Biliary atresia: neurodevelopment and quality of life
Rodijk, Lyan
DOI:
10.33612/diss.133865199
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Rodijk, L. (2020). Biliary atresia: neurodevelopment and quality of life. University of Groningen.
https://doi.org/10.33612/diss.133865199
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
General discussion
Thesis aims and main findings
Biliary atresia (BA) is a dreadful liver disease and the most common cause of end-stage liver disease and liver transplantation (LTx) in children worldwide.1–3 Improvements in the care for these patients has led to increased survival rates.4 However, the majority of patients do need a LTx at pediatric age and, with or without transplantation, require lifelong surveillance. BA is a chronic disease and, therefore, warrants knowledge of long-term morbidity. To further improve the prognosis, it is essential to recognize the impact of chronic disease on a patient’s physical and mental wellbeing. The main goal of this thesis was to assess the impact of BA on the neurodevelopment of children and the quality of life (QoL) of children and their families.
Our results demonstrate that BA significantly affects the lives of patients; yet less those of their parents. Children with BA are at risk of impaired neurodevelopmental outcomes, especially motor skills and one in four children require special education. Their health-related quality of life (HrQoL) is lower than that of their healthy peers and their physical HrQoL is generally lower than that of children with a chronic condition. However, parental QoL seems relatively unaffected, although specifically mothers persistently report high levels of anxiety, especially in the first years after BA diagnosis. While family activities are reduced, families report strong family cohesion. In the following sections the impact of BA on neurodevelopment and thereafter on QoL will be discussed in the light of existing literature, and areas for future research will be indicated.
Neurodevelopment
In a systematic review we demonstrated that children with a liver disease are at increased risk of neurodevelopmental impairments (Chapter 2). However, data on motor skills and school performance in children with a liver disease had been limited so far. Our evaluation of neurodevelopmental outcomes in Dutch children with BA, clearly showed that especially motor skills were affected (Chapter 4, 5). The neurodevelopmental outcomes in Dutch children with BA, at different childhood ages, are shown in the timeline in Figure 1. At school age, one in four children required special education. Below, these findings will be discussed more in detail.
Figure 1. Timeline of neurodevelopmental outcomes in children with biliary atresia. Outcomes
are defined as impaired in case of an overall score below the 10th percentile (early motor repertoire) or an age- and gender-adjusted score of 1 standard deviation or more below the population mean (motor skills and cognition).
Motor development in infancy
Most strikingly, almost half of BA patients show already impaired motor development at infant age (Chapter 3, 4). Prior to surgical treatment a Kasai portoenterostomy (KPE), 46% of the infants already showed an impaired early motor repertoire, suggesting neurological impairment (Figure 1).
Early infancy is a time of critical brain development with high brain plasticity, which means that the brain is influenced by, and can adapt to, external, environmental factors.5 The motor behavior of infants influences muscle and bone growth and development of the neuromotor system.6 Active use of the motor cortex in this specific age period is required to prevent the loss of cortical connections and movement
function.7,8 Infants with BA are frequently hospitalized and often in a poor nutritional status at diagnosis, due to nutrient malabsorption during cholestasis. Half of the infants with BA suffered from severe growth deficits, both before and four weeks after KPE (Chapter 3, 4). Growth deficits might be associated with neurodevelopmental impairments (Chapter 2)9, although we were not able to identify a significant relationship between growth percentiles and the early motor repertoire (Chapter
3, 4). Many infants receive medication via intravenous infusion, which might hinder
body movement. Prone position is important for motor development in infants, for example to increase upper body strength.10 However, infants with BA are less in prone position due to abdominal distension either by hepatomegaly and/or ascites. All of these factors might hamper adequate environmental stimulation and subsequently, reduce motor development.
Motor skills in toddlers and school-aged children
When children grew older, motor impairments persisted in an alarming proportion of children (Figure 1). In toddlers with BA, motor development was significantly delayed compared to healthy peers (Chapter 4). At school age, motor skills were severely impaired, with only 25% of children scoring within the normal range (Chapter 5). A proportion of children (7%) was not able to complete the motor tests due to the severity of their psychomotor delay. In the other children, all domains were affected, that is fine skills, ball skills and balance.
In addition to the previously described risk factors for impaired motor development in infants with BA, the majority of children require a LTx during childhood. Major abdominal surgery might hinder adequate motor development through the confinement to bed.7,8 Previous studies showed that children who had undergone a LTx 8 years ago have less muscle strength (Z-score ranged between -1.4 and -0.4) and reported more fatigue (Z-score ranged between -2.33 and -0.4) than their healthy peers.11,12 Impaired muscle strength and fatigue could also contribute to the encountered impaired motor skills of BA patients in this thesis. Whether this is a cause or consequence of impaired motor skills has not been investigated, hence requires further research.
Greater motor proficiency has been associated with more physical activity and better physical fitness in children.13,14 The impaired motor skills in children with BA might have enduring consequences, since adolescents with a chronic condition,
including BA patients, participate less in sports compared to their healthy peers.15,16 Bos et al. published data on the physical activity of children who had received a LTx (n=26, including n=14 BA patients) from our center.12 They showed that only 7% of young LTx recipients met national recommendations for physical activity, although it should be mentioned that less than half of their healthy peers met these recommendations.12 It might be difficult to promote healthy children to perform sufficient physical activity, but this might even be more difficult in children with a chronic illness. Parents and caregivers of children with a chronic condition may be overprotective and withdraw the children from participating in sports, as they underestimate the child’s physical abilities or feel that physical activity might be risky.17 However, knowledge of the relationship between social stimulation and physical activity in LTx recipients is lacking. Sports participation is of importance, as physical activity is believed to have a positive effect on a child’s physical status, such as physical fitness and walking capacity, as well as on neurodevelopmental outcomes and, subsequently, HrQoL.18–23
Cognitive outcomes in toddlers and school-aged children
Toddlers with BA had significantly lower scores on cognitive development compared to the general population, although scores were within the normal range (Chapter
4). At school age, children showed impaired performance IQ, attention abilities,
visuomotor integration, perceptual abilities and planning (Chapter 5).
