JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO.

21, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.03.572

Preterm Birth and Risk of Heart Failure

Up to Early Adulthood
Hanna Carr, BS,a Sven Cnattingius, MD, PHD,a Fredrik Granath, PHD,a Jonas F. Ludvigsson, MD, PHD,b,c
Anna-Karin Edstedt Bonamy, MD, PHDa,d

ABSTRACT

BACKGROUND In small clinical studies, preterm birth was associated with altered cardiac structure and increased
cardiovascular mortality in the young.

OBJECTIVES The goal of this study was to determine the association between preterm birth and risk of incident heart
failure (HF) in children and young adults.

METHODS This register-based cohort study included 2,665,542 individuals born in Sweden from 1987 to 2012 who
were followed up from 1 year of age to December 31, 2013. The main study outcome was diagnosis of HF in the National
Patient Register or the Cause of Death Register. The association between preterm birth and risk of incident HF was
analyzed by using a Poisson regression model. Estimates were adjusted for maternal and pregnancy characteristics,
socioeconomic status, and maternal and paternal cardiovascular disease.

RESULTS During 34.8 million person-years of follow-up (median 13.1 years), there were 501 cases of HF. After exclusion
of 52,512 individuals with malformations (n ¼ 196 cases), 305 cases of HF remained (0.88 per 100,000 person-years).
Gestational age was inversely associated with the risk of HF. Compared with individuals born at term ($37 weeks’
gestation), adjusted incidence relative risks for HF were 17.0 (95% confidence interval [CI]: 7.96 to 36.3) after extremely
preterm birth (<28 weeks) and 3.58 (95% CI: 1.57 to 8.14) after very preterm birth (28 to 31 weeks). There was no risk
increase after moderately preterm birth (32 to 36 weeks) (relative risk: 1.36; 95% CI: 0.87 to 2.13).

CONCLUSIONS There was a strong association between preterm birth before 32 weeks of gestation and HF in
childhood and young adulthood. Although the absolute risk of HF is low in young age, our findings indicate that preterm
birth may be a previously unknown risk factor for HF. (J Am Coll Cardiol 2017;69:2634–42) © 2017 by the American
College of Cardiology Foundation.

B etween 5% and 13% of all live births occur

before term (<37 weeks of gestation) (1,2).
Although prematurity is still the main cause
of neonatal death globally, high-income countries
have experienced dramatic increases in survival rates
in preterm infants over the past few decades (2,3).
Knowledge about how the burdens of prematurity
may be carried into later life in these steadily growing
generations of new survivors is important for
improving neonatal care, for meeting the future
medical needs of these subjects, and for developing
appropriate preventive measures.
Results from previous studies suggest that survi-
vors of preterm birth are at increased risk of hyper-
tension, stroke, and cardiovascular mortality but not
ischemic heart disease (4–8). To the best of our
knowledge, the association between preterm birth
and risk of heart failure (HF) has not previously been
explored. HF in children and young adults is an un-
usual but dangerous condition with high mortality

