Long‐Term Survival of Individuals Born With Congenital Heart Disease: A Systematic Review and Meta‐Analysis
Background Estimates of long‐term survival are required to adequately assess the variety of health and social services required by those with congenital heart disease (CHD) throughout their lives.
Methods and Results Medline, Embase, and Scopus were searched from inception to June 2015 using MeSH headings and keywords. Population‐based studies that ascertained all persons born with CHD within a predefined area and reported survival estimates at ≥5 years were included. Unadjusted survival estimates for each CHD subtype at ages 1 year, 5 years, 10 years, and so forth were extracted. Pooled survival estimates for each age were calculated using meta‐analyses. Metaregression was performed to examine the impact of study period on survival. Of 7840 identified articles, 16 met the inclusion criteria. Among those with CHD, pooled 1‐year survival was 87.0% (95% CI 82.1–91.2), pooled 5‐year survival was 85.4% (95% CI 79.4–90.5), and pooled 10‐year survival was 81.4% (95% CI 73.8–87.9). There was significant heterogeneity of survival estimates among articles (P<0.001 for 1‐, 5‐, and 10‐year survival). A more recent study period was significantly associated with greater survival at ages 1 year (P=0.047), 5 years (P=0.013), and 10 years (P=0.046). Survival varied by CHD subtype, with 5‐year survival being greatest for those with ventricular septal defect (96.3%, 95% CI 93.7–98.2) and lowest for those with hypoplastic left heart (12.5%, 95% CI 0.0–41.4).
Conclusions Among persons with CHD, the mortality rate is greatest during the first year of life; however, this systematic review and meta‐analysis showed that survival decreases gradually after infancy and into adulthood.
Congenital heart disease (CHD) composes the largest group of congenital anomalies and affects ≈1% of births in the United States and Europe.1, 2, 3 CHD is a leading cause of stillbirth and infant death and accounts for 4.2% of neonatal deaths in the United States.4 Babies with severe CHD subtypes require complex surgeries for survival. With advances in medical, surgical, and intensive care interventions, an estimated 83% of babies with CHD now survive infancy in the United States.5 Although 1‐year survival estimates have been described,3, 6, 7, 8, 9, 10, 11 long‐term survival estimates are not well researched, and survival may continue to decrease into adulthood.
A previous systematic review of the long‐term prognosis of CHD included only hospital‐based studies that ascertained cases postsurgically or in adulthood; estimates were not representative of all persons with CHD.12 We conducted a systematic review and meta‐analysis of population‐based studies reporting long‐term survival of persons born with CHD. The aim was to assess and quantify long‐term survival to inform health services planning and decision making.
We conducted comprehensive literature searches of Medline, Embase, and Scopus from inception (1946, 1974, and 1996, respectively) to June 18, 2015. MeSH terms and keywords were entered systematically into the databases. The keywords included congenital and heart or cardiac or cardiovascular and subject heading searches such as “exp Heart Defects, Congenital/ep, mo” but varied according to database. The list of search terms is available from the authors.
After systematic searches of each database, the citations were extracted, and titles and abstracts were screened according to the inclusion criteria. Full articles were retrieved for all relevant citations. Reference lists of included articles were scanned and examined, and key journals were searched using keywords.
Population‐based original studies were included if they (1) ascertained all persons born with CHD within a predefined geopolitical area; (2) reported survival estimates (or the number of patients born and the number or proportion alive) at age ≥5 years; (3) reported survival estimates for all CHD combined or a single CHD subtype including ventricular septal defect, pulmonary valve stenosis, atrial septal defect, aortic valve atresia or stenosis, atrioventricular septal defect, coarctation of aorta, common arterial truncus, pulmonary valve atresia (with ventricular septal defect or with intact ventricular septum), tetralogy of Fallot, total anomalous pulmonary venous return, transposition of great vessels, tricuspid atresia, single ventricle, hypoplastic left heart, and Ebstein's anomaly; (4) were available from the British Library or the Internet and were written in the English language.
Articles were excluded if patients were not followed from birth (eg, follow‐up began in adulthood or after surgical correction); patients were not born in well‐defined regions (ie, hospital‐based); survival was not estimated as a proportion of those born with CHD (eg, age‐specific population mortality rates); survival was reported only for certain subtype groups (eg, “severe” CHD). For multiple articles reported on the same data set, the largest study or the study with the most recent study period was included. Both articles were included if they reported survival for different CHD subtypes or ages.
