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PEDIATRICS Vol. 105 No. 5 May 2000, pp. 1082-1089
,
, , ¶,
From the Divisions of * Cardiology, Neurology, and
§ Neonatology at Children's Hospital of Philadelphia; Departments of
Pediatrics and ¶ Neurology at the University of Pennsylvania School
of Medicine; # Department of Psychology at Children's Seashore House;
and ** Department of Anesthesiology at the Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Objectives. The purposes of this study are to describe the quality of life and cognitive function in school-aged children who have undergone staged palliation for hypoplastic left heart syndrome (HLHS), and to identify factors that are predictive of neurodevelopmental outcome in this population.
Methods. School-aged survivors with HLHS who had undergone palliative surgery at our institution were identified and mailed a questionnaire to assess subjectively quality of life, school performance, and incidence of medical complications. A subgroup of local patients underwent standardized testing of cognitive function and neurologic examination. These patients were compared with the larger (remote) group of questionnaire respondents to determine whether results may be generalizable to the entire HLHS population. Potential predictors of neurologic and cognitive outcome were tested for their association with test scores using multivariate regression analysis.
Results. Questionnaire results were obtained from 115 of 138 eligible children (83%; mean age: 9.0 ± 2.0 years). Standardized testing was performed in 28 of 34 (82%) eligible local patients (mean age: 8.6 ± 2.1 years). The majority of parents or guardians described their child's health as good (34%) or excellent (45%) and their academic performance as average (42%) or above average (42%). One third of the children, however, were receiving some form of special education. Chronic medication usage was common (64%); the incidence of medical complications was comparable to that previously reported in children with Fontan physiology. Cognitive testing of the local group demonstrated a median full scale IQ of 86 (range: 50-116). Mental retardation (IQ: <70) was noted in 18% of patients. In multivariate analysis, only the occurrence of preoperative seizures predicted lower full scale IQ.
Conclusions. Although the majority of school-aged children with HLHS had IQ scores within the normal range, mean performance for this historical cohort of survivors was lower than that in the general population. Key words: hypoplastic left heart syndrome, neurodevelopmental outcome, quality of life.
Hypoplastic left heart syndrome (HLHS) is a congenital
heart defect (CHD) with an incidence of 1 in 4000 to 1 in 6000 live births1 and is the second most common congenital heart lesion presenting in the first week of life.2 Without palliative surgical procedures, this lesion is uniformly fatal in early
infancy. In 1980, Norwood and colleagues3 reported the
first successful palliative operation for an infant with HLHS, and
reports of neonatal transplantation soon followed.4 Survival after stage I palliation has improved to >75% in several centers, and recent data suggest that the operative mortality risks for
intermediate staging procedures and the Fontan operation are
<5%.5-7 As surgical and medical management continue to
improve, increased attention has now focused on functional outcome in
the survivors of staged palliation.
Children with CHD are at risk for neurologic and cognitive
impairment,8 and the HLHS population may be especially vulnerable. Radiologic and pathologic examination have demonstrated a
high incidence of congenital brain anomalies in children with HLHS.9 Neonates with HLHS may present with circulatory collapse in the newborn period and sustain hypoxic-ischemic injury before palliative surgery.6,10 Surgical palliation requires both cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) in the newborn period, and subsequent operations may require additional CPB and DHCA. Both DHCA and CPB have
been associated with neurodevelopmental deficits in
children.11-15 Risk factors for neurodevelopmental
impairment in the HLHS population that have been shown to impact
cognitive function in children with other forms of CHD, including
prolonged cyanosis, chronic congestive heart failure, cerebrovascular
accidents, and poor nutritional status.16-22
Previous evaluations of preschool-aged children with HLHS have
demonstrated varying degrees of neurologic impairment both after staged
palliation and transplantation.1023-26 In an early
report, Rogers and colleagues23 found that 7 of 11 children with HLHS who had undergone staged palliation had major
developmental disabilities. In more recent reports, Kern and
colleagues26 demonstrated moderate cognitive impairment
with a median IQ of 88 in 12 preschool subjects, whereas Goldberg and
colleagues24 described mean IQ scores within the normal
range for 19 subjects with HLHS 3 to 7 years of age. For the most part,
these studies have examined preschool-aged children, in whom the
predictive value of testing for later school function is
low.27 To date, little is known about cognitive and
neurologic function in older children with HLHS. The purposes of this
study are to characterize the functional, neurological, and cognitive
outcome for intermediate-term survivors of staged palliation for HLHS
and to identify factors that are associated with poor outcome.
