical consultation. We also thank Shaye Moore and Shelly Robinson for help with manuscript preparation.
FOOTNOTES
Accepted May 18, 2005.
No conflict of interest declared.
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Department of Radiology Department of Newborn Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
ABSTRACT
Cerebellar hemorrhage (CBH) in premature infants is increasingly diagnosed secondary to improved neuroimaging techniques and survival of very small preterm infants. Information is limited, however, on the incidence, topography, and risk factors for CBH in the preterm infant.
Objectives. To define the incidence of CBH in preterm infants diagnosed by neonatal cranial ultrasound (US), describe the sonographic features of CBH, and identify maternal and perinatal risk factors associated with this lesion.
Methods. A systematic electronic database search identified preterm infants born 1998–2002 with US diagnosis of CBH. For 35 cases of CBH we double-matched (according to gestational age, gender, and year of birth) 70 preterm controls with normal cranial USs and performed detailed medical-record reviews for both patients and controls.
Results. Unilateral CBH was seen in 25 patients (71%), vermian hemorrhage was seen in 7 (20%), and combined bihemispheric and vermian hemorrhage was seen in 3 (9%). Isolated CBH occurred in 8 patients (23%); the remaining infants had associated supratentorial lesions. The incidence of CBH in preterm infants weighing <750 g at birth showed significant increase over the study period. Univariate analyses identified maternal, intrapartum, and early postnatal hemodynamic risk factors; multivariate regressions indicated that emergent caesarian section, patent ductus arteriosus, and lower 5-day minimum pH independently increased the odds of CBH. Neonatal mortality and morbidity were significantly higher among patients with CBH compared with preterm controls.
Conclusions. CBH is an important complication of extreme preterm birth and has been underrecognized in surviving preterm infants. Predictors of CBH seem to be multifactorial and include combined maternal, intrapartum, and early postnatal factors.
Key Words: cerebellar hemorrhage premature infants cranial ultrasound incidence risk factors
Abbreviations: CBH, cerebellar hemorrhage US, ultrasound/ultrasonographic GM-IVH, germinal matrix-intraventricular hemorrhage PVHI, periventricular hemorrhagic infarction PDA, patent ductus arteriosus BPD, bronchopulmonary dysplasia OR, odds ratio CI, confidence interval
Hemorrhage into the immature cerebellum is an underrecognized complication of premature birth. However, improved survival of very preterm infants and advanced neonatal neuroimaging techniques have made possible the early and accurate diagnosis of this lesion.1–3 Previous reports suggest that in preterm infants cerebellar hemorrhage (CBH) often occurs concomitantly with supratentorial hemorrhage and is associated with high mortality.3,4 More recently, CBH in preterm infants (birth weight of <1500 g) has been reported to be clinically silent in presentation (ie, diagnosed on routine cranial ultrasound [US]) and not associated with significant supratentorial bleeding.2
The exact incidence of CBH is unknown, although existing neuropathologic studies suggest that CBH is more common than clinically appreciated. In fact, CBH is reported to occur in 15% to 25% of low birth weight infants postmortem.5,6 To date, there are few clinical studies defining the nature and frequency of CBH in the premature infant.2
Identification of CBH by conventional US through the anterior fontanelle is complicated by the highly echogenic tentorium and cerebellar vermis.7,8 Recent use of the mastoid fontanelle, the thinnest region of the temporal bone at the junction of the squamosal, lambdoidal, and occipital sutures,9 has vastly improved visualization of the posterior fossa.9 Use of this mastoid-window approach has increased the detection of CBH1,10,11 and has become part of the neonatal US protocol at many centers, including our own. However, to date, the topographic characteristics of CBH by US in the preterm infant remain poorly defined. In addition, no study has systematically characterized the incidence of and risk factors for CBH in the preterm infant. Given these gaps in our understanding of CBH, the objectives of this study were to define (by neonatal US) the incidence of CBH in preterm infants, to describe its sonographic features, and to identify maternal and perinatal risk factors associated with this lesion.
