PEDIATRICS Vol. 121 No. 5 May 2008, pp. 906-914 (doi:10.1542/peds.2007-0770)
ARTICLE |
Patterns of Brain Injury in Neonates Exposed to Perinatal Sentinel Events
a Departments of Paediatrics and Neonatal Medicine
b Imaging Sciences, Medical Research Council, Clinical Sciences Centre, Imperial College, Hammersmith Campus, London, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVES. We studied (1) the pattern of brain injury in term neonates with encephalopathy with evidence of a preceding hypoxic sentinel event, (2) prenatal and perinatal risk factors, and (3) the correlation between neuroimaging findings and developmental outcomes.
METHODS. We identified, among 500 term neonates with encephalopathy who were studied with MRI between 1992 and 2005, 48 infants with evidence of a preceding acute hypoxic event, and we reviewed their MRI scans retrospectively. Prenatal and perinatal data were compared with those for term normal low-risk infants. Neurodevelopmental outcomes were assessed at a minimum of 12 months.
RESULTS. Five patterns of brain injury were identified, as follows: pattern I, basal ganglia and thalami lesions associated with severe white matter damage (n = 6; 14%); pattern II, basal ganglia and thalami lesions with mild or moderate white matter changes (n = 24; 56%); pattern III, isolated thalamic injury (n = 2; 5%); pattern IV, moderate white matter damage only (n = 1; 2%); pattern V, mild white matter changes or normal findings (n = 10; 23%). No scan showed evidence of long-standing injury. The internal capsule was abnormal in 93% of infants with patterns I and II, and 86% of those infants died or developed cerebral palsy. Infants with patterns III and IV had developmental delay and diplegic cerebral palsy, respectively. Pattern V was associated with normal outcomes. Case infants were significantly more often of African descent, born to pluriparous or hypertensive mothers. Uterine rupture followed previous cesarean section in 8 of 11 cases. Cord prolapse accompanied undiagnosed breech presentation in 4 of 9 cases.
CONCLUSIONS. Basal ganglia and thalami lesions are the imaging signature in term neonates exposed to hypoxic-ischemic sentinel events. Patterns of central gray matter and secondary white matter injury were associated with higher risks of severe morbidity and death. Affected infants did not seem intrinsically different from our low-risk population. These data support the need for anticipating sentinel events and expediting delivery.
Key Words: hypoxic ischemia • encephalopathy • sentinel event • magnetic resonance imaging • basal ganglia
Abbreviations: BGT—basal ganglia and thalami • WM—white matter • HIE—hypoxic-ischemic encephalopathy • TOBY—total-body hypothermia • CP—cerebral palsy • GA—gestational age • BW—birth weight • HC—head circumference • CS—cesarean section • PLIC—posterior limb of the internal capsule • DQ—developmental quotient
Cerebral hypoxic ischemia remains a major cause of perinatal brain injury. A sentinel event in late pregnancy or the intrapartum period may have an acute profound effect on a previously neurologically intact fetus. Sentinel events may cause a significant acute disruption of maternal-fetal gas exchange, leading to the development of hypoxic-ischemic encephalopathy (HIE).1–4 Although it is generally accepted that damage to the central gray matter after a sentinel event is characteristic, it is important from clinical and medicolegal perspectives to know the spectrum of brain injuries and outcomes seen.5–8 MRI is the optimal modality for the early evaluation of brain injury and the prediction of outcomes for term neonates.9–11 To our knowledge, no study has determined how specific the pattern of neonatal brain damage is after different acute events or whether some infants are affected by the different causes of sentinel events before occurrence of the events. The aims of this study were (1) to evaluate the patterns of brain injury in term neonates with encephalopathy who were born after a sentinel event, (2) to identify any prenatal or perinatal differences between these neonates and a neurologically normal, low-risk group of control infants, and (3) to assess whether the clinical outcomes were those expected for the patterns of brain injury found with MRI.
