Congenital heart disease
ORIGINAL ARTICLE
1
Department of Public Health
and Clinical Medicine, Umeå
University, Umeå, Sweden
2
Department of Molecular and
Clinical Medicine, Sahlgrenska
Academy, University of
Gothenburg, Gothenburg,
Sweden
3
Department of Molecular
Medicine and Surgery,
Karolinska Institutet,
Stockholm, Sweden
4
Department of Clinical
Sciences, Uppsala University,
Uppsala, Sweden
5
Department of Medical and
Health Sciences, Linköping
University, Linköping, Sweden
6
Department of Clinical
Sciences, Lund University and
Skåne University Hospital,
Lund, Sweden
Correspondence to
Dr Bengt Johansson,
Department of Public Health
and Clinical Medicine, Umeå
University, Umeå 90187,
Sweden;
bengt.johansson@umu.se
Received 9 December 2015
Revised 17 May 2016
Accepted 1 June 2016
Published Online First
21 July 2016
To cite: Berglund E,
Johansson B, Dellborg M,
et al. Heart
2016;102:1835–1839.
High incidence of infective endocarditis in adults
with congenital ventricular septal defect
Elisabeth Berglund,1 Bengt Johansson,1 Mikael Dellborg,2 Peder Sörensson,3
Christina Christersson,4 Niels-Eric Nielsen,5 Daniel Rinnström,1 Ulf Thilén6
ABSTRACT
Objective Ventricular septal defects (VSDs),
if haemodynamically important, are closed whereas small
shunts are left without intervention. The long-term
prognosis in congenital VSD is good but patients are still
at risk for long-term complications. The aim of this study
was to clarify the incidence of infective endocarditis (IE)
in adults with VSD.
Methods The Swedish registry for congenital heart
disease (SWEDCON) was searched for adults with VSD.
779 patients were identified, 531 with small shunts and
248 who had the VSD previously closed. The National
Patient Register was then searched for hospitalisations
due to IE in adults during a 10-year period.
Results Sixteen (2%) patients were treated for IE, 6
men and 10 women, with a mean age of 46.3
±12.2 years. The incidence of IE was 1.7–2.7/1000 years
in patients without previous intervention, 20–30 times
the risk in the general population. Thirteen had small
shunts without previous intervention. There was no
mortality in these 13 cases. Two patients had undergone
repair of their VSD and also aortic valve replacement
before the episode of endocarditis and a third patient
with repaired VSD had a bicuspid aortic valve, all of
these three patients needed reoperation because of their
IE and one patient died. No patient with isolated and
operated VSD was diagnosed with IE.
Conclusions A small unoperated VSD in adults carries
a substantially increased risk of IE but is associated with
a low risk of mortality.
INTRODUCTION
In the current era, patients with a ventricular septal
defect (VSD) in general have a favourable long-
term prognosis.1 In regions with a developed
healthcare system, shunts of haemodynamic
importance are diagnosed early in life and surgi-
cally closed before irreversible pulmonary hyper-
tension occurs. Small shunts are usually left
without intervention and the long-term prognosis
is, in general, good.2 The current European guide-
lines suggest that patients with a VSD are followed
in clinic at intervals ranging from 1 to 5 years
depending on clinical factors such as type of VSD,
associated lesions and symptoms.3 Besides problems
emanating from associated lesions such as aortic
valve disease, infective endocarditis (IE) may be a
concern.4
Recent guidelines have restricted prophylaxis for
endocarditis in patients with congenital heart disease
to a few high-risk lesions that do not include VSD.5
One rationale for this is that prophylaxis has not
Berglund E, et al. Heart 2016;102:1835–1839. doi:10.1136/heartjnl-2015-309133
proved effective.6 7 On the other hand, there is evi-
dence that the incidence of IE has increased after
application of the more restrictive guidelines in the
UK.8 Among all patients with IE, 10–13% have an
underlying congenital heart lesion.9 10 The inci-
dence of IE in patients with VSD is difficult to assess
due to inclusion bias and heterogenic populations.
The reported incidence in adults varies between
1.45 and 8/1000 years.2 4 11 In children 0–18 years,
however, an incidence of 0.24/1000 years has been
reported.12 Such estimations must, however, be
related to the risk in the general population. In
Sweden, the contemporary incidence of endocarditis
in the general population is reported to be 0.08
cases/1000 years.13
In the present study, all adult patients with VSDs
in the national registry of congenital heart disease
were identified. The National Patient Register was
then searched for hospital admissions for IE in
order to determine the incidence of IE in adults
with VSDs and, if possible, identify subgroups of
patients with higher or lower risk.
PATIENTS AND METHODS
The Swedish National Register on Congenital
Heart Disease
This registry study is based on data in the Swedish
National Register on Congenital Heart Disease
(SWEDCON, http://www.ucr.uu.se/swedcon/). The
registry has since 1998 covered all seven healthcare
regions in Sweden, although registration started
earlier in some centres. All seven Swedish univer-
sity hospitals are participating and an increasing
number of the county hospitals. Data are collected
by each centre and contains information on diagno-
ses, interventions, demographics, functional class,
symptoms, quality of life (EQ-5D), social variables,
ECG, exercise tests, self-reported level of physical
exercise, echocardiography, medications and pace-
makers/implatable cardioverter defibrillators. Since
the merging of the paediatric and adult congenital
heart registry in 2008, patients are entered into the
registry as children by paediatric cardiologists and
subsequently reported to the adult part of the regis-
ter at age 18. The register is updated at every clinic
visit and the addition of retrospective data is sup-
ported and encouraged. All data collected until 17
February 2013 were considered. Data were
obtained from the last available clinic visit/test.
Patients
The SWEDCON adult congenital heart disease
section which at the time of data extraction
1835
 Congenital heart disease

