Background

Congenital heart disease (CHD) is one of the most common structural abnormalities of the cardiovascular system, occurring in 9.41 of every 1000 live births [1]. Advances in pediatric health care over recent decades, such as approaches in pediatric cardiac catheterization, have enabled the majority of children with CHD (more than 97%) to enter adulthood successfully [2]. In recent years, new “noncardiac” problems in children with CHD [2, 3], such as developmental delay or long-term neurodevelopmental impairments characterized by delayed motor development, cognitive impairments, and stunted growth, have been recognized [4, 5].

Studies have shown that the period from 0 to 5 years of age is a critical period for heart development, with rapid growth in size and weight [6]. Strong evidence suggests that infants and toddlers under 5 years old should carry out unstructured physical activity every day in line with the characteristics of motor development [7, 8], and compared with other periods, reasonable physical activity at this stage can promote the development of heart and lung function, promote bone health and brain development, and provide lifelong benefits [9]. However, many studies have pointed out that children with CHD have lower levels of physical activity than healthy children of the same age, and this gap is more significant in infancy [9]. Impaired sensory and motor development may further negatively affect a child’s psychosocial development, resulting in further isolation from peers [10]. The lack of physical activity in children with CHD may be related to excessive parental protection, which has been reported as a contributing factor to stunted growth in children with CHD [10, 11]. Although there is strong evidence that early exercise interventions can help children recover more quickly, reduce the risks of developmental delay, and prevent stunting [12, 13], patient-reported limitations in sports participation are common, resulting in markedly reduced physical activity and a sedentary lifestyle with an increased risk of related complications [14,15,16]. Moreover, the lack of physical activity reduces social interactions, and delayed development can cause school-aged children with CHD children to adapt poorly to school life, resulting in poor academic performance. These problems may persist into young adulthood, leading to a low quality of life for these children and their families [17].

Although exercise training is safe and effective and abundant scientific evidence has demonstrated that physically active people of all ages and ethnicities have higher levels of cardiorespiratory fitness [18,19,20], the majority of children with CHD only receive very limited access to rehabilitation facilities, indicating that these services need to be arranged more effectively [21]. Moreover, the COVID-19 pandemic has led to social distancing and relatively few direct interactions between healthcare professionals and patients; therefore, patients who need intensive interactions with healthcare professionals have suffered to a greater extent [22]. Home-based cardiac rehabilitation has been widely used in adults and adolescents with CHD, and numerous studies have confirmed that home-based cardiac rehabilitation is safe and feasible and has high patient compliancee [23,24,25,26]. Focusing rehabilitation services on home-based exercise, training and expert supervision of parents may be an effective way to ensure positive outcomes for children with CHD, especially during the pandemic. A preliminary study showed that a customized home-based exercise program was beneficial for very young children [27]; however, high-quality randomized controlled trials are urgently needed. This randomized controlled trial was conducted to evaluate the impact of a customized home-based exercise program on (1) the motor abilities of children with CHD after cardiac catheterization; (2) the bone quality, cardiac function and structure, and physical development of children with CHD after cardiac catheterization; (3) parental anxiety and caregiver burden; and (4) parental quality of life.

Methods

Participants

This study was a prospective, single-blinded, randomized controlled trial conducted at Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine from January 2016 to December 2019. It was approved by the Ethics Committee, which is recognized by the Strategic Initiative for Developing Capacity in Ethical Review in collaboration with the Forum for Ethical Review Committees in Asia and the Western Pacific Region (Chinese Clinical Trial Registry: ChiCTR-IOR-16007762, January 14, 2016). The full protocol, including detailed descriptions of the intervention and statistical analysis plan, has been published previously (in the supplementary material) [28]. Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this research.