METHODS
Using a retrospective case-control design and a detailed and systematic electronic database search of all neonatal cranial US reports, we identified all preterm infants (<37 weeks' gestational age) with an US diagnosis of CBH admitted to the Brigham and Women's Hospital neonatal intensive care unit (NICU) from January 1998 through December 2002. Clinically indicated cranial US studies at our center have incorporated a mastoid view as part of the routine cranial US protocol since the mid-1990s. All cranial US studies were reviewed by 2 experienced radiologists (C.B.B. and D.N.D.) who were blinded to the clinical course and outcome of these infants and to each other's findings. For 2 cases in which there was disagreement regarding the diagnosis, these investigators reviewed the US studies together and reached a consensus.
We included all preterm infants (<37 weeks' gestational age) admitted to the Brigham and Women's Hospital NICU over the 5-year study period (1998–2002) with a sonographic diagnosis of CBH. We specifically excluded term infants or preterm infants with known or suspected brain malformation, dysmorphic features or congenital anomaly suggestive of a genetic syndrome, metabolic disorder, chromosomal abnormality, or central nervous system infection.
For each preterm infant with a diagnosis of CBH, we matched 2 control infants on the basis of gestational age, gender, and year of birth. We defined our control group as preterm infants with normal cranial US studies throughout their NICU stay. Detailed medical-record reviews were performed for all infants for pertinent demographic, maternal, and neonatal data. Our institution's Committee on Clinical Investigation approved this study.
US Criteria
The routine clinical US protocol in our NICU includes 2 cranial US studies performed during the first week of life and a third US study at 30 days of age, with additional studies performed when clinically indicated. Posterior fossa views have been part of the routine protocol since 1995. All cranial USs were reviewed blindly to confirm the diagnosis of CBH and distinguish between parenchymal and extra-axial hemorrhage. We defined CBH as a unilateral or bilateral echodense lesion in the cerebellar hemispheres or vermis. The cerebellar parenchyma was also examined for the presence of architectural distortion (eg, central hypoechoic foci, peripheral echogenic foci, folia disruption). By examining all serial US studies, we carefully distinguished posterior fossa subarachnoid hemorrhage (in which the echodense areas were outside and surrounding the cerebellum) from CBH (in which the echodense areas were within the confines of the cerebellar parenchyma).
We defined supratentorial lesions by cranial US using previously published criteria.12 We graded the severity of germinal matrix-intraventricular hemorrhage (GM-IVH) as follows: grade I, the hemorrhage was confined to the germinal matrix with no or minimal intraventricular hemorrhage; grade II, echogenic blood filled <50% of the ventricular area; and grade III, a large blood clot filled >50% of the ventricular area, often distending the lateral ventricles. Periventricular hemorrhagic infarction (PVHI) was defined as a unilateral globular or fan-shaped echogenic lesion located most commonly in the frontal and/or parietal region. Periventricular leukomalacia was defined as bilateral echodensity in the white matter dorsal and lateral to the lateral ventricles with evolution into echolucent cysts.
Clinical Data Collection
We performed medical-record reviews and collected demographic, prenatal, intrapartum, and acute postnatal and short-term outcome data on all identified infants. Demographic data included gestational age at birth, birth weight, head circumference, and gender. Maternal data included mode of conception, single versus multiple gestation, pregnancy-induced hypertension, prenatal infection, and use of tocolysis and antenatal steroids. Intrapartum factors included fetal heart rate abnormalities (sustained fetal bradycardia with <100 beats per minutes, decreased variability, and late decelerations), vaginal versus cesarean birth, emergent cesarean section, meconium-stained amniotic fluid, maternal fever (temperature of >38°C within 72 hours of delivery), vaginal bleeding, Apgar score at 1 and 5 minutes, and need for respiratory and cardiovascular resuscitation (with or without medications). We also collected data from placental pathology reports for the presence of chorioamnionitis, placental abruption, or infarction.