These findings are in line with previous studies showing that children with a liver disease are at risk of cognitive impairments (Chapter 2).24–37 Children with a liver disease who still had their native liver scored significantly lower on cognitive subtests compared to healthy peers26–29, whereas children who had undergone a LTx scored within the low-average range.24,25,30–32,34–38 Throughout all studies with BA patients, at the indicated toddler and school age, we found no statistically significant differences in cognitive outcomes between those who still had their native liver and those who had undergone a LTx (Chapter 4, 5). We did find that children with a native liver did score somewhat higher on cognitive tests than children with a LTx, but the differences were not statistically significant (Chapter 4, 5). The Childhood Liver Disease Research Network (ChiLDReN) reported impaired cognitive outcomes in infants and young children with BA who survived with their native liver.39 In a follow-up study of BA patients at preschool and school age, cognitive outcomes were no longer impaired, with even higher IQ scores than test norms.40 However, patients with end-stage liver disease and other BA-related complications, such as severe growth failure, had either
received a LTx and were therefore excluded from that study, or had died. Native liver survivors might have better cognitive outcomes compared to LTx recipients because those patients represent the clinically best patients with BA.
Children with a chronic condition more often require special education and are less likely to obtain an academic degree, compared to their healthy peers.15 In our cohort of school-aged children with BA, one in four received special education (Chapter 5). It is essential to early recognize the need for special education to ensure that action is undertaken to meet a child’s needs. In the Netherlands, special education is provided for those children who cannot participate in the regular educational system. Eighty percent of the children who receive special education are children with physical disabilities or a chronic condition that hinders regular education, and children with psychiatric or serious behavioral problems, such as autism.41 Timely referral to special education will avoid uncertainty and stress for both children and their parents, and will support a child to develop to its full potential.
Behavioral outcomes in toddlers and school-aged children
A significant proportion of school-aged children with BA showed behavioral problems (Chapter 5). Substantial internalizing (e.g. anxiety, depression, social withdrawal) and externalizing (e.g. conflict with others and violation of social norms) behavioral problems, as well as hyperactivity and attentional problems, were reported by their parents (Chapter 5). The prevalence of behavioral problems, again as reported by parents, was lower in toddlers than in school-aged children with BA (Chapter 4,
5). This is to be expected as behavioral problems generally become more evident
when children age.42 Children at school-aged are more likely to have experienced adverse medical events and hospitalizations. Moreover, older children might be more conscious of the consequences of living with a chronic disease like BA.
It is well recognized that children with a chronic condition are at increased risk of behavioral and emotional problems.19 Previous studies showed that those children have three times higher odds of behavioral problems and five times higher odds of emotional and psychological problems.43,44 Behavioral problems and social incompetence in children are strongly related to parenting stress and parenting behavior.45 The parents of young children with BA report high levels of anxiety and stress (Chapter 7).46 This might influence their child’s behavior and vice versa.45
Behavioral problems, such as attention deficit hyperactivity disorder (ADHD), are often accompanied by neurodevelopmental impairments and psychological distress.19,47 In school-aged children with BA, poor attention abilities were significantly associated with IQ scores.
Risk factors for impaired neurodevelopment
The neurodevelopmental impair-ments in patients with BA have several possible causes (Figure 2). In liver failure, concentrations of cytokines and liver toxins, such as bilirubin, ammonia and lactate, in the brain can be increased and cause neuroinflammation.48 Previous studies described a relation between markers of liver disease and neurodevelopmental outcomes.40,49,50 In children with cholestatic liver disease, prolonged cholestasis before LTx is associated with more pronounced alterations in neurochemistry.49 These findings suggest that prolonged exposure to cholestasis might be the culprit for neurodevelopmental deficits in a cholestatic liver disease such as BA. In our cohorts of BA patients, all infants had elevated levels of bilirubin before KPE. However, we did not find a significant association between serum bilirubin levels and the
quality of the early motor repertoire or later neurodevelopmental outcomes (Chapter 3, 5). This may be because we assessed only one single bilirubin measure per time-point and not the overall exposure to hyperbilirubinemia. It would be interesting to assess the relationship between the longitudinal bilirubin trajectory and neurodevelopmental outcomes. Alternatively, it may not be the accumulation of hyperbilirubinemia that is the culprit but rather the accumulation of other compounds during cholestasis, which not necessarily have to concur with conjugated bilirubin levels.
Figure 2. Potential risk factors for neuro-
developmental impairments in patients with biliary atresia.
In patients with BA, increased permeability of the blood-brain barrier might result in higher exposure of the brain to liver disease-related compounds in toxic concentrations. Recent studies point towards a relationship between alterations in the gut microbiome and neurodevelopmental outcomes, via the gut-liver-brain
axis.51,52 BA is associated with changes in the gut microbiome, even before KPE.53,54 Alterations in the gut microbiota might disturb the epithelial barrier of the bowel (‘leaky gut’), allowing leakage of unwanted molecules into the circulation. This might subsequently be responsible for vascular barrier breakdown of the blood-brain barrier.55 Increased intestinal permeability has already been associated with some neurological disorders like; autism spectrum disorder, schizophrenia, Parkinson’s and Alzheimer’s disease in elderly patients.52,55 However, understanding of the interactions between the gut microbiome and neurodevelopmental disorders is still a developing science.56
Poor nutritional status and impaired growth are other risk factors for
neurodevelopmental impairments.57 An adequate nutritional status might not only improve the medical outcomes of BA patients9,58, but also their neurodevelopment (Chapter 2). Severe growth deficits were evident in an alarming proportion (~50%) of young BA patients around the time of diagnosis and shortly thereafter (Chapter 3,
4). These findings were in line with those of other research groups.28,39 BA patients are prone to develop nutritional deficits due to malabsorption and abnormal metabolism of nutrients.59 Children with end-stage liver disease are in a hypermetabolic state, with higher resting and total energy expenditure.59 Growth deficits affect BA patients especially in early infancy, which is a period of rapid brain development (Chapter
3, 4), and were less evident in older children (Chapter 4, 5). Although it seems
reasonable that the growth deficits in BA are related to the neurodevelopmental impairments, we were not able to identify any significant associations growth percentiles and neurodevelopmental outcomes.
