Transplant physicians have been attempting to describe the functional outcomes of children who have received liver transplantation for more than 10 years. However, validated instruments that measure functional outcomes and health-related quality of life (HRQOL) in pediatric patients have become available only within the last 3 to 5 years (1–3). These newly available instruments include domains that are of vital importance to pediatric populations, including cognitive and academic performance, self-esteem, social role function, and family function. Analysis of these domains will help physicians gain new insights regarding how children adapt to life with a liver transplant and how their families view and cope with their children's chronic medical condition.
Outcomes following liver transplantation can be highly variable. The prognosis for survival appears to be best for children with chronic liver disease who receive transplants before they experience advanced complications and worst for children with acute or chronic liver failure who receive their transplant while in an intensive care setting (4,5). However, post-transplant events, such as surgical complications and graft rejection, also play a major role (6).
The factors that contribute to a good longstanding quality of life are less clear. Several investigators have attempted to measure functional outcomes in this population (7–12). However, most studies have surveyed only small groups and have used tools that do not address some of the pertinent domains. These studies, although limited, have suggested that a subset of children who receive liver transplantation do not have normal functional outcomes (8,10). Previous work at our institution has examined quality of life and the relationship between functional outcomes and chronic medical disability in long-term survivors (13). Our findings suggested that quality of life was significantly lower than that of healthy controls but that functional outcomes could not be predicted by the level of chronic medical disability. The functional scale chosen for that work, The Health Utilities Index Mark II, was the best available tool at the time and remains to be the only tool that allows calculation of a global health utility score (14). However, we were concerned that the assessment of function provided by this tool was not sensitive enough to detect differences among members of this population and that the impact of the chronic transplant condition may be on domains that are not included in the tool, such as self-esteem, social function, and family dynamics.
The Child Health Questionnaire is a comprehensive validated instrument that measures physical and mental health, role function, self-esteem, and family dynamics (2). It is available in both parent and child report versions and has been tested in both normative populations and groups of children with various chronic diseases. The following is a pilot study of the health-related quality of life (HRQOL) and functional outcomes of pediatric liver transplant recipients using a parental report form of the CHQ.
This study used a cross-sectional survey of children who were long-term survivors of liver transplantation. The survey was administered by mail and included The Child Health Questionnaire-Parental Form 50 (CHQ-PF50) and a standard demographic tool. The CHQ-PF50 is a 50-question instrument, validated with reference to normal children ages 5 to 18 years that measures physical and mental health, role function, and family dynamics. The form is completed by either parent and includes 12 subscales that are scored from 0 to 100, with the higher scores reflecting better outcomes. Summary scores for physical and psychosocial function have been derived from the 12 subscales by factor analysis (2). Medical information and additional patient demographics were collected by chart review. The Institutional Review Board reviewed and approved the study design, measures, and procedures.
Potential study candidates were identified from the Liver Transplant Follow-up Clinic at Children's Memorial Hospital. This program includes all surviving children who received liver transplants at that institution from 1997 to the present and a subset of children who received liver transplants at the University of Chicago between 1984 and 1997 who later transferred their follow-up care to Children's Memorial Hospital. Inclusion criteria included: 1) 5 to 18 years of age, 2) received follow-up care during the calendar year of 1999, 3) survived at least 2 years after their last liver transplant, and 4) English-speaking parents. Six patients with parents who did not speak English were excluded because validated versions of the CHQPF-50 were not available in foreign languages during the study period. Children who were actively awaiting retransplantation at UNOS status 2B or greater were also excluded. These patients were not eligible because it was judged that their functional outcome would be strongly affected by medical disability related to graft failure, so the findings in these patients could not be generalized to the target population.
The primary outcome variables were children's performance on the CHQ-PF50. Sample mean subscale and summary scores were compared with national normative data and data from other chronic disease populations by single sample Student t tests (2). To reduce the risk of type 1 error secondary to multiple analyses, a Bonferroni adjusted P value of 0.01 was considered significant. Secondary analysis included assessment of the relationship between CHQ-PF50 scores and demographic variables, original diagnosis, age at transplant, interval from transplant, type of transplant (living donor vs. cadaveric), and measurements of disease-specific medical disability. For this analysis, associations among categorical outcome variables were assessed using χ2 tests for independence; relationships among categorical and continuous variables were assessed through independent t tests; and Pearson correlation coefficients were used to assess the relationships between two continuous variables. In addition, a multiple regression analysis was performed that included type of liver transplant (living donor vs. cadaveric), days hospitalized in the previous 6 months, and z score for height, with CHQ-PF50 subscale and summary scores as dependent variables. All analyses were conducted in SPSS version 10.0.