Listen to this manuscript’s

audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aClinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; bDepartment of
Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; cÖrebro University Hospital, Örebro, Sweden;
and the dDepartment of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden. This study was funded by the
Swedish Research Council for Health, Working Life and Welfare (Dr. Bonamy, 2010-0643), Swedish Society for Medical Research
(Dr. Bonamy), Stockholm County Council (Dr. Bonamy, clinical research appointment), the Swedish Heart and Lung Foundation
(Dr. Bonamy, 20160578), and the Karolinska Institutet Distinguished Professor Award (Dr. Cnattingius). All other authors have
reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received October 14, 2016; revised manuscript received February 19, 2017, accepted March 20, 2017.
JACC VOL. 69, NO. 21, 2017
MAY 30, 2017:2634–42
rates (9,10). Congenital heart disease and cardiomy-
opathies, particularly idiopathic dilated cardiomyop-
athy, are the main causes of HF at young age (11–13).
Incidence data for pediatric HF are scarce but were
estimated to be 0.87 per 100,000 person-years in a
study in the United Kingdom and Ireland of HF
caused by cardiac muscle disease (14). Between 1987
and 2006, the incidence of HF among young adults in
Sweden increased by 50%, and the proportion of
cardiomyopathies as an underlying cause of HF
increased from 15% to 25% (15).
Preterm birth entails exposure of the immature
infant heart to extrauterine conditions. Evidence
from animal models and small studies of preterm
infants shows that preterm birth interferes with
normal cardiac development in the neonatal period
(16–19). In a cardiac imaging study of adults born
preterm, ventricular mass in adulthood was seen to
increase with lower gestational age at birth. Preterm
birth was also associated with further alterations in
cardiac structure and function (20).
SEE PAGE 2643
We hypothesized that preterm birth is associated
with an increased risk of later HF. In a nationwide
Swedish cohort study including >2.6 million live
births, we investigated the association between
gestational age at birth and risk of incident HF in
childhood and young adulthood.
PATIENTS AND METHODS
STUDY DESIGN AND POPULATION. This registry-
based cohort study included 2,665,542 individuals
born in Sweden and registered in the Medical Birth
Register between 1987 and 2012 (Figure 1). Individuals
were followed up from 1 year of age until death,
emigration, first diagnosis of HF or ischemic heart
disease, or end of study (December 31, 2013), which-
ever came first. Start of follow-up was set to 1 year of
age to avoid measuring HF as an immediate compli-
cation during neonatal care.
A unique personal identity number given to all
Swedish residents allows for comprehensive
cross-linking with other national registries (21). The
caregivers are required by law to contribute informa-
tion to these registries. The Medical Birth Register was
started in 1973 and covers >98% of all births in Sweden
(22). Since 1982, it is based on copies of standardized
clinical record forms used in all antenatal care clinics
and delivery and neonatal wards in the country, and it
contains data on both mother and infant. The National
Patient Register contains data on patient diagnoses
and medical and surgical procedures (23). The registry
Carr et al. 2635
Preterm Birth and Risk of HF
covers all hospitalizations in Sweden from ABBREVIATIONS
1987 onward, and information on hospital- AND ACRONYMS
based outpatient care is included from 2001.
CI = confidence interval
The Cause of Death Register provides infor-
HF = heart failure
mation on causes and dates of death in
ICD = International
Sweden from 1961 (24). The Multi-Generation
Classification of Diseases
Register was created in 2000, and it includes
RR = relative risk
individual index-persons born after 1932 who
were alive in 1961 and links them to their parents (25).
Information on educational level was collected from
the Swedish Register of Education (26). Date of
emigration was retrieved from the Register of the
Total Population (27).
EXPOSURES. Data on the main exposure (i.e., gesta-
tional age at birth) were retrieved from the Medical
Birth Register and categorized into 22 to 27 weeks
(extremely preterm), 28 to 31 weeks (very preterm), 32
to 36 weeks (moderately preterm), and $37 weeks
(term). Since the early 1990s, all pregnant women in
Sweden are offered a diagnostic ultrasound scan in
the early second trimester, usually between weeks 17
and 20, and >96% accept (28). When no information
on ultrasound dating of pregnancy was available, the
last menstrual period was used for assessing gesta-
tional age.
Data on size at birth were calculated as deviation
from the estimated weight for gestational age and
sex, based on the Swedish reference curve for intra-
uterine growth (29). Individuals were categorized as
very small (<2 SD), small (2 SD to <1 SD), appro-
priate (1 SD to 1 SD), large (>1 SD to 2 SD) or very
large (>2 SD). These data were also used to statisti-
cally correct for the possibility that an association
between preterm birth and later HF is confounded by
low birth weight for gestational age, a proxy for poor
fetal growth.
OUTCOMES. The primary outcome was a diagnosis of
incident HF without a previous diagnosis of ischemic
heart disease in the National Patient Register or the
Cause of Death Register. The International Classifi-
cation of Diseases (ICD)-9th revision (ICD-9; used
