RESEARCH Open Access
Tetralogy of Fallot in Spain: a nationwide
registry-based mortality study across 36
years
Laura Llamosas-Falcón1, Eva Bermejo-Sánchez2, Germán Sánchez-Díaz2,3,4, Ana Villaverde-Hueso2,3,
Manuel Posada de la Paz2,3 and Verónica Alonso-Ferreira2,3*
Abstract
Background: Tetralogy of Fallot (TOF) is the most frequent cyanotic congenital heart defect. TOF mortality has
fallen remarkably in recent years due to therapeutic advances. Accordingly, the aim of this study was to assess
temporal and spatial variability in TOF-related mortality in Spain across the period 1981–2016, using data drawn
from the nationwide population-based registry.
Methods: Annual deaths due to TOF were sourced from the Spanish National Institute of Statistics database by
reference to International Classification of Diseases (ICD), 9th and 10th Revision codes, namely, ICD-9 code 745.2
(period 1981–1998) and ICD-10 code Q21.3 (period 1999–2016). Age-specific and age-adjusted mortality rates were
calculated, as were standardised mortality ratios (SMRs) by province, district and municipality for the period 1999–2016.
Results: A total of 1035 deaths were attributed to TOF (57.78% of them were men and 42.22% were women). The age-
adjusted mortality rate ranged from 0.75 per 1,000,000 inhabitants (95% confidence interval [CI]: 0–1.36) in 1981 to 0.03
per 1,000,000 (95% CI: 0.01–0.06) in 2016 for both sexes. In 2011, there was a change in the mortality trend, with a
significant decrease of 49.22% per year (p < 0.001). In terms of geographical analysis, some areas with a significantly
higher risk of TOF mortality were identified in the south of Spain, though no specific spatial pattern was in evidence.
Conclusion: The decrease in TOF mortality may be related to improvements in diagnostic and treatment techniques.
More studies are needed to analyse regions with a higher mortality risk, in order to improve medical planning and
resource allocation, and identify risk factors and preventive measures.
Keywords: Congenital heart defect, Tetralogy of Fallot, Mortality, Spain, Temporal-analysis, Spatial-analysis
Background
Tetralogy of Fallot (TOF) is a structural congenital heart
defect characterised by the presence of four cardiac defects:
infundibular stenosis of the pulmonary artery, overriding
aortic root, ventricular septal defect, and right ventricle
hypertrophy [1, 2]. TOF has an estimated world-wide
prevalence of 3 cases per 10,000 live births and can thus be
considered a rare disease [3, 4]. Despite its low prevalence,
it ranks among the most frequent congenital heart defects
(CHD). The global birth prevalence of CHD in the general
population is 0.8%, and TOF represents 5–10% of all CHD
[5, 6]. A CHD study conducted at a regional level in Spain
confirmed that TOF is the most frequent cyanotic CHD,
with a birth prevalence of 0.41% [7]. At a European level,
EUROCAT (the European population-based consortium
registry on congenital anomalies) data show a significant
increase in TOF prevalence from 2004 to 2012 [8]. In
contrast, a recent nationwide registry-based study in Spain
reported decreasing trends in mortality rates due to con-
genital anomalies from 1999 to 2013 [9].
In the absence of treatment, TOF’s natural disease course
leads to high morbidity and mortality [10]. Although mor-
tality from this cause has been reduced as a consequence
of the impact of surgical interventions, patients still have a
high risk of premature death, as compared to the general
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: valonso@isciii.es
2Institute of Rare Diseases Research (IIER), Instituto de Salud Carlos III, 28029
Madrid, Spain
3Centre for Biomedical Network Research on Rare Diseases (CIBERER), 28029
Madrid, Spain
Full list of author information is available at the end of the article
Llamosas-Falcón et al. Orphanet Journal of Rare Diseases           (2019) 14:79 
https://doi.org/10.1186/s13023-019-1056-y
population [11]. This serves to highlight the interest that
lies in analysing and monitoring mortality directly related
to TOF. Mortality analyses provide information on demo-
graphic change, and allow for socio-economic strategies to
be designed with the aim of improving the health and
well-being of the population [9, 12].
