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Objectives: To define the 1-year neurodevelopmental outcome for survivors of moderate (Sarnat stage 2) neonatal hypoxic-ischaemic encephalopathy (HIE) to facilitate appropriate parental counselling.
Methods: Hospital-based retrospective review of admissions to a tertiary newborn intensive care unit between 1988 and 2000. All babies admitted for seizures were reviewed and those in whom the probable diagnosis was moderate HIE were identified from chart review. Perinatal variables, number of anticonvulsants, duration of hospital stay and 1-year neurodevelopmental outcome was recorded in survivors.
Results: Fifty-three babies who survived probable moderate HIE were identified. Forty-two of these were seen at 1 year of age. Of these, 22 (52%) had normal development and neurological examination and four (9.5%) had mild developmental delay with normal neurological examination. Thirteen babies (31%) had cerebral palsy, 11 of whom also had developmental delay. Two infants (5%) who had been severely impaired at 6 months died before 1 year of age. Overall, 36% of survivors of the neonatal period had significant disability and or had died by 1 year of age. Duration of anticonvulsant treatment and length of hospital stay were significantly related to adverse outcome.
Conclusions: These data suggest morbidity rates after moderate HIE in the upper end of the range previously described in the literature. Systematic longer-term follow up of this high-risk group of infants is needed.
Despite the fall in incidence of hypoxic-ischaemic encephalopathy (HIE) in term infants1, perinatal asphyxia still contributes significantly to neonatal morbidity and mortality. The overall incidence of HIE has been estimated to be between 0.4 and 3.7/1000 live births1−5, and the incidence of death or severe neurological impairment following perinatal asphyxia in developed countries is 0.2−1.3/1000 live births2,4.
One of the most challenging aspects of the management of a baby with probable HIE is counselling the parents about the likely prognosis. While many investigations have been explored as predictors of poor outcome, probably still the best tested and most widely used parameter is the severity of the encephalopathy. This is usually classified according to the three grades first described by Sarnat and Sarnat6. There is consistency in the literature that the outcome of babies with mild HIE (grade 1) is good (almost 100% of patients are normal at follow up) and also that the outcome for severe HIE (grade 3) is poor, with a rate of death or survival with disability close to 100%7. The situation is more difficult for babies with moderate HIE (grade 2) where the rates of poor outcome reported in the literature are quite variable, ranging from 20 to 50% in different papers1,5,8−10. The figures used by many clinicians for counselling reflect an amalgamation of these studies, such as the 25% poor outcome figure quoted by the review of Bohr and Greisen11.
It was our clinical impression in survivors of moderate HIE that 25% poor outcome rate was optimistic and that our poor outcome rate was higher than this. It was decided therefore to review the 1-year outcome of survivors of moderate HIE over a 12-year period so that our counselling could accurately reflect the recent experience of an Australian tertiary neonatal intensive care unit (NICU).
The aim of this study was to determine the 1-year neurological outcome for children admitted to John Spence Nursery between 1988 and 2000 with Sarnat grade 2 HIE and to determine any possible clinical factors that are predictive of poor outcome.
Patients and methods
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- Patients and methods
Full-term neonates (37 or more completed weeks of gestation) born between 1988 and 2000 and admitted to the John Spence Nursery (inborn or outborn) were examined retrospectively. The data were collected from the department's admission database, which has recorded a comprehensive dataset on all admissions to the NICU and special care baby unit (SCBU) during that time period. The initial search included all babies admitted with seizures and/or low Apgar Score (less than eight at 5 min). The medical records of all these cases retrieved on this initial search were then reviewed. Babies included in this report fulfilled three criteria:
It was considered likely that there had been perinatal asphyxia using, as far as possible, criteria as defined by the consensus statement on perinatal asphyxia and cerebral palsy12
They had abnormal neurological behaviour compatible with moderate hypoxic-ischemic encephalopathy.
They were seen in our high-risk neurodevelopmental follow-up clinic at 1 year of age or, in the case of two babies that died between 6 and 12 months, their outcome was known.
Infants were excluded if the low Apgar score and/or fits were not considered to be due to asphyxia or if they had mild or severe HIE. It should be noted that the Sarnat classification was based on clinical criteria as electroencephalogram (EEG) information was not available on all babies.
The following parameters were collected, where available, for all included babies: gestational age, birthweight, Apgar Score at 1 and 5 min, cord pH or blood pH if collected in the first half hour of life and possible fetal/maternal causes for asphyxia. In cases where a pH and base excess either from cord or blood were not carried out, we looked at the renal and/or liver function as evidence of postasphyxial multisystem dysfunction. The number of drugs administered to control seizures was recorded as a measure of the severity of the seizures. Anticonvulsant medication was administered to a standard unit protocol that is initially intravenous phenobarbitone (20 mg/kg), repeated once if seizures persisted, followed by intravenous phenytoin (20 mg/kg) for persisting seizures. Third-line anticonvulants were more variable and included midazolam, lorazopam, clonazepam and paraldehyde. From this, the number and duration of anticonvulsant medications were recorded. We also recorded the length of hospital stay as a measure of recovery from the encephalopathy.