between 1987 and 1996) and 10 (ICD-10; introduced in
1997) were used to define HF (ICD-9 code 428 and
ICD-10 code I50) and ischemic heart disease (ICD-9
codes 410 to 414 and ICD-10 codes I20 to I25).
OTHER VARIABLES. From the Medical Birth Register,
we included information on maternal factors such
as age at delivery, country of birth, singleton or
multiple pregnancy, diagnosis of hypertension, pre-
eclampsia, diabetes mellitus, or gestational diabetes.
Data on maternal smoking in the Medical Birth
Register were divided into 2 groups according
to information collected at the first antenatal visit,
2636 Carr et al.
Preterm Birth and Risk of HF
F I G U R E 1 Study Population
Live births in Sweden 1987-2012, n=2,714,789
Missing personal identification number, n=22,828
Missing information on gestational age, n=3,217
Missing or unreasonable birth weight, n=8,896
Death <1 year of age, n=9,399
Emigration <1 year of age, n=3,881
Diagnosis of heart failure <1 year of age, n=753
Diagnosis of ischemic heart disease <1 year of age, n=81
Did not reach 1 year of age before 31 Dec 2013, n=192
Final study population, n=2,665,542
Flow chart of inclusions and exclusions in the study.
usually in weeks 8 to 12 of pregnancy. This informa-
tion has been routinely collected since 1983, but data
are sometimes missing, particularly for mothers of
preterm individuals. Information on highest attained
level of maternal education was retrieved from the
Education Register and was categorized as #9 years,
10 to 12 years, or $13 years of education.
Individuals born with malformations that could
possibly correlate with risk of HF were identified by
searching the Medical Birth Register and the National
Patient Register for 1 of the following ICD-9 or ICD-10
diagnoses: malformations of the circulatory system
(745.0 to 747.9 or Q20 to Q28), congenital malforma-
tion syndromes due to known exogenous causes not
classified elsewhere (759.8 or Q86), other specified
congenital malformation syndromes affecting multi-
ple organ systems (743.0/755/756.0/756.7/756.8/757.1/
758.6/759.8 or Q87), other congenital malformations
not classified elsewhere (759.0 to 759.9 or Q89), or
chromosomal abnormalities (758.0 to 758.9 or Q90 to
Q99). Children with a diagnosis of patent ductus
arteriosus (747A or Q25.0) were not excluded from
our analysis because this condition is very common
after preterm birth and is a possible mediator of HF.
By using the Multi-Generation Register, it was
possible to trace the registered father for almost 99% of
individuals in the cohort. This approach enabled a
search for both maternal and paternal diagnoses of HF
or ischemic heart disease or death from HF or ischemic
heart disease in the National Patient Register and Cause
of Death Register, using the aforementioned ICD-9
and ICD-10 codes plus the earlier ICD version 8 codes
for HF (428) and ischemic heart disease (410 to 414).
JACC VOL. 69, NO. 21, 2017
MAY 30, 2017:2634–42
STATISTICAL ANALYSIS. The association between
preterm birth and HF was assessed in a Poisson
regression analysis. Relative risks (RRs) (adjusted
incidence rate ratios) and corresponding 95% confi-
dence intervals (CIs) for each gestational age category
were modeled by using log (person-years at risk) as an
offset. Covariates for the adjusted models were cho-
sen on the basis of an association with our main
outcome at a level of p #0.20. Birth year period (1987
to 1995, 1996 to 2003, and 2004 to 2012), attained age
during follow-up (in 5-year intervals), maternal age
and education, subject sex, and birth weight were
included as covariates in the first adjusted model (or
gestational age in analyses of the association between
birth weight for gestational age and risk of HF). In the
second model, we also adjusted for maternal or
paternal HF or ischemic heart disease. Adjusted
models 1 and 2 were applied both before and after
excluding individuals with malformations. Because of
the large number of missing data on maternal smok-
ing among preterm individuals, we adjusted for
maternal smoking habits in a separate model,
including individuals with complete data on all
covariates.
Incidence rates for HF were also calculated on the
basis of gestational age at birth and attained age at
time of diagnosis (Online Table 1). Using a Poisson
regression model, we estimated unadjusted incidence
rate ratios for the same age intervals, also presented
in Online Table 1. All data were analyzed by using SAS
version 9.4 software (SAS Institute, Inc., Cary, North
Carolina).
ETHICS. Ethical permission was obtained from
the Regional Ethical Vetting Board in Stockholm
(Etikprövningsnämnden) with the registration
number 2011/195-31/2.
RESULTS
Among 2,665,542 individuals included in the study,
156,879 (5.9%) were born preterm; 5.14% were
moderately preterm, 0.56% very preterm, and 0.18%
extremely preterm (Online Table 2). Preterm
individuals were more often low birth weight for
gestational age than individuals born at term.
Mothers of preterm individuals were more likely to be
younger (#19 years of age) or older ($35 years of age),
to have lower levels of education, to be smokers, and
of non-Nordic origin. Maternal pregnancy complica-
tions and multiple pregnancies were more common in
women with preterm births.
During follow-up (beginning at 1 year of age),
there were 501 cases of HF. Three of these cases were
deaths caused by HF. Total time of follow-up was
JACC VOL. 69, NO. 21, 2017 Carr et al. 2637
MAY 30, 2017:2634–42 Preterm Birth and Risk of HF

