Objective. To define normal and abnormal patterns, test interobserver variability, and the prognostic accuracy of amplitude-integrated electroencephalography (aEEG) soon after the onset of neonatal encephalopathy.
Methods. Consecutive cases of neonatal encephalopathy (n = 56; gestation median, 40; range, 35–42 weeks) and healthy infants (n = 14; gestation median, 40; range, 39–40 weeks) were studied. aEEG was recorded using a cerebral function monitor, at median, 0, range, 0–21 days of age. Of the infants, 24 of the 56 with encephalopathy and all of the normal infants were studied within 12 hours of birth (median, 5; range, 3–12 hours). Forty infants were suspected of having suffered birth asphyxia. Criteria for normal and abnormal patterns were defined and the interobserver variability of these classifications determined. Results were compared with neurodevelopmental outcome assessed at 18 to 24 months of age. aEEG also was compared with a standard EEG and with magnetic resonance imaging.
Results. The median upper margin of the widest band of aEEG activity in the control infants was 37.5 μV (range, 30–48 μV), and median lower margin was 8 μV (range, 6.5–11 μV). We classified the aEEG background activity as normal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin >5 μV; moderately abnormal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin ≤5 μV; and suppressed amplitude, the upper margin of the band of aEEG activity <10 μV and lower margin <5 μV. Recordings were analyzed further for the presence of seizures, defined as periods of sudden increase in voltage accompanied by a narrowing of the band of aEEG activity.
Tests of interobserver variability showed excellent agreement both for assessment of amplitude (κ statistic = 0.85) and for identification of seizures (κ statistic = 0.76)
There was a close relationship between the aEEG and subsequent outcome: 19 of 21 infants with a normal aEEG finding were normal on follow-up at 18 to 24 months of age, whereas 27 of 35 infants with a moderately abnormal or suppressed aEEG and/or seizures died or developed neurologic abnormalities. Thus, aEEG predicted outcome with a sensitivity of 0.93, a specificity of 0.70, positive predictive value of 0.77, negative predictive value of 0.90, and the likelihood ratio of a positive result of 3.1 and a negative result of 0.06. For the 24 infants studied within 12 hours of birth, the corresponding results were sensitivity, 1.0; specificity, 0.82; positive predictive value, 0.85; negative predictive value, 1; likelihood ratio of a positive result, 5.5; and likelihood ratio of a negative result, 0.18.
Conclusion. The aEEG is a simple but accurate and reproducible clinical tool that could be useful in the assessment of infants with encephalopathy.
- EEG =
- electroencephalography •
- aEEG =
- amplitude-integrated electroencephalography •
- CFM =
- cerebral function monitor •
- MRI =
- magnetic resonance imaging •
- GQ =
- general quotients •
- OS =
- optimality score •
- PPV =
- positive predictive value •
- NPV =
- negative predictive value •
- PP =
- predictive probability •
- LR =
- likelihood ratio
The early assessment of prognosis after neonatal encephalopathy is important for clinical management, irrespective of the underlying cause. Unfortunately, clinical assessment is complicated by a changeable course, and investigations such as cerebral imaging and standard electrophysiologic techniques may not be sufficiently accurate or readily available.
Several studies have confirmed that the electroencephalogram (EEG), when performed within a few days of a hypoxic–ischemic insult, predicts neurologic outcome accurately.1–4 However, standard EEG requires considerable skill for recording and interpretation and may not be rapidly available in most general hospitals. Continuous 2- to 4-channel EEG may be a more practical and equally accurate prognostic tool,5 ,6 but the equipment is costly and interpretation also requires considerable experience.
An alternative technique is the amplitude-integrated EEG (aEEG) recorded with a cerebral function monitor (CFM).7–9 A single-channel EEG signal is obtained from biparietal electrodes; frequencies <2 Hz and >15 Hz are filtered selectively, and the amplitude-integrated signal is recorded onto an integral printer. The aEEG correlates well with the standard EEG10 ,11 and has been shown to predict neurologic outcome accurately very soon after birth asphyxia.12 ,13 However, there are few published data of normal data, and previous studies have relied on semisubjective visual recognition of patterns of aEEG activity to classify records. Moreover, there are no data on interobserver variability of the technique. Also most previous studies of newborn infants have examined the value of the aEEG after birth asphyxia, and its value in an unselected group of encephalopathies is undefined.
