Hemodynamic and Antecedent Risk Factors of Early and Late Periventricular/Intraventricular Hemorrhage in Premature Infants
* Royal Prince Alfred Hospital Sydney
Royal North Shore Hospital, Sydney, NSW, and the University of Sydney, Australia
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ABSTRACT |
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Objectives. To determine hemodynamic and antecedent risk factors for early and late periventricular/intraventricular hemorrhage (P/IVH) in premature infants.
Methods. Two prospective cohort studies of 126 (1995–1996) and 128 (1998–1999) infants born <30 weeks’ gestation. Head ultrasounds were performed at <6 hours of age, and at 7 and 28 days of age. P/IVH was classified as early (present on initial scan) and late (developed subsequently). Echocardiographic measurement of the superior vena cava (SVC) flow was performed at <6, 10, and 24 hours of age.
Results. Infants with early P/IVH were significantly more likely to be born by vaginal delivery in both cohorts (1995–1996 adjusted odds ratios [OR]: 13.29; 1998–1999 adjusted OR: 18.15). An association with a 1-minute Apgar 
4 was only significant in the 1998–1999 cohort (adjusted OR: 9.14). Low SVC flow was the only independent risk factor for late P/IVH in both cohorts (1995–1996 adjusted OR: 20.39; 1998–1999 adjusted OR: 5.16). Adjusted for perinatal risk factors, low SVC flow was associated with lower gestation and higher average mean airway pressure in both cohorts, and with a large diameter ductus diameter only in the 1995–1996 cohort.
Conclusions. Early and late P/IVH have distinct and different risk factors. Early P/IVH is associated with vaginal delivery and possibly low Apgar scores. Late P/IVH is associated with antecedent low SVC flow in the first day.
Key Words: premature infant • regional blood flow • superior vena cava • intraventricular hemorrhage • echocardiography
Abbreviations: P/IVH, peri/intraventricular hemorrhage • DA, ductus arteriosus • SVC, superior vena cava • MAP, mean airway pressure • RDS, respiratory distress syndrome • OR, odds ratio • CI, 95% confidence interval
Periventricular/intraventricular hemorrhage (P/IVH) is a strong predictor of neurodevelopmental disability in very preterm infants.1 Identifying the antecedent risk factors and underlying mechanisms for P/IVH has the potential to allow the development of effective strategies for prevention of cerebral injury in preterm infants. Almost all P/IVH occurs in the first 4 days after birth, but a proportion of these P/IVHs are present within the first few hours after birth.2–7 It is likely that these early P/IVH have risk factors that relate to the intrapartum period,3–10 whereas those that occur after the first day may well relate to early postnatal hemodynamic factors, particularly low blood flow.2,6,7 Most risk factor analyses of large cohorts for P/IVH fail to distinguish early P/IVH as a separate group because the outcome is based on a single ultrasound scan after day 4.1,11,12 Studies that have analyzed early P/IVH separately have had only limited early hemodynamic information with which to analyze risk factors for late P/IVH.
As a result of 2 large cohort studies, we have collected complete data for a separate risk factor analysis of early and late P/IVH in 254 unselected infants born before 30 weeks’ gestation. The first cohort (1995–1996) was studied with the aim of defining the preceding hemodynamic of late P/IVH,7 and the second cohort (1998–1999) was part of a study examining effects of circulatory support measures.13 The aim of this article is to determine the hemodynamic and antecedent risk factors for early and late P/IVH in the second of these cohorts and to examine the reproducibility and consistency of these risk factors by comparison with the first cohort.
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METHODS |
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The 1998–1999 study was a 2-center, prospective cohort study of premature infants born <30 weeks’ gestation. The study was conducted in the Royal Prince Alfred and Royal North Shore Hospital Neonatal Intensive Care Units, Sydney, Australia between October 1998 and December 1999. The ethics committees of Central Sydney and Northern Sydney Area Health Services approved the study. Informed consent was obtained from all parents. Infants born <30 weeks’ gestation and <24 hours of age were eligible. Informed consent was obtained antenatally where possible. Infants were excluded if parental consent was refused, a major congenital abnormality or cardiac abnormality was identified, the infant was considered by the attending clinician to be nonviable, or if inotrope or indomethacin had been given previously.