34.8 million person-years, yielding an incidence of

T A B L E 1 Cohort Characteristics in Relation to Outcome: Children Born in Sweden
1.4 per 100,000 person-years. After exclusion of 1987–2012, Follow-Up From 1 Yr of Age
52,512 individuals born with malformations (as
Unadjusted IRR
specified in the Patients and Methods section), there No. of Incidence (95% CI)
were 305 cases of HF in 34.2 million person-years of Total % Cases Rate* for HF

follow-up (incidence 0.89 per 100,000 person-years). All subjects 2,665,542 100.0 501 1.44 –

The median individual time of follow-up for all Subject characteristics

Sex
subjects was 13.1 years (IQR: 6.1 to 20.1 years).
Female 1,296,690 48.6 211 1.25 1.00 (reference)
Cohort characteristics in relation to outcome are
Male 1,368,852 51.4 290 1.62 1.30 (1.09–1.56)
presented in Table 1. Individuals diagnosed with HF
Birth period
were more often male than the healthy population. 1987–1995 1,009,608 37.9 381 1.77 1.72 (1.25–2.35)
Mothers of children later diagnosed with HF were 1996–2003 711,370 26.7 77 0.84 0.81 (0.56–1.18)
more often smokers and had lower levels of educa- 2004–2012 944,564 35.4 43 1.03 1.00 (reference)
tion. Maternal and paternal HF or ischemic heart Malformations

disease was also more frequent in subjects with HF. Yes 52,512 1.98 196 30.7 34.5 (28.8–41.2)
No 2,613,030 98.0 305 0.89 1.00 (reference)
PRETERM BIRTH AND RISK OF HF. Numbers and
Patent ductus arteriosus
incidence rates of HF in relation to gestational age Yes 8,840 0.33 45 43.6 33.2 (24.4–45.1)
at birth are presented in Table 2. Incidence rates of No 2,656,702 99.7 456 1.31 1.00 (reference)
HF were inversely related to gestational age at birth. Maternal and pregnancy characteristics
Preterm birth was associated with an increased risk Age

of HF across all 3 categories of prematurity, and risks #19 yrs 38,255 1.44 12 2.15 1.39 (0.78–2.50)
20–24 yrs 389,956 14.6 85 1.46 0.95 (0.73–1.22)
increased with decreasing gestational age.
25–29 yrs 861,936 32.3 187 1.55 1.00 (reference)
After exclusion of individuals with major congen-
30–34 yrs 868,124 32.6 143 1.34 0.87 (0.70–1.08)
ital malformations and adjustment for maternal 35–39 yrs 415,752 15.6 54 1.15 0.75 (0.55–1.01)
characteristics, subject sex, birth period, and birth $40 yrs 91,519 3.43 20 2.01 1.30 (0.82–2.07)
weight for gestational age, the risk of HF was 17 times Education
higher in subjects born extremely preterm, and 3.6 #9 yrs 264,007 10.0 76 2.17 1.75 (1.34–2.29)

times higher in subjects born very preterm, compared 10–12 yrs 1,203,184 45.6 245 1.45 1.17 (0.97–1.42)
$13 yrs 1,174,185 44.5 176 1.24 1.00 (reference)
with subjects born at term (Table 2). Additional
Missing data 24,166 4 – –
adjustment for parental cardiovascular disease only
Smoking habits (at first antenatal visit)
minimally attenuated relative risks for HF. Adjusting
Nonsmoker 2,152,861 85.5 361 1.36 1.00 (reference)
for maternal smoking habits did not alter the Smoker 366,709 14.6 102 1.66 1.22 (0.98–1.52)
described associations (Online Table 3). There was no Missing data 145,972 38 – –
significant increase in risk of HF for subjects born Country of birth
moderately preterm in the adjusted models. Sweden 2,194,530 82.7 418 1.41 1.00 (reference)