The primary aims of this study were to define normal values, determine interobserver variability, and examine the prognostic accuracy of the aEEG in nearly full-term and term infants presenting with acute encephalopathy, including a subgroup of infants presenting within 12 hours of birth. To investigate the reason for any failures of aEEG to predict outcome, in a large subgroup of infants we also compared standard EEG and magnetic resonance imaging (MRI) with aEEG.
We studied all infants with encephalopathy admitted to our neonatal units from January 1995 to December 1996 and, for comparison, normative data also were obtained from a control group of healthy newborn infants studied very soon after birth.
The Research Ethics Committee of the Hammersmith Hospitals Trust approved the study of healthy control infants, and oral consent was obtained from the parents of the study infants. Infants with acute encephalopathy were investigated according to our routine clinical practice.
The aEEG was recorded in 14 healthy full-term infants with a birth weight of 2.69 kg to 3.93 kg for at least 1 hour at a median (range) 7.2 (3–11.40) hours after a normal birth. These infants formed the control group.
A total of 56 infants with a median weight of 3.14 kg at birth (range, 2.05–4.929) and a median gestation of 39 weeks (range, 35–42) who presented with acute encephalopathy to the neonatal units at Hammersmith or Queen Charlotte's and Chelsea hospitals were studied at a median age of 18 hours after delivery (range, 2 hours, 21 days). In 24 of these 56 infants, the aEEG was recorded within 12 hours of birth (median, 5; range, 3–12). The aEEG was performed at a median of 15 hours (2 hours, 10 days) in the 40 infants suspected of having suffered asphyxia. Encephalopathy was diagnosed if there was rapid appearance of abnormal neurologic signs, defined as seizures or lethargy or irritability, together with abnormal tone or reflexes. The principle clinical diagnoses assigned by the attending physician in this group were birth asphyxia (n = 40), cerebral infarction (n = 5), postnatal collapse (n = 2), nemaline myopathy (n = 1), neonatal hemachromatosis (n = 1), Wooster-Drought syndrome (n = 1), and unknown (n = 6).
Birth asphyxia was suspected if the infant developed encephalopathy within 24 hours of birth, if there had been evidence of fetal distress (meconium staining of liquor or abnormal cardiotocograph), and if at least one of the following were present: Apgar score <6 at 5 minutes, or pH <7 or base deficit greater than −15 mmol/l on cord blood or a blood sample obtained within 60 minutes of birth. Infants suspected of having suffered birth asphyxia were born at a median gestational age of 40 weeks (range, 35–42), with a median birth weight of 3.357 kg (range, 2.264–4.45). The median Apgar scores at 5 and 10 minutes were 5 and 6, respectively, and the median pH and base deficit were 7.05 and −12.3. Fourteen infants developed Sarnat14 encephalopathy grade I, 17 grade II, and 7 grade III. The encephalopathy could not be assessed in 2 infants who required mechanical ventilation and received paralyzing agents because of severe respiratory distress very soon after birth. The combined clinical details of the other infants are shown in Table 1.
The aEEG was recorded in all infants with a Lectromed CFM (CFM 5330, Lectromed UK, Herts, UK) from biparietal needle or adhesive electrodes and displayed on the integral printer at 6 cm/h. At least 30 minutes of recording was analyzed. A line was drawn through the upper and lower margins of the band of aEEG activity and the voltage measured from the scale on the printer paper as described by Thorenberg.9 Individual spikes that were clearly separate from the dense band of aEEG activity were ignored. If the trace changed during the recording, the most abnormal section of the trace was analyzed. Administration of anticonvulsants or sedatives or handling of the infant was recorded by nursing staff. The CFM also records the impedance across the electrodes. We excluded from analysis the aEEG record within 30 minutes of anticonvulsant administration.
In normal infants, a band of aEEG activity altering in width with changes in sleep and wakeful periods occurs.9 ,15 The median and range for the upper and lower margins and the duration of the bands in sleep and awake states were calculated from the normal infants.
After the definition of normative data, criteria for abnormal aEEG patterns were defined and two pediatric residents without specialist training or research interest in aEEG were given brief training in aEEG interpretation. The criteria were demonstrated and explained, and they were provided with written descriptions and example traces for reference during aEEG interpretation.