Early postnatal data were collected in the first 5 days of life and included blood gases (pH, PCO2, PO2, plasma bicarbonate concentration), blood cell counts and platelets, need for cardiopulmonary support (use of inotropic agents and/or volume expanders), highest level of mechanical ventilation, presence of a patent ductus arteriosus (PDA), pulmonary hemorrhage, and infection (confirmed by positive blood, urine, or mucosal culture or clinical suspicion resulting in a full course of antibiotic treatment). The diagnosis of PDA was based on confirmatory echocardiogram before day of life 5 or on a clinical diagnosis before day of life 5 with subsequent confirmation by echocardiogram.
Short-term outcome data included neonatal mortality, duration of mechanical ventilation, supplemental oxygen requirement, length of hospitalization, neonatal seizures, necrotizing enterocolitis, operative procedures (eg, PDA ligation, bowel surgery), retinopathy of prematurity (stage III or higher), and radiologic evidence of bronchopulmonary dysplasia (BPD).
Statistical Analysis
To examine the incidence of CBH over time by birth weight, we categorized infants into 3 birth weight categories: <750, 750 to 999, and 1000 to 1499 g. In each birth weight category, we used an exact trend test and exact logistic regression to assess trends over time (StatXact 5.0; Cytel Software Corporation, Cambridge, MA).
US characteristics of CBH were analyzed by using means and standard deviations (SDs) for continuous data and proportions for categorical data.
Potentially clinically important risk factors were grouped into 3 domains: prenatal, intrapartum, and early postnatal factors. Univariate analyses with conditional logistic regression were used to determine the effects of these factors on the odds of CBH. All variables significant at the 5% level were considered in our multiple conditional logistic-regression model. After arriving at an initial main-effects model through stepwise selection, clinically important variables were entered individually into the model to test for statistical significance at the 5% level and to assess confounding. In our assessment of the initial main-effects model and potential additional terms, we preferred to include conditions rather than treatments to avoid confounding by indication. Potential nonlinear effects of continuous variables were tested by adding a set of design variables identifying the quartile of the distribution of the variable to the regression containing the linear term and examining whether the joint effect of the design variables was statistically significant at the 5% level by using the likelihood ratio test. Clinically plausible interactions were tested for significance at the 5% level by using the Wald test.
Early clinical outcomes were then compared between infants having CBH and controls by using linear regression with a fixed effect to adjust for matching for continuous variables and conditional logistic regression for dichotomous variables. These statistical analyses were completed by using Stata 8.2 (StataCorp, College Station, TX).
RESULTS
Incidence of CBH in Preterm Infants
A total of 1242 preterm infants weighing <1500 g were born at the Brigham and Women's Hospital from January 1998 through December 2002 (Table 1). The overall proportion of infants diagnosed with CBH showed a significant positive trend across the 5-year study period, with the odds of CBH increasing 44% per year (P = .005). When CBH was analyzed by birth weight category over the 5-year period, the only significant positive trend in the proportion of infants with CBH was for preterm infants weighing <750 g at birth, for whom the odds of CBH increased 88% per year (P < .001). It is interesting to note that among all 259 live births of <750 g over the study period, mortality within the first 5 days of life decreased across the study period. Specifically, for preterm infants at <750 g birth weight, the mortality rate in the first 5 days of life decreased from 48% (n = 49) between 1998 and 1999 to 30% (n = 35) between 2000 and 2002.
US Findings
We identified 35 preterm infants born between the years 1998 and 2002 who met our diagnostic criteria for CBH. Table 2 summarizes the US findings in this study population. Unilateral focal CBH was seen in 25 infants (71%), with a twofold predominance in the right cerebellar hemisphere (64% right versus 36% left). The hemorrhages were either circular or lentiform in shape and located primarily inferior and toward the dorsal periphery of the cerebellar hemisphere (Fig 1). CBH that involved the vermis occurred in 7 patients (20%), and concomitant infratentorial extra-axial hemorrhage was observed in 20 patients (57%). Extensive CBH (ie, diffuse hemorrhage involving both cerebellar hemispheres and the vermis) was seen in 3 patients (9%) (Fig 2). CBH resulted in cerebellar atrophy in 13 patients (37%) by follow-up US at 73.4 ± 4.9 days (range: 61–96 days) (Fig 3).
