Effects of Exercise Training in Postoperative Patients With Congenital Heart Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background The purpose of this meta-analysis is to assess the effects of exercise training on quality of life, specific biomarkers, exercise capacity, and vascular function in congenital heart disease (CHD) subjects after surgery. Methods and Results We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from the date of the inception of the database through April 2019. Altogether, 1161 records were identified in the literature search. Studies evaluating outcomes before and after exercise training among postoperative patients with congenital heart disease were included. The assessed outcomes were exercise capacity, vascular function, serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels and quality of life. We analyzed heterogeneity by using the I2 statistic and evaluated the evidence quality according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. Nine randomized controlled trials were included. The evidence indicated that exercise interventions increased the one of the quality of life questionnaire score (mean difference=3.19 [95% CI, 0.23, 6.16]; P=0.03; I2=39%) from the score before the interventions. However, no alterations in exercise capacity, vascular function, NT-proBNP or quality of life were observed after exercise training. The results of the subgroup analysis showed that NT-proBNP levels were lower in the group with exercise training than in the group without exercise training over the same duration of follow-up. The evidence quality was generally assessed to be low. Conclusions In conclusion, there is insufficient evidence to suggest that physical exercise improves long-term follow-up outcomes of congenital heart disease, although it has some minor effects on quality of life.

Clinical Perspective

What Is New?

This study is a systematic review of the literature on the effects of exercise training in patients with congenital heart disease (CHD).

The findings suggest that CHD‐TNO/AZL Adult Quality of Life (CHD‐TAAQOL) questionnaire (impact) scale scores increase after exercise training.

What Are the Clinical Implications?

The current meta‐analysis provides weight to the increasing evidence supporting exercise training as a postoperative strategy to improve the prognosis of CHD patients.

Compared with the usual interventions, exercise interventions have been shown to improve quality of life among patients with CHD.

Introduction

Congenital heart disease (CHD) is one of the most common birth defects in the world.1 Reportedly, the total CHD birth prevalence worldwide is 8.0% to 9.1%,2, 3 and ≈1.35 million infants are born with CHD every year.3 From 2000 to 2010, the CHD prevalence rates increased by 11% and 57% among children and adults, respectively.4 With the improvement of CHD medical care, catheter interventions, and surgical procedures over the past 2 decades, increasing numbers of CHD patients can be treated, which improves survival for these patients.5, 6, 7 However, research on cardiac surgery in patients with CHD has shown cognitive dysfunction,8 affected hemodynamics, abnormal psychosocial development,9 renal dysfunction, restrictive lung disease, anemia, cirrhosis, and reduced quality of life.10 Thus, multi‐aspect management is becoming progressively more important for cardiac surgery in patients with CHD.

An exercise training program is part of the multi‐aspect management for postoperative patients with CHD and is recommended by the American Heart Association11 and the European Society of Cardiology.12 Exercise training can be considered beneficial to postoperative patients with CHD, as it enhances cardiovascular fitness, improves cardiac function, regulates renewal and regeneration capability, reduces inflammatory responses, elevates quality of life, and decreases the long‐term risk of acquired heart disease.13, 14, 15

To date, few studies have focused on the effects of exercise training programs on cardiac surgery in patients with CHD.16, 17, 18, 19, 20, 21, 22, 23 Moreover, with the above studies including small samples and reaching different conclusions, the exact effects of exercise training programs remain unclear. Additionally, the recruitment of participants in different age groups in different trials may weaken the generalizability of previous results to the broader population of CHD patients. Previously, a similar meta‐analysis focused on aerobic capacity and pulmonary function,24 although few randomized clinical trials were included, which may result in increased bias. To our knowledge, no systematic reviews and meta‐analyses of randomized clinical trials have addressed exercise training in postoperative CHD patients thus far. The goal of this study was to estimate the effects of exercise training on exercise capacity, vascular function, disease‐specific biomarkers, and quality of life in postoperative CHD patients.

Method

The authors declare that all supporting data are available within the article (and its supplementary files).