Fifty aEEG records then were scored independently by 1) an expert in aEEG (D.A.) and 2) the two pediatric residents. Each record was rated without access to the patients' name, clinical details, neuroimaging or other investigational findings, or neurodevelopmental outcome. The sample was chosen to cover the spectrum of possible aEEG traces and included infants with normal outcome as well as severe neurodevelopmental impairment.
Standard EEGs and MRI
These were performed at the request of the attending physicians and were not always carried out if the infant made a good recovery. The EEG was recorded in 44 infants, usually on the same day of the aEEG, using a standard EEG system and modified 10–20 montage or from 2 channels of a Medilog EEG recorder (Oxford Medical, UK) with the electrodes placed in F 3P3 andF 4P4 position. A neurophysiologist who was unaware of the aEEG result assessed the EEG for continuity,16 asymmetry or epileptiform patterns (spikes or sharp waves), and seizures.
MRI was performed in 43 infants, with a 1.0 Tesla Picker HPQ system using T1-weighted spin-echo (860/20 ns) inversion recovery (3800/30/950) and T2-weighted spin-echo (3000/120 ns) sequences.17 Experienced MRI specialists blinded to the aEEG result assessed the MRI.
This was assessed at 18 to 24 months of age by neurologic examination and estimation of the Griffith's General Quotients (GQ).18 Because the GQ is inappropriate in some infants with severe damage, an optimality score (OS)19 was obtained, as described previously.17 Briefly, this examination assessed posture, tone, spontaneous motility, elicited motility, reflexes, eye movement, and interaction. Each category was scored from 1 to 3, and the overall score therefore could range from 7 (extremely abnormal) to 21 (completely normal). Neurologic outcome was classified as:
normal, no abnormal neurologic signs, an OS ≥20 and Griffith's GQ ≥85; or
abnormal, neuromotor abnormalities and/or OS <20 and/or Griffith's GQ <85.
Interobserver variability was assessed by calculating the unweighted κ statistic for 3 observers, and also by comparing each resident separately with the expert opinion.
The predictive value of the aEEG for determining neurodevelopmental prognosis was assessed by calculation of sensitivity and specificity and positive and negative predictive values (PPV and NPV, respectively). A Bayesian approach was used to further analyze the value of the test. β Density curves were calculated, and the predictive probability (PP) value of a correct prediction determined, together with 95% confidence limits for that value. Likelihood ratios (LRs) also were calculated.
The primary analysis was made by assessing the predictive value of abnormal background activity and/or seizure activity. A series of subsidiary analyses also were made. First, to determine whether detection of seizures had a significant effect on prognostic value, we analyzed the effect of examining background activity alone. Second, to examine the value of the technique in suspected birth asphyxia, we excluded infants without defined characteristics of intrapartum hypoxia–ischemia. Third, to determine whether the method could be used very soon after birth, we examined aEEG traces obtained within 12 hours of birth.
aEEG was recorded successfully and changes in the width of the band of aEEG activity could be observed in all infants (Fig 1, A). Medians and range for the minimum and maximum activity of broad and narrow bands are shown in Table 2. The duration of the wider band of aEEG activity (which is reported to be associated with quiet sleep)9 ranged from 15 to 25 minutes (median, 20 minutes), whereas the narrower band (associated with active sleep or wakefulness) lasted between 30 and 90 minutes (median, 45 minutes).
Categories of aEEG
Based on the values of normal infants, the aEEG background activity was classified as follows:
Normal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin >5 μV;
Moderately abnormal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin ≤5 μV; and
Suppressed amplitude, the upper margin of the band of aEEG activity <10 μV and lower margin <5 μV, usually accompanied by bursts of high-voltage activity (“burst suppression”).
In addition, any of these three groups could be accompanied by seizures. These were manifest as periods of sudden increase in voltage, accompanied by a narrowing of the band of aEEG activity and followed by a brief period of suppression.
Examples of aEEG traces in each of the classifications are shown inFigs 1 and2. In the primary analysis, all aEEG traces that were not classified as group 1 without seizures were assigned to the poor prognosis group. In the subsidiary analysis of background activity alone, infants with background activity in group 1 were regarded as normal, regardless of the presence of seizures.