K.E.B. performed the literature searches, screened citations, and reviewed 40 full papers. J.R. screened 10% of the titles and all abstracts to confirm decisions about inclusion, and extracted data from all included papers. There were no discrepancies between reviewers regarding article inclusion.
Study characteristics including study design, quality, data sources, prevalence estimates, and the percentage of cases with extracardiac anomalies (ie, cases of CHD occurring with another congenital anomaly not of the cardiovascular system, such as Down syndrome or cleft lip) were extracted from each article. If it was unclear whether cases with extracardiac anomalies were included, the authors were contacted.
Kaplan–Meier survival estimates and corresponding 95% CIs were obtained from each included study at ages 1 year, 5 years, 10 years, and so forth. If 95% CIs were not reported, the authors were contacted. If this was unsuccessful, the number of patients born and the proportion that survived were used to estimate binomial 95% CIs, assuming no cases were censored. Survival estimates for all CHD subtypes combined and for each CHD subtype were extracted. If survival estimates were presented only graphically, the authors were contacted for survival estimates. If this was unsuccessful, survival estimates were extracted using Plot Digitizer software.13, 14
If there were at least 3 studies reporting survival, pooled estimates of survival were calculated using a meta‐analysis with random effects. Weighting for each article was allocated using the inverse of the variance. If the number of studies is small, the estimation of between‐study variance is thought to be imprecise in random‐effects models.15 Consequently, if there were only 3 studies reporting survival, the pooled survival was also estimated using fixed‐effects meta‐analysis to allow comparison. To stabilize the variance and adjust the study weights, a simplified double‐arcsine transformation was performed on the survival estimates and 95% CIs.16 The Cochrane Q test and the I2 statistic were used to test for heterogeneity in survival estimates between articles, with I2>50% indicating substantial heterogeneity.17 Random‐effects metaregression was performed for all CHD subtypes combined to assess year of delivery as a source of heterogeneity. In this analysis, the year in which the study commenced was used as an explanatory variable. The adjusted R2 value was used to estimate the proportion of between‐article variation accounted for by the year of study commencement. A bubble plot was used to present the fitted metaregression model. In this analysis, bubbles represent each article, with sizes dependent on the precision of the survival estimates. Publication bias was assessed with the Egger test.18
Analysis was performed in Stata 13 (StataCorp), and P<0.05 was considered statistically significant.
Quality appraisal was based on 4 of the 6 domains developed by Hayden et al to assess potential bias in systematic reviews of prognostic studies.19 The domains used were study ascertainment, study attrition, outcome ascertainment, and analysis. The domains relating to confounding and prognostic factors were not relevant to this review because the primary aim was to investigate unadjusted survival estimates.
Figure 1 shows a Preferred Reporting Items for Systematic Reviews and Meta‐Analyses diagram for the flow of articles through the review. Of 7840 identified articles, 16 met the inclusion criteria.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35
All included studies were conducted in high‐income Western populations, with 10 in Europe and 6 in the United States (Table 1). Although several articles reported survival of subsets of the same population, all were included because survival was reported for different CHD subtypes or at different ages. The oldest article included patients born between 1973 and 1997,22 and the most recent article included patients born between 1991 and 2007.35 Of the 16 included articles, 9 included cases with extracardiac anomalies, with ≈20% of cases occurring with other congenital anomalies in each article.23, 24, 25, 26, 28, 30, 33, 34, 35 Four articles excluded patients with trisomy 13 (Patau syndrome) and 18 (Edward syndrome) only.21, 22, 27, 29 Two articles excluded cases of CHD with any extracardiac anomalies,20, 32 and 1 did not state whether cases with extracardiac anomalies were included.31 Prevalence estimates were reported by most studies and ranged from 3.730 to 10.226 per 1000 live births when considering all CHD as a composite group.