Survey packets were mailed to the caregivers of the 86 eligible patients. Completed surveys were received from the families of 55 of the 86 children, for a response rate of 64%. The 31 families who did not respond were compared with the 55 respondent families for patient gender, age, race, parental marital status, and insurance status by χ2 analysis. Respondent families were more likely to be Caucasian (P < 0.0001) and to have received private insurance health care benefits within the previous 6 months (P < 0.003). There was no difference in age, gender, or parental marital status between respondents and nonrespondents.
Table 1 describes the demographic characteristics of the patient and parent populations. The respondent population was predominantly Caucasian, and most respondents had some formal education beyond high school. Eighty-five percent of the respondents were currently married, and 85% had private health care benefits.
The median age of the study population at the time of LT was 2.9 ± 2.8 years (range, 2 months–9.5 years). The original indications for liver transplant included: biliary atresia (51%), biliary cirrhosis not caused by biliary atresia (20%), acute liver failure (9%), metabolic liver disease (9%), and other diagnoses (11%). Nine children had received more than one transplant. The last graft received was cadaveric for 36 of the recipients and living donor for 19. The median age at the time of survey was 9.5 ± 3.1 years (range, 5–17 years), resulting in a median interval from the last transplant of 6.0 ± 2.6 years (range, 2.2–11.9 years). Forty-seven of the respondents had undergone clinical follow-up within the 6 months preceding the study. Table 2 summarizes the clinical data obtained closest to the time of survey for these patients. Disease-specific medical disability was calculated for the 47 patients with recent medical follow-up using the Liver Transplant Disability Scale (LTDS) (13). The mean LTDS score for the group was 1.5 ± 1.6, which falls within the mild disability range, and 6 of the 47 (13%) had scores in the moderate disability range (LTDS score 4–6). None of the patients had severe disease-specific disability.
Child Health Questionnaire
Physical Health Scales
As seen in Table 3, the general health scale was the only subscale in the physical domain that differed significantly from the general population [t (53) = 7.75; P < 0.0005]. This scale is comprised of four items. In the first, parents rate their child's health as being excellent, very good, good, fair, or poor. Then they answer true or false to three statements: “My child seems to be less healthy than other children I know,” “My child has never been seriously ill,” and “I worry about my child's health more than other people worry about their child's health.” Parents of patients who had undergone transplant responded with general health perceptions that were lower than the population norm. There were no statistical differences in the physical health scales between the original diagnosis (biliary atresia vs. other), type of graft received last, and number of previous transplants (none vs. >1).
Psychological Health Scales
With regard to the measures of children's psychological functioning and impact of children's health on parents, Table 3 shows that only the emotional impact of the child's health on the parents of patients who had undergone liver transplant was lower than that of the population norm [t (52) = 4.50; P < 0.0005]. The emotional impact scale is comprised of two items that ask parents to rate the degree of emotional suffering they have experienced recently regarding their child's physical health and emotional well-being. There were no significant differences with regard to the original diagnosis (biliary atresia vs. other), type of graft received last, or number of previous transplants (none vs. >1) for any of the psychological scales.
Family Functioning Scales
On the family activities scale, parents of patients who had undergone liver transplant scored lower than did the population norm. The mean scores were 71.6 and 89.7 for these two groups, respectively [t (54) = 7.65; P < 0.0005]. This scale is comprised of two items that ask parents to rate how frequently their child's health limits the activities that they can do as a family and how often daily family activities, such as eating meals and watching television, are interrupted.
In terms of family cohesion, study parents faired slightly better than the population norm. The mean scores for both groups were 78.1 and 72.3, respectively [t (53) = 2.48; P = 0.017]. The family cohesion scale contains a single item that asks parents to rate their family members' ability to get along with one another. There were no statistical differences in the family functioning scales by the original diagnosis (biliary atresia vs. other), type of graft received last, or number of previous transplants (none vs. >1).