contained information on 9864 patients was searched using the
following inclusion criteria: adult age (≥18 of age), main diag-
nosis VSD and at least one clinical visit. Patients with associated
complex congenital heart defects were excluded (eg, tetralogy of
Fallot, coarctation of the aorta, transposition of the great arter-
ies, Eisenmenger physiology and single ventricle), whereas those
with simple associated lesions (ie, aortic valve disease, atrial
septal defects and persistent ductus arteriosus) were included.
After application of these criteria, 779 patients remained for
analysis. The study was approved by the Regional Ethical Board
in Umeå (Dnr 08-218 M and 2012-445-32 M).
The National Patient Register
In Sweden, The National Board of Health and Welfare records
all diagnoses at hospital discharges in the National Patient
Register. All hospitals are by law required to report all dis-
charges, including discharge diagnosis, to the National Board of
Health and Welfare.
All patients with VSD identified in the SWEDCON were then
matched with the National Patient Register, using the unique
10-digit personal identifier that all people permanently residing
in Sweden are given. All matching hospital discharges for the
treatment of IE were identified for the last 10 years but for
patient age >18 years. All episodes of endocarditis were manu-
ally edited to avoid errors, such as transferrals between
hospitals, for example, cases with first diagnosis in the local hos-
pital with transferral to a regional cardiology department and
finally intervention in an institution for cardiothoracic surgery
was recorded as one episode of endocarditis. None of the
patients reported by The National Board of Health and Welfare
had a previous episode of endocarditis in the SWEDCON
register.
Statistics
Means and standard deviations were calculated for continuous
variables. Student’s t-test and χ2 tests were applied to compare
patients with and without intervention. CIs were calculated for
the mortality rates.14 Data were processed in Excel and SPSS
V.22 (IBM, Armonk, New York, USA).
RESULTS
All patients
Seven hundred and seventy-nine patients were identified, 386 men
and 393 women, with a mean age of 39.0±14.7. 531 had small
shunts without previous intervention, whereas 248 had their VSD
closed. Associated lesions were more common in patients with a
closed VSD. The clinical data are shown in table 1. Patients with a
previous intervention were more often on medication, had un-
dergone interventions for other simple lesions and had more
complications than those without a previous intervention (table 1).