While several studies have specifically analysed TOF
patient mortality following surgical repair of the defect
[11, 13–15], others have focused on overall CHD mortal-
ity [16–18]. In addition, some other TOF studies report
on long-term outcome and survival analyses [19–23].
As regards geographical variability, Garcia et al. [24]
reported significant differences in the distribution of
CHD cases with postnatal diagnosis in Colombia but
failed to find any specific pattern in this distribution. In
China, a progressive increase in the prevalence of atrial
septal defect and patent ductus arteriosus was observed
in areas of higher altitude [25]. A cluster of births with
TOF was found in a largely agricultural area of North
Carolina (USA) but there was insufficient evidence to
conclude that this was due to any given environmental
factor [26]. In Spain, a temporal and spatial analysis of
CHD prevalence was carried out in the Valencian Region
(Comunidad Valenciana) in the east of Spain, where the
authors found a heterogeneous geographic pattern [27].
In a recent study mentioned above [9], a high risk of
premature death due to congenital anomalies was specif-
ically identified in the south of Spain but, apart from this
analysis, no population-based studies on TOF-attributed
mortality in Spain have been reported to date, and there
is no nationwide study on the subject, all of which make
the present study unique.
Accordingly, the aim of this study was to analyse the
mortality trends due to TOF in Spain over a lengthy
period of time spanning 36 years (1981–2016), in order
to assess whether there has been some kind of trend,
and to try and discern possible geographical differences
in the risk of death attributed to this disease.
Results
A total of 1035 TOF-related deaths were identified in
Spain during the period 1981–2016 (631 from 1981 to
1998, and 404 from 1999 to 2016), 57.78% of which were
males (598 males vs. 437 females). The mean age of
death was 16.28 ± 19.41 years and the median was 5
years, with no statistically significant differences between
the sexes (p = 0.100). In both sexes combined, the age
groups “less than 1 year” and “1–4 years” registered the
highest percentage of deaths (19 and 29.5% respectively),
meaning that 48.5% of the 1035 TOF deaths occurred
before the age of 5 years.
Figure 1 depicts the age-specific mortality rates, with
the mortality rate being highest among children under
one year of age (12.98 per 1,000,000) and then dropping
sharply after 5 years of age (0.26 per 1,000,000). The same
pattern was observed for both males and females.
In terms of the trend over time, the crude TOF mortality
rate was seen to drop from 1.11 per 1,000,000 in 1981 to
0.03 in 2016. The age-adjusted mortality rate, likewise for
both sexes, decreased from 0.75 per 1,000,000 inhabitants
(95% confidence interval [CI]: 0–1.36) in 1981 to 0.03 per
1,000,000 (95% CI: 0.01–0.06) in 2016 (non-smoothed
values). The Joinpoint model (Fig. 2a) showed that there
was no significant trend in the adjusted rates from 1981 to
2010 but that from 2011 onwards there was a decrease of
49.22% per year (p < 0.001). The trend in age-adjusted
rates is shown for each sex in Fig. 2b (smoothed values).
In recent decades, a progressive decrease was in evidence,
Fig. 1 Annual age-specific mortality rates attributed to Tetralogy of Fallot by sex
Llamosas-Falcón et al. Orphanet Journal of Rare Diseases           (2019) 14:79 Page 2 of 8
with the trend in smoothed rates being similar for both
sexes, whether considered jointly or separately.
Insofar as the geographical analysis is concerned,
the variability in SMRs across the period 1999–2016
is depicted in Fig. 3 with a breakdown by province,
district and municipality. A heterogeneous distribu-
tion is observed without any evident defined spatial
pattern. It would, however, seem that regions with
SMRs higher than 1 are located mainly, though not
exclusively, in areas of southern Spain. When the
TOF mortality in adjacent regions (smoothed data not
shown) was taken into account, the variability de-
tected in the smoothed model was completely blurred,
with no differences among municipal results.
