Need for long-term follow-up and focus on cognitive and behavioral outcomes
Because the majority of studies have focused on detecting major developmental abnormalities at a very young age, still little is known about the milder difficulties children may experience in the long run. Recently, however, research has started to focus more on the subtle problems of children without major neurological deficits [
8,
23,
32,
35,
43,
44,
46]. Knowledge of the outcome for this group of children is important because these subtle problems can affect later scholastic achievement and behavioral adjustment.
Cognitive and behavioral difficulties can be expected because of the patterns of brain injury that have been associated with NE. The hippocampus and striatum are among the brain structures that can be affected [
7,
21,
31,
42,
56]. These structures have been associated with specific cognitive functions such as memory and attention and hypothesized to play a role in the pathogenesis of ADHD, autism and schizophrenia [
14‐
16,
28,
57].
To gain insight into the long-term effects of NE on development, follow-up is required throughout the school-age period. Specific cognitive functions continue to develop throughout childhood. As it is impossible to examine a function that has not developed yet, short-term follow-up cannot exclude minor cognitive and behavioral difficulties at school age. Moreover, subtle functional deficits usually do not become apparent until a child faces increasing demands to master complex abilities in school.
The aim of this review was to discuss the results of previously published studies on the possible effects of NE on general cognitive functioning, educational achievement, neuropsychological functioning and behavior from infancy through adolescence. A literature search was performed using Web of Science. Studies were screened that had been published before October 2006. Search terms were ’asphyxia neonatorum,’ ‘neonatal encephalopathy,’ ‘newborn encephalopathy,’ ‘hypoxic-ischemic encephalopathy’ and ‘perinatal asphyxia’ combined with the terms ‘cognition/cognitive’ and ‘behavior(-al)’. Reference lists of retrieved articles were screened for additional relevant publications. Studies were selected that reported the developmental outcome of NE or HIE following PA of children until the age of 18 years. The presence of NE was required for selection. When no additional indicators of PA were used, the asphyxial etiology of the NE had to be assumed by the authors. Studies were excluded when NE was partially caused by other conditions than PA, for example [
17,
34]. Also, studies were excluded in which outcome was presented in preset categories (e.g., normal versus abnormal), in which several outcome measures were combined, for example [
11,
18,
26]. In these cases it was not possible to judge whether a child had been assigned to the category ‘abnormal’ because of cognitive or behavioral problems or because of other problems, e.g., motor difficulties. A third reason for excluding studies from this review was the selection of children from a larger group of eligible patients. For example, some researchers selected only those children with abnormal findings on MRI in order to examine the correlation with outcome [
61]. In this review, outcome is reported according to grade of NE (mild, moderate or severe). Most authors of the included studies used the classification system of Sarnat when determining the severity of the NE. However, in three cases the authors significantly deviated from this system [
32,
47,
53]. In order to increase comparability across studies, the patients in these studies were reclassified according to Sarnat criteria. Articles were reviewed that reported general intellectual ability, levels of specific cognitive functions and/or behavioral problems. Details of the samples, inclusion criteria, outcome measures and results are described in Tables
1,
2,
3,
4,
5,
6,
7 and
8.
Table 1
Griffiths Mental Development Scale* at 1 year
| Moderate NE, N=13 | Moderate NE, N=27 |
• N=10: <−2 SD | • N=4: between −2 SD and −1 SD |
• N=1: between −2 SD and −1 SD | • N=23: >−1 SD |
• N=1: >−1 SD | |
• N=1: untestable | |
| Moderate NE, N=10 | Moderate NE, N=9 |
• N=9: <55 | Mean =118 (N=1 not assessed) |
• N=1: 87 | |
Thompson et al. (1997) [ 55] | No grades of NE recorded, N=16 | No grades of NE recorded, N=24 |
Mean =47, range: 7–101 | Mean =16, range 94–128 |
Barnett et al. (2004) [ 9] | | No grades of NE recorded, N=59 |
| Mean =100.34, SD=15.05, range: 55–130 |
Rutherford et al. (1996) [ 49] | Moderate NE, N=8 | Mild NE, N=4 |
All below normal (cut-off point not reported) | All normal |
Severe NE, N=1 | |
Below normal | |
Table 2
IQ at 2–6 years (no CP)