Not only children with a liver disease but also patients who undergo major surgery
in infancy for other diagnoses appear to be at risk of neurodevelopmental
impairments.60,61 Previous studies showed impaired cognitive development and motor skills in children with a congenital diaphragmatic hernia, esophageal atresia, and anterior abdominal wall defects.60,61 Neonatal surgery was associated with alterations in brain structure and white matter signaling.61 However, the exact pathophysiology of these brain alterations remains speculative. A higher number of surgical interventions
and longer duration of mechanical ventilation was associated with adverse neurodevelopmental outcomes.60 General anesthesia has been suggested as a risk factor for neurodevelopmental impairments62, but in relatively minor surgery, general anesthesia had no significant effect on later neurodevelopmental outcomes.63,64 In our systematic review of studies with children with a liver disease, general anesthesia was not identified as a risk factor for neurodevelopmental impairments (Chapter 2). After LTx, patients require lifelong treatment with immunosuppressants, among which calcineurin inhibitors such as tacrolimus. Tacrolimus is associated with impaired neurocognitive functioning and white matter hyperintensities.65 Even medications that appear innocent, such as acetaminophen, might be neurotoxic to the early developing brain.66 In this thesis, we did not investigate the relationship between medication usage and adverse neurodevelopmental outcomes. However, as there seemed to be no differences in outcomes between children with and without native liver, one might speculate that the role of immunosuppressants can be refuted. Our finding of the impaired early motor repertoire in infants with BA even before they underwent major surgery, demonstrates that the cause of the neurodevelopmental impairments cannot be attributed to this early anesthesia or surgery (Chapter 3). In the light of cholestasis as the main culprit of neurodevelopmental impairments, major surgery such as KPE and LTx might even improve neurodevelopmental outcomes, by relieving cholestasis. Correspondingly, there are indications that neurocognitive outcomes improve after LTx.50 Studies on motor skills after LTx are more controversial, and range from no improvement over time, to a gradual normalization over the first four years after LTx.67,68 In our cohort, neurodevelopmental impairments persisted after surgery in the form of a KPE and LTx (Chapter 4). Neither age at KPE nor age at LTx was associated with neurodevelopmental outcomes (Chapter 4, 5).
Intracranial hemorrhage is another possible cause of neurodevelopmental
impairments. A possible complication of BA is a vitamin K deficiency, hence an increased risk of intracranial hemorrhage.69 However, none of the BA infants in our cohort had suffered an intracranial hemorrhage (Chapter 3, 4).69,70 Despite an absence of intracranial hemorrhage in infants with BA, neurodevelopmental impairments were present in an alarming proportion of patients. This suggests that intracranial hemorrhage cannot be accountable for the worse neurodevelopmental outcome in these children.
Psychosocial and environmental factors can also affect the developing brain.
Disease-related restrictions in physical activity, for example due to pain, illness, surgery or hospitalization, can hinder the development of the central nervous system.7,8 Additionally, as previously mentioned, concerned or overprotective parents or other caregivers might deter physical activity, and subsequently motor development.17 It seems reasonable to assume that BA causes early life stress or disruptions in family functioning, which has been associated with negative emotional outcomes in infancy.71,72 Therefore, it is likely that psychosocial and environmental factors are contributing to the neurodevelopmental impairments in children with BA. In summary, data on neurodevelopmental impairments in BA patients indicate a relatively high frequency of neurodevelopmental impairments. Especially motor skills are affected in a disturbing proportion of children. The neurodevelopmental impairments are likely to be multifactorial and caused by physiological, disease-related factors, as well as secondary psychosocial factors (Figure 2) (Chapter 2-5).19 Most indications point towards a role of cholestasis and (consequences of) chronic liver failure, in combination with poor nutritional status and growth deficits. Although the inclusion ratio in our cohorts was high, the sample sizes were nevertheless relatively small due to the low incidence of BA. Unfortunately this has limited thorough analysis of risk factors. International collaboration is essential to identify risk factors for neurodevelopmental impairments, to further improve care for rare diseases as BA.
Quality of life and family functioning
Health-related quality of life in children
Children with BA appeared to be at risk of an impaired HrQoL, especially physical HrQoL (Chapter 6). In almost half of the children, the parent-proxy physical HrQoL summary score was more than 1 standard deviation lower than the population mean (Chapter 6). Approximately 25% of the children scored their physical functioning as impaired. As a result, one in six children, and the parents of one in five children, reported that the child experienced limitations in their daily activities or activities with friends. The overall physical HrQoL of school-aged BA patients was not only lower compared to healthy peers, but also remarkably lower compared to other children who had undergone major surgery in infancy or to children with a chronic disease (Chapter 6). Possibly, BA affects a patient’s daily life to a greater extent than those other diseases. Children with BA might require more daily treatments, such as medication, suffer from more adverse medical events, and experience more limitations in daily life due to illness, bodily pain, itching or abdominal distention. Not only the physical but also the psychosocial HrQoL of school-aged children with BA was lower compared to their healthy peers (Chapter 6). In one in three children, the parent-proxy psychosocial HrQoL summary score was more than 1 standard deviation lower than the population mean. Parents reported more problems in the mental health of their child, such as symptoms of anxiety or depression than parents of healthy children. This may be because children with BA feel insecure and worry about their future. For example, children who still have their native liver might worry about the future necessity of a LTx, whereas LTx recipients might fear graft rejection. As a result of emotional problems, 20% of children with BA experienced limitations in their daily activities and activities with friends. These findings are in line with data on the HrQoL of children who received kidney transplantation, who showed a significantly higher frequency of mental problems, compared to their healthy peers.73 Adult BA patients reported comparable HrQoL to their healthy peers.74–77 This suggests that the negative impact of BA reduces as patients age. This phenomenon might be explained by the ‘response shift’ theory, meaning that the perception of a patient’s HrQoL is influenced by personal experiences.78 In a small cohort of adult BA survivors, patients retrospectively reported a similar achievement of developmental milestones, regarding autonomy and psycho-sexual development, to their healthy peers.16 This suggests that the disease-related restrictions in the overall course of
life, as experienced by adult BA patients, are limited. Notwithstanding these findings, longitudinal studies on HrQoL in BA patients that follow patients into adulthood are scarce. Therefore, the longitudinal HrQoL trajectory within an individual, and the role of disease-related and environmental risk factors, remain speculative.
Factors associated with health-related quality of life in children
Both BA patients who survive with their native liver, as well as children who receive a LTx are at risk of impaired HrQoL (Chapter 6). Several studies, including our own, reported no significant differences between these groups.46,76,77,79,80 Native liver survivors and transplanted children share commonly identified risk factors for an impaired HrQoL. As presented in Figure 3, in literature, several risk factors have been associated with HrQoL in BA patients.
Figure 3. Factors that are associated with health-related quality of life (HrQoL) in patients with
biliary atresia. Factors that are positively related to HrQoL are presented in green and factors that are negatively related to HrQoL are presented in red. *factors identified in personal data.