The median age at diagnosis of HF was 16.5 years Other Nordic country 71,440 2.69 19 1.75 1.11 (0.85–1.44)
Other 387,934 14.6 62 1.56 1.23 (0.78–1.95)
(IQR: 5.2 to 19.7 years). Online Table 1 displays age-
Missing data 11,638 2 – –
specific incidence rates for HF in relation to gesta-
Hypertensive disease
tional age at birth. Incidence rates dropped after the No 2,572,282 96.5 484 1.44 1.00 (reference)
first 5 years of life and then rose again after 16 years of Hypertension 16,310 0.61 2 1.02 0.71 (0.18–2.83)
age. Subjects born before 32 weeks of gestation had Preeclampsia 76,950 2.89 15 1.54 1.07 (0.64–1.79)
the highest incidence rates of HF across all age cate- Diabetes
gories. The same pattern was seen after excluding No 2,630,853 98.7 498 1.45 1.00 (reference)
Diabetes mellitus 10,666 0.40 1 0.71 0.49 (0.12–1.95)
subjects born with malformations.
Gestational diabetes 24,023 0.90 2 0.76 0.53 (0.07–3.76)
BIRTH WEIGHT FOR GESTATIONAL AGE AND RISK
Multiple pregnancy 71,997 2.70 17 1.88 1.32 (0.81–2.14)
OF HF. We also found an association between low Maternal or paternal HF or ischemic heart disease
birth weight for gestational age and increased risk of Maternal 17,981 0.67 16 4.61 3.28 (1.99–5.40)
HF (Table 3). Compared with infants born with Paternal 65,682 2.47 24 1.90 1.34 (0.89–2.03)
appropriate birth weight for gestational age, those Missing data 21,058 – – –

born very small for gestational age (>2 SDs below the
*Events per 100,000 person-yrs.
mean) had a 3-fold risk of subsequent HF in the CI ¼ confidence interval; HF ¼ heart failure; IRR ¼ incidence rate ratio.
unadjusted analysis. After excluding subjects with
2638 Carr et al. JACC VOL. 69, NO. 21, 2017

Preterm Birth and Risk of HF MAY 30, 2017:2634–42

T A B L E 2 Associations Between Gestational Age at Birth and Incident HF: Unadjusted and Adjusted IRRs (95% CIs) for Incident HF in
Relation to Gestational Age at Birth

Unadjusted IRR Adjusted Model 1: IRR Adjusted Model 2: IRR

N No. of Events Incidence Rate* (95% CI) (95%CI)† (95% CI)‡

All subjects, N ¼ 2,665,542

Gestational age at birth
<28 weeks 4,845 11 20.1 15.0 (8.25–27.3) 13.0 (7.08–23.8) 12.9 (7.06–23.7)
28–31 weeks 14,951 9 4.71 3.52 (1.82–6.80) 2.60 (1.33–5.09) 2.60 (1.33–5.08)
32–36 weeks 137,083 42 2.32 1.73 (1.26–2.38) 1.54 (1.11–2.12) 1.54 (1.11–2.12)
$37 weeks 2,508,663 439 1.34 1.00 (reference) 1.00 (reference) 1.00 (reference)
Subjects with malformations excluded, n ¼ 2,613,030
Gestational age at birth
<28 weeks 4,219 7 14.2 16.8 (7.95–35.7) 17.1 (8.00–36.4) 17.0 (7.96–36.3)
28–31 weeks 13,656 6 3.38 4.01 (1.79–9.01) 3.57 (1.57–8.11) 3.58 (1.57–8.14)
32–36 weeks 131,522 21 1.20 1.43 (0.92–2.23) 1.36 (0.87–2.12) 1.36 (0.87–2.13)
$37 weeks 2,463,328 271 0.84 1.00 (reference) 1.00 (reference) 1.00 (reference)

