Published online June 9, 2008
PEDIATRICS Vol. 122 No. 1 July 2008, pp. e46-e52 (doi:10.1542/peds.2007-3305)
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ARTICLE

Risk Factors for Adverse Outcome in Preterm Infants With Periventricular Hemorrhagic Infarction

Elise Roze, BSca, Jorien M. Kerstjens, MDa, Carel G.B. Maathuis, MD, PhDb, Hendrik J. ter Horst, MDa and Arend F. Bos, MD, PhDa

a Division of Neonatology, Department of Pediatrics
b Center for Rehabilitation, University Medical Center Groningen, University of Groningen, Groningen, Netherlands


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Our objective was to identify risk factors that were associated with mortality and adverse neurologic outcome at 18 months of age in preterm infants with periventricular hemorrhagic infarction.

METHODS. This was a retrospective cohort study of all preterm infants who were <37 weeks' gestation, had periventricular hemorrhagic infarction, and were admitted between 1995 and 2006. Ultrasound scans were reviewed for grading of germinal matrix hemorrhage, localization and extension of the infarction, and other abnormalities. Several clinical factors were scored. Outcome measures were mortality, cerebral palsy, and Gross Motor Function Classification System level. Odds ratios were calculated by univariate and multivariate logistic regression analyses.

RESULTS. Of 54 infants, 16 (30%) died. Twenty-five (66%) of 38 survivors developed cerebral palsy: 21 mild (Gross Motor Function Classification System levels 1 and 2) and 4 moderate to severe (levels 3 and 4). Several perinatal and neonatal risk factors were associated with mortality. After multivariate logistic regression, only use of inotropic drugs and maternal intrauterine infection were predictors of mortality. In survivors, only the most extended form of periventricular hemorrhagic infarction was associated with the development of cerebral palsy but not with severity of cerebral palsy. Cystic periventricular leukomalacia and concurrent grade 3 germinal matrix hemorrhage were associated with more severe cerebral palsy.

CONCLUSIONS. In preterm infants with periventricular hemorrhagic infarction, mortality occurred despite optimal treatment and was associated with circulatory failure and maternal intrauterine infection. In survivors, motor development was abnormal in 66%, but functional abilities were good in the majority. Extension and localization of the periventricular hemorrhagic infarction were not related to functional outcome.

Key Words: periventricular hemorrhagic infarction • venous infarction • preterm infants • cerebral hemorrhage • perinatal risk factors • mortality • cerebral palsy • GMFCS

Abbreviations: PVHI—periventricular hemorrhagic infarction • GMH—germinal matrix hemorrhage • CP—cerebral palsy • PHVD—posthemorrhagic ventricular dilation • PVL—periventricular leukomalacia • GMFCS—Gross Motor Function Classification System • OR—odds ratio

Periventricular hemorrhagic infarction (PVHI), formerly described as a grade 4 germinal matrix hemorrhage (GMH), is seen in ~10% to 15% of preterm infants with GMH.1 It is presumably caused by pressure of the GMH on the periventricular terminal vein that drains the cerebral hemisphere.2–4 This leads to venous congestion in the periventricular white matter and subsequently to ischemia and hemorrhage. PVHI, or venous infarction, is now considered a complication of the GMH instead of an extension of the GMH.4

Mortality in preterm infants with PVHI has been found to range between 38% and 60%.1,5–7 Surviving preterm infants with PVHI are at high risk for developing cerebral palsy (CP) and for an abnormal neurologic examination beyond 12 months' adjusted age.8–11 Several factors in the perinatal period are associated with PVHI. These include lower gestational age, emergency cesarean section, low Apgar scores, need for respiratory resuscitation, pneumothorax, pulmonary hemorrhage, patent ductus arteriosus, acidosis, and neonatal seizures.1,6,7,12,13

It is unknown, within a group of preterm infants with PVHI, which perinatal and neonatal characteristics are associated with mortality and adverse neurologic outcome. The aim of this study was therefore to identify perinatal and neonatal risk factors for mortality and adverse neurologic outcome at 18 months of age in preterm infants with PVHI.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
In a retrospective analysis, we studied infants who had been admitted to the NICU of the University Medical Center Groningen between 1995 and 2006. We intended to include preterm infants (gestational age: <37 weeks) with PVHI diagnosed by cranial ultrasonography. To this end, we searched the patient database (which contains all diagnoses of every infant admitted to the NICU) on infants who had a diagnosis of PVHI, venous infarction, GMH grade 4, and parenchymal cerebral bleeding. We excluded patients with major chromosomal and congenital abnormalities.