Study participants were recruited from the outpatient clinic, and the disease severity was classified with the categories “simple CHD,” “CHD of moderate complexity,” and “CHD of great complexity” using the system adopted by the Bethesda conference [29]. The inclusion criteria were children who (1) had echocardiography findings confirming a simple CHD subtype, including patent ductus arteriosus (PDA), pulmonary stenosis (PS), ventricular septal defect (VSD), and atrial septal defect (ASD); (2) children who were 0–5 years old; and (3) children who were scheduled to undergo cardiac catheterization. The exclusion criteria were (1) children with CHD of moderate and high complexity; (2) children with CHD combined with arrhythmia; (3) children with CHD combined with genetic disorders or other congenital musculoskeletal deformities; (4) children with CHD combined with liver or kidney diseases; (5) children with CHD combined with heart failure with a modified Ross score ≥ 3; (6) children with a history of heart surgery; (7) children with a history of surgery on other organs; (8) children who received previous rehabilitation treatment; and (9) children with illnesses that may preclude their participation as identified by the study physician [30]. Each participant’s parents signed a written informed consent form before participating in the trial.

Randomization and blinding

Randomization was computer-generated with allocation concealment by opaque sequentially numbered sealed envelopes. Eligible participants were randomized to receive either a home-based exercise program (an add-on home-based exercise program with supervision in addition to home-based exercise education) or home-based exercise education alone in a 1:1 allocation ratio. Outcome assessors were blinded to group allocation.

Procedures

In the intervention group, each patient and their parents participated in a home-based exercise program consisting of home-based exercise with supervision and home-based exercise education [28]. The degree of developmental delay and the achievement of age-appropriate skills were identified using the Peabody Developmental Motor Scales, 2nd edition (PDMS-2) before catheterization. Taking the degree of developmental delay, developmental age according to age-appropriate skill achievement, and CHD severity into consideration for each child, an individualized home-based exercise protocol was jointly designed by a multidisciplinary team, including a pediatric cardiologist, rehabilitation physician, and physical therapists specializing in pediatric rehabilitation, with input from the parents. The individualized home-based exercise protocol was then adjusted as the child’s skills developed at 1 and 3 months postcatheterization.

Parents received one-on-one personalized guidance until they understood and were able to demonstrate the capability of completing at least one whole session of the exercise program. The parents of participants at all included stages of growth were advised to incorporate these activities and preferred behaviors into their daily schedules (Additional file 1: Table S1). At least one of the children’s parents was asked to complete the entire exercise program at home 30 min daily for no less than 5 days per week over a 6-month period, with a weekly reminder from the intervention team, and compliance was recorded based on parent feedback through a Micro Message Public Platform or phone call one or two times per week. The intervention team also maintained phone contact with the parents to provide exercise guidance.

Both the intervention and control groups received the same home-based exercise education program, which consisted of an explanation of the precatheterization assessment results and educational materials. The educational materials were released through a WeChat subscription account twice monthly, which shared various forms of CHD knowledge, including approaches and matters needing attention regarding exercise and general care. Daily outdoor activities were also recommended.

Outcomes

Each child was assessed before catheterization and at 1, 3, and 6 months after surgical catheterization by the evaluation team that was blinded to the group assignments. The age range between 0 and 5 years old is the most rapid developmental period, and surgical procedures during this time can delay regular growth [31]. The primary outcome was motor development, including the gross motor quotient (GMQ), fine motor quotient (FMQ), and total motor quotient (TMQ). Secondary outcomes included bone strength examined by quantitative ultrasound at the tibia, cardiac structural indexes determined by echocardiography and the modified Ross score, and physical development indicators. Children’s physical development indicators were also evaluated as additional secondary outcomes, including height, weight, body mass index (BMI), head circumference, chest circumference, and upper arm circumference. We also measured parental anxiety, caregiver burden, and parental quality of life at each assessment using the Self-Rating Anxiety Scale (SAS) [32], a modified version of the Zarit Caregiver Burden Scale (ZCBS) [33, 34], and the 36-item Short-Form Health Survey (SF-36) [35]. Adverse effects occurring during the trial and any event that could be related to the exercise performed, such as abnormal heart failure or bone fracture, were considered adverse events (AEs). AEs were monitored and reported directly to the researchers by parents using phone or WeChat.