Infants from the 1998–1999 cohort were eligible for inclusion in a sequential, 2-intervention study of cardiovascular treatments. The first intervention study examined the hemodynamic effects of indomethacin given early to infants with a large ductus arteriosus (DA). The second intervention examined the effect of volume (normal saline) and inotrope (dobutamine or dopamine) given to infants with low systemic blood flow (superior vena cava [SVC] flow <41 mL/kg/min).13 The 1998–1999 cohort of infants is compared with a previous cohort of 126 infants born <30 weeks’ gestation during 1995–1996. This previously described cohort7 had similar enrollment criteria but was an observational study in which infants received cardiovascular interventions determined by the treating physicians who were blinded to the results of the echocardiography.
Clinical and Physiologic Data
Clinical perinatal variables including gestation in weeks, birth weight, birth weight percentile, gender, use of antenatal steroids, maternal antihypertensives, labor, vaginal delivery, transfer ex utero to level 3 center, Apgar scores at 1 and 5 minutes, use of mechanical ventilation, average mean airway pressure (MAP) in the first 12 hours, respiratory distress syndrome (RDS), significant DA on initial echocardiography, and use of surfactant were recorded prospectively in all infants enrolled. All infants with a clinical diagnosis of RDS were given surfactant. Clinical outcomes included P/IVH grade, mortality to discharge, radiographically or surgically proven necrotizing enterocolitis, and periventricular leukomalacia. Cerebral ultrasound was performed using a 7-MHz transducer at 3 hours (1998–1999 cohort) or 5 hours (1995–1996 cohort), and then at 10 to 12 and 24 hours. Any P/IVH was noted and classified according to Papile grading. Routine head ultrasounds were performed between days 4 and 7 and on day 28 by a radiologist blinded to echocardiographic information. Early P/IVH was defined as any P/IVH seen on the initial head ultrasound. These were recorded on videotape at the time of echocardiography. All early P/IVH was confirmed as being present on subsequent ultrasound by an independent radiologist or a single investigator (N.E.). Late P/IVH was defined as P/IVH occurring in infants with a previously normal head ultrasound before 6 hours of age. Periventricular leukomalacia was diagnosed on the day 28 ultrasound.
Echocardiographic Monitoring and Blood Flow Measurement
For the 1998–1999 cohort, echocardiographic monitoring was performed routinely at 3, 5 to 10, and 24 hours of age. The scan at 5 to 10 hours is taken as the scan before commencement of volume and inotropes, if given, or the scan closest to 10 hours of age. An Acuson (Mountain View, CA) a 128/XP10 ultrasound scanner was used with a 7-MHz vector array transducer incorporating color flow and pulsed-wave Doppler. The scan was recorded on to VHS videotape and the measurements were then taken from the videotape. Structural normality of the heart was established on the initial scan. SVC flow was determined as described previously.14 A clinically significant patent DA was defined as a ductus at the 3-hour scan with a color Doppler diameter >1.6 mm from previous studies.2,15 For the 1995–1996 cohort, echocardiographic monitoring was performed at 5, 12, and 24 hours as previously described.7 Although part of the same research group, echocardiograms were performed by different observers in the 2 cohorts (first cohort: N.E. and M.K.; second cohort: D.O.).