Cranial Ultrasonography Classification
According to the routine scanning protocol of our unit, the first ultrasound scan was made within 72 hours after birth and then at a minimum of weekly intervals until stabilization or the disappearance of any abnormality. The scans were performed by means of real-time mechanical sector scanners equipped with a 7.5-MHz transducer.

All infants who are admitted to our NICU are subjected to the scanning protocol when they match 1 of the following criteria: gestational age <35 weeks, birth weight <1500 g, complicated delivery with a risk for brain injury, perinatal asphyxia, and suspected congenital cerebral malformation.

Three experts (Drs Bos, Kerstjens, and ter Horst) reviewed the serial ultrasound scans of the infants who were included after the patient database search to determine whether PVHI was present. The experts were blind as to the infants' outcome. The final study group was defined after this review.

We scored several characteristics of the PVHI. These included unilateral or bilateral infarction, left- or right-sided infarction, localization and extension of the infarction (frontal, parietal, occipital, or combinations), and residual abnormalities (eg, porencephalic cysts). When bilateral, the localization and extension were based on the side that was affected most. Next we scored additional cerebral abnormalities. These included grade of GMH (grade 1, 2, or 3),14 unilateral or bilateral GMH, presence or emergence of posthemorrhagic ventricular dilation (PHVD), and cystic periventricular leukomalacia (PVL). PHVD was defined as a lateral ventricle size of >0.33 according to Evans' index (the right and left lateral horn width divided by the maximum internal skull width).15 Cystic periventricular leukomalacia was classified as stage 2 or worse, according to deVries et al.16

When the experts disagreed, the scans involved were reevaluated by all experts, together. In all cases, a consensus was reached on a final score.

Perinatal Risk Factors
We reviewed the medical charts of the infants for perinatal and neonatal risk factors. These included signs of maternal intrauterine infection, early-onset sepsis, asphyxia, intrauterine growth restriction, respiratory failure, circulatory failure, and neonatal seizures. Maternal intrauterine infection was based on such clinical signs as fetal tachycardia and maternal fever (>38°C), often combined with the use of maternal antibiotics. We also scored the presence of premature rupture of membranes (>24 hours) and histologic characteristics of the placenta for signs of inflammation. Early-onset sepsis was diagnosed by a positive blood culture and/or clinical signs within the first 48 hours of life. Asphyxia was determined by Apgar scores after 1 and 5 minutes (<5), resuscitation (external heart massage and/or use of epinephrine), and umbilical cord pH (arterial pH < 7.10). Intrauterine growth restriction was scored when birth weight was below the 10th centile according to the Dutch intrauterine growth standards.17 Respiratory failure, defined as need for ventilatory support, was scored by mode and duration of the support, idiopathic respiratory distress syndrome, pneumothorax, and the presence of respiratory acidosis. Circulatory failure was defined as hemodynamic instability and scored by the need for fluid resuscitation and use of inotropic drugs during the first week, often combined with metabolic acidosis (pH < 7.15).

Late-onset morbidity was also recorded. This included retinopathy of prematurity, late-onset sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. Late-onset sepsis was diagnosed by a positive blood culture and/or clinical signs after the first 5 days of life. BPD was defined as oxygen dependence beyond 36 weeks' postmenstrual age.

Outcome
We determined the mortality rate and cause of death in the study group. Follow-up of the survivors was part of the regular follow-up program of preterm infants and consisted of a pediatric and neurologic examination at 3, 6, 12, and 18 to 24 months' corrected age, based on work by Touwen.18 The presence or absence of CP was determined when infants had reached the age of at least 18 months, following Hagberg's criteria.19

In case of CP, gross motor functioning was scored by a physiatrist using the Gross Motor Function Classification System (GMFCS).20 This is a functional, 5-level classification system for CP that is based on self-initiated movement with particular emphasis on sitting (truncal control) and walking. A higher level correlates with more serious impairment of functional abilities. Level 1 represents children who walk without restrictions but have limitations in more advanced gross motor skills (eg, coordination, balance). Level 2 represents those who walk without assistive devices but have limitations in walking outdoors and in the community (eg, running, jumping). Level 3 represents children who walk with assistive mobility devices and have limitations in walking outdoors and in the community. Level 4 represents those with limitations in self-mobility; these children use power mobility outdoors and in the community. Level 5 represents those with severely limited self-mobility even with the use of assistive technology.20 To investigate whether the outcome of preterm infants with PVHI at our NICU changed over time, we studied mortality rate, development of CP, and GMFCS throughout the study period.