Search Strategy

Two independent authors (C.X. and X.S.) searched all scientific publications reporting follow‐up outcomes of an exercise training program in patients with CHD who had undergone cardiac surgery. PubMed, Embase, and Web of Science were searched from inception to April 1, 2019. The search strategy combined 3 concepts: the disease of interest (CHD), method of intervention (exercise training program), and outcome of interest (follow‐up). We applied Medical Subject Headings to ensure precise keyword terms. The keyword terms are listed in Table S1. The search strategy was in accord with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines.25 No language or other restrictions were applied. This study is registered with PROSPERO (CRD42019128366).

Study Selection

After integrating all searched articles to EndNote software, duplicate studies were removed (n=56). The remaining studies were reviewed by 2 independent investigators (C.X. and X. S.) to determine eligibility according to inclusion and exclusion criteria. If ambiguity arose, the third author (S.Y.M.) made a final decision. The flow chart is presented in Figure 1.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow chart.

Data Analysis and Statistics

The Newcastle–Ottawa Quality Assessment Scale for Cohort Studies was analyzed to assess the quality and risk of bias of included studies.26

The exercise capacity (peak oxygen uptake [VO2]), vascular function (systolic blood pressure [SBP], heart rate [HR]), disease‐specific biomarkers (serum NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide] levels), and quality of life (Short Form 36 item [SF‐36] health survey and CHD‐TNO/AZL Adult Quality of Life [CHD‐TAAQOL] questionnaire) were selected as evaluated outcomes of our concern. The SBP and HR values contain the resting and max conditions. SF‐36 scores were combined into 2 higher‐ordered clusters: the physical component summary and the mental component summary. CHD‐TAAQOL contains 3 subscales: symptoms, worries, and impacts of the medical examinations.

Because the outcomes of several studies were reported as medians and interquartile ranges only, we replaced means with medians and replaced standard deviations with interquartile ranges divided by 1.35 in the case of data with a normal distribution according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines (Cochrane Handbook for Systematic Reviews of Interventions).

Review Manager software version 5.3 (The Cochrane Collaboration) and Stata version 12.0 (StataCorp, College Station, TX) were used in the present study. The I2 statistic was used to assess the heterogeneity of the results. A random‐effects model was used when moderate or high heterogeneity was detected, and a fixed‐effects model was used when no or low heterogeneity was observed. The results are presented as the standardized mean differences and 95% CIs as well as forest plots. Sensitivity analysis, which involved computing the meta‐analysis estimate after omitting 1 study at a time, was calculated to evaluate the contribution of each study. We conducted a meta‐regression analysis with changes in NT‐proBNP level or SBP or the CHD‐TAAQOL worries scale as the dependent variable and the following characteristic variables as independent variables: sample size, age, percentage of patients with New York Heart Association (NYHA) class I and male patients, and β‐blocker use. Follow‐up time was extracted from every included study.

We performed Egger's test to assess the risk of publication bias for each outcome. The risk of bias of every included study was assessed according to the recommendation by the Cochrane Collaboration.27 The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the quality of the evidence for each outcome.

Result

Study, Patient, and Intervention Characteristics

Eight of 9 studies were published after 2012 and were performed in Europe (Table). The median follow‐up was 12 weeks, with 6 studies reporting at least 12 weeks of follow‐up and 1 reporting a follow‐up of 3 years. Although some included studies were multicenter studies (5 participating centers of pediatric cardiology;22 4 centers16, 18), a total of 167 samples were included (median n=20; range 9 to 24). In all, a number of 66 subjects (≈40% of all participants) resulted from the 3 large multicenter trials contributing. The exercise interventions in each study were not identical. Each study had its own sports training program, which differed in terms of frequency and duration. In most studies, the intervention groups engaged in aerobic exercise, and the control group members were requested to continue their habitual daily activities. The intensity of each aerobic exercise was moderate, and training exercises included brisk walking, jogging, running, or bicycling. One study's intervention was divided into 3 phases,20 and the duration and frequency of exercise were increased incrementally in each. Two studies focused on standardized exercise training.17, 22 Other studies’ interventions mostly consisted of training sessions.