Low systemic blood flow was defined as SVC flow <41 mL/kg/min at any time in the first 24 hours from previous data in healthy preterm infants.14 SVC blood flow is a measure of upper body and brain blood flow that overcomes the inaccuracies of ventricular outputs as measures of systemic blood flow in the first day after birth. These inaccuracies are attributable to presence of shunts across the adapting heart (foramen ovale and DA) that can cause measurements of ventricular outputs to overestimate systemic blood flow by up to 100%.16
Statistical Analysis
Data were analyzed with a PC-based statistics package (SPSS release 10.0.7 for Windows) using the independent sample t test, 
2, or Fisher exact test where appropriate. Nonparametric variables were analyzed using the Mann-Whitney U test. Multivariate analyses were performed to determine perinatal predictors of early and late P/IVH after adjusting for perinatal confounders and subsequently perinatal predictors of low SVC flow. Backward stepwise logistic regression was used with variables included in the base model if they were not considered to be an intervening variable, were significant in univariate analysis (P < .2), and the estimate of effect was stable in direction between univariate and multivariate analysis. Potential confounders were retained in the model if they affected the estimate of effect of the explanatory variable by at least 10%. Birth weight was not included because it allows misclassification of growth-restricted infants. Instead, gestation in weeks and a measure of growth restriction (birth weight <10th percentile) were used. Patent DA was included in the model although it may be considered an intervening variable for low flow. All other perinatal clinical, hemodynamic, and echocardiographic variables listed were eligible for inclusion in the analysis. The Nagelkerke R2 was used to express the proportion of variance of the dependent variable explained by the model. The 2 cohorts are analyzed separately in view of baseline differences in perinatal variables, and differences in timing of echocardiography and methods of targeting cardiovascular interventions.
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RESULTS |
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Between October 1998 and December 1999, 160 infants from 23 to 29 weeks’ gestation were admitted to the 2 neonatal units (100 to the Royal Prince Alfred Hospital and 60 to the Royal North Shore Hospital). Consent was not obtained or an investigator was not available for 32 (20%) infants. The mean gestation (27.1 vs 26.8 weeks) and birth weight (1078 vs 988 g) of nonenrolled infants were not significantly higher than enrolled infants. A total of 128 infants with consent underwent clinical and echocardiographic monitoring in the first 24 hours after birth. Echocardiography was performed on 122 infants at 3 hours, 126 infants at 5 to 10 hours, and 119 infants at 24 hours. Eighty infants with a large DA (>1.6 mm diameter) were treated with indomethacin, and 42 infants with low SVC flow were enrolled in the volume and inotrope study.13 The 126 infants enrolled in the 1995–1996 cohort represent 85% of eligible infants, as has been described previously.7
Perinatal Risk Factors and Outcomes: 1995–1996 Versus 1998–1999 Cohorts
The cohorts were similar in mean gestation (27.0 vs 26.8 weeks) and birth weight (992 g vs 988 g), growth restriction <10th percentile, gender, use of antenatal steroids, maternal antihypertensives, vaginal delivery, ex utero transfer, 5-minute Apgar <7, and use of mechanical ventilation. Significant differences between the cohorts include a lower rate of preterm labor in the 1998–1999 cohort (87% vs 70%; P = .002), lower MAP in the first 12 hours (9.5 vs 7.4 cm H2O; P < .001), increased incidence of RDS treated with surfactant (61% vs 73%; P = .05), and a higher incidence of DA >1.6 mm on initial echocardiography (50% vs 63%; P = .009), which probably related to the earlier time of the initial echocardiogram (3 vs 5 hours). There were trends to lower rates of 1-minute Apgar scores 4 (51% vs 40%; P = .08) and infants with SVC flow <41 mL/kg/min in the first 24 hours (45% vs 34%; P = .08). For outcomes, the 2 cohorts were similar for incidences of late P/IVH (14% vs 15%), necrotizing enterocolitis (2% vs 3%), and periventricular leukomalacia (3% vs 5%). The 1998–1999 cohort had a significantly higher incidence of early P/IVH (7% vs 15%; P = .05) and a trend to higher mortality (18% vs 28%; P = .06).