Table 1 Overview of all patients

All No intervention Intervention
patients (for VSD) (for VSD) p Value

Sex, n (%)
Male 386 (49.6) 257 (48.4) 129 (52.2) 0.35
Female 393 (50.4) 274 (51.6) 119 (48.0)
Age (years), 39.0 (14.7) 39.2 (15) 38.8 (14.2) 0.72
mean±SD
NYHA-class, n (%) 0.29
I 552 (87.6) 378 (89.4) 174 (84.0)
II 49 (7.8) 27 (6.4) 22 (10.6)
III 14 (2.2) 8 (1.9) 6 (2.9)
Not defined 15 (2.4) 10 (2.4) 5 (2.4)
BMI (kg/m2), 24.6 (4.5) 24.8 (4.4) 24.7 (4.8) 0.68
mean±SD
Systolic BP, mean±SD 125 (16) 125 (17) 124 (16) 0.56
Medication (yes), n (%) 131 (16.8) 69 (13.2) 62 (25.4) <0.001
Atrial fib/flutter (yes), n 14 (1.8) 5 (0.9) 9 (4.0) 0.018
(%)
PM/ICD, n (%) 23 (2.9) 6 (1.1) 17 (6.8) <0.001
Other interventions, n
ASD 46 (5.9) 2 (0.4) 44 (17.7) <0.001
PDA 21 (2.7) 3 (0.6) 18 (7.2) <0.001
AVR 19 (2.4) 3 (0.6) 16 (6.4) <0.001
LV function, n (%) <0.001
Normal 631 (93.8) 445 (97.2) 186 (86.5)
Mildly impaired 20 (3.0) 8 (1.7) 12 (5.6)
Mod impaired 17 (2.5) 4 (0.9) 13 (6.0)
Severely impaired 5 (0.7) 1 (0.2) 4 (1.9)
Smoking, n (%) 0.20
Yes 84 (12.1) 57 (11.1) 27 (11.4)
Previous 27 (3.9) 18 (3.5) 9 (3.8)
No 581 (84.0) 391 (76.2) 190 (80.2)
Overview of the patients with a VSD with or without intervention. The p values derive from tests between patients with and without intervention. Values in bold denote p<0.05.
ASD, atrial septal defect; AV, atrio-ventricular block; AVR, aortic valve replacement; BMI, body mass index; BP, blood pressure; ICD, implatable cardioverter defibrillator; LV, left
ventricle; MR, mitral regurgitation; ND, no data; NYHA, New York Heart Association Class; PDA, persistent ductus arteriosus; PM, pacemaker.

1836 Berglund E, et al. Heart 2016;102:1835–1839. doi:10.1136/heartjnl-2015-309133

 Congenital heart disease

Table 2 Overview of the patients with infective endocarditis

Age Age IE Sex PI Smoking LV function Surgery at IE Additional diagnosis Outcome

1 72 62 F No Normal No PS Alive
2 36 26 M No Normal No Alive
3 35 26 M No Normal No Alive
4 52 45 F No Normal No Alive
5 44 39 F No Normal No Alive
6 65 57 F No Mod depressed No Alive
7 56 49 F Unknown Normal No Alive
8 61 58 M Unknown Normal No Alive
9 51 43 F No Normal No Alive
10 60 54 F Unknown Normal No Alive
11 65 60 F No Normal No Alive
12 52 47 M No Normal No PS Alive
13 41 32 F No Normal No Alive
14 31 27 F 1 No Mildly depressed Yes BAV, AV I-II Alive
15 41 39 M 2 Yes Normal Yes MR, AR, CoA Alive
16 54 54 M 3 No ND No PS, BAV Deceased
Overview of the 16 patients with infective endocarditis (IE).
1, closure of ventricular septal defect (VSD), pacemaker, aortic valve replacement (AVR); 2, commissurotomy, closure of VSD, AVR; 3, closure of VSD, pacemaker, coronary artery bypass
graft; AR, aortic regurgitation; AV I–II, atrio-ventricular block degree I–II, BAV, bicuspid aortic valve; CABG, coronary artery by-pass grafting; CoA, coarctation of the aorta; F, female;
M, male; PI, previous intervention; PS, pulmonary stenosis; VSD, ventricular septal defect.