Statistical Analysis
We calculated odds ratios (ORs) by univariate logistic regression to determine which perinatal and neonatal factors and which cerebral characteristics were related to mortality. We repeated these calculations in the survivors for the development of CP. We used {chi}2 for trend to relate the severity of CP to the risk factors and cerebral characteristics and to calculate the changes in outcome throughout the study period. Finally, we used backward multivariate logistic regression analysis to determine which risk factors detected by the univariate analyses (with P < .10) had independent prognostic value for outcome. Throughout the analyses, P < .05 was considered to be statistically significant. SPSS 14.0 software for Windows (SPSS Inc, Chicago, IL) was used for all analyses.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Between 1995 and 2006, 4022 patients with a gestational age of <37 weeks were admitted to our NICU. After database search, 66 infants were selected with (suspected) intraparenchymal hemorrhages. After reviewing the cranial ultrasound scans, 54 infants with PVHIs were included in the study. This is 1.3% of all infants (gestational age <37 weeks) who were admitted to the NICU during the study period. Table 1 gives an overview of the patient demographics.


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  		TABLE 1 Patient Demographics

 
The PVHI was unilateral in 45 (83%) infants: left-sided in 26 (48%) and right-sided in 19 (35%). Nine (17%) infants had bilateral PVHI. The PVHI was localized to the frontoparietal region in 14 (26%) infants, localized to the parieto-occipital region in 25 (46%) infants, and extended throughout the entire periventricular region (frontoparieto-occipital) in 15 (28%) infants. For 37 (69%) infants, the PVHI was associated with a GMH grade 1 or 2 and for 17 (31%) infants with a GMH grade 3. Sixteen (30%) infants developed PHVD. Seven of them did not need drainage of cerebrospinal fluid, 5 needed a temporary ventricular drain, and 4 required a permanent shunt. Bilateral subtle echodensities, not related to the PVHI, developed into cystic PVL in 2 (4%) infants.

Mortality
Of the 54 infants, 16 (30%) died. Fourteen infants died despite optimal treatment. For 6 infants, the cause of death was respiratory failure, and 5 infants died of combined respiratory and circulatory failure. One infant died because of a necrotizing enterocolitis, 1 because of a late-onset sepsis, and 1 because of extensive bilateral hemorrhage with a persistent flat-trace electroencephalogram. Two infants died after life support was withdrawn. In both cases, the prognosis was considered to be poor, on the basis of the combination of severe respiratory and neurologic signs.

Table 2 gives an overview of the perinatal and neonatal factors that were associated with mortality. A lower gestational age, signs of circulatory failure (use of inotropic drugs and metabolic acidosis), maternal intrauterine infection, and neonatal seizures were associated with increased mortality. Table 3 gives an overview of the characteristics of the PVHI and additional cerebral abnormalities in relation to mortality. Localization and extension of the PVHI were not associated with death or survival. Only 3 infants had PVHI limited to the frontal region, and all 3 survived. Of additional cerebral abnormalities, GMH grade 3 was present more frequently in infants who died than in survivors. As a consequence, GMH grades 1 and 2 were present more frequently in survivors.


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  		TABLE 2 Perinatal and Neonatal Risk Factors in Relation to Mortality

 

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  		TABLE 3 Characteristics of PVHI and Additional Cerebral Abnormalities in Relation to Mortality

 
Neurologic Outcome
Of the 38 surviving children, 13 (34%) were normal and 25 (66%) had developed CP. Four (11%) infants had CP with moderate to severe functional limitations, GMFCS levels 3 (n = 1) and 4 (n = 3). These 4 infants all had bilateral CP. Twenty-one (55%) infants had mild, unilateral CP, GMFCS levels 1 (n = 10) and 2 (n = 11).

Table 4 gives an overview of the cerebral characteristics on ultrasound in relation to the development of CP and GMFCS levels. All children with extensive PVHI (fronto-parieto-occipital, n = 8) developed CP, with GMFCS level 1 or 2 (OR: >4.7; P = .04). We could not identify any other localization of the PVHI that correlated with the development and severity of CP. Concerning additional cerebral abnormalities, GMH grade 3 was associated with higher GMFCS levels, thus with more severe CP. Only 4 infants had GMFCS level 3 or 4. In 2 of them, bilateral cystic PVL (and GMH grade 3) was present; in the other 2, we could not identify any reason for why these infants in particular developed a more severe CP.