Early P/IVH
In the 1998–1999 cohort, 19 (15%) infants had a P/IVH seen on the initial scan (Table 1). Of these, 13 (68%) were grade 1, 4 (21%) grade 2, and 1 each grade 3 and 4 on the initial scan. The highest subsequent grade of P/IVH reached by these infants was 8 (42%) with grade 1, 4 (21%) with grade 2, 2 (11%) with grade 3, and 5 (26%) with grade 4. Infants with early P/IVH were of significantly lower gestation (26.0 vs 27.0 weeks), much more likely to be born by vaginal delivery (89% vs 35%) or after the onset of labor, and more likely to have a 1-minute Apgar 4 (79% vs 33%) compared with infants with no early P/IVH. No infant with an early P/IVH had a birth weight <10th percentile but this did not reach significance. Infants with an early P/IVH had similar mean SVC flow at 3 hours of age, and similar rates of low SVC flow in the first 24 hours to infants without. Four of the 7 infants with a progressive P/IVH had low SVC flow identified in the first 24 hours.
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Logistic regression for prediction of early P/IVH (Table 2) found vaginal delivery (odds ratio [OR]: 18.15; 95% confidence interval [CI]: 3.56–91.60) and 1-minute Apgar
4 (OR: 9.14; 95% CI: 2.23–37.49) were significant predictors of early P/IVH. The final model explained 42% of the variance (Nagelkerke R2 = 0.42).
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In the 1995–1996 cohort (Table 1), vaginal delivery was a significant risk factor for early P/IVH in univariate analysis (89% vs 34%). Mean SVC flow at 5 hours of age was also significantly higher in infants with early P/IVH than infants without (73.4 vs 54.7mL/kg/min; P = .04). However, overall rates of low SVC flow in the first 24 hours were similar (33% vs 46%; P = .5). Gestation and 1-minute Apgar
4 were not significantly different. In logistic regression for prediction of early P/IVH (Table 2), vaginal delivery remained a significant risk factor for early P/IVH (OR: 13.29; 95% CI: 1.52–116.35), whereas mean SVC flow at 5 hours did not (OR per 10 mL/kg/min increase: 1.06; 95% CI: 0.87–1.29).
Late P/IVH
In the 1998–1999 cohort, 19 (15%) infants had a late P/IVH (Table 3). Of these, 6 (32%) infants were grade 1, 3 (16%) infants were grade 2, 1 infant was grade 3 (5%), and 9 (47%) infants were grade 4. Infants with late P/IVH were significantly more likely to have had preceding low SVC flow (74% vs 28%) than infants without a late P/IVH. Fourteen infants had low SVC flows identified in the first 24 hours. Four of 5 infants who suffered a late P/IVH without preceding low SVC flow identified had a low 1-minute Apgar after vaginal delivery. One other infant was a severely growth-restricted 25-week-old infant, born to a mother with preeclampsia. Infants with a late P/IVH were of significantly lower gestation (25.7 vs 27.0 weeks) and birth weight (872 vs 1009 g). They were significantly less likely to be born to a mother receiving a complete course of antenatal steroids and after transfer ex utero.
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Logistic regression for prediction of late P/IVH (Table 2) found low SVC flow (OR: 5.16; 95% CI: 1.59–16.71) remained the only independent risk factor for late P/IVH after adjustment. The final model explained 25% of the variance.
In the 1995–1996 cohort, significant risk factors for late P/IVH included lower gestation and birth weight, 1-minute Apgar score 4, higher average MAP in the first 12 hours, RDS, a large DA, and low SVC flow. In logistic regression (Table 2), low SVC flow remained the only significant risk factor for late P/IVH (OR: 20.39; 95% CI: 2.54–163.89). Gestation was of borderline significance (OR/week decrease 1.42; 95% CI: 0.99–2.02). The final model explained 42% of the variance.
Low SVC Flow
In the 1998–1999 cohort, 44 infants (34%) were identified with low SVC flow in the first 24 hours after birth (Table 4). Low SVC flow was identified in 13 of 122 (11%) infants at 3 hours, 39 of 126 (31%) infants at 5 to 10 hours, and 4 of 119 (3%) infants at 24 hours. Infants with low SVC flow were of significantly lower gestation (25.8 vs 27.4 weeks) and birth weight (916 vs 1027 g). Infants with low flow were significantly less likely to be born after complete antenatal steroid cover and less likely to be delivered to a mother receiving antihypertensives. Other significant differences on univariant analysis are shown in Table 4.