Patient Population
A cross-sectional study was performed between June 1, 1997 and
April 1, 1998 to include all school-aged survivors of staged palliation
for HLHS. During this time, primary transplantation was not performed
for any patient with HLHS. Patients were identified by review of the
surgical database at the Children's Hospital of Philadelphia. Patients
were eligible if they were born before January 1, 1992 and underwent
staged palliation at our institution for HLHS or its variants, such as
unbalanced complete common atrioventricular canal. Children with
interrupted aortic arch and heterotaxy were excluded. The overall
4-year survival for patients undergoing staged palliation for HLHS from
1984 to 1991 was 36%.28 Patients living outside of North
America at the time of the study were not included and subjects who had
undergone takedown of the Fontan or cardiac transplantation were not
eligible. Before contact of the patient's family, the cardiologist for
each eligible patient was contacted to obtain the patient's address
and telephone number as of March 1, 1997. The study was approved by the
committee for the protection of human subjects at the Children's
Hospital of Philadelphia. Signed informed consent was obtained from the
participating families.
Part I (Questionnaire)
Questionnaire
A questionnaire was mailed to the family of each child to be
completed by the parents or guardians. If no response was received in 6 weeks, a second questionnaire was mailed. If after another 6 weeks no
response was received, the families were contacted by telephone. The
questionnaire addresses issues of functional status, academic
performance, socioeconomic status (SES), and interim medical history
and has been used previously in the follow-up of patients with single
ventricle.29
Medical History
Medical records, operative notes and perfusion data were
reviewed for all study patients. Variables considered to be potential predictors of neurocognitive outcome are outlined in Table
1. In our study total support (TS)
duration represents the combined CPB and DHCA times.
TABLE 1
METHODS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
Candidate Predictors of Cognitive Outcome
Part II (Standardized Testing and Neurologic Evaluation)
Patient Population A subgroup of the patients receiving the questionnaire was invited to undergo standardized neurocognitive evaluation. To minimize selection bias related to SES, patients were eligible for this portion of the study only if they lived within a local geographic region defined by 6 telephone area codes, all within an ~100-mile radius from our center. Patients were not eligible if English was not the primary language used at home. SES for each subject was assessed with the Hollingshead Index of Social Status.30
Measures of Outcome
Psychoeducational and Motor Measures Formal tests were administered by clinic psychologists (M.G. and E.M.M.) at a single morning session.
Cognitive Testing The Wechsler Intelligence Scale for Children, Third Edition (WISC-III) was administered to assess cognitive function. The WISC-III is a widely used, standardized assessment tool shown to be both valid and reliable.31 The scales are comprised of 10 verbal and performance subtests and yield a full scale, verbal, and performance IQ scores (expected mean: 100 ± 15).
Achievement Testing Subjects were evaluated with the Woodcock-Johnson Psychoeducational Battery (WJPB)-Revised.32 The tests assess academic performance in reading (letter identification and passage comprehension) and math (calculation and applied problems) and are scaled with a mean 100 ± 15.
Language Testing Language skills were assessed by the Clinical Evaluation of Language Fundamentals-Revised (CELF-R).33 Both receptive and expressive language are evaluated are assessed and scores calculated from 3 subtests (mean: 100 ± 15).
Tests of Motor Function The Developmental Test of Visual Motor Integration (VMI) was used to assess visual spatial and visual motor integration ability (mean: 100 ± 15).34 The test involves copying of geometric forms and is designed to identify potential learning problems. Patients with hemiparesis used the unaffected extremity to complete the VMI.
Assessment of Behavior Problems and Competencies The Achenbach Child Behavior Checklist is a subjective measure of behavioral problems and competencies and is completed by the parents.35 There 8 subtests, which are calculated according to a T score (borderline: >68; clinical: >70).