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METHODS |
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Study Infants
MRI brain scans are routinely obtained for term infants with encephalopathy who were born at or referred to Hammersmith and Queen Charlotte's and Chelsea Hospitals. From our prospectively maintained database from 1992 of >500 of such infants, 48 fulfilled the following criteria: (1)
36 weeks of gestation; (2) evidence of a sentinel event immediately before delivery or during labor (umbilical cord prolapse, uterine rupture, placental abruption, maternal collapse, or other causes of major prepartum hemorrhage); (3) evidence of fetal distress; (4) abnormal tone, seizures, and poor feeding in the first 48 hours after delivery12; (5) brain MRI scans obtained within 6 weeks after birth; and (6) assessment of outcome at a minimal age of 12 months. The severity of encephalopathy was staged according to criteria described by Sarnat and Sarnat.12 Ethical permission for the study was obtained from the Hammersmith Hospital research ethics committee. Infants were excluded if there was evidence of congenital malformations, major dysmorphic features, congenital viral infection, or a metabolic syndrome. Infants who fulfilled our criteria but had been enrolled in the Total-Body Hypothermia (TOBY) trial for treatment of perinatal asphyxial encephalopathy were included for the analysis of the prenatal and perinatal data but those who underwent cooling were excluded from MRI analysis of the pattern of brain injury, because hypothermia seems to reduce hypoxic-ischemic brain injury.13,14 Clinical outcomes are not available at this time for any infants in the TOBY trial.
Control Infants
A total of 229 low-risk term infants were recruited from the postnatal wards at Queen Charlotte's Hospital between 1996 and 1997. All infants had normal routine postnatal check results and underwent a detailed neurologic examination performed by an experienced neonatal neurologist, and they were considered neurologically normal.15 One half of the cohort underwent follow-up assessments, and no subjects had signs of cerebral palsy (CP) or developmental delay at 12 or 18 months.16,17 These infants are referred to as control infants.
Detailed prenatal, perinatal, and postnatal information for each case infant was collated and compared with the equivalent existing information for the control infants. Infant characteristics included gender, gestational age (GA), birth weight (BW), head circumference (HC), multiplicity, and race. GA and gender were used to calculate the BW and HC percentiles from the British Growth Reference tables.18 Prenatal factors included parity, maternal age, infertility treatment, family history of seizures, maternal hypertension, urinary tract or viral infection, autoimmune or thyroid disease, gynecologic or thrombotic problems, depression, and cholestasis. Perinatal factors included type of sentinel event, onset of labor, mode of delivery, labor complications, and meconium-stained fluid. Elective cesarean section (CS) was defined as a prelabor CS for reasons unrelated to fetal concerns. Where >1 sentinel event occurred, we took the significant event as recorded by the treating obstetrician. Infants with a true knot and tight nuchal cord were not included because of uncertainty regarding the timing of the hypoxic-ischemic insult. Postnatal factors included Apgar scores, cord pH, resuscitation measures, and neurologic abnormalities.
MRI and Analysis
Case infants underwent imaging with a 1.0-, 1.5-, or 3-T MRI scanner, with conventional T1-weighted spin echo, inversion recovery, and T2-weighted spin echo sequences. Only infants scanned within 6 weeks after birth were included, because early imaging is better for defining perinatally acquired lesions.11 Images were interpreted by an experienced neuroradiologist (Dr Rutherford), according to our previously published criteria and with knowledge of the evolution of lesions.10,19,20 The low-risk control infants did not undergo MRI.
Basal ganglia and thalami (BGT) lesions were classified as follows: mild, focal subtle abnormalities, with normal appearance of the posterior limb of the internal capsule (PLIC); moderate, multifocal lesions with equivocal or abnormal signal intensity within the PLIC; severe, widespread abnormalities involving all BGT structures and the PLIC. White matter (WM) changes were classified as follows: mild, periventricular WM changes difficult to differentiate from normal appearances and therefore not classified as abnormal; moderate, small focal lesions without loss of gray matter/WM differentiation; severe, larger areas of abnormality with loss of gray matter/WM differentiation, consistent with infarction.
Cortical abnormalities included both a loss of markings, as seen with loss of gray matter/WM differentiation (usually detected during the first week), and cortical highlighting (usually detected after the first week). Areas of abnormal signal intensity in the brainstem, cerebellum, and hippocampus were also documented.