Survival was reported to age 5 years in 5 articles,20, 21, 23, 28, 29 to age 8 years in 1 article,35 to age 10 years in 3 articles,25, 26, 27 to age 15 years in 2 articles,22, 31 to age 20 years in 1 article,32 to age 25 years in 3 articles,30, 33, 34 and to age 30 years in 1 article.24
For all CHD (as a composite group), pooled 1‐year survival from 6 articles was 87.0% (95% CI 82.1–91.2), pooled 5‐year survival from 8 articles was 85.4% (95% CI 79.4–90.5), and pooled 10‐year survival from 4 articles was 81.4% (95% CI 73.8–87.9) (Figure 2). It was not possible to pool estimates beyond 10 years because there were too few articles; however, Figure 3 shows the survival estimates plotted over increasing age, up to age 25 years. The fitted metaregression showed that survival decreases very gradually with increasing age over 25 years. There was no evidence of publication bias according to Egger tests (P=0.748 for 1 year, P=0.237 for 5 years, and P=0.601 for 10 years). There was significant heterogeneity between articles for survival at 1 year (I2=99.0%, P<0.001), 5 years (I2=99.6%, P<0.001), and 10 years (I2=99.5%, P<0.001). Metaregression showed that a more recent study period was significantly associated with increased 1‐, 5‐, and 10‐year survival (P=0.047, P=0.013, and P=0.046, respectively) (Figure 4). According to the adjusted R2 values, study period accounted for 50.9%, 62.8%, and 87.0% of the between‐article variance for 1‐, 5‐, and 10‐year survival. After adjustment for study period, however, substantial residual heterogeneity remained that was attributable to between‐study heterogeneity (I2=98.2% at age 1 year, I2=98.4% for survival at age 5 years, and I2=93.7% for survival at age 10 years).
Table 2 shows the survival estimates and pooled survival estimates for persons with CHD by subtype. Pooled 1‐year survival was lowest for those with hypoplastic left heart (17.4%, 95% CI 0.0–54.5) and greatest for those with ventricular septal defect (95.5%, 95% CI 89.0–99.2). There was significant heterogeneity of survival estimates among articles for all CHD subtypes, with the exception of tetralogy of Fallot (I2=0%, P=0.169). Heterogeneity of estimates for single ventricle was of borderline statistical significance (I2=65.0%, P=0.057). Pooled 5‐year survival varied by subtype, with survival for hypoplastic left heart at 12.5% (95% CI 0.0–41.4) and survival for ventricular septal defect at 97.7% (95% CI 93.5–99.8). With the exception of tetralogy of Fallot (I2=0.0%, P=0.957) and single ventricle (I2=26.9%, P=0.250), there was significant heterogeneity of survival estimates among articles (Table 2). It was possible to calculate pooled 15‐year survival estimates for aortic valve atresia or stenosis, atrioventricular septal defect, common arterial truncus, and coarctation of aorta but not for any other CHD subtypes. There were too few studies to calculate pooled survival beyond age 15 years, although in the few studies that reported survival into adulthood, survival was still gradually declining.
For subtypes for which just 3 studies reported survival, pooled estimates were also calculated using fixed‐effect meta‐analysis (Table 2). Pooled survival estimates were generally similar for the random‐ and fixed‐effects models, with the exception of the 10‐ and 15‐year pooled estimates for common arterial trunk (28.9% versus 35.4% and 36.5% versus 54.4%, respectively).
Quality appraisal is shown in Table 3. All articles satisfied the study ascertainment domain because, by definition, population‐based studies are representative of the population. The attrition domain was satisfied by 31% of articles because of studies failing to report the proportion of untraced cases; however, many of the studies classed unmatched cases as alive, so it is possible that all cases were traced. The outcome ascertainment domain was satisfied by 94% of studies, and the analysis domain was satisfied by 81%. Studies that did not satisfy the analysis domain were those that did not perform survival analysis and instead reported the proportion alive, which does not account for case censorship. This may have slightly inflated survival in these studies.
In this systematic review and meta‐analysis, we found that 87.0% of individuals born with CHD survived to age 1 year, 85.4% survived to age 5 years, and 81.4% survived to age 10 years. Few studies reported survival beyond age 10 years, but survival appeared to continue to gradually decrease into adulthood. There was substantial variation in survival estimates among articles, some of which was accounted for by study period, which positively affected survival.
The main strength of this systematic review is its restriction to population‐based studies. Although including hospital‐based studies would have increased the amount of data available, such studies underascertain milder CHD subtypes that do not require major medical intervention. In addition, children with severe CHD may travel to centers with specialist expertise; therefore, the survival estimates reported by hospital‐based studies can be unrepresentative of the general population of individuals with CHD. The robustness of the individual rates of bias was examined using a quality assessment with previously published domains and items.19 Although each study failed to satisfy at least 1 quality item because of the population‐based study designs, the potential for bias in each domain remained low. Moreover, for all CHD, we did not identify any significant publication bias according to the Egger test.
A further strength is the comprehensive nature of our search strategy. Three databases were searched for relevant citations, along with key journals and reference lists; therefore, the likelihood of missing key studies was limited. Full articles were reviewed by both authors to ensure that they fully met the inclusion criteria and that data were extracted correctly. A further strength is that we reported pooled estimates calculated from fixed‐ and random‐effects meta‐analyses if there were just 3 studies reporting survival. Random‐effects meta‐analysis may calculate pooled estimates using an imprecise between‐study variance if the number of studies is low.15 The pooled estimates from the fixed‐effect meta‐analyses were broadly similar to those from the random‐effects meta‐analyses but with smaller confidence intervals.