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  		TABLE 4 Characteristics of PVHI and Additional Cerebral Abnormalities in Relation to CP and GMFCS in Survivors

 
Perinatal and neonatal factors (including late-onset morbidity) did not correlate with the development and severity of CP; only intrauterine growth restriction nearly reached significance (P = .06). Of the survivors, 2 children were born after intrauterine growth restriction; 1 had GMFCS level 2, and 1 had level 4.

Trends in Outcome Over Time
Mortality decreased from 1995 to 2006 (P = .03). In addition, the incidence of CP in surviving children decreased (P = .01). The severity of CP, measured by the GMFCS level, did not change during the study period.

Multivariate Logistic Regression Analysis
Because the clinical and cerebral characteristics are likely to be interdependent, we performed a multivariate logistic regression analysis to investigate which factors contributed independently to mortality. Perinatal and neonatal factors and cerebral characteristics that had shown associations with mortality at P < .10 were entered as predictors: gestational age, maternal intrauterine infection, Apgar score at 1 minute, pneumothorax, signs of circulatory failure, neonatal seizures, GMH grade 3, bilateral GMH, and fronto-parieto-occipital extension of the PVHI. Only maternal intrauterine infection (OR: 12.2 [95% confidence interval (CI): 1.2–127.0]; P = .04) and signs of circulatory failure (use of inotropic drugs during the first week, OR: 31.2 [95% CI: 2.6–373.0]; P = .007) remained in the model. We did not perform a multivariate logistic regression analysis on survivors to determine independent predictors for the development and severity of CP, because only 1 association was found in the univariate analyses for both development and severity of CP.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We identified several risk factors that were predictive of mortality and adverse neurologic outcome at 18 months of age in preterm infants with PVHI. A low gestational age, neonatal seizures, signs of circulatory failure (use of inotropic drugs and metabolic acidosis), maternal intrauterine infection, and an associated GMH grade 3 were related to mortality. Independent predictors were circulatory failure and maternal intrauterine infection. Sixty-six percent of the survivors developed CP. Only the most extended PVHI (fronto-parieto-occipital) was associated with the development of CP. Characteristics of the PVHI (localization and extension) were not related to the severity of CP; however, additional cerebral abnormalities such as GMH grade 3 and cystic PVL were associated with more severe CP.

We found a lower mortality (30%) compared with previous studies, which reported percentages from 38% to 60%.1,5–7,21 It is striking that in our study, the extension of the PVHI was not related to mortality. This association was reported by Guzzetta et al in 19865 and recently by Bassan et al.22 An explanation for the difference might be the characteristics of the study groups. Both studies reported a higher percentage of infants with extended lesions (50%–66%) than this study (28%). The percentage of infants with associated GMH grade 3 in these studies was also much higher (80%–88% vs 31%).5,22 This suggests that morbidity of the infants in this study might have been less severe than in the previous studies. Advances in neonatal care, better imaging techniques, and decisions regarding withdrawal of life support might also have influenced the association.22 In this study, most of the infants who died had sustained respiratory or circulatory failure that was unresponsive to treatment.

We found that mortality in infants with PVHI was associated with low gestational age, maternal intrauterine infections, signs of circulatory failure, an associated GMH grade 3, and neonatal seizures. After multivariate logistic regression analysis, only circulatory failure (use of inotropic drugs) and signs of maternal intrauterine infection were independent predictors of mortality. Circulatory failure, leading to disturbances of systemic and cerebral hemodynamics, was identified as a risk factor for the emergence of PVHI in several studies.7,12,13 Apparently, this factor is associated not only with the emergence of PVHI but also with a considerably increased risk for dying (OR: 31.2) in case of PVHI. The association of mortality with maternal intrauterine infections in this study was less strong and just reached significance. Intrauterine (perinatal) infections and inflammation have been associated in particular with PVL23 and not with PVHI13,24; however, other, larger studies demonstrated that intrauterine infections, chorioamnionitis, placental inflammation, and early sepsis were associated with GMH grade 3 and PVHI.25–27 Although the percentage of infants with signs of maternal intrauterine infection was low in this study, our data suggest that its presence increases the risk for dying.