Table 1

Characteristics of the Included Studies

Author, Y	% of Male	Location	Age (Y)	Sample Size	CHD Subtype	NYHA Class I (%)	β‐Blocker Used (%)	Intervention	Outcome Assessment	Follow‐Up Time
Winter, 201216	38	Netherlands and Italy	31±10	24	TGA	75	20.8	Exercise training protocol of 10 consecutive weeks	NT‐proBNP; peak VO2; SF‐36; CHD‐TAAQOL; Hemodynamics	10 wk
Westhoff‐Bleck, 201320	54	Germany	29.9±3.1	19	D‐TGA	54.2	16.7	6‐month aerobic exercise training	Peak VO2	24 wk
Dulfer, 201422	72.2	Netherlands	15.2	20	ToF	NP	NP	Three training sessions of 1 h per week, over a 3‐month period	SF‐36; CHD‐TAAQOL	12 wk
Duppen, 2015a17	74.5	Netherlands	16.1±2.6	24	ToF	78.7	NP	A 12‐wk standardized aerobic dynamic exercise training program	NT‐proBNP	12 wk
Duppen, 2015b17	72.1	Netherlands	14.8±3.7	23	Fontana	72.1	NP	A 12‐wk standardized aerobic dynamic exercise training program	NT‐proBNP	12 wk
van der Bom, 201518	59	Netherlands and Italy	31±11	22	TGA	72.7	13.6	Exercise training protocol of 10 consecutive wks	NT‐proBNP; peak VO2; SF‐36; CHD‐TAAQOL; Hemodynamics	3 y
Novakovic, 2018a19	22	Slovenia	36.2±6.8	9	TOF	100	11.1	Interval training	Hemodynamics; NT‐proBNP; peak VO2; SF‐36	12 wk
Novakovic, 2018b19	44	Slovenia	40.1±10.4	9	TOF	100	33.3	Continuous training	Hemodynamics; NT‐proBNP; peak VO2; SF‐36	12 wk
Therrien, 200323	58.8	Canada	NP	17	ToF	NP	NP	Structured exercise program	Peak VO2, heart rate max	12 wk

Age, mean±SD. CHD‐TAAQOL indicates CHD‐TNO/AZL Adult Quality of Life; NP, not reported; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; SF‐36, Short Form 36 item; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; VO2, oxygen uptake.

Fontan circulation.

All the participants included had complex CHD. The average age of the recruited participants ranged from 14.8 to 40.1 years. The subjects of 3 studies were adolescents, and those of the remaining 5 were adults. Most participants were NYHA class I (median n=75%; range 54.2% to 100%), and fewer people used β‐blocker drugs (median n=16.7%; range 11.1% to 33.3%).

Outcome Results

NT‐proBNP

Three studies (n=87) reported the effect of exercise training intervention on serum NT‐proBNP among postoperative CHD subjects (Figure S1A), and no statistically significant change in serum NT‐proBNP was found with exercise training intervention (mean difference=−17.53 [95% CI, −80.48, 45.42]; P=0.59; I2=99%). After excluding the population with biventricular CHD, the result suggested that exercise training intervention does not reduce serum NT‐proBNP levels among postoperative CHD subjects (mean difference=−25.68 [95% CI, −101.25, 49.89]; P=0.51; I2=99%) (Figure S1B).

Quality of life

Participants demonstrated a slight but significant increase in the CHD‐TAAQOL impact scales after exercise training (3 studies: mean difference=3.19 [95% CI, 0.23, 6.16]; P=0.03; I2=39%), as shown in Figure 2. However, no significant differences in SF‐36 (physical and mental health) and CHD‐TAAQOL (symptoms and worries) scores were found between the exercise training intervention and control groups (Figure S2).

Figure 2

Forest plot for the role of exercise training in CHD postoperative patients with CHD‐TAAQOL impact score16, 18, 22 CHD indicates congenital heart disease; CHD‐TAAQOL, CHD‐TNO/AZL Adult Quality of Life.

Hemodynamics

A total of 3 studies focused on hemodynamic outcomes, ie, SBP (resting), SBP (max), HR (resting), and HR (max); 1 research study focused on the HR (max) outcome. After meta‐analysis, there were still no significant differences in hemodynamic outcomes between CHD patients with exercise training intervention and controls (Figure S3; SBP resting: mean difference=2.14 [95% CI, −4.79, 9.07], P=0.55, I2=64%; SBP max: mean difference=−2.30 [95% CI, −10.67, 6.07], P=0.59, I2=0%; HR resting: mean difference=1.28 [95% CI, −3.22, 5.77], P=0.58, I2=0%; HR max: mean difference=−2.33 [95% CI, −10.23, 5.57], P=0.56, I2=0%).