Neurologic Examination Subjects were evaluated between June 1997 and March 1998 by a single pediatric neurologist (R.R.C.). Historical information was gathered concerning seizures, school performance, attention and behavior problems, and sleep patterns. Physical examination included measurement of head circumference; microcephaly was defined as a head circumference less than the second percentile for age. The children were also assessed for abnormalities in muscle tone, coordination, fine motor skills, deep tendon reflexes, and balance. Based on the findings from history and physical examination, children were clinically diagnosed with cerebral palsy, epilepsy, and/or attention deficit hyperactivity disorder (ADHD; present/absent).
Statistical Analysis
The results of the patient groups are compared with age-matched
standards where appropriate. We compared questionnaire, perioperative, and operative data of the local patients who underwent standardized pschyometric testing to data from the remaining patients who only completed the questionnaire (remote group). Perioperative and operative
data from the nonresponders, which includes patients lost to follow-up,
were also analyzed. Comparison between the local group, the remote
group, and the nonresponder group was performed with Students
t test or analysis of variance for continuous variables and
2 or Fisher's exact test for categorical
variables. Analysis of the potential predictors of neurocognitive
outcome and the scores on psychometric testing was performed with
multiple linear and logistic regressions. Independent variables were
considered candidate predictors in the multivariate model if the
corresponding P value was <.10. Variables remained in the
model if the P value was <.05. Analysis was performed with
STATA 5 (College Station, TX).
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RESULTS |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Part I (Questionnaire)
Study Patients There were 143 early survivors of the Fontan procedure who resided in North America. Heart transplantation subsequent to the Fontan procedure had been performed in 2 patients. No patients had undergone takedown of the Fontan baffle. There were 3 late deaths after the Fontan procedure. Of the remaining 138 patients, 11 (8.0%) were lost to follow-up. The questionnaire was mailed to 127 patients. Responses were received from 115 of 138 of the eligible patients (83.3%). The mean age of patients at the time the questionnaire was completed was 9.0 ± 2.1 years. The oldest respondent was 17.4 years of age. There were 42 female (36.5%) and 73 male (63.5%) respondents.
Questionnaire Data The parents completed the questionnaire for 111 subjects (96.5%) and other relatives completed the questionnaire for 4 subjects (3.5%). Questionnaire data relating to functional status and academic performance are shown in Tables 2 and 3. Responses concerning the use of medications are shown in Figs 1 and 2.
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Part II (Standardized Testing)
Patient Population There were 34 of 127 questionnaire respondents who met eligibility criteria for standardized testing. Of these, 28 (82.3%) participated in this portion of the study. The mean age of these children was 8.9 ± 2.1 years (range: 6.0-13.6 years). The mean score on the Hollingshead Four Factor Index of Social Status for the 28 subjects was 37.0 ± 14.6, which is comparable to that described in a previous study of children undergoing the Fontan operation.36 Neurologic examinations were performed in 23 of 34 local patients (67.6%). Those subjects who underwent evaluation by a neurologist had mean age of 8.7 ± 2.6 years.
Questionnaire Data (Local Versus Remote) The results of questionnaire data from the local patients who participated in standardized testing were compared with the results from all other questionnaire responders. There was no statistically significant difference between the 2 groups with respect to age, gender, parental level of education, parental assessment of the child's health and functional status, the incidence of medical complications, or educational setting.
Medical History Patient-related data obtained from review of the medical records are shown in Table 4. Results are shown for the local group (n = 28), the remote group (n = 87), and the nonresponder group (n = 23). There was no statistical difference among the groups with respect to patient-related or procedure-related variables (Tables 4 and 5).