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In the 1998–1999 cohort, logistic regression for prediction of low SVC flow in the first 24 hours found significant associations with gestation (OR/week decrease 1.53; 95% CI: 1.19–1.96) and average MAP in first 12 hours (OR/1 cm H2O increase 1.23; 95% CI: 1.03–1.47). A large DA was not significantly associated with low SVC flow. Maternal antihypertensives and birth weight <10th percentile were not independently significant in the multivariate model but were significant together (
2 = 6.45, 2 df; P = .04).
In the 1995–1996 cohort, significant perinatal risk factors for low SVC flow (Table 2) included lower gestation, 5-minute Apgar 7, higher average MAP in the first 12 hours, RDS, and a large DA. Maternal antihypertensives were significantly protective against low SVC flow. In logistic regression, gestation (OR/week decrease 1.41; 95% CI: 1.08–1.83), average MAP in first 12 hours (OR: 1.28; 95% CI: 1.06–1.55) and DA >1.6 mm (OR: 2.56; 95% CI: 1.10–5.99) were significant independent risk factors for low SVC flow in the first 24 hours after birth.
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DISCUSSION |
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This study has highlighted in 2 large prospectively studied cohorts that early and late P/IVH have distinct and different risk factors. In the beagle puppy model, P/IVH is precipitated by inducing a single severe hypoperfusion-reperfusion cycle.17 The data from both these cohorts would suggest that the same process is occurring in infants with late P/IVH. The majority of infants with late P/IVH have low SVC flows detected in the first day after birth, mainly between 3 and 10 hours of age, with P/IVH usually developing after improvement of SVC flows. In both cohorts, low SVC flow was the dominant independent risk factor for late P/IVH on multivariate analysis. Infants with low flows were >4 times more likely to die and have a late P/IVH. This provides additional support for the associations found in the first cohort. Importantly, infants with low SVC flow on the first day after birth in the first cohort also had significantly greater incidence of motor impairment and cerebral palsy at 3 years.18
There was also consistency between the cohorts in risk factors for the development of low SVC flow. In both cohorts, low SVC flow in the first day after birth was inversely related to gestational age and directly to average MAP in the first 12 hours. We have previously described the inverse relationship between low SVC flow and higher vascular resistance.7 This suggests that factors with the potential to affect blood flow in preterm infants include an immature myocardium with an inability to pump against a high systemic vascular resistance and severe respiratory disease associated with higher MAPs that may reduce cardiac output or venous return to the heart. Systematic review of randomized trials of antenatal steroids found that they reduced neonatal mortality and P/IVH.19 However, antenatal steroids in the second cohort were no longer significant predictors of mortality or late P/IVH after adjustment for confounding, whereas low SVC flow remained significant. This suggests that antenatal steroids may reduce neonatal mortality and P/IVH by maintaining blood flow in the first day after birth. This may be through reduced respiratory morbidity or by maturing the heart to allow the immature myocardium to adapt to increased systemic resistance after birth. In the first cohort, a large DA was also predictive of low SVC flow. After adjustment, the second cohort did not find this association. The second cohort received indomethacin if a large DA was diagnosed on an early echocardiogram, which may explain the lack of an effect of a large DA on SVC flow in this cohort.