The sample mean physical summary score of 48.1 was significantly lower than the population mean of 53.0 (P < 0.05). There was no statistical difference between the sample and population means in the psychosocial summary scores. Original diagnosis (biliary atresia vs. other), type of graft received last, and number of previous transplants (none vs. >1) were not significantly related to either of the two summary scores.
Comparison with Other Chronic Diseases
The mean physical and psychosocial summary scores of the sample were compared with mean scores for attention deficit hyperactivity disorder (ADHD), asthma, juvenile rheumatoid arthritis (JRA), and epilepsy published in the CHQ manual (2) (see Table 4). The physical function of the liver transplant group was significantly better than that of children with JRA, a chronic condition with a relatively high level of physical disability, but less than that of children with ADHD. In contrast, the psychosocial summary scores of ADHD children were significantly lower than that of the liver transplant group.
Correlation with Secondary Variables
Correlation analyses examined the relationships among illness variables, patient demographics, and CHQ subscale/summary scores. Pearson correlations for CHQ subscale and summary scores were not significantly related to patient age at transplant, interval from transplant, z score for height, z score for weight, bilirubin, prothrombin time, gamma glutamyl transpeptidase, albumin, presence of portal hypertension, or history of complicated infections.
Multiple regression was performed on the CHQ on all subscales of the CHQ, including physical and psychosocial summary scores using the following predictor variables: age at transplant, type of last graft, z score for height, and hospital days during the 6 months before the survey. None of these variables had a significant impact on CHQ scores (see Table 5).
In general, the current physical and psychological functioning of this sample of pediatric liver transplant survivors was good. In comparison to other groups of children with chronic disease, the LT group had better physical function and similar psychosocial function. Parental assessment of patient self-esteem was virtually equal to that of the normative sample. Role function as influenced by physical and emotional factors appeared normal, as did the patients' general behavior. There is no escaping the fact that these liver transplant recipients have been seriously ill. The reduction in the physical summary score in the sample group was almost exclusively attributable to the questions pertaining to previous and current health events. Although these children have more frequent health events, their functional status does not appear to be significantly compromised by these events.
Despite the high functional outcomes of these children, the status of their parents and other family members was not entirely normal. Parents of transplant recipients reported that they experienced significantly more emotional distress and that their family activities were significantly more disrupted than did parents in the general population. Both of these subscales were strongly significant, and neither are factored into the patient summary scores. This trend appeared to be independent of inpatient hospitalizations for the child. Interestingly, family cohesion in our group was higher than the normative population. Eighty-five percent of our study families listed themselves as currently married, compared with 80% for the normative group (2). The relationships among chronic emotional stress, disruption of family activities, and family dynamics warrants further investigation.
The CHQ-PF50 did appear to capture the relevant aspects of HRQOL in this sample of liver transplant recipients. Subscale scores varied across a wide range, and as expected for a population of children with chronic disease, the mean subscale scores measuring the physical domain tended to be lower than those of the normative group. This tool also detected differences in social functioning among individual patients and identified a group difference in family dynamics. The response rate was acceptable for a mail survey, but the racial and insurance status distribution of the respondents versus the nonrespondents suggests that the socioeconomic status of families may have contributed to selection bias. The racial distribution and education level of our sample were similar to the normative sample, making our comparisons valid. However, families with lower educational levels and less financial resources may be less likely to return a mailing survey, and alternative methods of administration, such as on-site survey or structured interview techniques, may improve the socioeconomic mix in future studies.