Peak VO2

CHD patients who received exercise training intervention had similar postoperative physical fitness, measured by peak VO2, as patients who did not receive exercise training (mean difference=−1.63 [95% CI, −3.63, 0.36]; P=0.11; I2=0%, Figure S4).

Sensitivity Analysis

Meta‐analyses of the changes in serum NT‐proBNP levels and SBP rest levels (the 2 outcomes with high heterogeneity) after exercise training intervention were conducted after both including and excluding each study. After performing the sensitivity analysis, the results of the SBP rest levels were not changed, while the results of the serum NT‐proBNP levels were changed (Figure S5). Therefore, we retained studies with the same follow‐up times in a subgroup analysis and found that after exercise intervention, NT‐proBNP levels were significantly reduced (Figure S6), suggesting that follow‐up time had a substantial impact on NT‐proBNP levels, which should be noted in future meta‐analyses.

Meta‐Regression Analysis

For serum NT‐proBNP levels, we found that the follow‐up time of the population was the only significant predictor of NT‐proBNP changes (β=0.17; P=0.003) in a meta‐regression analysis, as illustrated in Figure S7. Other variables, such as the percentage of male patients (P=0.88), mean age (P=0.77), sample size (P=0.62), and percentage of NYHA class I patients (P=0.45), were not correlated with the standardized mean differences of the change in NT‐proBNP levels.

For resting SBP levels, we observed no significant correlations between the percentage of male patients (P=0.32), mean age (P=0.16), sample size (P=0.12), percentage of NYHA class I patients (P=0.12), percentage of β‐blockers used (P=0.96), follow‐up time (P=0.50), and resting SBP levels.

Publication Bias

We performed Egger's test and graphed it with funnel plots (Figure S8). No evidence of publication bias (P=0.351) for the CHD‐TAAQOL impact scale was observed in the present study.

Risk of Bias

Overall, a low or unclear risk of bias existed in the included studies (Figure S9). Although all included studies were randomized clinical trial studies, 1 study had a high risk of bias because of nonblinded allocation.19 In addition, performance and detection biases were unclear because of insufficient information regarding whether participants and personnel were blinded and insufficient information regarding whether investigators were blinded and, if so, who was blinded, to all clinical conditions of the participants. No other overt bias was presented in the reports of all included studies.

Quality of Evidence Assessment

According to the GRADE guidelines,28, 29, 30, 31, 32, 33, 34, 35, 36 the quality of evidence of each outcome is presented in Tables S2 through S5. We evaluated the inconsistency by comparing the results of the included studies. Because the existing selection, performance, and detection biases were in the included articles, all the outcomes were downgraded for risk of bias. In summary, the quality of evidence for the effects of exercise training on exercise capacity, vascular function, disease‐specific biomarkers, and quality of life in postoperative CHD patients was assessed as low and unclear.

Discussion

This study is the first to systematically review and meta‐analyze exercise interventions for patients with CHD after surgery. Our results showed that CHD‐TAAQOL (impact) scale scores were increased after exercise training. However, exercise training did not increase exercise capacity, and most quality of life questionnaire scales as well as serum NT‐proBNP, peak VO2, and hemodynamics parameters were stable. The NT‐proBNP results of the sensitivity analysis suggested that heterogeneity still existed. After removing the study with the different follow‐up duration, we observed that NT‐proBNP levels were significantly decreased in the exercise training intervention group. Additionally, no publication bias was found in our study, and the risk of bias and the quality of evidence presented in the study was low or unclear.