Records were a) assigned to group 1, 2, or 3 and b) the presence of seizures was assessed separately. The residents did not note any particular difficulties in assigning the scans to groups.
Classification of Background Activity
Overall agreement in classification of groups 1 through 3 among 3 observers was 0.85. Taken separately, residents' agreement measures with the expert were 0.75 and 0.87.
Classification of Seizures
The overall classification of seizures between among the 3 observers was 0.76. Taken separately, the agreement measures between the 2 residents were 0.79 and 0.73.
Infants With Encephalopathy
Changes in the band of aEEG activity as seen in association with sleep and wakefulness were observed in only 18 of the 56 infants. The aEEG was of normal amplitude in 21 infants, moderately abnormal amplitude in 9 infants, and suppressed amplitude in 6 infants. In addition, seizures were identified in 20 infants, 6 with normal amplitude, 8 with moderately abnormal amplitude, and 6 with suppressed amplitude in the interictal aEEG.
Relation Between aEEG and Neurologic Outcome
This is summarized in Table 3 for the group as a whole and in Table 4 for the subset of infants studied within 12 hours of delivery. There was a close relationship between the findings on aEEG and neurologic outcome: 19 of 21 infants with a normal amplitude aEEG were normal on follow-up, whereas 13 of 15 infants with moderately abnormal or suppressed amplitude died or developed neurologic abnormalities. Among the 20 infants in whom seizures were identified, 4 of the 6 with normal amplitude aEEG had a normal neurologic outcome, whereas 12 of 14 infants with moderately abnormal or suppressed amplitude died or subsequently had an abnormal neurologic outcome.
The predictive value of an abnormal aEEG (moderately abnormal amplitude or suppressed amplitude or seizures) for predicting an abnormal neurologic outcome or death in encephalopathic infants is shown inTable 5.
Relation Between aEEG Within 12 Hours of Birth and Neurologic Outcome
The predictive value of aEEG applied at a median of 5 hours of age is given in Table 5. Of the 24 infants studied, 20 were suspected of having suffered birth asphyxia. Of these 20 possibly asphyxiated infants, 9 had normal aEEG and all were normal on follow-up. Two infants had moderately abnormal amplitude: 1 had a normal outcome, whereas the other infant also had seizures and died. Nine infants had a suppressed-amplitude aEEG: 6 infants (all also with seizures) died; of the 3 survivors, 2 developed severe neurologic abnormalities (infants 9 and 10 in Table 6) and the other developed moderate neurologic problems (infant 11 in Table 6). The aEEG amplitude had returned to normal at 12 hours of age in this infant.
Four of the 24 infants studied within 12 hours of birth had encephalopathy that was not thought to be associated with birth asphyxia. One infant with a cerebral infarct had seizures but the aEEG background activity was classified as normal amplitude and the child was normal on follow-up. Another infant suffered a cerebral hemorrhage, had moderately abnormal amplitude aEEG and developed severe neurologic abnormalities (infant 3 in Table 6). The other 2 infants (suffering from nemaline myopathy and Wooster Drought syndrome) had moderately abnormal amplitude aEEG and both died.
Incorrect Prediction of Outcome by aEEG
The aEEG did not correctly predict the neurologic outcome for 10 of the 56 infants. Two of these infants had a normal amplitude aEEG but poor outcome: 1 (infant 12 in Table 6) had a normal aEEG and standard EEG in the first 14 hours but developed seizures and a moderately abnormal amplitude aEEG at 7 days and subsequently developed a hemiplegia. The other infant (infant 1 in Table 7) had evidence of an infarct in the brainstem and cerebellum on MRI and later died from complications related to abnormal brainstem function.
Four infants, all with suspected birth asphyxia, had a moderately abnormal amplitude aEEG, with seizures in 2 infants, and were normal on follow-up. The MRI showed abnormal signal in the cortex in 2 of these infants and mild cerebral edema in 1 infant; MRI was not conducted in the other infant.
The other 4 infants had seizures but normal amplitude aEEG and all had normal follow-up neurologic examinations. Three of these 4 infants had evidence of major artery infarction on MRI, whereas the other infant had a normal MRI and the diagnosis remained uncertain.
No infant with a suppressed aEEG had a normal neurodevelopmental outcome.