Table 1 shows the provinces, districts and munici-
palities with SMRs significantly above or below 1 for
the period 1999–2016. At a provincial level, whereas
mortality in Madrid was significantly lower than ex-
pected (for both sexes combined and for males alone),
it was significantly higher than expected (for both
sexes) in Las Palmas. At a district level, the risk of
mortality for both sexes combined was lower than ex-
pected in different districts of the province of Madrid
(“Sur Occidental” and “Área Metropolitana”), and
higher than expected in Las Palmas (“Gran Canaria”),
Seville (“La Sierra Sur”) and Murcia (“Suroeste”).
Among females, the SMR was also higher than ex-
pected in one district of the province of Murcia
(“Campo de Cartagena”), while among males the Madrid
district of “Area Metropolitana” was identified as having a
lower-than-expected SMR.
In the case of municipalities, as many as 27 had sig-
nificantly higher risks of premature death, when both
sexes were jointly analysed. Taking males and females
separately, the number of municipalities with SMRs sig-
nificantly higher than 1 was 22 and 13 respectively, and
only one municipality had an SMR significantly lower
than 1, in men. These municipalities were distributed
throughout the territory, without displaying any specific
spatial grouping.
Fig. 2 Age-adjusted mortality rates due to Tetralogy of Fallot in Spain, 1981–2016. a Mortality trend plotted using a Joinpoint regression model;
b Smoothed annual rates by sex
Llamosas-Falcón et al. Orphanet Journal of Rare Diseases           (2019) 14:79 Page 3 of 8
Discussion
This nationwide study, which is the first to analyse mor-
tality directly related to TOF in Spain over a period of
36 years, detected a significant decrease in mortality
rates since 2011 and a higher-than-expected risk of
death in certain regions of the country.
This observed decline over time in mortality can be
accounted for by several factors. Advances in prenatal diag-
nosis, that have enabled earlier detection of foetal anomal-
ies [23, 28–31], specifically in Spain [32–34], plus advances
in surgical intervention techniques [13, 14, 20, 35], also in
Spain [36], are the main factors identified as being respon-
sible for the decrease in mortality. In addition, this down-
turn has also been influenced by the implementation of and
improvement in cardiac rehabilitation programmes [37–39]
coupled with ambulatory management and follow-up [40].
An increase in the prevalence of CHD in the period
2004–2012 was detected in EUROCAT, the population-
based registry of congenital anomalies, and attributed to
the proliferation of the main risk factors associated with
CHD [8]. Similarly, prevalence of CHD was observed to
increase in the Valencian Region across the period 1999–
2008, possibly due to improvements in diagnostic tech-
niques [27]; and indeed, the spread in the use of such
techniques might also account for part of this same
rise. According to our data, the increase in prevalence
observed by these studies has not triggered an increase
in absolute TOF mortality figures in Spain, as might
Fig. 3 Geographical representation of standardised mortality ratios (SMRs) for tetralogy of Fallot in Spain, 1999–2016. a Provinces; b Districts;
c Municipalities
Llamosas-Falcón et al. Orphanet Journal of Rare Diseases           (2019) 14:79 Page 4 of 8
have been expected. While elective terminations of
pregnancy due to foetal anomalies (ETOPFA) are regis-
tered by EUROCAT, they do not appear in our analysis
because NSI mortality figures do not include ETOPFA
or stillbirths. In all probability, ETOPFA have contrib-
uted to the birth of a higher proportion of less severely
affected cases, with a consequently lower risk of associ-
ated mortality [41, 42].
With regard to early diagnosis, in some cases this con-
genital anomaly can only be diagnosed postpartum. All
intrauterine imaging methods have their limitations, des-
pite the fact that there have been significant advances in
these techniques [30]. Moreover, the prognosis for TOF
cases detected in the prenatal period is worse than for
those identified in the postnatal period, probably be-
cause the former tend to be more severely affected and
this leads to their early detection. In fact, a higher inci-
dence of chromosomal abnormalities, extra cardiac malfor-
mations and complex forms of TOF are usually associated
with cases detected in the prenatal stage [29, 31]. Despite
this, early diagnosis provides benefits when it comes to
maintaining a close follow-up of the pregnancy [43]. This
is also true for postnatally detected cases. The recent use
of pulse oximetry for the screening of critical CHD is cap-
able of detecting around six infants having a critical CHD
such as TOF, among 10,000 apparently healthy newborn
infants screened [44], and this will surely have an impact
on morbidity and mortality in future analyses.