There were also several limitations. The maximum follow‐up was just 30 years, with 5 of the included studies reporting survival to just 5 years. The greatest risk of death occurred in infancy, but survival continued to decrease over follow‐up, although at a much lesser rate. A study of CHD‐related mortality rates between 1999 and 2006 in the United States showed a high mortality rate of 41.5 per 100 000 in infancy, which decreased to 1.38 between ages 1 and 4 years and stabilized at ≈0.55 between the ages of 5 and 65 years. After age 65 years, the mortality rate doubled to 1.10 per 100 000.36
A further limitation is that longer term survival estimates may not be representative of children born with CHD today. Even in the most recent studies, 25‐year survival rates related to persons born in the 1990s; in our metaregression of 1‐, 5‐, and 10‐year survival, we showed that survival estimates improved over time.
All included studies were performed in high‐income Western populations. Evidence suggests that infant mortality rates associated with congenital anomalies are greater in low‐income countries.37 Consequently, the survival estimates in this review are not likely to be globally representative. Although we included only articles written in the English language, we did not identify any relevant articles written in other languages.
Most of the included articles included cases with extracardiac anomalies20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, 34; therefore, it is difficult to assess how much of the mortality was accounted for by CHD as opposed to the co‐occurring congenital anomalies. Nevertheless, cases with extracardiac anomalies accounted for only 20% of cases, and some extracardiac anomalies were not likely to be life threatening; therefore, the impact on survival is likely to be low. All articles used all‐cause mortality, meaning that deaths may not have been directly related to the CHD diagnosis.
Although this review provides insight into long‐term mortality associated with CHD, we did not account for morbidity. Research suggests that quality of life is lower in those with CHD and that those who live with CHD can have morbidities such as endocarditis, cerebrovascular accidents, myocardial infarctions, and arrhythmias.38, 39, 40 The American Heart Association has also reported that children with CHD are at increased risk of developmental disorders.41 Research suggests that children with CHD are more likely to require special education services, regardless of CHD severity.42
In our metaregression, we found that a more recent study period positively affected survival estimates; however, even after adjustment for study period, there was still a high degree of heterogeneity. Although we adjusted for study period using the year of study commencement, the lengths of the study periods varied by article; therefore, our adjustment for the year of study commencement is not likely to have fully accounted for the changes in survival over time. Further heterogeneity is likely attributable to a variety of sources. Case ascertainment is likely a major cause. Olsen et al reported lower survival estimates even after accounting for study period, but their prevalence of CHD was almost half that of other studies. Given that they included only cases diagnosed before age 1 year, it is likely that they underascertained cases with milder CHD subtypes, such as ventricular septal defect.30 The data sources used may also have contributed to variation in ascertainment, with articles using hospital records as opposed to congenital anomaly registers (which use multiple sources for ascertainment) contributing to lower survival estimates, likely due to the milder cases being underascertained.31
Variation in study periods is arguably the greatest source of heterogeneity for survival estimates. Survival has improved over time because of advances in surgical correction. The Fontan operation, for example, for repair of single ventricle, hypoplastic left heart, and tricuspid atresia and the conduit repair for cases of common arterial trunk were introduced in the late 1970s and developed throughout the 1980s and 1990s.43, 44 The arterial switch operation for treatment of transposition of the great vessels was introduced in 197545 and fully replaced the atrial switch operations in the early 1990s, resulting in improved long‐term survival.46 Survival is also likely to have improved over time because of advances in prenatal diagnosis. Greater prenatal diagnosis rates may have led to an increase in rates of termination (for fetal anomaly). If cases with the more severe subtypes were terminated, this would have resulted in better survival. Prenatal diagnosis also allows quicker intervention at birth or even in utero, which may also improve survival.47 In addition, survival is likely to have improved because of the introduction of prostaglandin, which underwent trials in neonates with cyanotic CHD in the 1970s,48, 49 although it was not frequently administered until the 1980s.
The improvement in survival rates over time has led to an emerging population of adolescents and adults with CHD. These patients require long‐term follow‐up, sometimes leading to reinvestigation and reoperation. Consequently, population‐based surveillance of CHD is crucial to adequately assess the variety of health and social services required by those with CHD throughout their lives.
Sources of Funding
Best is funded by the British Heart Foundation (FS/12/23/29511).