Relation Between aEEG and the EEG and MRI
Fourteen of 17 infants with a normal amplitude aEEG had a normal EEG; the EEG was asymmetric with low voltage or spikes in the other 3 infants. Twenty-six of 27 infants with an abnormal aEEG also had an abnormal EEG; 1 infant (infant 11 in Table 6) with a transiently suppressed aEEG had a normal aEEG and standard EEG at 2 days. This infant subsequently had moderate developmental delay and neurologic abnormalities on follow-up.
Apart from 1 infant with infarction of brainstem and cerebellum, the MRI findings in the infants with a normal amplitude aEEG consisted of evidence of transient cerebral edema, small hemorrhages, and subtle alteration in signal intensity in discrete areas in basal ganglia or cerebral cortex. Four of 5 infants with seizures and normal amplitude aEEG had evidence of unilateral cerebral artery infarction on MRI; the other infant had an intraventricular hemorrhage and abnormal signal in basal ganglia. Six of 16 infants with seizures and/or moderately abnormal amplitude aEEG had a normal MRI or minor abnormalities only. The other 10 infants and 10/11 infants with seizures and/or suppressed aEEG had severe multiple abnormalities usually affecting the white matter, basal ganglia, and thalami. One infant with a transiently suppressed aEEG had abnormal signal in the lentiform nucleus and had moderate developmental delay on follow-up (infant 11 in Table 6). Details of the EEG and MRI for infants with an abnormal neurologic outcome or who died are shown in Tables 6 and 7, respectively.
We have shown that the aEEG correlates closely with neurologic outcome in newborn infants with encephalopathy from different causes and also correlates with the results of other more specialized investigations.
Our aim was to study full or nearly full-term infants with encephalopathy. We deliberately chose an inclusive definition of encephalopathy and did not restrict the study to infants with a classical presentation of birth asphyxia. Previous work has demonstrated that aEEG is an accurate predictor soon after birth in infants preselected because of suspected asphyxia. However, the clinical diagnosis of birth asphyxia is difficult and frequently controversial and, for the clinician faced with an infant with encephalopathy, the cause of the problem frequently is of less importance than the prognosis. Consequently, we wished to know the value of aEEG in an unselected cohort of infants diagnosed as suffering from encephalopathy.
We did not investigate very preterm infants. Interpretation of the aEEG is more difficult in the preterm infant because of EEG changes related to gestational age: a burst suppression pattern observed in extremely preterm infants changes to a discontinuous pattern in the more mature infant.20 ,21 Only 2 of the study infants were born before 37 weeks' gestation (1 born at 35 and the other at 36 weeks' gestation). Therefore, it is very unlikely that immaturity influenced our results. Moreover, a suppressed pattern is probably ominous at any gestation.22
We did not observe any complications related to the aEEG or the use of needle electrodes; these were tolerated well for prolonged periods and did not cause any injury. In every case, aEEG was begun without difficulty, usually by nursing or junior medical staff. Although we did not examine systematically the influence of drugs on the aEEG, others have reported transient suppression of the aEEG after administration of anticonvulsants.8 ,12 Because only 1 infant had a briefly abnormal aEEG, it is unlikely that medications influenced the results. By excluding from analysis the parts of the records that were associated with drug administration or handling of the infant or where the impedance signal was disturbed, we minimized possible confounding effects.
We were able to obtain normative data from healthy infants soon after birth. These infants exhibited regular changes in aEEG voltage that have been ascribed to sleep state9 ,15; a wider band of aEEG, probably associated with quiet sleep and comparable with trace alternate pattern seen on EEG, alternated with a narrower band of activity, which is associated with active sleep or wakefulness. The duration of the wider band of aEEG activity was remarkably consistent at ∼20 minutes on most observations. These findings are similar to those reported from infants studied at 2 to 5 days after birth9 and suggest that the birth process does not have a prolonged influence on EEG activity. This normative dataset provides comparative data for those obtained from infants with encephalopathy very soon after birth.
We defined voltage criteria for classifying the aEEG because descriptions such as “continuous low voltage,” used in previous reports,13 may be ambiguous. The minimum lower voltage in the normal infants was 6.5 μV. We chose to set 5 μV as the lower limit of normal in our classification, for three reasons: 1) for simplicity of practical application because 5 μV is easily determined on the aEEG record; 2) to allow a small margin for error; and 3) because that value is very similar to the criteria set empirically by previous studies of the prognostic value of aEEG after birth asphyxia,8 ,12 thus allowing our results to be compared.