First, HrQoL might be affected by factors that are directly related to disease severity
of an adverse medical event in the past year, are associated with lower physical and psychosocial HrQoL.76,79 A higher bilirubin level, as a proxy for the degree of cholestasis, is associated with lower parent-proxy overall HrQoL.79 Symptoms such as abdominal distention and sleeping difficulties, that can occur in BA, are also associated with lower overall HrQoL.46,81 Adverse medical events might lead to illness, pain and hospitalization. This subsequently might limit daily activities, result in school absenteeism or hinder work abilities, which reduces the social life of patients. Adverse medical events may also lead to greater awareness of the disease, which might result in a lower perceived HrQoL.
Second, in children with BA who had received a LTx, the transplant-specific HrQoL is adversely related to a higher number of prescribed drugs.82,83 Drugs can coincide with side effects, such as abdominal pain, headache or sleeping problems, which have the potential to negatively influence HrQoL. Daily usage of drugs may also lead to greater awareness of the disease, resulting in a lower perceived HrQoL. A higher consultation frequency is positively related to transplant-specific HrQoL.82 Children who regularly visit specialists might feel more secure about their disease. In our cohort, we did not investigate the relation between the number of prescribed drugs or consultation frequency and HrQoL, as all LTx children generally received the same medical treatment and follow-up.
Third, HrQoL might also be influenced by socio-demographic factors. Overall HrQoL in children is better when the parents are married or living together.82 It is well-recognized that parental separation is associated with lower HrQoL in children.84 In our cohort of school-aged BA patients, the majority of parents (84%) was married or living together with a partner, making this a less contributing factor (Chapter 6). Sundaram et al. reported that Afro-American ethnicity was associated with lower overall HrQoL in children.79 In our cohort, we determined the relation with household education and income, rather than ethnicity. There was no significant association with household income and HrQoL in children with BA. Parent-proxy physical HrQoL in children with BA was positively associated with the educational level of parents (Chapter 6).
Age at HrQoL assessment was not significantly associated with HrQoL in our cohort
(Chapter 6). However, in literature, children with BA who were younger at the time of HrQoL assessment were more at risk of impaired overall and transplant-specific
HrQoL than older children.79,82 This might be because older children more often have reached a stable form of BA, or have adapted to the consequences of living with BA. Remarkably, post-LTx complications were positively associated with better transplant-specific HrQoL.82 It may also be a result of the previously described ‘response shift’, with patients more appreciating their current health, due to the complications that they have suffered after the LTx. However, older children seemed to be more at risk of impaired psychosocial HrQoL, as reported by their parents.79 This suggests that parents of older children believe that they are more aware of the disease-related impairments in daily life, or are more anxious about the future. Older children were also more at risk of impaired school functioning, which might subsequently impair their HrQoL.79
School functioning is one of the most severely impaired HrQoL domains in BA
patients.46,79,82,83 Children with a chronic disease like BA have the potential of school absenteeism due to their physical status or hospitalization.46 Additionally, children with BA are at an increased risk of neurodevelopmental impairments, and emotional or behavioral problems, which might result in learning difficulties (Chapter 5, 7). In our cohort, motor impairments and special education were significantly associated with lower physical HrQoL (Chapter 6). This is to be expected as physical HrQoL reflects not only physical functioning and bodily pain but also the consequences on daily activities, such as going to school. Behavioral problems were significantly associated with psychosocial HrQoL (Chapter 6). Learning difficulties might have long-lasting consequences for the lives of BA patients. In the Netherlands, adolescents with a chronic condition less often have a paid job, although they would like to be employed.15 This underlines the importance of adequate neuropsychological intervention in patients with BA to improve both neuropsychological outcomes and HrQoL.
Sports participation was positively related to overall HrQoL. It is well-known that
physical activity can positively influence HrQoL.21–23 This warrants the stimulation of sports participation in children with BA to improve their HrQoL.
In summary, children with BA and their parents report an impaired HrQoL, especially physical HrQoL. Their HrQoL was comparable to, or even lower than, children with another chronic condition. This suggests that children with BA face ongoing challenges as a result of BA. Children with a more severe form of BA and/or with adverse medical events appear to be at increased risk. Also the secondary consequences of BA might impair HrQoL, such as an impaired social life and school functioning.
Impact of biliary atresia on parental wellbeing and family functioning
After BA diagnosis, mothers of BA patients persistently report high levels of anxiety (Chapter 7). Symptoms of anxiety and stress in mothers were highest during hospitalization for KPE, with scores being respectively 36% and 24% higher than reference values from the general population. Prolonged KPE hospitalization was strongly related to more symptoms of anxiety and stress in mothers, as well as fathers. Anxiety symptoms declined over time, from being 36% higher than reference values during KPE hospitalization, to 23% higher at 1-2 months after KPE, and to 4% higher at 2-3 years of follow-up. Fathers reported fewer symptoms of anxiety and stress. Given that women might be more susceptible to developing anxiety symptoms than men, this is to be expected.85 In general, women have a higher tendency to worry and score higher on negative affectivity.85
It is well recognized that parents of children with a chronic condition are at risk of poor mental health.86 They suffer more from symptoms as anxiety and depression compared to the general population.86–88 Chronic stress can have negative effects on the mental and physical health of parents.86 Mothers of children with congenital anomalies have a higher risk of cardiovascular disease and even mortality than parents of healthy children.89 Fortunately, in parents of children with BA that had reached school age, symptoms of anxiety and stress were within the normal range (Chapter 8). This suggests that the psychosocial symptoms of anxiety and stress further decrease over time. However, a follow-up study that extends beyond the first three years after BA diagnosis is required to confirm this hypothesis.
Parents of school-aged patients with BA reported emotional worry and limitations in their time due to their child’s disease. Poor mental health in parents is associated with impaired parental QoL (Chapter 7).86,90 However, in both cohorts of BA patients, parental QoL was relatively unaffected (Chapter 7, 8). The relatively unaffected parental QoL could be partially explained by the high percentage of parents (>90%) that continued working and remained married or living together with their partner, after their child was diagnosed with BA (Chapter 7, 8). When children had reached school age, the parents of 76% of children lived together, which seems comparable to the general Dutch population. A single-parent household was associated with somewhat lower parental QoL, although this association was not statistically significant (Chapter 8).
In families of school-aged children with BA, family activities were impaired due to the consequences of having a child with a chronic disease (Chapter 6). Reduced family activities might affect all family members, including the patient’s siblings. Siblings of children with a chronic disease are at risk of impaired psychological wellbeing.91 Data on the psychosocial wellbeing of siblings of children with BA is lacking, hence an interesting area for future research.
Nevertheless, both children and their parents reported strong family cohesion. For a long time, family functioning is recognized as an important aspect of child health.92 Children with a chronic disease such as BA depend on their parents for care and treatment. Proper family functioning might reduce behavioral problems and improve medical adherence.93 Family members can offer social support and help the child to cope with the disease. It is reassuring that the family functioning seems adequate, as this will support BA patients to thrive along with their healthy peers and grow up to independent adults.