Hemorrhage was isolated to the cerebellum in 8 patients (23%), whereas combined CBH and supratentorial extraparenchymal or parenchymal hemorrhage occurred in 27 patients (77%). Specifically, CBH was associated with a maximal grade I GM-IVH hemorrhage in 7 patients (26%), grade II GM-IVH in 5 patients (19%), and grade III GM-IVH in 7 patients (26%). PVHI accompanied CBH in 7 patients (26%) and periventricular leukomalacia in 1 patient (4%). Table 2 summarizes the US characteristics of CBH in our cohort.
CBH was identified on cranial US studies later than were GM-IVH and PVHI. Specifically, CBH was first identified at a mean age of 5.2 ± 1.8 days (range: 1–12), whereas GM-IVH and PVHI were diagnosed at mean ages of 1.7 ± 1.9 days (range: 1–6) and 2.3 ± 1.9 days (range: 1–7), respectively (P < .01). There was no difference in the timing of identification of CBH in preterm infants with isolated CBH compared with those with combined CBH and supratentorial lesions (5.1 ± 1.8 vs. 5.2 ± 1.6 days, respectively).
Demographic Characteristics of the Patients and Controls
We double-matched our 35 preterm infants with CBH to 70 control infants with normal neonatal cranial US throughout the neonatal period according to gestational age, gender, and year of birth. Mean gestational age was comparable between the 2 study groups (CBH cases versus controls: 26.2 ± 2.2 weeks [range: 24–32] vs. 26.1 ± 1.8 weeks [range: 23.6–32]), as were birth weight (CBH cases versus controls: 787.7 ± 262.4 g [range: 460–1450] vs. 817.1 ± 228.0 g [range: 460–1490]) and head circumference at birth (CBH cases versus controls: 24.2 ± 2.5 vs. 24.0 ± 2.1 cm). There were no differences between the 2 groups in gender distribution (male patients versus male controls: 18 [51%] vs. 36 [51%]) and singleton births (patients versus controls: 21 [60%] vs. 43 [61%]).
Risk Factors Associated With CBH (Univariate Analyses)
Maternal Factors
The odds of CBH were nearly 5 times higher in infants after assisted conception (P = .006) (Table 3). Pregnancy-induced hypertension, antenatal infection and medications, prenatal abnormal fetal heart rate, and the presence of chorioamnionitis and placental abruption were not associated with CBH (Table 3).
Intrapartum Factors
Abnormal fetal heart rate, delivery by emergent cesarean section, and lower Apgar scores at 1 and 5 minutes all significantly increased the odds of CBH (P .03 for each) (Table 4). Maternal fever, vaginal bleeding and vaginal delivery, the need for respiratory resuscitation, cardiac compressions, and medication for resuscitation were not associated with CBH.
Early Postnatal Factors (First 5 Days of Life)
The need for high-frequency ventilation, pressor support and volume expanders, and the presence of PDA and pulmonary hemorrhage significantly increased the odds of CBH (P .04 for each) (Table 5). Lower 5-day minimum pH and plasma bicarbonate concentration, as well as lower 5-day minimum platelets and hematocrit were also significant risk factors for CBH (P .01; Table 5).
Risk Factors Independently Associated With CBH (Multiple-Regression Analysis)
Stepwise selection led to an initial main-effects model including emergent caesarian section, PDA, and 5-day minimum pH. No other clinically important variables individually entered into the model were statistically significant, and all confounding was either deemed minor or resulted from confounding by indication. The test for nonlinearity in the effect of 5-day minimum pH was not statistically significant (P = .93). Although it was thought clinically plausible to assess a potential interaction between 5-day minimum pH and emergent caesarian section, this interaction was not statistically significant (P = .12). Thus, emergent caesarian section independently increased the odds of CBH eightfold (odds ratio [OR]: 8.14; 95% confidence interval [CI]: 1.67–39.73; P = .01), and PDA increased the odds of CBH nearly sevenfold (OR: 6.91; 95% CI: 1.51–31.63; P = .01). Adjusting for these factors, the odds of CBH decreased by 10% for each 0.01 unit increase in 5-day minimum pH (OR: 0.90; 95% CI: 0.85–0.96; P = .002).