To assess the use of these criteria, we compared the classification of 50 aEEG records by 2 pediatric residents with an expert assessment. The value of the κ statistic was uniformly high, showing that there was very close agreement between the assessments, both for classification of amplitude and for recognition of seizures. The interpretation of the κ statistic is that values of 0.6 to 0.79 show substantial agreement, and values >0.8 show almost perfect agreement. This suggests that aEEG could be interpreted accurately by clinicians even in nonspecialist units after a modest period of training.
We defined the prognostic value of the test by calculating the conventional statistics of sensitivity, specificity, and positive and negative predictive value. We also applied a Bayesian approach and calculated the PP value of the test, which defines the probability that a single aEEG will predict correctly the prognosis of an infant to within 95% CIs, and is a useful summary statistic of the tests value. We also determined the likelihood ratios of positive and negative tests to facilitate further the application of the results.
In determining the prognostic value of the aEEG, we included death and neurodevelopmental impairment as a single outcome group. This is a practical classification, but might be incorrect if clinical decisions to discontinue care were made on the basis of the aEEG. In our unit, a decision that intensive care is not appropriate is never made on the basis of a single test, but rather after exhaustive investigation and discussion between professionals and parents have taken place. The close relation between aEEG, EEG, and MRI in both surviving and nonsurviving members of the poor outcome groups indicates that cessation of intensive care is unlikely to have introduced bias into our results.
We found a close association between the aEEG and the standard EEG, similar to findings from previous reports.10 ,11 A normal aEEG was associated very closely with a normal standard EEG and neurodevelopmental outcome. Only slight MRI abnormalities were identified in this group, apart from 1 infant with unusual patterns of abnormal signal in mesencephalon, brainstem, and cerebellum, but with normal cerebral hemispheres. However, infants with a unilateral cerebral infarct had normal-amplitude aEEG but focal abnormalities on the standard EEG. These data suggest that some deep-sited or focal lesions may be associated with a normal aEEG. Infants with moderately abnormal-amplitude aEEG had variable EEG and MRI findings, and the neurologic outcome correlated with findings on standard EEG and MRI. However, as has been reported previously,7 infants with suppressed amplitude or burst suppression pattern had a very poor prognosis, with all infants dying or surviving with multiple deficits. Although prognosis should be assessed after considering the results of all the investigations and will be dependent on the underlying diagnosis, our findings suggest that regardless of cause, encephalopathy associated with a suppressed aEEG is likely to have a very poor prognosis.
In infants with seizures, we found that the interictal aEEG activity correlated with subsequent outcome. Thus, 4 of the 6 infants with seizures and a normal-amplitude aEEG had a normal outcome, whereas 12 of 14 infants with seizures and a moderately abnormal or suppressed amplitude had a poor outcome. This was confirmed by the subsidiary analysis using only background activity to predict outcome. This showed that the PP value of the test was very similar to that when seizures were included, and well within the 95% CIs for the analysis. These results give confidence in the robustness of the technique.
Our findings confirm the high predictive value of aEEG soon after asphyxia. Eken and co-workers found the aEEG accurate for assessing prognosis within 6 hours of birth asphyxia.13 Our study was not designed to test the value of aEEG within 6 hours of delivery, and thus provides no direct data on the value of the technique in selecting infants for trials of neural rescue therapy, which need to be applied within this time. However, the predictive value of studies at a median age of 5 hours was greater than in later studies, which suggests that very early aEEG may be useful as a selection method for clinical trials.
In summary, our findings add to the evidence that the aEEG is a simple and valuable clinical tool that gives early and accurate prognostic information about unselected newborn infants presenting with encephalopathy.
We thank Dr N. Robertson and Dr R. Blumberg for participating in the tests of interobserver reliability; and Professor G. Bydder, Dr E. Maalouf, and Dr M. Rutherford for performing and reporting the MRI scans.
Ms C. Brayshaw performed and analyzed the standard electroencephalograms.
- Received October 26, 1998.
- Accepted March 10, 1999.
Reprint requests to (D.A.) Department of Paediatrics, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
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- Copyright © 1999 American Academy of Pediatrics