All babies were assessed by a neonatal paediatrician at 4 and 7 months. At 12 months, they were examined by a developmental paediatrician and a physiotherapist. They had a physical examination, including motor skills, and a standardized developmental assessment: the Griffiths Mental Development Scales. They were classified as normally developed if the development quotient (DQ) was less than one standard deviation (SD) below the mean, mildly delayed if DQ was one to two SD below the mean and severely delayed if greater than two SD below the mean.
Cerebral palsy was diagnosed clinically when there was a combination of motor delay and abnormalities of tone with reflex abnormalities usually present. Babies classified as normal at 1 year were not routinely seen subsequently.
The neurological outcome was expressed as a percentage of children affected/not affected.
Univariate analysis of single risk factors were tested using the χ2 and Fisher exact tests as deemed appropriate. A variable was significant if P < 0.05.
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This paper has described a 1-year mortality and major disability rate following moderate HIE of 36%, with a further 9.5% of babies showing developmental delay between one and two SD below the mean. These latter babies were analysed together with the normal babies as, conventionally, this is how such babies are reported. These findings are within the range described in previous publications where the reported rate of disability/mortality was usually between 20 and 30%1,9−11, but was as high as 50% in the report of Thomberg et al5. While this was a hospital-based study, all cases were either booked to deliver at this hospital or were transferred postnatally from low-risk hospitals, so it is likely these data are representative of the general population of babies with moderate HIE.
The two clinical factors significantly associated with abnormal outcome were duration of anticonvulsant therapy and length of hospital stay. Both of these factors could reflect several variables but it is likely that this would include both the severity of and the speed of recovery from the encephalopathy. These associations are consistent with previous observations in the literature that quick recovery from HIE is associated with a better outcome. However, our findings were not consistent with Finer et al.4 and Toh13 who found a 5 min Apgar Score < 4, cord arterial pH < 7.1 and base excess>20 were clinical predictors of adverse outcome.
There has been controversy recently about the diagnosis of HIE, which has resulted in the publication of the consensus statement12. It is inevitable in a retrospective study that not all the desirable diagnostic information is available in all babies. We included two babies who had a postnatal cardiorespiratory collapse with prolonged hypoxia as they subsequently developed a clinical picture of HIE and the mechanism of potential brain injury is likely to be similar to intrapartum hypoxia. Most of the other children had one or more criteria that would suggest an intrapartum hypoxic ischaemic event, such as a clear perinatal event12, base excess ≤129 or multiorgan system dysfunction. There were three babies who did not have a cord pH taken, whose liver and renal function were normal and no clear sentinel perinatal events were detected. In these babies, a pragmatic decision had to be made that intrapartum hypoxia ischaemia was the likely diagnosis. It is recognized that not all babies diagnosed with HIE have multiorgan dysfunction14, but we acknowledge a degree of diagnostic uncertainty. It is also a limitation of this study that 20% of babies were lost to follow up and so their outcome is unknown. Most studies suggest that babies lost to follow up have a higher rate of problems than those seen15, so our reported disability rate may be an underestimate. The short follow-up period is also a limitation of this and many other studies of outcome after HIE. Most biological injuries occur in continuums, as is highlighted by the small group with mild developmental delay. There is emerging evidence that the group of babies classified as ‘normal’ at 1 year are at higher risk of minor motor dysfunction and memory impairment, which only becomes apparent at school age16. Barnett et al.17 found 36% of a cohort with probable HIE had cerebral palsy at 2 years of age. However, of 34 babies considered normal at 2 years, eight had minor neurological dysfunction and/or perceptual-motor difficulties and one had cognitive impairment when assessed at early school age. Robertson et al.18 also found increased rates of delayed school performance in 8-year-old non-impaired survivors of moderate HIE. Such observations would be consistent with the follow-up experience after extreme preterm birth.
In this study we have focused on clinical predictors and we did not consider neurophysiological and imaging results, such as EEG and magnetic resonance imaging (MRI), both of which have been demonstrated to have some correlation with the neurological outcome4,19,20. These test were not carried out routinely in our NICU over the whole time period considered. Whether these tests are better than clinical factors alone remains to be proven; however, we are now collecting data prospectively on both EEG and MRI.
In conclusion, this hospital-based study has described an adverse outcome rate after moderate HIE within the range previously described in the literature. However, particularly if babies with mild disability are considered, the rate was higher than many of the previous studies in the literature. There is a need for longer-term follow up of babies such as this to collect more accurate information on more minor degrees of neurological dysfunction.