Neurologic outcome at the age of 18 months was normal in 34% of the survivors. The remaining infants developed CP, which was mild in most cases. The percentage of infants who developed CP after PVHI in this study was similar to previous studies, ranging from 60% to 90%.1,5,8,9,11,22 Of all cerebral characteristics investigated, only the most extended localization (fronto-parieto-occipital) was associated with the development of CP. This was also found by Bassan et al.22 There is controversy about anterior frontal lesions. Rademaker et al8 demonstrated in a small study of 20 infants that a localization of PVHI in the occipital region was associated with the development of CP. A localization more frontally, anterior of the trigonum, was associated with a normal outcome.8 Bassan et al22 found the opposite: anterior frontal involvement of the PVHI was associated with an abnormal neuromotor examination at the age of 1 year. We could not confirm any of these results. In our study, we found that some infants with frontal, frontoparietal, and parieto-occipital lesions developed CP, but others did not. Concerning perinatal and neonatal risk factors, no associations existed with the development of CP.

Functional limitations in children who developed CP were mostly mild, with GMFCS levels 1 and 2. Only a few infants had CP with more severe functional limitations. This was associated with additional cerebral abnormalities, such as cystic PVL and an associated GMH grade 3. It is known that cystic PVL causes more severe neurologic sequelae than PVHI.1,11,28 To our surprise, GMFCS levels were not related to localization and extension of the PVHI or to any other perinatal or neonatal risk factor. Other studies of infants with PVHI and functional outcomes are scarce and did not report about outcomes of the infants in terms of functional abilities and limitations.

As a retrospective analysis, this study is subject to potential limitations. We took care to include all children with PVHI, but perhaps we still missed some. Being a single-center study, caution should be taken to generalize our results to other centers. Perinatal and neonatal care has changed considerably during the long range of years covered by this study (1995–2006). During the past 20 years, the incidence of severe intracranial hemorrhages has declined rapidly.26 Factors that were risk factors in the past are not necessarily risk factors at present.

We did not confirm the PVHI on cranial ultrasound scans using MRI for all infants. We are confident, however, that we could reliably make the diagnosis of PVHI by cranial ultrasonography alone. Earlier studies comparing MRI with cranial ultrasonography in PVHI showed that ultrasonography is a reliable method for diagnosing PVHI.1,10 The distinction between bilateral PVHI and cystic PVL is sometimes difficult to make.1,10 We used the criteria mentioned by De Vries et al1 to differentiate between the 2 types of brain lesions. In our opinion, we could reliably make this distinction because ultrasound scans were performed at least at weekly intervals. Only 2 infants had both PVHI and cystic PVL. This incidence is similar to other studies.1,10

All surviving children were examined at follow-up at a minimum of 18 months' corrected age. We realize that 18 months is a bit young to determine the GMFCS level reliably. It is known that the GMFCS is a rather stable measure from the age of 2 onward.29 In this study, most children had already turned 2. With this in mind, the GMFCS levels in the majority of the infants who had developed CP would remain low, indicating good gross motor functioning.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We identified several risk factors that were predictive of mortality and adverse neurologic outcome at 18 months of age in preterm infants with PVHI. Thirty percent of the infants died, mostly with respiratory and/or circulatory failure that was unresponsive to treatment. Circulatory failure and maternal intrauterine infection but not characteristics of the PVHI were independently predictive of mortality. Sixty-six percent of the survivors developed CP, which was mild in most cases. Only the most extended PVHI (fronto-parieto-occipital) was associated with the development of CP. Characteristics of the PVHI (localization and extension) were not related to the severity of CP, but the presence of concurrent GMH grade 3 and cystic PVL was associated with more severe CP.


   ACKNOWLEDGMENTS
 
This study was part of the research program of the postgraduate school, Behavioral and Cognitive Neurosciences, University of Groningen, and supported by a Junior Scientific Masterclass grant of the University of Groningen.

We greatly acknowledge the help of Dr T. Brantsma-van Wulfften Palthe for correcting the English.


   FOOTNOTES
 
Accepted Jan 9, 2008.

Address correspondence to Elise Roze, BSc, University Medical Center Groningen, Department of Pediatrics, Division of Neonatology, Hanzeplein 1 9713 GZ Groningen, Netherlands. E-mail: e.roze{at}student.rug.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.


What's Known on This Subject

PVHI is seen in 10%–15% of preterm infants with a GMH. Mortality ranges between 38% and 60%. Surviving infants are at high risk for developing CP. PVHI is considered a devastating lesion.

 

What This Study Adds

Mortality is associated with circulatory failure and intrauterine infection. Functional abilities were good in the majority of survivors. Characteristics of the infarction were not related to mortality and functional outcome. PVHI should no longer be considered a devastating lesion and be associated with the withdrawal of care.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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Periventricular hemorrhagic infarction in preterm infants: the importance of size and location
Jeroen Dudink, et al.
Pediatrics Online, 14 Jul 2009 [Full text]
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