Future perspectives
With this thesis we provide unique data on the impact of BA on neurodevelopmental outcomes and HrQoL in children, the wellbeing of their parents, and family functioning. We feel that our data warrant attention, especially regarding the impaired motor development and physical functioning in BA patients. In the light of personalized medicine, patient-reported outcome measures become increasingly important in optimizing patient management. As described in this thesis, both children and parents report impairments in physical functioning and, therefore, physical HrQoL. The next logical step is to assess at what stage and by what means we can optimize care for these vulnerable patients and their families.
Neuropsychological screening
In the era with increasingly more interest in personalized medicine, there is a high importance of early identification of subgroups at risk of morbidity to timely start a targeted intervention. In the Netherlands, to date, there is no standardized neuropsychological screening or follow-up program for BA patients. As the quality of the early motor repertoire has a high predictive value for the neurodevelopmental impairments in toddlers with BA, especially for motor skills (Chapter 3), we advocate for the implementation of General Movement Assessment (GMA) in the regular medical follow-up of these patients. As the period between hospital admission and
KPE is rather short and infants suffer from cholestasis, the first outpatient visit after KPE appears to be the earliest, most suitable, time point for General Movement Assessment. In this way, infants with BA who are prone to neurodevelopment impairments can be identified early. This will allow the initiation of targeted intervention at an early stage when it is believed to have the greatest benefits.5 We propose a standardized neuropsychological screening and follow-up program as shown in the flowchart in Figure 4. During a potential screening for LTx, and at follow-up assessment at 2-3 years of age, motor skills should be assessed by a physical therapist, and cognitive and speech-language development by a neuropsychologist and, if required, a speech-language therapist. Behavioral problems should be identified by use of the Child Behavior Checklist and during an interview with the parents.94
In the first years after BA diagnosis, special attention is warranted for the wellbeing of parents, especially for mothers. The state-trait anxiety inventory, as described in Chapter 7, could then be used to identify parents who experience high levels of anxiety after BA diagnosis.95 A standard consultation with a social worker after BA diagnosis might identify parents who would benefit from psychological support early.
Neuropsychological intervention
Early developmental intervention has proven to be beneficial in several pediatric patient groups, such as infants with cerebral palsy and preterm born infants.6,96 Short-
Figure 4. Flowchart of standardized
neuropsy-chological screening for children with BA. *e.g. physical therapy, psychology or speech lan-guage therapy.
and medium-term neurodevelopmental outcomes improved more in children that received standardized intervention programs, compared to children who received standard follow-up.96 As our results on the neurodevelopmental outcomes of BA patients are generally in line with those described for preterm born infants, similar intervention programs might also be beneficial for BA patients.96
Our data warrant the development of a targeted neuropsychological intervention program with the following aims; (1) to optimize motor, cognitive, behavioral and language development; (2) to optimize school performance; (3) to optimize the HrQoL in children; (4) to support parents or caregivers in coping strategies to reduce parental stress and anxiety, and to improve child-parent interaction.
Intervention programs should focus on infant development, e.g. in the form of physical therapy, speech-language therapy or psychology, and on the parent-infant relationship.96 Developmental interventions should use task-specific practice and stimulate child-initiated actions and independent task performance.97 Interventions based on physical activity are believed to have a positive effect on the child’s physical status, such as physical fitness and walking capacity, as well as on neurodevelopmental outcomes, including motor skills, academic achievements, social skills, attention, and executive functioning, and might subsequently improve HrQoL.18–23 Therefore, guidance by a physical therapist is warranted not only for those infants with impaired motor development but also for other children at risk of impaired physical HrQoL, such as children who are in a poor physical condition. Each child with BA should be stimulated to practice sports, as this would benefit both physical and social activity.
Based on the results from the multidisciplinary neuropsychological screening, professionals should decide, for each child, which targeted interventions are required, for example physical therapy, psychology and/or speech-language therapy. Additionally, the multidisciplinary team should guide and advise the parents in decisions regarding educational services, such as the need for special education. Psychosocial intervention for parents of newly diagnosed BA patients should be initiated after BA diagnosis. Parental support might improve parental health by reducing symptoms of anxiety and stress. Parental support might not only be beneficial for parental wellbeing, but may also improve neurodevelopment,
emotional outcomes, and HrQoL of their children.71,93 It might improve the parent-infant relationship and optimize the management of behavioral problems in children with BA.98
Where neuropsychological intervention is based on optimizing neuropsychological outcomes, the identification of risk factors might help to early identify infants who have an increased risk of neuropsychological problems and subsequently to reduce the potentially negative effects of BA on the lives of its patients. International collaboration is warranted to obtain a larger sample size to allow for a more thorough analysis of modifiable and non-modifiable risk factors for impaired neurodevelopmental outcomes or HrQoL. As prolonged cholestasis might be one of the main culprits of neurodevelopmental impairments, timely restorative surgery is essential. Studies to further improve screening for, and therefore the early identification of, BA are ongoing.99 As many infants with BA suffer from poor nutritional status and growth deficits, more aggressive nutritional support seems warranted. Future studies should outline methods to improve the nutritional status of infants with BA.
Conclusions
We can conclude that biliary atresia (BA) has a significant impact on the lives of children. We show that neurodevelopmental impairments are present already in early infancy and persist until, at least, school age. As a result, ~25% of children with BA require special education. Motor skills are most affected, with half of the children showing severe impairments. Neurodevelopmental impairments are, in turn, associated with a lower health-related quality of life (HrQoL). The HrQoL in children with BA is lower compared to healthy peers, and their physical HrQoL is generally lower than in children with other major surgery in infancy or a chronic condition. In the first years after BA diagnosis, parental wellbeing is affected, with particularly mothers reporting high levels of anxiety. Nevertheless, the overall quality of life of parents is rather unaffected. It is essential to identify problems in neurodevelopmental or psychosocial outcomes early, to start targeted intervention at the moment with the highest chance of therapeutic success. The results of this thesis warrant, and form the basis for, the development of standardized, targeting, neuropsychological intervention programs to improve the care for, and prognosis of, patients with BA and their families.
References
1. De Vries W, De Langen ZJ, Groen H, et al. Biliary atresia in the Netherlands: Outcome of patients diagnosed between 1987 and 2008. J Pediatr. 2012;160:638-644.