Several potential dependent variables were chosen for multivariate analysis. Original diagnosis was dichotomized as biliary atresia versus other to help determine if limiting future studies to a more homogenous group of patients would be likely to yield different findings. Although our analysis suggested that diagnosis did not affect summary scores, our sample size was not large enough to detect subtle differences. Age at transplant was selected because younger age at onset of liver disease and at liver transplant has previously been linked to lower cognitive outcomes (15–17). Standardized linear growth was selected because many children have delayed growth after transplant, and growth failure is a reasonable marker for significant chronic illness in this population (18,19). The type of graft received was included to help determine if elements inherent to living donor LT (i.e., elective timing of transplant or parental participation in the transplant process) had a positive impact on long-term functional outcomes. Inpatient hospitalization was uncommon in this population but was used to determine the impact of prolonged or repeated hospitalizations. Outpatient hospital encounters, number and type of medications, and frequency of blood draws were not assessed. None of these chosen indicators had a significant effect on CHQ scores. In general, the LT group had stable medical conditions and thus a larger cohort with more variability in these categories would be needed to exclude these factors conclusively.
In summary, this small pilot study confirms that pediatric liver transplant recipients have functional outcomes in the physical domain that are lower than those of normal children. Self-esteem and mental health in this group appeared normal. The most striking findings were the impact of illness on the parents and families of the transplant patients. Future studies should include a larger population to allow a better assessment of predictors of HRQOL and should address the stress and impact of transplantation on patients' parents and family members.
1. Varni J, Burwinkle T, Katz E, et al. The PedsQL in pediatric cancer. Cancer 2002; 94:2090–106.
2. Landgraf J, Abetz L, Ware J. The CHQ User's Manual.
1st ed. Boston: The Health Institute, New England Medical Center; 1996.
3. Eiser C. Children's quality of life measures. Arch Dis Child 1997; 77:350–4.
4. Kelly D. Nutritional factors affecting growth before and after liver transplantation. Pediatr Transplant 1997; 1:80–4.
5. Ryckman F, Alonso M, Bucuvalas J, et al. Liver transplantation in children. In: Suchy F, Sokol R, Balistreri, eds. Liver Disease in Children. Philadelphia: Lippincott Williams & Wilkins; 2001: 949–73.
6. Group SR. Studies of pediatric liver transplantation
(SPLIT): year 2000 outcomes. Transplantation 2001; 72:463–76.
7. Zitelli B, Miller J, Gartner C, et al. Changes in life-style after liver transplantation. Pediatrics 1988; 82:173–80.
8. Chin SE, Shepherd RW, Cleghorn GJ, et al. Survival, growth and quality of life in children after orthotopic liver transplantation: a 5 year experience. J Paediatr Child Health 1991; 27( 6): 380–5.
9. Sokal EM. Quality of life after orthotopic liver transplantation in children. An overview of physical, psychological and social outcome. Eur J Pediatr 1995; 154:171–5.
10. Apajasalo M, Rautonen J, Sintonen H, et al. Health-related quality of life
after organ transplantation in childhood. Pediatr Transplant 1997; 1:130–7.
11. Asonuma K, Inomata Y, Uemoto S, et al. Growth and quality of life after living-related liver transplantation in children. Pediatr Transplant 1998; 2:64–9.
12. Burdelski M, Nolkemper D, Ganschow R, et al. Liver transplantation in children: long-term outcome and quality of life. Eur J Pediatr 1999; 158:S34–42.
13. Midgley D, Bradlee T, Donohoe C, et al. Health-related quality of life
in long-term survivors of pediatric liver transplantation
. Liver Transpl 2000; 6:333–9.
14. Torrance GW, Feeny DH, Furlong WJ, et al. Multiattribute utility function for a comprehensive health status classification system. Health Utilities Index Mark 2. Med Care 1996; 34( 7): 702–22.
15. Stewart S, Uauy R, Kennard B, et al. Mental development and growth in children with chronic liver disease of early and late onset. Pediatrics 1988; 82:167–72.
16. Stewart SM, Uauy R, Waller DA, et al. Mental and motor development, social competence, and growth one year after successful pediatric liver transplantation
. J Pediatr 1989; 114(4 Pt 1):574–81.
17. Stewart S, Campbell R, McCallon D, et al. Cognitive patterns in school-age children with end-stage liver disease. Developmental and Behavioral Pediatrics 1992; 13:331–8.
18. Codoner-Franch P, Bernard O, Alvarez F. Long-term follow-up of growth in height after successful liver transplantation. J Pediatr 1994; 124( 3): 368–73.
19. McDiarmid S, Ja G, DeSilva P, et al. Factors affecting growth after pediatric liver transplantation
. Transplantation 1999; 67:404–11.