Neurodevelopmental Outcomes
Outcomes were determined by using a standardized neurologic assessment and, where appropriate, Griffiths Mental Developmental Scales, from which a developmental quotient (DQ) was calculated.21–23 CP was defined according to published criteria.24,25 Head growth was documented.19 Outcomes were classified as follows: normal, DQ of >85 and normal neurologic examination results; developmental delay, DQ of <85 but >70, motor impairment without CP, or nonmotor impairment; CP, bilateral spastic, dystonic, or athetoid CP; death, resulting from neurologic causes.
Statistical Analyses
Data were analyzed with StatsDirect 1.9.8 statistical software (StatsDirect Ltd, Altrincham, Cheshire, United Kingdom). Prenatal and perinatal data for the case and control groups were compared by using unpaired Student's t tests or Mann-Whitney U tests for continuous variables and 
2 tests or Fisher's exact tests for categorical variables. Data were assessed for normality by using the Shapiro-Wilk test. Where appropriate, odds ratios and confidence intervals were determined. P values of <.05 were considered statistically significant, and P values of <.001 were considered highly significant.
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RESULTS |
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Study Group
Sixty-four term neonates fulfilled the entry criteria; none of the remaining infants in our cohort had evidence of a sentinel event. Sixteen infants were excluded, 9 with insufficient prenatal and perinatal data and 7 because MRI scans were performed >6 weeks after delivery. Forty-eight infants were included in the study.
Infant Characteristics and Prenatal Factors (n = 48)
There were more boys among the case infants than among the control infants, but this difference was not significant. More case infants were of African descent (P = .0065). The case and control infants were comparable with respect to GA, BW, HC, and multiple births even when BW and HC were corrected for differences in gender and GA. Case infants were more likely than control infants to be born to pluriparous mothers (P = .003). Maternal hypertension (essential or pregnancy-induced) was significantly (P = .03) more common in the case group than in the control group. None of the other factors we examined differed significantly between case infants and our low-risk control infants. Four of the case mothers but none of the control mothers were diagnosed as having placenta previa (Table 1).
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Sentinel Events and Perinatal Factors
The most-common sentinel events identified were placental abruption and uterine rupture The 2 causes of prepartum hemorrhage other than placenta previa were an umbilical cord separation and a velamentous insertion of the cord into the placenta. Eight of 11 cases of uterine rupture followed a previous CS. Four of 9 cases with cord prolapse were associated with breech presentation (Table 2).
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Only 2 of the 229 control infants had a preceding sentinel event. Both infants were born after prepartum hemorrhage, both had Apgar scores of >7 at 1 and 5 minutes and umbilical cord pH values of >7.30, and neither developed encephalopathy. The case infants had significantly higher rates of emergency CS and unlike 9% of the control infants (P = .031) none was delivered through elective CS. Rates of instrumental delivery were comparable. More case infants than control infants were born breech (P = .029). None of the case breech presentations was diagnosed before delivery, whereas all breech control infants were delivered through elective CS.
All except 1 case infant required resuscitation at birth; 42% needed major resuscitation (intubation with ventilation, cardiopulmonary resuscitation, or adrenaline), compared with 2% of control subjects. The case infants had significantly lower Apgar scores at 1 and 5 minutes, that is, 1 (range: 0–9) and 4 (range: 0–9), compared with control scores of 9 (range: 5–10) and 10 (range: 8–10), respectively; 67% of case infants had Apgar scores of <5 at 5 minutes. The differences were all significant at P < .0001. Cord pH values were available for 
80% of case and control infants. The case infants were significantly more acidotic than control infants (umbilical cord pH, mean ± SD: case: 6.84 ± 0.19; control: 7.33 ± 0.06; P < .0001); pH values were <7.00 for 66% of case subjects, whereas all control subjects had values of >7.20 (P < .0001). Of the 48 case infants, the severity of encephalopathy was stage 1 in 11 infants (23%), stage 2 in 18 (37%), and stage 3 in 19 (40%). No case infant was thought to have neonatal neurologic concerns.15
MRI Analysis (n = 43)
Scans Evaluated
MRI scans were obtained at a median age of 10 days, with 9 being imaged later than 21 days. The 5 infants cooled as part of the TOBY trial were excluded from further analysis, and MRI scans of the remaining 43 infants were evaluated. Five distinct patterns of brain injury were observed, as summarized in Table 3.