2. Hartley J, Davenport M, Kelly D. Biliary atresia. Lancet. 2009;374:1704-1713.
3. Spada M, Riva S, Maggiore G, et al. Pediatric liver transplantation. World Journal of
Gastroenterology. 2009;15:648–674.
4. Rowe MI, Rowe SA. The last fifty years of neonatal surgical management. Am J Surg.
2000;180:345–52.
5. Cioni G, Inguaggiato E, Sgandurra G. Early intervention in neurodevelopmental
disorders: Underlying neural mechanisms. Dev Med Child Neurol. 2016;58:61–66.
6. Novak I, Morgan C, Adde L, et al. Early, accurate diagnosis and early intervention in
cerebral palsy: Advances in diagnosis and treatment. JAMA Pediatr. 2017;171:897-907.
7. Eyre JA. Corticospinal tract development and its plasticity after perinatal injury.
Neurosci Biobehav Rev. 2007;31:1136-1149.
8. Martin JH, Chakrabarty S, Friel KM. Harnessing activity-dependent plasticity to
repair the damaged corticospinal tract in an animal model of cerebral palsy. Dev
Med Child Neurol. 2011;53:9-13.
9. Holden KR. Malnutrition and brain development: a review. J Pediatr. 1969;74:667-679. 10. Majnemer A, Barr RG. Association between sleep position and early motor
Development. J Pediatr. 2006;149:623-629.
11. Krasnoff JB, Mathias R, Rosenthal P, Painter PL. The comprehensive assessment
of physical fitness in children following kidney and liver transplantation.
Transplantation. 200682:211-217.
12. Bos GJFJ, Lelieveld OTHM, Scheenstra R, Sauer PJJ, Geertzen JHB, Dijkstra PU.
Physical activity and aerobic fitness in children after liver transplantation. Pediatr
Transplant. 2019;23:e13465.
13. Wrotniak BH, Epstein LH, Dorn JM, Jones KE, Kondilis VA. The relationship between
motor proficiency and physical activity in children. Pediatrics. 2006;118:e1758-65.
14. Haga M. Physical Fitness in Children With High Motor Competence Is Different From
That in Children With Low Motor Competence. Phys Ther. 2009;89:1089-1097.
15. van Hal L, Tierolf B, van Rooijen M, van der Hoff M. Een Actueel Perspectief Op
Kinderen En Jongeren Met Een Chronische Aandoening in Nederland: Omvang, Samenstelling En Participatie. Verwey-Jonker Insituut: Utrecht; 2019.
16. Potgieser ARE, De Vries W, Sze YK, et al. Course of life into adulthood of patients with
biliary atresia: The achievement of developmental milestones in a nationwide cohort. J Adolesc Heal. 2012;50:641-644.
17. Moola F, Fusco C, Kirsh JA. The perceptions of caregivers toward physical activity
and health in youth with congenital heart disease. Qual Health Res. 2011;21:278-91.
18. Coleman N, Nemeth BA, Leblanc CMA. Increasing Wellness Through Physical
Activity in Children with Chronic Disease and Disability. Curr Sports Med Rep. 2018;17:425-432.
19. King-Dowling S, Proudfoot NA, Obeid J. Comorbidity Among Chronic Physical Health
Conditions and Neurodevelopmental Disorders in Childhood. Curr Dev Disord
Reports. 2019;6:248-258.
20. Donnelly JE, Hillman CH, Castelli D, et al. Physical activity, fitness, cognitive function,
and academic achievement in children: A systematic review. Med Sci Sports Exerc. 2016;48:1197-1222.
21. Evaristo S, Moreira C, Lopes L, et al. Muscular fitness and cardiorespiratory fitness
are associated with health-related quality of life: Results from labmed physical activity study. J Exerc Sci Fit. 2019;28:631-635.
22. Redondo-Tébar A, Ruíz-Hermosa A, Martínez-Vizcaíno V, et al. Associations between
health-related quality of life and physical fitness in 4–7-year-old Spanish children: the MOVIKIDS study. Qual Life Res. 2019;28:1751-1759.
23. Kotte EMW, de Groot JF, Winkler AMF, Huijgen BCH, Takken T. Effects of the Fitkids
Exercise Therapy Program on Health-Related Fitness, Walking Capacity, and Health-Related Quality of Life. Phys Ther. 2014;94:1306-1318.
24. Stevenson T, Millan MT, Wayman K, et al. Long-term outcome following pediatric
liver transplantation for metabolic disorders. Pediatr Transplant. 2010;14:268-275.
25. Krull K, Fuchs C, Yurk H, Boone P, Alonso E. Neurocognitive outcome in pediatric liver
transplant recipients. Pediatr Transplant. 2003;7:111-118.
26. Abu Faddan NH, Shehata GA, Abd Elhafeez HA, Mohamed AO, Hassan HS, Abd El
Sameea F. Cognitive function and endogenous cytokine levels in children with chronic hepatitis C. J Viral Hepat. 2015;22:665-670.
27. Caudle SE, Katzenstein JM, Karpen SJ, et al. Language and Motor Skills Are Impaired
in Infants with Biliary Atresia Before Transplantation. J Pediatr. 2010;156:936-940.
28. Caudle SE, Katzenstein JM, Karpen S, McLin V. Developmental Assessment of Infants
With Biliary Atresia. J Pediatr Gastroenterol Nutr. 2012;55:384-389.
29. Srivastava A, Yadav SK, Borkar V V, et al. Serial evaluation of children with ALF
with advanced MRI, serum proinflammatory cytokines, thiamine, and cognition assessment. J Pediatr Gastroenterol Nutr. 2012;55:580-586.
30. Gritti A, Di Sarno AM, Comito M, De Vincenzo A, De Paola P, Vajro P. Psychological
impact of liver transplantation on children’s inner worlds. Pediatr Transplant. 2001;5:37-43.
31. Kaller T, Langguth N, Petermann F, Ganschow R, Nashan B, Schulz KH. Cognitive
performance in pediatric liver transplant recipients. Am J Transplant. 2013;13:2956-2965.
32. Sorensen LG, Neighbors K, Martz K, et al. Cognitive and Academic Outcomes after
Pediatric Liver Transplantation: Functional Outcomes Group (FOG) Results. Am J
Transplant. 2011;11:303-311.
33. Sorensen LG, Neighbors K, Martz K, Zelko F, Bucuvalas JC, Alonso EM. Longitudinal
Study of Cognitive and Academic Outcomes after Pediatric Liver Transplantation.
J Pediatr. 2014;165:65-72.e2.