Statistical analysis

Normality tests were initially performed on the data. Nonnormally distributed data are reported as medians with interquartile ranges (IQRs) and were compared between the intervention group and the control group using an independent sample nonparametric test (Mann–Whitney U test). Data were also compared between the baseline assessment and each follow-up assessment within each group using a matched sample nonparametric test (Wilcoxon rank sum test). Categorical data are reported as numbers with percentages and were analyzed using the chi-squared test. Mixed-model analysis was used to compare the primary and secondary outcomes between the intervention and control groups among the four assessments. Z scores for speed of sound (SOS) are used to represent the difference between each patient’s value and the age-specific mean value divided by the standard deviation of the reference group, which was based on data for age-matched SOS values from the manufacturer’s data bank (not differentiated by race) [36]. We used intention-to-treat (ITT) analysis according to group allocation as the main analytical method in this study and included all patients who were randomly assigned, regardless of whether they received treatment. Statistical analysis was performed using the software package SPSS 25.0, and GPower 3.1.9.2 was used for sample size estimation. P values of < 0.017 were considered statistically significant, while the Bonferroni method was carried out to correct multiple comparison.

Results

Prerecruitment assessments were performed for 420 children with CHD, resulting in 228 children being excluded before recruitment. Of these children, 214 children did not meet the inclusion criteria, the parents of 8 children declined to participate in the trial, and 6 children were excluded for not meeting the inclusion criteria in the final preenrolment evaluation. We included a total of 192 children with CHD, including 64 with PDA, 26 with PS, 64 with VSD, and 38 with ASD (Fig. 1). There were no significant differences in baseline characteristics between the intervention (n = 95) and control (n = 97) groups (Table 1). Although most patient families (~ 70%) were from other regions of China and had to arrange family travel to Shanghai for the 3 follow-up assessments, 183 children (retention rate: 95%) completed the 6-month rehabilitation study, including 92 in the intervention group and 91 in the control group. The reasons for drop-out were attributed to parent work relocations (n = 2) and personal matters (n = 7). No serious AEs were reported during the study.

Fig. 1
figure 1

CONSORT diagram. Prerecruitment assessments were performed in 420 children, resulting in 228 children being excluded before recruitment and 192 children being included in the study. At the end of the study, 91 children in the intervention group and 92 patients in the control group completed the 6-month follow-up. Intention-to-treat (ITT) analysis was performed including the 95 originally recruited children in the intervention group and 97 patients in the control group. No adverse events were reported during this study

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Table 1 Preoperative assessment of the enrolled children with CHD
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The trends of motor quotients after 6 months, within and between the treatment groups, were examined (Fig. 2). The intervention group demonstrated a trend of increasing motor quotients over the course of the study, whereas the control group demonstrated relatively small increases in both the FMQ and TMQ. This difference in motor quotient trends between the groups resulted in the mean postcatheterization change in the GMQ at the 6-month assessment being nearly 15-fold higher in the intervention group (5.74; 95% confidence interval (CI) 4.52–6.96) than in the control group (0.39; 95% CI − 1.14–1.92). The GMQ of the control group decreased 1 month postcatheterization and returned to baseline after 6 months (Fig. 2).