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BGT and WM Abnormalities
Thirty-two of the 43 infants sustained injury to the central gray matter. BGT lesions were classified as mild in 4 infants, moderate in 20, and severe in 8. In 6 infants, BGT lesions were associated with severe WM damage (pattern I, Fig 1). Twenty-four infants had basal ganglia or BGT lesions with mild or moderate WM changes (pattern II, Fig 2). Two infants had thalamic involvement only (pattern III, Fig 3). Eleven infants had no BGT involvement; 1 had moderate WM injury (pattern IV, Fig 4) and 10 had mild WM signal changes or normal imaging results (pattern V, Fig 5).
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Cortical Abnormalities
Cortical involvement (loss of gray matter/WM differentiation or overt infarction) was seen in all 6 infants with pattern I. Cortical highlighting was seen in 13 infants with pattern II, 1 infant with pattern III, the 1 infant with pattern IV, and 4 infants with pattern V.
PLIC Abnormalities
The signal intensity from myelin in the PLIC was abnormal or absent in 28 infants, all of whom had basal ganglia injury. One infant with pattern I had mild BGT lesions and widespread WM abnormalities but normal signal in the PLIC. Both infants with isolated thalamic lesions (pattern III) had normal PLIC findings.
Abnormalities at Other Sites
Additional sites of abnormality were seen only with imaging patterns I and II. Brainstem abnormalities were identified in 13 infants and hippocampal lesions in 7. Three infants had mild cerebellar abnormalities, 1 mild vermal hypoplasia, 1 asymmetry of the cerebellar hemispheres, and 1 abnormal increased signal intensity within the dentate nuclei, consistent with perinatal injury.
Relationship of Patterns of Injury to Types of Sentinel Events (n = 43)
Of the 6 infants with brain injury pattern I, 5 had experienced placental abruption and 1 cord prolapse after small vaginal bleeding episodes. All 9 infants born after uterine rupture developed pattern II, as did both neonates whose mothers collapsed and the 2 infants born after hemorrhaging resulting from umbilical cord separation and velamentous insertion. Both infants born after prepartum hemorrhage resulting from placenta previa developed pattern III (Table 4).
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Neurodevelopmental Outcomes (n = 41)
Of the 48 patients who met our inclusion criteria, the outcomes for the 7 infants enrolled in the TOBY trial are not yet available (Table 5). Of the remaining 41 infants, 34 were examined at the Hammersmith Hospital (Dr Cowan), and outcomes for the other 7 were obtained directly from the local consultant pediatrician; no child was lost to follow-up monitoring. The median age of available follow-up information was 27 months (range: 12–66 months). Outcome data were categorized as shown in Table 5.
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Eight infants (20%) died as a result of neurologic problems, 6 in the neonatal period, 1 at 18 months, and 1 at 3 years. Of those infants, 1 had brain injury pattern I and 7 had pattern II. The outcomes for the infants with BGT lesions and some WM involvement were dominated by the severity of their BGT damage. No infant with only mild or moderate cortical or WM injury died.
Of the 33 infants who survived, 17 have CP. Thirteen have spastic quadriplegia, 3 an athetoid type, and 1 diplegia; all except 1 infant had some degree of BGT damage. Associated problems included poor head growth (16 infants), squint (8 infants), visual impairments (11 infants), lack of speech (12 infants), hearing impairment (2 infants), feeding difficulties (14 infants), and persistent seizures (7 infants). Only 4 children with CP were assessable with the Griffiths scales; all had DQ values of <60, but 2 of the 3 children with athetoid CP were thought to have age-appropriate cognitive function at 2 years. The infant with mild diplegia and speech delay was the only example of pattern IV and was a twin conceived through in vitro fertilization.