Finally, there were no differences between the effects on the odds of having isolated CBH and the effects on the odds of having combined CBH and supratentorial lesions of PDA (P = .05) and 5-day minimum pH (P = .17).
Short-Term Outcome
Neonatal mortality was significantly higher among infants who developed CBH (14%) compared with the control group (1%) (P = .04) (Table 6). Median postnatal age at death in infants with CBH was 6 days (range: 4–15 days) versus the age at death of the 1 infant in the control group, which was 18 days. Survivors of CBH were far more likely to require longer assisted ventilation than control infants (P = .001) and to have extended oxygen requirements (P = .004). Subacute complications such as necrotizing enterocolitis, PDA ligation, BPD, and retinopathy of prematurity (stage III or higher) were significantly more frequent in infants with CBH, and length of hospitalization was greater (P .04 for each).
DISCUSSION
In this study, we describe the sonographic characteristics of CBH in infants born prematurely. Our results indicate that the incidence of CBH in the preterm infant is inversely related to birth weight. In fact, we show a significant increase in the incidence of CBH in the extremely low birth weight infants (<750 g) across the 5-year study period. We then demonstrate that risk factors associated with the development of CBH are multifactorial and include combined maternal and intrapartum factors as well as acute early postnatal cardiorespiratory derangements. Taken together, these factors point to a greater degree of fetal–early-neonatal illness preceding the CBH, as well as a greater risk for subsequent neonatal morbidity and mortality.
The incidence of CBH in the premature infant has not been well defined. Although neuropathologic studies5,6 have reported CBH in up to 25% of low birth weight infants and suggest that CBH is more common than clinically appreciated at present, very few clinical studies have addressed this issue. Of these, the reports addressed the incidence of CBH in combined preterm and term populations, and in this population the incidence has been estimated at 2.5% to 3.6%.1,2 Although the overall incidence of CBH in our cohort of preterm infants was 2.8%, the incidence of this lesion increased to 8.7% in infants born at <750 g. In fact, in the latter 3 years of this study period, the incidence of CBH was 15.0% in these extremely low birth weight infants. This trend likely reflects the decrease in mortality among the sickest and most immature infants, a decrease evident in our population over the course of our study period. In addition, increasing expertise with the mastoid-view approach might have increased detection of CBH. Our data suggest that CBH is an important and increasingly diagnosed complication in infants surviving extreme preterm birth.
The topography of CBH in our cohort was primarily focal, and unilateral, within the peripheral parenchyma of the cerebellar hemisphere. The vermis was involved in slightly less than one third of patients. Subpial germinal matrix bleeding within the external granular cell layer may account for the intrahemispheric CBHs identified along the peripheral parenchyma of the cerebellum. The subpial external granular cell layer is thickest at 24 weeks' gestation and begins to involute by 30 weeks' gestation.12,13 Cases of vermian hemorrhage likely represent hemorrhages within the germinal matrix located in the subependymal layer of the roof of the fourth ventricle.12,14
The exact pathogenesis of CBH is unknown, but undoubtedly multifactorial, and likely includes intrapartum factors and circulatory events related to prematurity. In the context of our study, we sought to characterize the risk profile associated with the development of CBH in preterm infants. A number of prenatal, intrapartum, and early postnatal risk factors were found to be associated with CBH. Recent studies have shown an association between the development of GM-IVH and assisted methods of conception.15,16 Although we found assisted conception to be associated with the development of CBH in our univariate analyses, this association was not supported in our multiple-regression analyses when controlling for other risk factors. It is notable that inflammatory markers were implicated recently in the genesis of fetal and neonatal brain injury.16,17 However, we found no relationship between CBH and maternal fever, documented maternal infection, chorioamnionitis confirmed by placental pathology, or postnatal infection.