Patients with endocarditis

Sixteen patients with IE were identified, 6 men and 10 women, Table 3 Incidence of infective endocarditis
with a mean age of 46.3±12.2 years at the time of IE. Thirteen Endocarditis Observed
episodes of IE were identified among the 531 patients with Group (n) years Incidence
small shunts without previous intervention. None of the patients
VSD without intervention 8 4720 1.7/1000(95% CI
with small shunts needed intervention and none of them died. (previously known in the 0.7to 3.3/1000)
In addition, we found 3 cases of IE among the 248 patients register)
who had had their VSD previously closed. Among those three, VSD without intervention (all) 13 4765 2.7/1000 (95% CI
two had in addition aortic valve replacement >3 months, prior 1.4 to 4.7/1000)
to the IE. The third patient with closed VSD had the infection All VSD(±intervention) 16 6954 2.3/1000 (95% CI
localised to a bicuspid aortic valve. Eight of the patients with 1.3 to 3.7/1000)
small shunts were known in the registry prior to the IE and five Closed VSD 0 2189 0
were included after or in relation to their infection. The three Incidence of infective endocarditis in relation to inclusion in the registry before or
patients with previous aortic valve disease were known in the after the IE, in all patients with or without previous closure of the shunt and those
with previous closure of the shunt.
registry before the IE. All these three needed reintervention VSD, ventricular septal defect.
on the aortic valve and one of them died from complications
(table 2). None of the patients with an isolated and previous
closed VSD had IE. also regarded to have a limited selection bias.11 15 Neumayer
et al reported an incidence of 8/1000 patient-years, around four
times higher than in our study. However, emanating from a ter-
Incidence of IE
tiary referral centre makes selection bias and overestimation of
For all patients, the incidence was 2.3/1000 years, for those
the risk very probable.4 In a single-centre study of 91 patients
with an isolated VSDs and previously known in the registry 1.7/
followed up to 40 years after closure VSD, the cumulative inci-
1000 years and including all patients with isolated VSDs 2.7/
dence of endocarditis was 4%. In one of these cases, the infec-
1000 years (table 3). There was no obvious change in the inci-
tion was pacemaker related.16
dence of IE over time.
When compared with the general population, the influence of
age must be considered, generally the risk of IE doubles from
DISCUSSION the age of 40 to 60.17 The mean age in our patient cohort was
This study on IE in adult patients with VSD is to our knowledge 39 and, considering the exclusion of those younger than
the largest so far presented and it demonstrates an incidence 18 years of age, this is clearly lower than the mean age in the
exceeding 2/1000 patient-years, at least a 20-fold to 30-fold general population if children <18 years are excluded. The
increased risk compared with the general population. In terms mean age at the time of IE in our series was 46 that should be
of ratios, 2% of the cohort was diagnosed with endocarditis. compared with 66 years in IE in general in Sweden.13 Thus, if
Despite this high prevalence, no mortality was observed in age-matched, the increased risk of IE in VSD might even be
patients with an isolated VSD and IE. higher than the above-mentioned 20–30 times.
The risk of selection bias should be low as this study is based IE in general as well as in valvular heart disease has a male
on a national registry in contrast to, for example, reports from predominance, not because of the sex per se but rather to differ-
single centres. It is, therefore, not surprising that our findings ences in the distribution of underlying cardiac lesions and differ-
on the incidence harmonise with two earlier but smaller studies ences in life style.17 However, in our study, the overall sex
Berglund E, et al. Heart 2016;102:1835–1839. doi:10.1136/heartjnl-2015-309133 1837
 Congenital heart disease
distribution is equal, as expected in VSD, but females dominate
when it comes to IE, 9 out of 13 with an isolated VSD and IE
were women. There is no obvious reason for that and it might
be just by chance as the numbers are small.
The importance of associated lesions, particularly aortic valve
disease, in this context, is emphasised by our findings. A pros-
thetic aortic valve increases the risk of IE and also carries a high
risk of a complicated course and reoperation. The higher inci-
dence of IE when there are associated lesions could support
the opinion that the risk of IE in congenital heart disease is not
the risk of the lesion with the highest risk but rather the sum
of the risks of the individual lesions.
All 13 patients with IE and a VSD without previous interven-