SF‐36 and CHD‐TAAQOL were 2 of the most common scales for assessing quality of life among CHD subjects. Three studies reported both SF‐3618, 19, 22 and CHD‐TAAQOL16, 18, 22 scores. Our findings indicated an increase in CHD‐TAAQOL (impact) scores after exercise training, which was consistent with a previous report.22 We speculated that a significant result existed in only 1 included study. The reason may be that the original purpose of the CHD‐TAAQOL questionnaire design is for patients with CHD aged 17 to 32 years,37 while the mean age of subjects from the other 2 studies was over 31 years old.16, 18 The CHD‐TAAQOL (impact) questionnaire principally contains routine cardiac testing and medical follow‐up questions,38 and the significant increase in the CHD‐TAAQOL impact scales after exercise training suggested that exercise may improve cardiac function and reduce drug use in patients after CHD surgery. However, the specific impact needs to be determined by more specific questionnaires and laboratory tests. Although our study found that the SF‐36 scale scores were negative before and after the intervention, Novakovic et al reported that SF‐36 mental scores were increased in the continuous training group but not in the interval training group.19 It appears that continuous training may have positive effects on postoperative patients with CHD, although the molecular mechanisms need further study. The remaining included studies showed no differences in SF‐36 or CHD‐TAAQOL quality of life scores after exercise training.

Regarding hemodynamics, no differences among SBP (resting), SBP (max), HR (resting), and HR (max) were found between baseline and follow‐up in the present meta‐analyses. However, Winter et al found that exercise interventions can reduce resting SBP.16 Neither our meta‐analyses nor the meta‐regression results were able to address the positive findings, and the small sample size may be 1 of the reasons.

We found that the peak VO2 was unchanged after exercise training. Four of the included studies found that exercise contributed to peak VO2 elevation.16, 19, 20, 23 The rest of the included articles showed no significant difference, and we speculate that the reason for this finding is that exercise is not helpful in improving peak VO2, which may have been because of a long follow‐up period of up to 3 years,18 suggesting that exercise may not be effective for long‐term cardiopulmonary exercise capacity. Moreover, peak VO2 is affected by many factors, such as muscle oxygenation, endothelial function, and muscle mass. In addition, our results are negative because the sample size is not large enough; furthermore, because of individual differences, the standard deviation of the peak VO2 measurement results is large.

In our meta‐analysis, serum NT‐proBNP levels were similar at baseline and follow‐up. Notably, interval training could decrease serum NT‐proBNP.19 NT‐proBNP plays a role in predicting prognosis in patients with heart failure,39, 40 as it is mainly secreted by cardiomyocytes. Low NT‐proBNP levels may predict good clinical outcomes and prognoses. The increased serum NT‐proBNP concentrations were considered to be associated with impaired long‐term prognosis of CHD.41 We speculated that interval training may have caused depressed NT‐proBNP because interval training weakens the elevating effect of exercise treatment; furthermore, exercise itself possibly helps prevent heart failure. Moreover, we observed high heterogeneity in this outcome. Sensitivity analysis and meta‐regression both indicated that the time of follow‐up may be the reason for the high heterogeneity. This suggests that age may interfere with the effect of exercise training on NT‐proBNP levels. However, studies have shown that NT‐proBNP levels are not associated with age42 or that NT‐proBNP levels are positively correlated with age, although only among those older than 60 years.43 Although we excluded 1 study in our analysis in which the follow‐up time was 3 years,18 the result showed that exercise training can significantly reduce the serum NT‐proBNP concentration, although this could also be because of other biasing factors that we did not consider and the small sample size. Thus, more studies are needed to explain the effects of exercise training intervention and aging on serum NT‐proBNP among postoperative patients with CHD.

The strengths of this meta‐analysis were that all the included publications were randomized controlled studies, which helped to reduce bias. In the present study, we were able to evaluate the effects of exercise training on NT‐proBNP, peak VO2, hemodynamics, and quality of life simultaneously in a larger study sample through a meta‐analysis of different studies and the attempt to adjust several confounding factors. Indeed, we used a meta‐regression method and found that follow‐up time was a potential predictor of exercise training results, as indicated by changes in serum NT‐proBNP levels.