In contrast, early P/IVH is not related to low SVC flow at 3 hours or in the first 24 hours after birth. Almost all of the infants with a P/IVH found at 3 hours of age were born by vaginal delivery and, in the later cohort, were more likely to have a low 1-minute Apgar score. We speculate that the same hypoperfusion-reperfusion cycle, as described for late P/IVH, has occurred here but that the hypoperfusion has occurred during labor and our hemodynamic measures are recording the reperfusion phase of the cycle. Previous studies examining perinatal risk factors for early P/IVH2–9 have found associations with lower gestation,8 lack of antenatal steroids,3,7,8 active labor,4,9 vaginal delivery,3,5,7 and lower cord pH.8 The timing of the insult producing early P/IVH is presently uncertain but the association of early P/IVH with active labor and vaginal delivery suggests that the injury is occurring intrapartum. However, trials of cesarean section for the small infant are yet to demonstrate a significant reduction in mortality or P/IVH in infants delivered electively this way.20–24 Although some observational studies have found delivery via cesarean section to be protective against P/IVH,25,26 most prospective studies analyzing antenatal risk factors for P/IVH have found no difference.27–32 Few of these studies differentiated early from late P/IVH. It is possible that cesarean delivery may be transferring the risk for the infant from early to late P/IVH.5 In view of the limited power of current trials to detect a moderate difference in neonatal morbidity or mortality,20 additional trials are warranted.
The infants with late P/IVH and normal SVC flow had a high rate of vaginal delivery and low 1-minute Apgar score suggesting that in some infants an intrapartum insult may predispose to late P/IVH. For both time periods, the fact that the hemorrhage does not occur immediately after flow improves may point to an intermediary role for impaired cerebral autoregulation in this causal pathway. In animal models,33,34 hypoxia-ischemia compromises autoregulation, and other groups have described impaired autoregulation as a risk factor for P/IVH in preterm infants.35,36
Future research should be directed at determining the timing of the early cerebral injury in preterm infants. Potential strategies include fetal cerebral imaging and detection of cerebral hypoperfusion in fetuses of mothers in preterm labor. The role of chorioamnionitis and inflammatory mediators in causing early cerebral injury needs elucidating.37,38 Potential strategies for preventing cerebral injury are likely to differ for early and late P/IVH. For early P/IVH, these include identifying infants at risk of antenatal cerebral injury before or during labor and targeting early delivery for those at risk. For late P/IVH, potential antenatal strategies include those aimed at maintaining blood flow and preventing cerebral injury in preterm infants such as antenatal corticosteroids19 and magnesium sulfate.39 Of the postnatal strategies used to prevent P/IVH, only prophylactic indomethacin has been shown to prevent late P/IVH40 in preterm infants but does not prevent long-term neurologic disability.41,42 Commonly used cardiovascular interventions including use of volume expansion43 and inotropes13,44 have not yet been shown to reduce P/IVH. Few trials of volume and inotropes in preterm infants have enrolled infants with low systemic blood flow and used a measured of systemic blood flow to demonstrate response. For interventions used in this cohort of infants, we found that indomethacin had little effect on SVC flow 1 hour after the dose,45 volume produced short-term increases in SVC flow and dobutamine at the highest dose was more effective than dopamine at increasing SVC flow.13 Future trials of cardiovascular support of preterm infants should identify infants at high risk of low systemic blood flow. Because a large proportion of cerebral injury appears to be occurring intrapartum or in the first day after birth, such trials should consider a preventative rather that a therapeutic approach.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSHAS THE EMPEROR BEEN...REFERENCES |
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In 2 cohorts of infants enrolling a total of 254 infants, there was considerable consistency in risk factors for early and late P/IVH and for low SVC flow. Early and late P/IVH have distinct and different risk factors. Early P/IVH is strongly associated with vaginal delivery and possibly low Apgar scores. Late P/IVH is strongly associated with antecedent low SVC flow in the first day after birth. Low blood flow is usually detected between 3 and 10 hours of age. Infants of earlier gestation and more severe respiratory disease are more likely to have low flows.
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HAS THE EMPEROR BEEN NAKED? |
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"The practice of peer review is based on faith in its effects, rather than on facts."
White C. Little evidence for effectiveness of scientific peer review. BMJ. 2003;326:241
Submitted by Student
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FOOTNOTES |
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Received for publication Jul 1, 2002; Accepted Nov 27, 2002.
Reprint requests to (D.A.O.) Department of Neonatal Medicine, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW, Australia 2050. E-mail: david.osborn{at}email.cs.nsw.gov.au
Supported by the National Health and Medical Research Council of Australia and the North Shore Heart Research Foundation, Sydney, Australia.
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