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Standardized Psychometric Testing
Measures of Cognitive Outcome Twenty-eight children completed the WISC-III, VMI, and WJPB, 25 subjects completed the CELF-R. Table 6 lists the results of psychometric testing. Figure 3 demonstrates that 10 children (35.7%) scored in the borderline low range for full scale IQ (score: 70-85), and 5 subjects (17.8%) scored <70 and, hence, fall into the range of mentally retarded. The median performance IQ scores were lower than the verbal IQ scores (83 vs 90, respectively). The results of the achievement tests also demonstrate mean scores for the group below expected values. Learning disability, defined as an achievement score 15 points lower than the full scale IQ score, was noted in 4 patients (14.2%). The scores for the CELF-R were significantly lower than expected for the normal population. The median score for the study population was 74. The median scores on the receptive and expressive portions of the test were 76 and 73, respectively.
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Neurologic Evaluation
A neurologic examination was performed on 23 of 34 local patients (67.6%). A significant percentage of the children 16 of 23 (69.5%) had evidence of ADHD by history and physical examination. Of these 16 patients, 2 were receiving pharmacological treatment for ADHD. Microcephaly was present in 3 (13.0%), fine motor abnormalities were noted in 11 (47.8%), and gross motor abnormalities were identified in 9 (39.1%). Four subjects (17.4%) met criteria for cerebral palsy. Hemiparesis was noted in all 4 subjects with cerebral palsy. No patient was found to have spastic quadriplegia. Seven children (30.4%) had speech problems and 2 (8.7%) had mood disturbances. Only 3 of the 23 patients (11%) were thought to be completely normal with respect to all historical and observational data.
Predictors of Neurodevelopmental Outcome
Analysis was performed to determine which patient-related and procedure-related variables were associated with cognitive outcome for the patients participating in standardized testing. The variables listed in Table 1 were tested for their association with the outcome measures: full scale and subtest IQ, VMI, achievement test, and CELF-R. In multivariate analysis, only preoperative seizures were associated with lower full scale IQ scores (P = .01). Preoperative seizures were also associated with lower verbal IQ (P = .004). Preoperative seizures and longer cumulative CPB duration were associated with lower performance IQ (P = .02 and P = .007, respectively). SES did not predict full scale IQ, nor did length of DHCA time. Longer cumulative CPB was associated with lower scores on WJTA-Math (P = .02) and WJTA-Reading (P = .007). There were no factors significantly associated with the CELF-R or VMI scores.
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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This study describes both the subjective assessment of caregivers and objective measures of neurodevelopmental outcome in school-aged survivors of staged palliation for HLHS. The majority of caregivers perceived their child's health to be either excellent or good, and the majority of children had slight or no limitations to physical activity. As with previous follow-up studies of patients with Fontan physiology,19,29 medical complications are not uncommon in the HLHS population. Parental reporting suggests that school-aged children with HLHS have a significant incidence protein-losing enteropathy, neurologic-based disorders, arrhythmias, and sinus node dysfunction necessitating placement of a pacemaker. Over one third of the children were taking no medications, although 20% were taking 3 or more medications on a regular basis. Although this may represent some variation in medical management, it also illustrates the range of outcome for children with HLHS.
The majority of parents described their child's school performance as average or above average. Despite this, many of the children were receiving some form of special education and objective testing demonstrated median scores ~1 standard deviation below expected values. This discrepancy between the objective measures of academic standing and the parental assessment of school performance may be related to parental expectation and the so-called vulnerable child phenomenon, which has been seen to a lesser degree in previous evaluations of children with CHD.25 In this unique initial cohort of now school-aged patients, survival was considered an extraordinary achievement at the time of palliative surgery and long-term outcome uncertain. Interestingly, among the 28 patients who underwent standardized testing, there was a correlation between parental assessment and full scale IQ. It is possible that a similar discrepancy exists in the assessment of the subjects' functional status and objective measures of exercise capacity. Although by parental report 88% of patients had slight or no limitations to activity, previous studies have shown that patients with Fontan physiology tend to overrate their exercise performance.37
Data obtained from standardized psychometric testing of the 28 local patients demonstrate that half of the subjects scored at or above 85 on full scale IQ testing. There is, nonetheless, a significant incidence of cognitive impairment with mean scores well below expected values, and 17.8% of the subjects obtaining scores in the mentally retarded range. As has been reported in children with other congenital heart lesions, the performance IQ is lower than the verbal IQ.17,38 This cohort of children also demonstrated significant impairment in both receptive and expressive language function. Although previous studies have not consistently reported deficits in language function, problems with language may not be apparent until the children approach school age39,40 and may be less apparent in older patients attributable to recovery or compensation.38
The analysis of risk factors for predicting lower IQ scores demonstrated that the occurrence seizures before the stage I procedure was significantly associated with poorer cognitive outcome. Seizures before stage I surgery most likely result from hypoxic-ischemic insult at presentation. In our study population, the majority of neonates with HLHS had neither clinical seizures nor end-organ injury in the preoperative period. When such events do occur, however, they may be particularly predictive of a poor cognitive outcome. Prompt diagnosis of HLHS and early institution of prostaglandin therapy may be able to reduce the incidence of preoperative insult. In our study population, prenatal diagnosis was not associated with improved neurologic outcome. However, prenatal diagnosis was relatively uncommon in this era and only 3 of 28 patients were diagnosed in utero.