Fig. 2
figure 2

Postcatheterization changes in motor development quotients. The X-axis shows the time points (months) of the follow-up, with “0” representing the preoperative assessment. The Y-axis shows the mean changes in the values of the developmental quotients, as calculated by subtracting each of the preoperative values from the postoperative assessment values. GMQ indicates gross motor quotient. FMQ indicates fine motor quotient. TMQ indicates total motor quotient. * indicates that the GMQ, FMQ, and TMQ scores of the intervention group were significantly greater than those of the control group at the 6-month assessment (p < 0.017)

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Next, we compared the pre- and postcatheterization assessments for each group. For the intervention group, all motor quotients had significantly increased at 1 month postcatheterization (Wilcoxon rank sum test for paired samples, p < 0.001 in all motor quotients, Table 2). In contrast, the control group only had a significant increase in the FMQ in the first month postcatheterization and no significant changes at any follow-up measurements for the GMQ and TMQ. Furthermore, the GMQ, FMQ, and TMQ of the intervention group were significantly higher than those of the control group (mixed modeling: fixed effect = 2.52, 95% CI 1.35–3.70; fixed effect = 2.31, 95% CI 0.83–3.79; and fixed effect = 2.80, 95% CI 1.74–3.86, respectively, Table 3).

Table 2 The Wilcoxon rank sum test of primary outcomes (motor development quotients) against preoperative assessment
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Table 3 Mixed-model analysis of primary and secondary outcomes between the intervention and the control group (n = 192)
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The secondary outcomes of bone strength, including the bone mineral density (BMD) percentiles and Z score of SOS, were not significantly different at any stage of the study compared with the precatheterization assessment within either the intervention or control group (Wilcoxon rank sum test for paired samples, p > 0.017, Table 4). In contrast, there was a significant increase in the SOS in the control group at the 6-month postcatheterization assessment (p = 0.001; Table 4). There was no significant difference in the SOS between the two groups pre- and posttreatment (mixed model: fixed effect =  − 16.84, 95% CI − 41.60 7.93; Additional file 1: Table S3).

Table 4 The Wilcoxon rank sum test of secondary outcomes (bone strength and physical development indicators) against preoperative assessment
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Exercise had a slight effect when pooled across both treatment groups and all postcatheterization assessments compared with the precatheterization assessment (Additional file 1: Table S2). In a stratified analysis of different CHD subtypes, however, echocardiographic profiles varied significantly between the two groups (Fig. 3; Additional file 1: Fig. S1&2, Table S3a-d). The intervention group had a significantly higher left ventricular posterior wall thickness at end-systole (LVPWs) than the control group with ASD but a significantly lower left ventricular end diastolic dimension (LVDd) than the control group with VSD (Table 5). There were no significant differences in the modified Ross score between the groups or between pre- and postcatherization (Additional file 1: Table S4).

Fig. 3
figure 3

Exercise-related echocardiographic changes by the CHD subtypes. The X-axis shows the time points (months) of the follow-up, with “0” representing the preoperative assessment. The Y-axis shows the mean changes in the values of the cardiac ultrasound indexes, as calculated by subtracting each of the preoperative values from the postoperative assessment values. The echocardiographic trends differed across the studied CHD subtypes. ASD indicates atrial septal defect. LVDd indicates left ventricular end diastolic dimension. LVPWd indicates left ventricular posterior wall depth. LVPWs indicates left ventricular posterior wall thickness at end-systole. MPA indicates the main pulmonary artery diameter. PDA indicates patent ductus arteriosus. TV indicates tricuspid blood flow velocity. VSD indicates ventricular septal defect. * indicates that the parameters were significantly different between groups at the current assessment (p < 0.017)

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Table 5 Mixed-model analyses of echocardiography in CHD
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During the 6-month study period, in both treatment groups, we observed significant physical development, including height, weight, and upper-arm, chest, and head circumference (Table 4). Three months postcatheterization, the intervention group had significant increases in upper-arm and chest circumference, whereas physical development was slower in the control group, with significant increases observed at the 6-month assessment. Furthermore, increase was significantly greater in the intervention group as compared to the control group (mixed model: fixed effect = 0.35, Table 3).