Age-specific mortality rates are higher in the first year
of life and up to 5 years of age, decreasing thereafter
with increasing age. It is important to take this informa-
tion into account because it allows for those in charge of
medical care to focus a special follow-up on this specific
age range and monitor the different determinants of
early death [9].
The number of patients reaching adult ages is in large
part determined by the mortality arising from the sur-
gery required in some cases, and by the increase of
post-surgery survival over the years [13, 20, 22, 45–48].
This has given rise to an increasing number of surviving
adults with complex CHD. Nevertheless, these patients
still face premature death when they are young adults,
with the causes of death mainly being heart failure or
sudden death [17, 49]. The excess mortality in young
adults as compared to the general population renders
close specialist life-long follow-up of this group of pa-
tients advisable [17, 18, 50, 51].
In connection with age of death, studies suggest that,
in an elderly population, the medical conditions of co-
morbidity acquired throughout life, including heart
Table 1 Standardised mortality ratios (SMRs) by province, district and municipality in 1999–2016, and 95% confidence intervals, global
and by sex. Only those with statistically significant lower of higher-than-expected SMRs after indirect standardisation are shown
Risk Location Province District Municipalityb Both sexes Male Female
Low risk C Madrid 0.63 (0.43–0.89) 0.49 (0.27–0.75)
C Madrid Sur Occidental 0 (0.00–0.59) 0 (0.00–0.99)
C Madrid Area Metropolitana 0.52 (0.26–0.93)
C Madrid Madrid Horcajuelo de la Sierra 0.31 (0.10–0.74)
High risk SWa Las Palmas 1.80 (1.05–2.89)
SWa Las Palmas Gran Canaria 1.92 (1.05–3.22)
SW Seville Sierra Sur 5.09 (1.02–14.86)
SE Murcia Suroeste 2.88 (1.05–6.27)
SE Murcia Campo de Cartagena 3.90 (1.26–9.11)
NE Barcelona Osona Gurb 2.79 (1.02–6.07) 4.65 (1.25–11.90)
N Vizcaya Vizcaya Arrankudiaga 2.84 (1.22–5.59) 3.61 (1.32–7.87)
SE Murcia Suroeste Aledo 3.03 (1.01–6.59) 5.10 (1.37–13.05)
SW Cadiz La Janda Barbate 3.85 (1.04–9.87)
C Madrid Campiña Loeches 9.44 (1.06–34.07) 23.71 (2.66–85.60)
E Castellon Llanos Centrales Benasal 10.23 (1.15–36.92)
N Palencia Campos Villovieco 10.41 (1.17–37.58)
SWa Las Palmas Fuerteventura Oliva (La) 11.06 (1.30–41.88)
E Valencia Sagunto Segart 13.97 (1.57–50.44)
NE Barcelona Osona Tona 14.98 (1.68–54.08)
aIsland territories (Canary and Balearic Islands)
C = Centre; E = east; N = north; NE = north-east; NW = north-west; S = south; SE = south-east; SW = south-west; W =west
bSmall significant municipalities are not displayed because of the numerical instability (population < 5000 inhabitants and SMR > 20)
Llamosas-Falcón et al. Orphanet Journal of Rare Diseases           (2019) 14:79 Page 5 of 8
failure, diabetes, other chronic diseases and cancer, as
well as advanced age per se, have a greater impact on
mortality than suffering from a CHD [16, 52]. This could
also influence the lower risk observed by us of
TOF-related death at older ages, for which there might
well be a predominance of the above-mentioned causes.
In terms of geographical analysis, while some provinces
show a lower-than-expected risk, a series of significantly
higher-than-expected risks of TOF-related mortality were
observed in some demarcations, mostly in southern Spain.