Of 4 survivors with brain injury pattern I, 3 developed CP and 1, whose MRI findings were atypical (milder BGT injury and normal PLIC), did not develop CP but has microcephaly with severely delayed speech. Of 16 survivors with pattern II, 13 developed CP, 2 had mild motor impairment only, and 1 had a normal outcome. The 2 infants with thalamic lesions alone (pattern III) did not develop CP; 1 had an isolated mild gross motor delay and 1 had normal motor function but mild speech delay at 2 years. Nine of the 10 infants with pattern V had normal neurodevelopmental outcomes at 3 years. The other infant did not develop CP but is developmentally delayed and has problems consistent with Rubenstein-Taybi syndrome, which was not recognized at birth.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We aimed to establish the patterns of brain injury in neonates presenting with encephalopathy where there was documented evidence of a preceding sentinel event. Central gray matter injury occurred in 74% of these neonates, and the MRI scans of the others were classified as normal, with the exception of 1 infant (a twin) with moderate WM injury alone. Our study confirms that BGT lesions are the hallmark of acute perinatal hypoxic ischemia in term newborns.26–28 We did not find evidence of long-standing brain damage in this cohort. The patterns reported were consistent with findings of other investigators, confirming that events likely to lead to acute profound hypoxia do not result in widespread WM damage with sparing of central gray matter.1,4,7,29–31 Two control infants were exposed to a sentinel event but did not develop HIE or have any neurologic sequelae.
We confirmed that severe acute hypoxic ischemia is associated with lesions in the PLIC, brainstem, hippocampal region, and cortex. Cortical gray matter injury is seen as abnormal signal intensity of the cortex, particularly around the central fissure and insula. Gray matter neurons and early myelinating tissue within the immature brain have a higher metabolic rate than the surrounding WM, such that, although the duration of ischemia resulting from a sentinel event may be relatively short, the BGT, brainstem, hippocampi, and PLIC are significantly more vulnerable to acute anoxia than is the hemispheric WM.30 Loss of the normal signal intensity from the PLIC is associated strongly with adjacent BGT injury and is a reliable predictor of abnormal motor outcomes.32,33
We included in the study infants with scans obtained up to 6 weeks after birth. Many infants that we see undergo serial imaging as part of their routine clinical follow-up care, and we have shown that patterns of lesions evolve in a consistent way (Fig 1).20,34 Of those with very early MRI scans, none had evidence of injury that had characteristics associated with longer-standing injury. It is not possible, even with early diffusion-weighted imaging, to determine precisely when injury occurred, but all of the prenatal and neonatal clinical and early cranial ultrasound evidence from the infants included in this study supported the view that, up to the time of the sentinel event, the infants were developing normally.
BGT lesions were associated with severe WM damage in 14% of infants, as evidenced by a loss of gray matter/WM differentiation and consistent with overt infarction (pattern I). These infants had very poor outcomes. Severe WM injury in the presence of deep central gray matter damage suggests a more-prolonged hypoxic-ischemic insult. These infants with pattern I, however, were not more acidotic and did not require more-aggressive resuscitation than the infants with other lesion patterns. Infants with pattern I underwent imaging at a median age of 5.5 days, whereas infants with pattern II, whose WM appeared less severely damaged, underwent imaging at a median age of 10.5 days. We previously showed late changes in WM diffusion parameters 2 to 3 weeks after an acute insult to the BGT, where the WM initially appeared normal.20 The WM changes seen in the infants with pattern II may well be secondary to the central gray matter injury. Mercuri et al19 showed that secondary microcephaly is often associated with WM atrophy and may occur even if overt injury to WM is not seen on very early scans. Only 5 infants with BGT injury on initial scans had optimal head growth in follow-up assessments; these infants had mild or moderate BGT damage only and either developed athetoid CP, had fine motor difficulties, or were considered normal.
This is, to our knowledge, the first study comparing detailed prenatal and perinatal data for infants with encephalopathy who were exposed to a sentinel event with data for a large, neurologically low-risk, control group. Badawi et al2,35 in a study of prepartum and intrapartum risk factors proposed that the causal pathway for encephalopathy often begins before delivery and prenatal events may diminish fetal brain reserve at the onset of labor, reducing the brain's capacity to cope with hypoxia if it occurs. The authors concluded that prenatal risk factors are more prevalent than intrapartum factors. In contrast, we previously showed, using MRI in a large cohort of term neonates with encephalopathy, that lesions of prenatal origin were rarely found in this clinical group.4 Similarly, we showed here that the predominant pattern was BGT damage, rather than isolated WM injury, and that the only identifiable differences from our low-risk population were African race, maternal hypertension, pluriparity, and breech presentation.