Prolonged circulatory arrest is thought to be one of the factors responsible for neurocognitive impairment after neonatal open-heart surgery,12,13,3641-43 and the risks of neurologic impairment have been reported to increase if DHCA exceeds 45 to 50 minutes.13,14,44 In the largest prospective study to date examining the role of DHCA on cognitive function, 171 neonates were randomized to receive a either a predominant DHCA strategy or a predominant low flow CPB strategy during the arterial switch operation.36,45 At 4 years of age, neither full scale IQ scores nor overall neurologic status were related to duration of DHCA; however, other abnormalities, such as oromotor apraxia gross/fine motor coordination and cranial nerve/brainstem abnormalities, were related to assignment to prolonged DHCA.39
In the present study, neither duration of DHCA at the time of stage I surgery nor cumulative DHCA time for all operations were predictive of full scale IQ. This is most likely attributable to the fact that, in this cohort of patients, there was relatively little variation in either the duration of DHCA at stage I (which averaged nearly 1 hour), or the total duration of DHCA used in all procedures. In addition, the small size of the study population may have limited our ability to detect the effect of DHCA time. However, longer CPB time, possibly reflecting more complex procedures, was associated with significantly lower scores on performance IQ and achievement testing, areas which require visual-motor integration and higher reasoning.
Curiously, SES was not predictive of IQ. This is unusual because parental SES is usually correlated with IQ scores in healthy children as well as those who have undergone open-heart surgery.25,36,39 We used the Hollingshead Index to determine SES. Although there are some limitations to this scale, it has been shown to be reproducible and has been used in previous evaluations of children with CHD.24,25,36 Insufficient power in our small study population is the most likely explanation for our failure to demonstrate a correlation between SES and cognitive function. Because the degree of cognitive impairment is quite significant in some of our patients, the effect of SES on IQ may be overwhelmed by more potent preoperative procedure- and patient-related factors.
Previous reports examining neurodevelopmental outcome in children
with HLHS have focused primarily on the preschool population. Rogers et
al23 identified developmental disabilities in 7/11
patients, 11 months to 5 years of age, whereas more recently Goldberg
and colleagues24 reported that the mean full scale IQ in
19 children with HLHS 35 to 95 months of age was 97.9, which is within
the normal range. The variation in measured cognitive function between
these studies can be explained in part by the era in which the subjects
underwent palliative surgery. Those children studied by Rogers et al
underwent stage I reconstruction between 1986 and 1991, whereas those
subjects studied by Goldberg et al underwent palliative surgery in the
mid-1990s. In our study population (1984-1991), the duration of
cooling was short, which has been associated with adverse late
neurologic function,45 
-stat blood gas management, and
bubble oxygenators were used, which may also adversely affect the
central nervous system,46-48 and circulatory arrest time
at stage I approached 1 hour. It is likely that improvements in
preoperative, intraoperative, and postoperative management may result
in diminished neurologic insult for patients undergoing staged
palliation in the current era.