Even so, the data analysed do not fit any definite spatial
country-wide pattern. The study conducted by Nelson et
al. in North Carolina (USA) showed a cluster of TOF cases
in mainly agricultural areas but did not identify any spe-
cific environmental risk factors [26]. In their spatial ana-
lysis of CHD prevalence in the Valencian Region [27], the
authors also found a heterogeneous geographical distribu-
tion which they felt might be due to differences in diag-
nostic accuracy and coding at hospitals. A recent
nationwide registry-based study reported a higher risk of
death attributed to congenital anomalies in the south of
Spain [9]. Although the Spanish National Health System
(SNHS) guarantees equal access to basic health services,
variability between provinces might be related to different
determinants, such as access to highly specialised facilities,
longer or shorter follow-up of patients, or parents’ atti-
tudes to interruption of pregnancies in the case of foetuses
affected with severe congenital heart defects. The data
presented here did not allow for inference of any common
local characteristics shared by the affected areas, but they
constitute a body of evidence which should prompt new
analytic studies and thereby allow possible links to be
established between the disease’s distribution patterns and
possible underlying environmental risk factors. This would
generate new evidence and could lead to prevention at dif-
ferent levels.
As for measures that could reduce CHD mortality,
one would be the designation of referral centres spe-
cialised in the follow-up, care and treatment of these
anomalies. Other authors have observed that neonatal
mortality increases when fewer patients are treated at
specialised centres [53]. In Sweden, centralisation of
cases in institutions specialised in paediatric cardiac
surgery reduced mortality in patients who underwent
surgical interventions [54]. These specialised hospitals
helped to adopt new treatment strategies in more
complex cases and channel information about such
strategies to local hospitals more easily. In addition,
the policy served to stimulate interest in the field and
direct research activities on paediatric diseases with
surgical treatment. In Spain, a similar designation ex-
ists in the shape of SNHS Referral Centres, Services
and Units (Centros, Servicios y Unidades de Referen-
cia/CSUR). Our data might make it advisable to
review patients’ access to specific CSUR and their dis-
tribution across the country.
The limitations of this study include those usually at-
tributed to death statistics, in which the underlying
cause of death may be underestimated due to errors of
diagnosis or coding, or to deaths being assigned to
secondary complications instead of the disease itself, i.e.,
TOF. In addition, ETOPFA and stillborn cases were not
included in our data (as vital statistics in Spain do not
include these). Furthermore, the milder forms of TOF
(with a lower mortality risk) can escape detection until
older ages, potentially biasing the results towards more
severe subtypes and higher overall mortality figures at
younger ages.
Despite these limitations, the strength of this study lies
in providing population-based information about offi-
cially reported deaths associated with this rare disease in
Spain, over the span of 36 years. Its homogeneous, stan-
dardised and continuous methodology over time, allows
this study contributing to monitoring mortality directly
associated with TOF.
Conclusions
In conclusion, this is the first nationwide population-based
study to analyse the time trend and spatial variability of
TOF-related mortality in Spain. A decrease in mortality
since 2011 was detected, as well as a heterogeneous distri-
bution throughout the country. This study not only shows
the utility of spatial modelling using population mortality
data, but can also contribute to future studies focusing on
environmental and even epigenetic risk factors. Lastly, it
gives a global view of the country, which could be used for
further analyses on access to specialised care and other
health services, ranging from pre- and neonatal screening
and surgery at early ages, to long-term care for adults or
elderly living with CHD such as TOF. Our finding of a
decrease in TOF-related mortality -and thus more persons
surviving into adulthood- means that those reaching re-
productive ages will need to be adequately informed
about their risk of having affected offspring, informa-
tion that can be provided by specialists in Genetics.
Higher survival at adult ages also implies the need to
understand the clinical course of this disorder, in order
to provide optimal medical care and anticipate possible
complications, with the aim of equalising life expect-
ancy vis-à-vis that of the general population.
Methods
We designed and conducted an observational, retrospect-
ive, descriptive study. Annual deaths registered as due to
TOF were sourced from the National Statistics Institute
(NSI) of Spain. Deaths attributed to TOF as primary cause
of death were identified by reference to International
Classification of Diseases (ICD), 9th and 10th Revision
Llamosas-Falcón et al. Orphanet Journal of Rare Diseases           (2019) 14:79 Page 6 of 8
codes for the underlying cause of death, namely, ICD-9
code 745.2 for the period 1981–1998 and ICD-10 code
Q21.3 for the period from 1999 onwards.