34. Gilmour S, Adkins R, Liddell GA, Jhangri G, Robertson CM. Assessment of
psychoeducational outcomes after pediatric liver transplant. Am J Transpl. 2009;9:294-300.
35. Adebäck P, Nemeth A, Fischler B. Cognitive and emotional outcome after pediatric
liver transplantation. Pediatr Transplant. 2003;7:385-389.
36. Haavisto A, Korkman M, Törmänen J, Holmberg C, Jalanko H, Qvist E. Visuospatial
impairment in children and adolescents after liver transplantation. Pediatr
Transplant. 2011;15:184-192.
37. Gold A, Rogers A, Cruchley E, et al. Assessment of School Readiness in Chronic
Cholestatic Liver Disease: A Pilot Study Examining Children with and without Liver Transplantation. Can J Gastroenterol Hepatol. 2017;2017.
38. Sorensen LG, Neighbors K, Martz K, Zelko F, Bucuvalas JC, Alonso EM. Longitudinal
Study of Cognitive and Academic Outcomes after Pediatric Liver Transplantation.
J Pediatr. 2014;165:65-72.e2.
39. Ng VL, Sorensen LG, Alonso EM, et al. Neurodevelopmental Outcome of Young
Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study. J
Pediatr. 2018;196:139-147.
40. Squires JE, Ng VL, Hawthorne K, et al. Neurodevelopmental Outcomes in Preschool
and School Aged Children with Biliary Atresia and Their Native Liver. J Pediatr
Gastroenterol Nutr. 2020;70:79–86.
41. Centraal bureau voor de statistiek (CBS). (Speciaal) Basisonderwijs En Speciale
Scholen; Leerlingen, Schoolregio. Den Haag/Heerlen; 2018. http://statline.cbs.nl.
42. Ogundele MO. Behavioural and emotional disorders in childhood: A brief overview
for paediatricians. World J Clin Pediatr. 2018;7(1):9-26.
43. Blackman JA, Gurka MJ, Gurka KK, Oliver MN. Emotional, developmental and
behavioural co-morbidities of children with chronic health conditions. J Paediatr
44. McDougall J, King G, De Wit DJ, et al. Chronic physical health conditions and
disability among Canadian school-aged children: A national profile. Disabil
Rehabil. 2004;26:35-45.
45. Anthony LG, Anthony BJ, Glanville DN, Naiman DQ, Waanders C, Shatter S. The
relationships between parenting stress, parenting behaviour and preschoolers’ social competence and behaviour problems in the classroom. Infant Child Dev. 2005;14:133-154.
46. Lampela H, Pakarinen MP, Jahnukainen T, Jalanko H, Kosola S. Quality of Life and
Parental Worrying in a National Cohort of Biliary Atresia Children Living with Their Native Livers. J Pediatr Gastroenterol Nutr. 2017;64:883-887.
47. Missiuna C, Cairney J, Pollock N, et al. Psychological distress in children with
developmental coordination disorder and attention-deficit hyperactivity disorder.
Res Dev Disabil. 2014;35:1198-207.
48. Butterworth RF. Hepatic encephalopathy: A central neuroinflammatory disorder?
Hepatology. 2011;53:1372-1376.
49. Talcott JB, Beath S V., Patel T, Griffiths G, Kelly DA. Long-Term Effects of Cholestatic
Liver Disease in Childhood on Neuropsychological Outcomes and Neurochemistry.
J Pediatr Gastroenterol Nutr. 2019;69:145-151.
50. Sun Y, Jia L, Yu H, Zhu M, Sheng M, Yu W. The Effect of Pediatric Living Donor Liver
Transplantation on Neurocognitive Outcomes in Children. Ann Transplant. 2019;2:446-453.
51. Jiang NM, Cowan M, Moonah SN, Petri WA. The Impact of Systemic Inflammation
on Neurodevelopment. Trends Mol Med. 2018;24:794-804.
52. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and
physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451-1463.
53. Tessier MEM, Cavallo L, Yeh J, et al. The Stool Microbiome May Predict Outcomes in
Infants with Biliary Atresia. Gastroenterology. 2019;156:S-137.
54. Wang J, Qian T, Jiang J, et al. Gut microbial profile in biliary atresia: a case-control
study. J Gastroenterol Hepatol. 2020;35:334-342.
55. Spadoni I, Fornasa G, Rescigno M. Organ-specific protection mediated by
cooperation between vascular and epithelial barriers. Nat Rev Immunol. 2017;17:761-773.
56. Warner BB. The contribution of the gut microbiome to neurodevelopment and
neuropsychiatric disorders. Pediatr Res. 2019;85:216-224.
57. John CC, Black MM, Nelson CA. Neurodevelopment: The Impact of Nutrition
and Inflammation During Early to Middle Childhood in Low-Resource Settings.
Pediatrics. 2017;139:S59-S71.
58. DeRusso PA, Ye W, Shepherd R, et al. Growth failure and outcomes in infants with
biliary atresia: A report from the biliary atresia research consortium. Hepatology. 2007;46:1632-1638.
59. Greer R, Lehnert M, Lewindon P, Cleghorn GJ, Shepherd RW. Body composition and
components of energy expenditure in children with end-stage liver disease. J
Pediatr Gastroenterol Nutr. 2003;36:358-363.
60. Stolwijk LJ, Lemmers PMA, Harmsen M, et al. Neurodevelopmental Outcomes After
Neonatal Surgery for Major Noncardiac Anomalies. Pediatrics. 2016;137:e20151728.
61. Moran MM, Gunn-Charlton JK, Walsh JM, et al. Associations of Neonatal Noncardiac
Surgery with Brain Structure and Neurodevelopment: A Prospective Case-Control Study. J Pediatr. 2019;212:93–101.
62. Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia
on neurodevelopment in children: An updated systematic review with meta-regression. PLoS One. 2014;9:e85760.
63. Davidson AJ, Disma N, De Graaff JC, et al. Neurodevelopmental outcome at 2
years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): An international multicentre, randomised controlled trial. Lancet. 2016;387:239-250.
64. McCann ME, Berde C, Soriano S, et al. Neurodevelopmental outcome at 5 years of
age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019;393:664-677.
65. Pflugrad H, Schrader AK, Tryc AB, et al. Longterm calcineurin inhibitor therapy and
brain function in patients after liver transplantation. Liver Transplant. 2018;24:56-66.
66. Parker W, Hornik CD, Bilbo S, et al. The role of oxidative stress, inflammation and
acetaminophen exposure from birth to early childhood in the induction of autism.
J Int Med Res. 2017;45:407-438.