Both black maternal race and hypertensive disease are risk factors for placenta previa and placental abruption.36,37 Pluriparity, found in 75% of the case infants, may be relevant because previous CS increases the risk of placenta previa and uterine rupture.38 Pluriparity has not been singled out in previous studies of HIE, and indeed primiparity has been associated with neonatal stroke.39 All 11 cases of uterine rupture occurred in pluriparous women, 8 of whom had had previous CSs and underwent a trial of scar, which resulted in scar dehiscence and emergency CS. The likelihood of scar dehiscence was reported as 1%.37 Landon et al40 found that HIE was significantly more frequent when women underwent a trial of labor rather than having elective repeat CS delivery. Seven case infants had undiagnosed breech presentations and, of those deliveries, 4 were complicated by umbilical cord prolapse during vaginal delivery. Although both breech presentation and cord prolapse are known to occur independently at a rate of 3% to 4% of term pregnancies, the rate of cord prolapse increases to 5% to 15% with flexed or footling breech positions.37,38 It is thought that >25% of breech presentations are not diagnosed before labor, making this an important risk factor for hypoxic ischemia.37
The brain injury patterns on MRI scans generally predicted the severity of neurodevelopmental outcomes in our case cohort. Identification of injury patterns I or II has major prognostic implications; 29% of infants with these findings died and 57% developed CP, predominantly spastic or dystonic quadriplegia, with significant feeding, visual, and hearing difficulties. No infant developed a stroke or hemiplegia. Infants with normal scan findings, however, largely had normal outcomes. This supports the view that MRI scans obtained soon after birth in HIE may act as an early surrogate outcome marker.1,10,32
The population occurrence rates of sentinel events and ensuing brain injury patterns cannot be interpreted from our study because we function as a tertiary referral center. However, the striking uniformity of the patterns of injury suggests that, if we had had the opportunity to scan all infants exposed to sentinel events, it is unlikely that different injury patterns would have been found. A limitation of our study in terms of the prenatal factors was that our control subjects came from a single center and were recruited over a 2-year period, whereas the case subjects were referred from within the wider region we serve. However, the differences that we found were consistent with causes known to increase the risk of sentinel events.
This study has confirmed that the brain imaging signature in term infants exposed to an acute perinatal hypoxic event is central gray matter damage. We did not find evidence to suggest preceding long-standing problems, and we did not find severe WM injury in the absence of injury to the BGT. The patterns of outcomes were as expected from the MRI scan findings. Our data suggest that the infants were normal before their sentinel event and hypoxic-ischemic insult, which emphasizes the importance of anticipating sentinel events, to expedite delivery, to minimize the degree of brain injury, and to optimize neurologic outcomes.
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ACKNOWLEDGMENTS |
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We are grateful for the support of all staff members at the Robert Steiner Unit, the Medical Research Council, the Academy of Medical Sciences, the Health Foundation, and Philips Medical Systems. We thank the families of the children in this study and the medical and nursing staff members who participated in caring for the infants.
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FOOTNOTES |
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Accepted Sep 6, 2007.
Address correspondence to Frances M. Cowan, MRCPCH, PhD, Department of Paediatrics and Neonatal Medicine, 5th Floor, Ham House, Hammersmith Hospital, Du Cane Rd, London, W12 OHS, United Kingdom. E-mail: f.cowan{at}imperial.ac.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject It is generally accepted that damage to the central gray matter after a sentinel event is characteristic, and MRI is the optimal modality for the early evaluation of brain injury and the prediction of outcomes for term neonates.
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| What This Study Adds Lesions of basal ganglia and thalami are the imaging signature in term neonates with encephalopathy exposed to hypoxic-ischemic sentinel events. Patterns of central gray matter and secondary white matter injury were associated with higher risks of severe morbidity and death.
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