In addition to collecting data on age, sex, year of birth,
place of residence, registered year and place of death, we
also obtained annual Spanish population data, broken
down by sex, age and place of residence from the NSI,
which we used to calculate annual sex- and age-group
specific rates for each of the years studied.
We calculated the mean age at death, and compared
the median age of death of men and women using the
Mann-Whitney U test. Age-specific mortality rates and
annual age-adjusted mortality rates were calculated by
sex (direct standardisation using the standard European
population as reference). The age-adjusted mortality
rates were smoothed according to the non-parametric
method T4253H [55] and the time trends were assessed
using the Joinpoint regression model. All rates were
expressed per 1,000,000 inhabitants.
The study area encompassed all of Spanish territory,
made up of a total of 52 provinces, 326 districts and
8112 municipalities. For comparability reasons, geo-
graphical analysis considered the period 1999–2016 in
which municipality identification was available in all
TOF deaths. Standardised mortality ratios (SMRs) were
calculated by province, district and municipality using
the Spanish population as a reference (indirect method),
with these data also being furnished by the NSI. The
SMRs were subsequently smoothed taking into account
information pertaining to adjacent geographical units, in
accordance with the model proposed by Besag, York and
Molliè [56]. No additional data transformation was made.
All statistical analyses were performed using the SPSS
v15 (IBM Corporation, Chicago, IL, USA), EPIDAT v4.2
(General Directorate of Public Health, Galicia, Spain),
Joinpoint v4.5.0.1 (National Cancer Institute, Bethesda,
MD, USA) and R-INLA (Norwegian University of Sci-
ence and Technology, Trondheim, Norway) computer
software programmes, while QGIS v2.18.17 was used for
cartographic representation purposes.
Abbreviations
CHD: Congenital heart defects; CI: Confidence interval; ETOPFA: Elective
terminations of pregnancy due to foetal anomalies; ICD: International
Classification of Diseases; NSI: National Statistics Institute; SMR: Standardised
mortality ratio; SNHS: Spanish National Health System; TOF: Tetralogy of
Fallot
Acknowledgements
The authors would like to thank Michael Benedith for the valuable language
support and English editing of the manuscript.
Funding
This research was funded by Instituto de Salud Carlos III, Spanish Strategy
Action for Health (AESI), project TPY1238/15. The author G.S.D. received a
research grant from the Spanish Ministry of Education, Culture and Sport,
FPU14/03914.
Availability of data and materials
The datasets generated and/or analysed during the current study are available
in the National Statistics Institute (NSI) repository, at https://www.ine.es/
Authors’ contributions
Conceptualization, VA-F, EB-S and MPdlP; Methodology, VA-F, EB-S, LLL-F;
Validation, GS-D and AV-H; Formal Analysis, LLL-F and GS-D; Investigation, LLL-F,
EB-S and MPdlP; Resources, AV-H and VA-F; Data Curation, GS-D and AV-H;
Writing—Original Draft Preparation, LLL-F, EB-S and VA-F; Writing—Review &
Editing, LLL-F, VA-F, AV-H, GS-D, MPdlP and EB-S; Visualization, GS-D;
Supervision, VA-F and EB-S; Project Administration, VA-F; Funding Acquisition,
VA-F. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki,
and the protocol was approved by the Ethics Committee of the Instituto de
Salud Carlos III (CEI 50/2013).
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1Preventive Medicine and Public Health, Hospital Universitario 12 de Octubre,
28041 Madrid, Spain. 2Institute of Rare Diseases Research (IIER), Instituto de
Salud Carlos III, 28029 Madrid, Spain. 3Centre for Biomedical Network
Research on Rare Diseases (CIBERER), 28029 Madrid, Spain. 4Department of
Geology, Geography and Environmental Sciences, University of Alcala, 28801
Alcalá de Henares, Spain.
Received: 31 January 2019 Accepted: 1 April 2019
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