Barnett et al. (2004) b [ 9] | 2 | N=45,f Griffiths: mean =103.53, SD=12.33 (range: 81–140) |
Robertson & Finer (1985) a [ 43] | 3.5 | N=66, Stanford-Binet: mean IQ =101.5, SD=14.0 | N=94 (21.3% handicapped) Stanford-Binet2: mean IQ =92.3, SD=23.2 | N=7, Stanford-Binet2: mean IQ =37.1, SD=26.7 |
| 5 | N=14,f McCarthy: 64%: >−1 SD, 86%: >−2 SD |
Barnett et al. (2002) b
d [ 8] | 5.5–6.5 | N=20, WPPSI-R: mean IQ =109.7, SD=14.6 (N=1: 76, rest: >90) | N=12, WPPSI-R: (N=1: untestable) N=11: mean IQ =106.2, SD=11.8 (N=1: 84, rest: >94) | |
Barnett et al. (2004) b [ 9] | 5–6 | N=53,f WPPSI-R 85%: >−1 SD, mean IQ =101.98, SD=16.06, range: 69–139 |
Robertson & Finer (1988) e [ 44] | 5.5 | N=56, Stanford-Binet: mean IQ =106, SD=12 | N=71, Stanford-Binet: mean IQ =99, SD=18) | |
Table 3
IQ at 7–9 years (no CP)
| 7 | | N=65, BAS-II: | |
Group 1 (N=34): GCS=112.3, SD=11.2 |
Group 2d (N=31): GCS=102.7, SD=13.2 |
Robertson et al. (1989) a [ 46] | 8 | N=56, WISC-R: mean IQ =106, SD=13 | N=66, WISC-R: mean IQ =102, SD=17 | 5, WISC-R: mean IQ =36, SD=7 |
| 9 | | N=64, WISC-R: mean IQ =100, SD=14 | |
Table 4
Scholastic abilities at 7–13 years (no CP)
Reading | Robertson & Finer (1989) [ 46] | 13% >1 grade level below expected level for age | 35% >1 grade level below expected level for agea
| 100% >1 grade level below expected level for ageb
|
| | 41% >1 grade level below expected level for aged
| |
Marlow et al. (2005) [ 32] | | Group 1: < control groupc
| |
| | Group 2f: < control groupd
| |
Moster et al. (2002) [ 35] | NE < control groupd
| NE < control groupd
| NE < control groupd
|
Writing | Marlow et al. (2005) [ 32] | | Group 1: = control group | |
Group 2f: < control groupe
|
Moster et al. (2002) [ 35] | NE = control group | NE = control group | NE = control group |
Spelling | Robertson & Finer (1989) [ 46] | 2% >1 grade level below expected level for age | 18% >1 grade level below expected level for agea
| 100% >1 grade level below expected level for ageb
|
Marlow et al. (2005) [ 32] | | Group 1: < control groupc
| |
Group 2f: < control groupd
|
Moster et al. (2002) [ 35] | NE = control group | NE = control group | NE = control group |
Math | Robertson & Finer (1989) [ 46] | 16% >1 grade level below expected level for age | 20% >1 grade level below expected level for agea
| 100% >1 grade level below expected level for ageb
|
| | 39% >1 grade level below expected level for aged
| |
Marlow et al. (2005) [ 32] | | Group 1: = control group | |
Group 2f: < control groupd
|
Moster et al. (2002) [ 35] | NE < control groupc
| NE < control groupc
| NE < control groupc
|
Table 5
Neuropsychological functions [
43,
44,
46]
Receptive vocabulary | Mild NE: in the mean range | Mild NE = control group | Mild NE = control group |
Moderate NE < mild NEa
| Moderate NE< mild NE+ control groupb
| Moderate NE< mild NE+ control groupa
|
Severe NE < mild + moderate NEa
| Severe NE: 100% < −1 SD c
| Severe NE < mild NE + control group c
|
Visual- motor integration | Mild NE: in the mean range | Mild NE = control group | Mild NE = control group |
Moderate NE < mild NEa
| Moderate NE < mild NE + control groupa
| Moderate NE < mild NE + control groupa Severe NE < mild NE + control group c
|
Severe NE < mild + moderate NEa
| Severe NE: 100% < −1 SD c
| |
Table 6
Neuropsychological functions (NEPSY): moderate NE compared to control group [
32]
Attention and executive | Group 1 = control group (p=0.08) | Group 2 < control group (p < 0.01) |
Language | Group 1 < control group (p=0.01) | Group 2 < control group (p < 0.01) |
Sensorimotor | Group 1 < control group (p=0.04) | Group 2 = control group (p=0.10) |
Visuospatial | Group 1 = control group (p=0.14) | Group 2 < control group (p=0.02) |
Memory and learning | Group 1 = control group (p=0.61) | Group 2 < control group (p < 0.01) |
Table 7
Verbal memory (Rey’s Auditory Verbal Learning Test)* [
31]
Total words learned trial 1–5 | NE: 52.5, SD=8.7 |
Control group: 57, SD=5.8 |
Delayed recall (p=0.034) | NE: 11.6, SD=2.2 |
Control group: 13.3, SD=1.6 |
Recognition (p=0.011) | NE: 14.2, SD=1.0 |
Control group: 15, SD=0.0 |
Table 8
Verbal memory (Children’s auditory verbal learning test)* [
47]
Level of learninga
| NE: 98, SD=16 |
Control group: 104, SD=15 |
Immediate recalla
| NE: 96, SD=18 |
Control group: 105, SD=15 |
Delayed recalla
| NE: 95, SD=15 |
Control group: 103, SD=16 |
Recognition accuracy | NE: 22% delayedb
|
Control group: 27% delayed |
Total intrusions | NE: 19% delayedb
|
Control group: 20% delayed |
Immediate attention | NE: 97, SD=15 |
Control group: 100, SD=15 |
Educational achievement
Relative strengths and weaknesses in cognitive functioning can become visible when children have to acquire specific scholastic abilities in school. A test of school readiness showed that 5.5-year-old children with mild and moderate NE were not significantly behind compared to comparison children [