We also identified several intrapartum risk factors associated with CBH, including abnormalities in fetal heart rate tracings, the need for emergent cesarean section, and low Apgar scores at 1 and 5 minutes. Previous studies have demonstrated a strong correlation between fetal distress and the development of other forms of hemorrhagic brain injury including GM-IVH and PVHI.18–23 Our findings demonstrate that fetal distress is also an important risk factor for CBH. Specifically, emergent cesarean section was a significant independent risk factor, suggesting that it may be an important marker for CBH.
Early postnatal factors for CBH identified in the first 5 days of life in our study strongly suggest that hemodynamic compromise is a significant mediator for CBH. We identified PDA as an independent risk factor for CBH. Cerebellar perfusion, particularly during diastole, may be compromised by a large PDA24 and has been associated with border-zone infarcts of the cerebellum.25 In addition, acidosis is known to impair cerebral pressure autoregulation,26,27 rendering the brain more vulnerable to hemodynamic perturbations. It is important that the need for high-frequency ventilation and for both inotropic pressor support and intravascular volume expanders were significantly associated with CBH on univariate analyses, but their effects became insignificant in the multivariate model. Collectively, these data suggest that several hemodynamic indices with potential impact on cerebral perfusion pressure may play a role in the genesis of CBH.
Our short-term outcome data suggest that mortality and morbidity are higher among premature infants who develop CBH. Although previous studies have suggested that CBH is a catastrophic complication for high-risk infants,4,8,28–31 our data suggest that currently the majority (86%) of premature infants with CBH survive the neonatal period, albeit with more frequent and severe neonatal morbidity. The neonatal complications in premature infants with CBH included, not surprisingly, prolonged ventilatory and oxygen requirements, a higher frequency of PDA ligation, necrotizing enterocolitis, and bowel surgery, BPD, severe retinopathy of prematurity (stage III or higher), and longer NICU stays.
Historically, the perceived role of the cerebellum has been limited to the domain of motor control. Recent experimental and clinical findings as well as neuroimaging studies in older children and adults have provided parallel evidence that the cerebellum controls not only movement but also aspects of social function and cognition.32–34 Survivors of extremely low birth weight demonstrate a high prevalence of long-term neuromotor, social, behavioral, and cognitive impairments,35,36 part of which may be attributable to underrecognized early-life cerebellar injury.37,38
Although we identified a number of risk factors associated with CBH, given the retrospective nature of our study design, causality-related inferences could not be examined. Also, the timing of cranial US was defined by our routine NICU clinical protocol and clinical decision-making; as a result, the exact timing of the injury and the distinction between early- and late-onset CBH are difficult to determine systematically, and our insights into the nature of the pathology are limited. Additionally, the mastoid view was incorporated into the cranial US protocol of our center in the mid-1990s. Therefore, the lower incidence of CBH in the first 2 years of our study period may relate to an initial lack of expertise with this approach, and hence the overall incidence of CBH may be underestimated in our study, particularly in the early study years. Finally, our study was not adequately powered to detect differences between the effects of risk factors and neonatal morbidity in infants having isolated CBH compared with those with combined CBH and supratentorial lesions.
CONCLUSIONS
We have demonstrated that CBH is an important complication of extreme premature birth. Determinants of CBH seem to be multifactorial and include hemodynamic derangements operating during different phases of the perinatal period that collectively seem to be associated with the development of CBH. At present, CBH seems to be underappreciated in the clinical setting but is likely to account for an appreciable portion of subsequent long-term neurodevelopmental disabilities in extremely preterm infants. A systematic and comprehensive neuroimaging and developmental follow-up study of this cohort is currently underway to determine the long-term consequences of early-life CBH in the premature infant.
ACKNOWLEDGMENTS
Dr Limperopoulos is supported by a postdoctoral fellowship from the Canadian Institutes of Health Research. We acknowledge support from the Hearst Foundation and LifeBridge Fund.
We thank Erica Briones for assistance with data entry and David Wypij for statistical consultation. We also thank Shaye Moore and Shelly Robinson for help with manuscript preparation.
FOOTNOTES
Accepted May 18, 2005.
No conflict of interest declared.
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