67. Almaas R, Jensen U, Loennecken MC, et al. Impaired motor competence in children
with transplanted liver. J Pediatr Gastroenterol Nutr. 2015;60:723-728.
68. van Mourik ID, Beath S V, Brook GA, et al. Long-term nutritional and
neurodevelopmental outcome of liver transplantation in infants aged less than 12 months. J Pediatr Gastroenterol Nutr. 2000;30:269-275.
69. Witt M, Kvist N, Jorgensen MH, Hulscher JBF, Verkade HJ. Prophylactic Dosing of
Vitamin K to Prevent Bleeding. Pediatrics. 2016;137:e20154222-e20154222.
70. van Hasselt PM, de Koning TJ, Kvist N, et al. Prevention of Vitamin K Deficiency
Bleeding in Breastfed Infants: Lessons From the Dutch and Danish Biliary Atresia Registries. Pediatrics. 2008;121(4):857-863.
71. Graham AM, Pfeifer JH, Fisher PA, Carpenter S, Fair DA. Early life stress is associated
with default system integrity and emotionality during infancy. J Child Psychol
Psychiatry Allied Discip. 2015;56:1212-22.
72. Moses-Kolko EL, Horner MS, Phillips ML, et al. In search of neural endophenotypes
of postpartum psychopathology and disrupted maternal caregiving. J
Neuroendocrinol. 2014;26:665–84.
73. Diseth TH, Tangeraas T, Reinfjell T, Bjerre A. Kidney transplantation in childhood:
Mental health and quality of life of children and caregivers. Pediatr Nephrol. 2011;26:1881–1892.
74. Parolini F, Boroni G, Milianti S, et al. Biliary atresia: 20–40-year follow-up with native
liver in an Italian centre. J Pediatr Surg. 2019;54:1440-1444.
75. Lind RC, de Vries W, Keyzer-Dekker CMG, et al. Health Status and Quality of Life in
Adult Biliary Atresia Patients Surviving with Their Native Livers. Eur J Pediatr Surg. 2015;25:60-65.
76. Wong CWY, Chung PHY, Tam PKH, et al. Long-term Results and Quality of Life
Assessment in Biliary Atresia Patients: A 35-Year Experience in a Tertiary Hospital.
J Pediatr Gastroenterol Nutr. 2018;66:570-574.
77. de Vries W, Lind RC, Sze YK, et al. Overall Quality of Life in Adult Biliary Atresia
Survivors with or without Liver Transplantation: Results from a National Cohort.
Eur J Pediatr Surg. 2016;26:e1.
78. Schwartz CE, Andresen EM, Nosek MA, Krahn GL. Response Shift Theory: Important
Implications for Measuring Quality of Life in People With Disability. Arch Phys Med
Rehabil. 2007;88:529-536.
79. Sundaram SS, Alonso EM, Haber B, et al. Health related quality of life in patients with
biliary atresia surviving with their native liver. J Pediatr. 2013;163(4):1052-1057.e2.
80. Ng VL, Haber BH, Magee JC, et al. Medical Status of 219 children with biliary atresia
surviving long-term with their native livers: Results from a North American multicenter consortium. J Pediatr. 2014;165:539-546.
81. Fredericks EM, Dore-Stites D, Calderon SY, et al. Relationship between sleep
problems and health-related quality of life among pediatric liver transplant recipients. Liver Transplant. 2012;18:707-715.
82. Kikuchi R, Mizuta K, Urahashi T, et al. Quality of life after living donor liver transplant
for biliary atresia in Japan. Pediatr Int. 2018;60:183-190.
83. Miserachs M, Parmar A, Bakula A, et al. Health-related quality of life in
pre-adolescent liver transplant recipients with biliary atresia: A cross-sectional study.
Clin Res Hepatol Gastroenterol. 2019;43:427-435.
84. Eymann A, Busaniche J, Llera J, De Cunto C, Wahren C. Impact of divorce on the
quality of life in school-age children. J Pediatr (Rio J). 2009;85:547-552.
85. McLean CP, Anderson ER. Brave men and timid women? A review of the gender
differences in fear and anxiety. Clin Psychol Rev. 2009:496–505.
86. Cohn LN, Pechlivanoglou P, Lee Y, et al. Health Outcomes of Parents of Children with
Chronic Illness: A Systematic Review and Meta-Analysis. J Pediatr. 2020;218:166-177.e2.
87. Pinquart M. Parenting stress in caregivers of children with chronic physical
condition—A meta-analysis. Stress Heal. 2018;34:197-207.
88. Cousino MK, Hazen RA. Parenting stress among caregivers of children with chronic
illness: a systematic review. J Pediatr Psychol. 2013;38:809-828.
89. Cohen E, Horváth-Puhó E, Ray JG, et al. Association between the birth of an infant
with major congenital anomalies and subsequent risk of mortality in their mothers.
JAMA - J Am Med Assoc. 2016;316:2515-2524.
90. Lawoko S, Soares JJF. Quality of life among parents of children with congenital
heart disease, parents of children with other diseases and parents of healthy children. Qual Life Res. 2003;12:655-66.
91. Sharpe D, Rossiter L. Siblings of children with a chronic illness: A meta-analysis. J
Pediatr Psychol. 2002;27:699-710.
92. Pless IB, Satterwhite B. A measure of family functioning and its application. Soc Sci
Med. 1973;7:613-621.
93. Kosmach-Park B. The impact of liver transplantation on family functioning in
pediatric recipients: Can “healthy” families contribute to improved long-term survival? Pediatr Transplant. 2013;17:321–325.
94. Verhulst F, van der Ende J. Manual for the Child Behavioural Checklist: 1.5-5 (CBCL,
in Dutch). Achenbach System of Empirically Based Assessments (ASEBA). 2000.
95. Spielberger C. Manual for the State-Trait Anxiety Inventory. Palo Alto (CA): Consulting
Psychologists Press; 1983.
96. Spittle A, Orton J, Anderson PJ, et al. Early developmental intervention programmes
provided post hospital discharge to prevent motor and cognitive impairment in preterm infants. Cochrane Database of Systematic Reviews. 2015;2015:CD005495.
97. Morgan C, Darrah J, Gordon AM, et al. Effectiveness of motor interventions in infants
with cerebral palsy: a systematic review. Dev Med Child Neurol. 2016;58:900-9
98. Whittingham K, Sanders MR, Mckinlay L, Boyd RN. Parenting intervention combined
with acceptance and commitment therapy: A trial with families of children with cerebral palsy. J Pediatr Psychol. 2016;41:531-542.