24]. However, children with moderate NE achieved lower scores in all domains, and 42% of them scored more than 1 SD below the average of the standardization group. Children with severe NE showed low school readiness scores at the age of 5.5 years. Table
4 gives an overview of the results of four studies, which assessed reading, writing, spelling and mathematics/arithmetic in school-aged children [
32,
35,
46,
47]. Survivors of mild NE compared to a comparison group were not significantly more often more than one grade behind in reading, spelling and arithmetic. In these domains, all children with severe NE were more than one grade behind the expected level for their age. The group with moderate NE appeared to have distinct difficulties in reading, spelling and arithmetic/mathematics. Writing has been found to be less developed in only one subgroup of one of the studies.
Neuropsychological functions
Studies of specific neuropsychological functions yielded results that are similar to the findings on general intellectual ability and educational achievement (Tables
5,
6,
7 and
8). Children who suffered from mild NE tended to show normal receptive vocabulary and visual-motor integration at 3.5, 5.5 and 8 years of age [
43,
44,
46]. As is the case in other cognitive domains, the severe group was impaired, and their ability levels were below those of children with mild or moderate NE and comparison groups. The moderate group showed an ambiguous pattern of performance. Deficits were found in receptive vocabulary, language and visual-motor integration. In contrast, attention and executive functions, visuospatial ability, and memory and learning were normal in a subgroup of 7-year-old children [
29]. Although memory and learning did not seem to be impaired in this subgroup, these children had difficulties in the sub-domains narrative memory and sentence repetition, compared to intact memory for faces, names, everyday events and intact orientation. In addition, auditory verbal learning and delayed recall was impaired in a group of 9- and a group of 16-year-old children with moderate NE [
31,
47]. Tests of other auditory skills in the former showed intact auditory attention and concentration, language and binaural separation, in contrast to impaired binaural integration, and sequencing and labeling [
47].
Behavioral problems
So far, few researchers have addressed the issue of behavioral problems in children with a history of NE. Four studies were identified that met the selection criteria. In general, hyperactivity was more often present in children with moderate NE, but not in children with mild NE [
32,
35,
44]. In addition, one study that used parent’s observations of their child’s behavior found more problems related to tractability, aggression, passivity and anxiety in a mixed group of children with NE compared to a control group [
35]. No differences were found, however, related to attention, habituation and impulsivity. A recent study reported an unexpectedly high proportion of children with moderate and severe NE that developed an autism spectrum disorder [
5]. However, the inclusion criteria differed considerably from those of Sarnat. Both groups can be classified as moderate NE when Sarnat’s criteria are applied. In addition, the authors explicitly did not exclude etiologies of NE other than PA.
Discussion and conclusion
In the introduction section of this review, problems were mentioned with regard to the comparability of different outcome studies of NE. Even after careful selection on the basis of predetermined criteria, comparing studies remained difficult. The main reason for this was the way test results were presented. In many cases, outcome of the children was reported in two or more categories, e.g., normal/mildly delayed/abnormal. One of the problems that arise due to such categorization, is the subjectivity involved in determining the cut-off points of the categories. Often, these cut-off points seemed to be chosen arbitrarily or not justified at all. Another issue that adds to this problem is the use of different tests of development, cognitive ability or behavioral problems. One can hardly compare, for example, the proportions of children with developmental delay in two studies when these are represented by a score below 85 on the Bayley Scales of Infant Development in one of the studies and by a score below 70 on the Griffiths Mental Developmental Scales in the other. To enable readers to compare studies, results of significance testing between subgroups of children with NE and comparison groups were added to the tables whenever available.