Thanks to Harper Gilmour, Saeed Dastgiri, Wendy Nembhard, Philip Moons and Ying Wang for providing further information on their studies. We thank Dr Svetlana Glinianaia, Prof Fiona Matthews and Dr Angela McBrien for their helpful comments on this manuscript.
- ↵Dolk H, Loane M, Garne E. Congenital heart defects in Europe: prevalence and perinatal mortality, 2000 to 2005. Circulation. 2011;123:841–849.
- ↵Oster ME, Lee KA, Honein MA, Riehle‐Colarusso T, Shin M, Correa A. Temporal trends in survival among infants with critical congenital heart defects. Pediatrics. 2013;131:e1502–e1508.
- ↵Bourdial H, Jamal‐Bey K, Edmar A, Caillet D, Wuillai F, Bernede‐Bauduin C, Boumahni B, Robillard PY, Kauffmann E, Laffitte A, Touret Y, Cuillier F, Fourmaintraux A, Alessandri JL, Gérardin P, Randrianaivo H. Congenital heart defects in La Réunion Island: a 6‐year survey within a EUROCAT‐affiliated congenital anomalies registry. Cardiol Young. 2012;22:547–557.
- ↵Plot Digitizer . 2015. Available at: http://plotdigitizer.sourceforge.net/. Accessed June 2015.
- ↵Borenstein M, Hedges L, Rothstein H. Introduction to meta‐analysis. 2007.
- ↵Barendregt JJ, Doi SA, Lee YY, Norman RE, Vos T. Meta‐analysis of prevalence. J Epidemiol Community Health. 2013;67:974–978.
- ↵Higgins J, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ. 2003;327:557–560.
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- ↵Dastgiri S, Gilmour WH, Stone DH. Survival of children born with congenital anomalies. Arch Dis Child. 2003;88:391–394.
- ↵Fixler DE, Nembhard WN, Salemi JL, Ethen MK, Canfield MA. Mortality in first 5 years in infants with functional single ventricle born in Texas, 1996 to 2003. Circulation. 2010;121:644–650.
- ↵Jackson M, Walsh KP, Peart I, Arnold R. Epidemiology of congenital heart disease in Merseyside—1979 to 1988. Cardiol Young. 1996;6:272–280.
- ↵Nembhard WN, Salemi JL, Ethen MK, Fixler DE, Dimaggio A, Canfield MA. Racial/Ethnic disparities in risk of early childhood mortality among children with congenital heart defects. Pediatrics. 2011;127:e1128–e1138.
- ↵Gilboa SM, Salemi JL, Nembhard WN, Fixler DE, Correa A. Mortality resulting from congenital heart disease among children and adults in the United States, 1999 to 2006. Clinical perspective. Circulation. 2010;122:2254–2263.
- ↵Rosano A, Botto LD, Botting B, Mastroiacovo P. Infant mortality and congenital anomalies from 1950 to 1994: an international perspective. J Epidemiol Community Health. 2000;54:660–666.
- ↵Knowles RL, Day T, Wade A, Bull C, Wren C, Dezateux C; Defects UKCSoCH . Patient‐reported quality of life outcomes for children with serious congenital heart defects. Arch Dis Child. 2014;99:413–419.
- ↵Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilén U, Kaemmerer H, Moons P, Meijboom F, Popelová J. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow‐up period the Euro Heart Survey on adult congenital heart disease. Eur Heart J. 2005;26:2325–2333.
- ↵Warnes CA. The adult with congenital heart diseaseborn to be bad? J Am Coll Cardiol. 2005;46:1–8.
- ↵Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor JW, Mussatto KA, Uzark K, Goldberg CS, Johnson WH. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management a scientific statement from the American Heart Association. Circulation. 2012;126:1143–1172.
- ↵Riehle‐Colarusso T, Autry A, Razzaghi H, Boyle CA, Mahle WT, Braun KVN, Correa A. Congenital heart defects and receipt of special education services. Pediatrics. 2015;136:496–504.
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- Harris EA
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- ↵Freud LR, McElhinney DB, Marshall AC, Marx GR, Friedman KG, Pedro J, Emani SM, Lafranchi T, Silva V, Wilkins‐Haug LE. Fetal aortic valvuloplasty for evolving hypoplastic left heart syndrome: postnatal outcomes of the first 100 patients. Circulation. 2014;130:638–645.
- ↵Olley PM, Coceani F, Bodach E. E‐type prostaglandins: a new emergency therapy for certain cyanotic congenital heart malformations. Circulation. 1976;53:728–731.