Parental self-reported anxiety, psychological burden, and quality of life also varied between treatment groups and over time (Additional file 1: Table S6 and Table S5). The intervention group demonstrated significantly higher scores in the quality-of-life assessment at 6 months than in the precatheterization assessment, as measured by the SF-36 total score (median (IQR) 678.0 (611.5–733.5) p = 0.001; Additional file 1: Table S5). This was also the case for both the physical (median (IQR) 359.0 (328.0–383.0); p = 0.002) and mental (median (IQR) 326.0 (287.5–349.5); p = 0.002) component scores (Additional file 1: Table S5). Overall, the postcatheterization SF-36 scores at 6 months were higher in the intervention group than in the control group (Additional file 1: Table S5); in addition, parents in the intervention group had significantly increased quality of life when compared to the those in the control group (mixed model: fixed effect = 33.2, 95% CI 6.25–60.15; Table 6).

Table 6 Mixed-model analysis of SAS, ZCBS and SF-36 between the intervention and the control groups (n = 192)
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Although the majority of study participants were from regions outside Shanghai (Additional file 1: Table S1), there were no significant differences in the precatheterization assessment findings among the CHD patients living in different regions (Additional file 1: Table S6). At the end of the study, we did not observe any significant differences in any outcomes between the Shanghai and non-Shanghai residents in the intervention group or the control group (Additional file 1: Table S7).

Discussion

This study is the first prospective randomized controlled trial to investigate the effects of a home-based exercise training program on the development of children with CHD following interventional cardiac catheterization. Our results demonstrated that after a supervised and customized home-based exercise program, children with CHD had significant improvement in their motor abilities as early as 1 month postcatheterization. The home-based exercise program also led to various direct improvements in cardiac structure, as assessed by echocardiography, for different CHD subtypes [37].

Grey matter in different areas of the brain is responsible for important functions, such as controlling muscle movement, sensory experiences, thinking and feeling, memory and speech, and greater volumes were found to be associated with better performance on a task-switching paradigm [38]. Smaller grey matter volumes were reported in toddlers with CHD before cardiac surgery, which may be related to impaired grey matter growth due to poor cerebral oxygen delivery [39]. Moreover, due to abnormal hemodynamics and hypoxia during gestation, neurodevelopmental delays and behavioral impairments are common in children with CHD [4, 12, 40]. Early surgical repair of the heart defect alone cannot prevent the onset of motor impairments [21, 41]. Therefore, an early empirical study suggested that postoperative (postcatheterization) exercise might compensate for neurodevelopmental delay [42] and induce adaptive changes in the cardiovascular system and natural cardiac remodeling [37, 43].

It has been shown that physical activity could promote brain remodeling by regulating epigenetics, neuroplasticity, and neurotrophins in animal models [44], and levels of physical activity, which could improve oxygen delivery to the brain, have been positively associated with several structural properties of grey matter [45]. Our results are congruent with those of Stieber et al., who found an increase in the rate of motor development to age-appropriate levels in children with CHD between 12 and 26 months of age with completion of a postoperative home-based rehabilitation program [46]. Our study expanded on this evidence base by including a larger sample size with older children and assessments at 4 different time points, including 3 postcatheterization assessments over 6 months in a randomized controlled trial.

No significant difference in bone strength was found in this study, although previous systematic reviews reported low- to moderate-quality evidence and suggested that increased or higher physical activity levels were positively associated with bone and skeletal health in the early years (aged 0–6 years) [47]. Given the absence of this information in the extant literature, there is a clear need to design experimental trials and prospective cohort studies to answer the question of whether a dose–response relationship exists between physical activity and health during this early period of the lifespan and, if so, what the nature of the relationship is.