Several potential limitations exist in the present meta‐analysis. First, the age span is large, and postoperative times were different in our included studies, which may dilute the positive effects of exercise intervention. A larger sample size and stratified analysis can help solve this problem. Second, the follow‐up times ranged from 10 weeks to 3 years; however, if the follow‐up time was too long, other factors, such as an individual's different exercise habits, may have interfered with the potential positive effects of exercise intervention. Third, other factors such as arrhythmia might have affected the outcome indicators we observed. However, some articles did not include arrhythmia information, and some articles regarded arrhythmia as an exclusion criterion,16, 20 so we were unable to conduct a subgroup analysis. Studies have reported that arrhythmia is associated with the NT‐proBNP level.44 Fourth, although the intervention groups were all exercise interventions, the specific intervention measures in each study were not exactly the same. Thus, the different effects of intervention measures could not be explained, and the possible effects could not be ruled out. Fifth, the standard deviations of some parameters were converted by quartiles. The handbook for systematic reviews of interventions suggested that the means and standard deviations could be replaced with medians and r interquartile ranges divided by 1.35; however, a possible bias should not be excluded (Cochrane Handbook for Systematic Reviews of Interventions). Sixth, appropriate multiple comparison methods will be required in the future. Finally, all included patients had complex CHD and were NYHA class I/II; the effect of exercise may not be applicable to simple CHD patients or NYHA class III/IV.

Conclusions

Our meta‐analysis suggests that there is currently little evidence from randomized studies supporting the idea that physical training improves the long‐term follow‐up prognosis of congenital heart defects, with the exception of some small effects on quality of life. Further explorations, including larger samples and well‐designed prospective studies, are warranted to address these issues.

Sources of Funding

This work was supported by funding from the National Natural Science Foundation of China (81900281), the Maternal and Child Health Research Project of Jiangsu Province (F201755), the China Postdoctoral Science Foundation (2018M630585), the Key Project of Science and Technology Development Fund of Nanjing Medical University (2017NJMUZD060), the National Key Research and Development Program of China (2016YFC1101001, 2017YFC1308105), the Nanjing Medical University School Project (NMUC2018012A), and the Key Project supported by the Medical Science and Technology Development Foundation, Nanjing Department of Health (YKK18139).

Disclosures

None.

Table S1. Search Strategy Details.

Table S2. Quality of evidence was assessed for hemodynamics using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines

Table S3. Quality of evidence was assessed for quality of life using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines

Table S4. Quality of evidence was assessed for peak VO2 using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines

Table S5. Quality of evidence was assessed for NT‐proBNP using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines

Figure S1. Forest plot of the role of exercise training in CHD postoperative patients with serum NT‐proBNP. A, Overall population. B, Biventricular population.

Figure S2. Forest plot of the role of exercise training in CHD postoperative patients with quality of life. A, SF‐36 physical component summary. B, SF‐36 mental component summary. C, CHD‐TAAQOL worries score. D, CHD‐TAAQOL symptoms score. CHD indicates congenital heart disease; SF‐36, Short Form‐36 item; CHD‐TAAQOL, CHD‐TNO/AZL Adult Quality of Life.

Figure S3. Forest plot of the role of exercise training in CHD postoperative patients with vascular function. A, Resting SBP. B, SBP max. C, Resting HR. D, HR max. HR indicates heart rate; SBP, systolic blood pressure.

Figure S4. Forest plot of the role of exercise training in CHD postoperative patients with peak oxygen uptake (VO2). CHD indicates congenital heart disease.

Figure S5. Sensitivity analysis for each outcome with high heterogeneity (I2>50%). A, The serum NT‐proBNP. B, The SBP rest. NT‐proBNP indicates N terminal pro‐B‐type natriuretic peptide; SBP, systolic blood pressure.

Figure S6. Subgroup analysis for serum NT‐proBNP. NT‐proBNP indicates N terminal pro‐B‐type natriuretic peptide.

Figure S7. Meta‐regression analysis of SMD in serum NT‐proBNP levels after exercise training in postoperative patients with CHD correlated with the mean follow‐up time of participants. Circles represent each study, and the size of each circle represents the weight of the study in the meta‐analysis. CHD indicates congenital heart disease; SMD, standardized mean difference.

Figure S8. Funnel plots with pseudo 95% CIs for evaluating the publication bias of the included studies. MD was plotted against SE for the CHD‐TAAQOL impact score. No evidence of publication bias was present in the data set. CHD‐TAAQOL indicates CHD‐TNO/AZL Adult Quality of Life; MD, mean difference.

Figure S9. The risk of bias was presented according to the Cochrane Collaboration. A, Risk of bias graph, based on assessment for each item. B, Risk of bias summary. Yellow, unclear risk of bias; red, high risk of bias; green, low risk of bias.

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