Children with a history of NE who suffer from CP at the age of 12 months are often also severely developmentally delayed. Estimates vary between 77% [
12] and 90% [
24]. Of the children without CP, those with mild NE have an excellent prognosis. Their intelligence, educational achievement and neuropsychological functions are comparable to healthy peers at least until middle childhood.
Children with severe NE appear to be impaired in every cognitive domain. They are less intelligent and perform worse at school and at neuropsychological tests than both healthy controls and children with mild or moderate NE.
As was expected, the children with moderate NE seem to form the most heterogeneous group. In general, these children are significantly less intelligent than children with mild NE and healthy peers, but their scores are still in the average range. And although these children are equally ready to go to school as other children at the age of 5.5 years, when measured in middle childhood, they perform less well in the domains reading, spelling and mathematics. On the basis of these results, it is possible that children with moderate NE fall behind in school, but do not show clear deficits at standardized testing. Another issue is raised by the relatively broad range of performance of children with moderate NE. Calculating mean IQ scores masks individual differences, which are large in groups of children with moderate NE. Therefore, means do not describe this group well, and it would be more informative to look at the distribution of scores. The description of neuropsychological functions in this review is based on six studies, in which five different tests were used in five different samples of children with moderate NE. These studies do not provide sufficient and comparable data to draw reliable conclusions about patterns of neuropsychological strengths and difficulties. The heterogeneous nature of the group of children with moderate NE raises the question whether these children really form one group. Marlow et al. [
32] divided a group of children with moderate NE according to the severity of the symptoms of the NE. The group with the least severe neonatal symptoms showed a few discrete neuropsychological difficulties, but was more intelligent and performed better in school than the group with the most severe neonatal symptoms. Marlow suggested a dose-response effect of hypoxia within this group with moderate NE. This idea of a continuum of casualty with regard to morbidity has already been proposed by Low [
29]. He suggested a theory of a critical threshold of asphyxia beyond which brain damage occurs. Beyond this threshold, a spectrum of minor and major deficits would occur. So, although the classification system of Sarnat [
50] appears to be very useful for the prediction of the outcome of children with mild or severe NE, in case of moderate NE this qualitative system lacks predictive power. Future research should therefore focus on developing a reliable, more gradual model of prediction.
Another issue regarding prediction of outcome after NE also mainly concerns moderately affected children. It is still unclear whether NE has a general effect on intellectual abilities or leads to specific patterns of cognitive strengths and difficulties. This review shows that systematic, detailed research of neuropsychological function is still scarce. A few case reports, which are not included in this review, have shown specific impairments in episodic memory (memory for events), with relatively intact semantic memory (memory for facts) [
21,
58]. However, these findings, which were based on small numbers of children, do not justify generalization to all children with NE and should therefore be replicated in larger, well-defined samples.
The introduction section of this review referred to possible associations between brain areas that are vulnerable to perinatal hypoxia and psychopathology, such as ADHD and autism. Long-term behavioral outcome of survivors of NE has received very little attention compared to neurological outcome and general intellectual ability. Only a few studies looked at the behavioral consequences of NE. Those studies found elevated rates of hyperactivity and autism in children with moderate NE. Evidence of hyperactivity and impulsive behavior has also been found in animal studies of PA [
1,
60]. These findings suggest that, in addition to cognitive impairment, children with NE could be at risk of developing behavioral problems. Because of the clinical implications this would have, future research should include behavioral monitoring of all children with NE.
Long-term follow-up of children with NE has been advocated before, including the optimal ages of assessment of specific functions [
48]. Recommendations include assessment of general cognitive and adaptive behavioral functioning at preschool age, and, in some cases, school achievement tests and a neuropsychological screening at school age. The authors of this review would like to go one step further in recommending standard screening for behavioral problems in all children with NE, regardless of their level of cognitive functioning. In addition, detailed neuropsychological assessment is recommended especially in all children with moderate NE.
From this review it is concluded that general intellectual, educational and neuropsychological outcomes are consistently positive for children with mild NE and negative for severely affected children. However, children with moderate NE form a more heterogeneous group with respect to outcome. On average, intelligence scores are below those of children with mild NE and age-matched peers, but within the normal range. Difficulties have been found in the domains reading, spelling and arithmetic/mathematics. So far, neuropsychological functioning of children with NE has received relatively little attention. The studies that were selected for this review have yielded ambiguous results in children with moderate NE. A few studies suggest elevated rates of hyperactivity in children with moderate NE and autism in children with moderate and severe NE. Therefore, behavioral monitoring is required for all children with NE. In addition, systematic, detailed neuropsychological examination is needed especially for children with moderate NE.