In addition, the increasing availability of fetal diagnosis may lower the incidence of circulatory collapse and secondary central nervous system hypoxic-ischemic damage. Routine intermediate staging with the bidirectional cavopulmonary anastomosis (BCPA) minimizes the symptoms of congestive heart failure and may improve cognitive and motor function. Recent advances in perfusion such as modified ultrafiltration can reduce the inflammatory response associated with CPB.7 The subjects in our study who underwent palliative surgery between 1984 and 1991 represent one of the earliest cohorts in the history of this pioneering procedure.49 Many of the aforementioned advances in management of patients with HLHS were not used at the time these children underwent palliative surgery.
The neurologic examination demonstrated a relatively high incidence of both gross and fine motor abnormalities. While most of these findings were modest, some children did have more profound abnormalities such as cerebral palsy. Furthermore, over two thirds of the children were thought to have attention/hyperactivity problems. The prevalence of ADHD in the general school-aged population is reported to be 3% to 5%.50 The prevalence of attention problems as measured by the Achenbach Child Behavior Checklist, although higher than that in the normal population, was not as high as that noted by neurologic examination. This discrepancy may again reflect the parents' favorable bias. Additional studies into the incidence of ADHD and the risk factors in this patient population are underway.
Study Limitations
The questionnaire used in this report has not been administered to children with other chronic illnesses or in healthy children. As such, it is difficult to compare the outcome for children with HLHS with that for children with other complex neonatal illnesses, such as low birth weight, congenital diaphragmatic hernia, or other forms of CHD. A second limitation is the retrospective analysis of risk factors: events such as clinical seizures may not be well-documented in the medical record. Finally, not all subjects who participated in standardized testing underwent neurologic examination. There were 5 subjects in whom examination by the pediatric neurologist could not be coordinated with other testing. Rather than using a second examiner, we choose to forego the examination in these patients.
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CONCLUSION |
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Abstract
Methods
Results
Discussion
Conclusion
References
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In summary, the children in this historical cohort with HLHS demonstrated an increased incidence of neurologic-based impairments. Early identification of neurologic, behavioral, and cognitive deficits in this at-risk population may allow for early intervention and improved outcome. Special attention must be paid to issues of language development and the possibility of hyperactivity and attention-related problems. Despite the high incidence of neurodevelopmental deficits, the majority of parents of school-aged survivors of HLHS described their child's health, exercise ability, and school performance as average or above average. A better understanding of the factors that contribute to cognitive impairment in this population is necessary. Finally, newer developments in CPB and cerebral protection hold promise for improved outcome in the survivors of staged palliation.
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ACKNOWLEDGMENTS |
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We thank Dr Thomas L. Spray for his critical review of the manuscript. We also acknowledge the assistance of the staff of the outpatient clinic of the Cardiac Center at the Children's Hospital of Philadelphia. Finally, we recognize the support in manuscript preparation by Maritza Lozada.
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FOOTNOTES |
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Received for publication Jan 4, 1999; accepted Jul 8, 1999.
This work was presented in part at the Annual Meeting of the American Academy of Pediatrics; October 1998; San Francisco, CA; and the 71st Scientific Sessions of the American Heart Association; November 1998; Dallas, TX.
Reprint requests to (G.W.) Cardiac Intensive Care Unit, Division of Cardiology, Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, PA. E-mail: wernovsky{at}email.chop.edu
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ABBREVIATIONS |
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HLHS, hypoplastic left heart syndrome; CHD, congenital heart defect; CPB, cardiopulmonary bypass; DHCA, deep hypothermic circulatory arrest; SES, socioeconomic status; TS, total support; WISC-III, Wechsler Intelligence Scale for Children, Third Edition; WJPB, Woodcock-Johnson Psychoeducational Battery; CELF-R, Clinical Evaluation of Language Fundamentals-Revised; VMI, developmental test of visual motor integration; ADHD, attention deficit/hyperactivity disorder; BCPA, bidirectional cavopulmonary anastomosis.
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REFERENCES |
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301. AbstractThis article has been cited by other articles:
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  J. Conway, K. K. Wong, C. O'Connell, and A. E. Warren Cardiovascular Risk Screening Before Starting Stimulant Medications and Prescribing Practices of Canadian Physicians: Impact of the Health Canada Advisory Pediatrics, October 1, 2008; 122(4): e828 - e834. [Abstract] [Full Text] [PDF]
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