Significant changes in the modified Ross scores for heart failure were not observed in this study, although different cardiac changes on echocardiography associated with specific CHD subtypes were demonstrated, including ASD, VSD, and PDA. Specifically, children with ASD have left-to-right shunts at the atrial level, causing excessive motion of the right ventricle with right ventricular volume overloa [48]. As a result, these children have increased blood volume in the left and right atrium, as well as increased right ventricular stroke volume. We found that the home-based exercise program could significantly reduce the velocity of tricuspid flow (TV), which would be beneficial to reducing right ventricular volume overload in children with ASD. Compared to children with ASD, children with VSD have left-to-right shunts at the ventricular level, causing increased pulmonary artery pressure and left atrial volume [49]. Echocardiographic observations suggest that training parents in a customized home-based exercise program, delivered under supervision, could help reduce the inner diameters of the left ventricular and pulmonary arteries and improve cardiac structure in children with VSD. For children with PDA, echocardiographic assessments also suggested that family exercise training could help reduce the left ventricle diameter and facilitate cardiac structural remodeling. Therefore, family exercise training might facilitate the improvement of cardiac structure in children with CHD.

With a CHD diagnosis in their children, the quality of life of parents is often impacted by anxiety caused by procedures and treatments, financial pressures relating to medical care, and the burden of caring for their children [50, 51]. These tensions can also affect their children’s health [52], suggesting that a family-focused postoperative treatment plan would potentially benefit both children with CHD and their parents. A randomized controlled trial of 56 families with children with CHD showed that four 90-min sessions of educational programs over 4 weeks increased the parents’ quality of life, as well as their self-efficacy, as assessed by the quality of life questionnaire (SF-36) and Generalized Self-Efficacy (GSE) scale [53]. Consistently, our findings demonstrate that intensive training and customized and supervised home-based exercise can effectively improve parents’ quality of life [53]. Moreover, with continuous support and professional instruction from study administrators, children with CHD and their parents performed exercises together and interacted more closely and frequently, which likely helped to foster better family relations and reduced the emotional pressure that the parents experienced. The improved motor development after exercise training in both the control and intervention groups likely also contributed to improved quality of life for the parents.

In this study, participating families who did not live locally and only traveled to Shanghai for catheterization and postcatheterization assessments, and daily rehabilitation exercises during the 6-month study period were completed under the remote guidance and supervision of the study team in Shanghai via WeChat and phone calls. It is likely that the multidisciplinary team approach in designing a safe, customized exercise program with close monitoring via telecommunication technologies was critical for achieving the high completion rate in this study, irrespective of distance to the studied hospital. Completing the program led to significant improvements regarding postoperative rehabilitation in children with CHD, as the largest changes were observed after 6 months. In addition, the nonsignificant difference between the results from Shanghai and rural areas provided strong evidence that a tertiary hospital can provide effective and low-cost rehabilitation services to a very large patient population via telehealth technologies. The use of such technologies also enabled families with children with CHD to save time and travel costs.

Our study was also limited by the use of telehealth technologies, such as the WeChat app, which presented challenges, particularly for participants living in rural areas. Occasional technical glitches discouraged some patients from participating, with several leaving the study (n = 7). Additionally, establishing physical activity levels from questionnaires remains challenging and is not an ideal estimate of physical fitness. After observing the overwhelmingly positive results in the 6-month assessment, we terminated this study earlier than originally planned, and therefore, we do not know whether the observed motor symptoms persisted beyond the intervention [28]. For future studies, we recommend large-scale, multicenter controlled investigations of children with CHD with longer follow-up periods to evaluate the long-term effects of home-based exercise. We also recommend more communication between parents and doctors and therapists to improve patients’ motivation to exercise and thus improve their motor functioning and physical performance.

Conclusions

In conclusion, the trial provides evidence that parental training in customized and supervised home-based exercise significantly increases motor quotient scores in CHD patients within 6 months of catheterization. This study therefore contributes to the evidence for the benefits of exercise among pediatric simple CHD patients. Furthermore, the high retention rate of our study, which used technological innovations to engage patients remotely, suggests a viable method for effective intervention for further studies and for patients requiring intervention during pandemic conditions. Future studies will monitor the progression of CHD within this cohort, and we are optimistic that, with continued supervision and guidance, these children with CHD will match their peers in terms of development.