tion were conservatively managed and all of them survived the
infection. Relatively young age and a low degree of comorbidity
could be factors contributing to the favourable outcome.
However, as the registry does not provide data on morbidity
and complications, such a statement should be read with
caution and it is clear that there is a need of deeper exploration
of the subject.
In the new ESC guidelines on endocarditis, patients with VSD
were not judged to belong to a high-risk group. Considering the
outcome of IE, our findings support that view as the mortality
rate appears to be low and that IE is not associated with the need
for surgery. No episode of IE was observed in patients with previ-
ously closed VSD. The observed numbers are, however, small
and it is difficult to conclude that closure of the VSD, based on
the present data, is associated with a lower risk of IE.
During the period of investigation, 2003–2013, the more
restrictive ESC recommendations on antibiotic prophylaxis were
introduced in Sweden. Moreover, we do not know to what
extent they have been applied and there is no information in the
SWEDCON registry on such prophylaxis. However, having the
low numbers in mind, there was no obvious change in incidence
of IE over time in our study.
In a small study also including children, VSD was the most
common underlying pathology in IE related to congenital heart
disease.18 This reflects that VSD is a common congenital heart
lesion and, also in children, the risk of IE is higher in cyanotic
heart disease and in AV-septal defects.12
Limitations
The conclusions are restricted to the patients within the
SWEDCON registry and it cannot be ruled out that there are
patients who are not followed up and therefore not found in
the registry. Besides mortality and surgical interventions, the
registry does not provide detailed information about complica-
tions and outcome, that is, there are no data in the register or in
the information provided by the National Board of Health and
Welfare with details on the localisation of the IE.
The detected number of cases is fairly small and it cannot be
ruled out that some observations, for example distribution of IE
between sexes, are affected by chance. Therefore, descriptive
statistics within the group of 16 patients with IE must be inter-
preted with caution. The prevalence of IE, however, has a
narrow 95% CI (2.3%, 95% CI 1.3 to 3.7%) and the incidence
reported here is in line with previous reports.
In conclusion, we demonstrate that a small VSD carries a sub-
stantially increased risk of IE, that closure of the ventricular
septal may reduce this risk and that IE in cases with a small VSD
without previous intervention is associated with a low risk of
mortality. Healthcare providers should be aware that this seem-
ingly simple heart lesion is associated with a high risk of IE.
1838
Key messages
What is already known on this subject?
There are data on the incidence of infective endocarditis, but
are based on fairly small cohorts and single-centre reports.
What might this study add?
Here, we add data from a national registry combined with
information from a national database on hospital discharges.
In adult patients with an isolated small ventricular septal defect,
the incidence of infective endocarditis is approximately 2/1000
patient-years, that is, 20–30 times as high as in the general
population. In contrast, when a ventricular septal defect is
closed, the risk of infective endocarditis is very low.
How might this impact on clinical practice?
Clinicians should be aware of this high risk of endocarditis. In
cases with borderline haemodynamic indication for closure of the
ventricular septal defect, the low risk of endocarditis after closure
may be an argument in favour of closure. The relative high risk of
endocarditis warrants that the patients are seen periodically,
although with long intervals, to be informed on, for example,
dental hygiene and symptoms of infective endocarditis.
Contributors EB: Planning of study, data collection, establishing of database,
analysis of data and drafting of manuscript. BJ: Planning of study, data collection,
analysis of data and drafting of manuscript. MD, PS, CC and N-EN: Planning of
study, data collection, critical revision and approving of manuscript. DR: Planning of
study, analysis of data, critical revision and approving of manuscript. UT: Planning of
study, data collection and drafting of manuscript.
Funding This study was supported by the Swedish Heart-Lung Foundation (Project
grant 2014–2017), Umeå University and the county councils of Västerbotten and
Västernorrland.
Competing interests None declared.
Ethics approval Regional Ethics Board, Umeå University.
Provenance and peer review Not commissioned; externally peer reviewed.
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