*Events per 100,000 person-yrs. †Model 1: adjusted for maternal age and education, subjects’ period of birth, attained age during follow-up, sex, and birth weight for
gestational age. ‡Model 2: in addition to the factors noted in model 1, also adjusted for maternal or paternal HF or ischemic heart disease.
Abbreviations as in Table 1.

malformations and taking maternal characteristics
and gestational age into account in the adjusted
models, this association was weakened and no longer
significant. There was no indication of confounding
by parental cardiovascular disease.
DISCUSSION
PRINCIPAL FINDINGS. This registry-based cohort
study of >2.6 million children and young adults
found that preterm birth was associated with an
increased risk of incident HF, also after adjustment
for birth weight for gestational age and potential
confounders. The RR was inversely related to gesta-
tional age at birth (Central Illustration). Individuals
born extremely preterm and very preterm faced a 17-
fold and >3-fold increased risk of HF, respectively;
corresponding risk was not significantly increased for
those born moderately preterm. A very low birth
weight for gestational age (>2 SDs below the mean)
was also associated with an increased risk of HF, but
this risk increase was not significant after adjustment
for potential confounding factors.
POTENTIAL MECHANISMS. The mechanisms
which preterm birth may influence subsequent risk of
HF in childhood and young adulthood remain elusive.
A review of existing evidence concluded that in-
dividuals born preterm have slightly higher resting
systolic blood pressure in early adulthood, which may
increase their risk of developing hypertension (4,5).
Hypertension is, in turn, 1 of the most important
risk factors for developing HF in adults, also in
the absence of ischemic heart disease (30,31).
In childhood, even mild, untreated elevation of blood
pressure may cause organ damage such as left ven-
tricular hypertrophy (31). Thus, it is plausible that an
elevation of blood pressure may contribute to the
increased risk of HF observed in preterm individuals
in our study.
Ischemic heart disease is a major cause of HF in
adults (32) but comprises a very small proportion of
HF in children and adolescents (15,33). Thus far, there
have been no data confirming a link between preterm
birth and ischemic heart disease (6,34,35). In the
present study, individuals with ischemic heart dis-
ease as first event were censored and no longer
contributed risk time in the study. Thus, ischemic
heart disease is an unlikely explanation for the
observed association between preterm birth and HF.
Instead, cardiomyopathies, including the diagnosti-
cally broad “idiopathic dilated,” are considered a
principal cause of HF in the younger population
(15,33). In individuals born preterm, such heart mus-
cle disease could be the result of cardiac remodeling
after preterm birth.
The current understanding of cardiac develop-
ment is that cardiomyocytes proliferate until late
by gestation and switch to an adult hypertrophic
growth mode shortly after birth (36–38). Animal
models show that the immature cardiomyocytes of
the preterm heart adapt to extrauterine conditions
through structural remodeling, which may have an
impact on future cardiac function (16,17). In a small
echocardiographic study of preterm infants, there
were signs of delay in maturation of the myocardium
at 28 days of age (18). The same study found signs of
left ventricular diastolic dysfunction and greater
dependence on atrial contraction in preterm infants.
JACC VOL. 69, NO. 21, 2017 Carr et al. 2639
MAY 30, 2017:2634–42 Preterm Birth and Risk of HF

T A B L E 3 Associations Between Birth Weight for Gestational and Incident HF: Crude and Adjusted IRRs (95% CIs) for Incident HF in
Relation to Birth Weight for Gestational Age

Unadjusted IRR Adjusted Model 1: IRR Adjusted Model 2: IRR

N No. of Events Incidence Rate* (95% CI) (95% CI)† (95% CI)‡

All subjects, N ¼ 2,665,542

Birth weight for gestational age
Very small 73,937 44 4.33 3.36 (2.45–4.61) 2.69 (1.94–3.73) 2.66 (1.92–3.70)
Small 366,036 87 1.80 1.40 (1.10–1.78) 1.31 (1.03–1.67) 1.25 (0.98–1.60)
Appropriate 1,794,551 301 1.29 1.00 (reference) 1.00 (reference) 1.00 (reference)
Large 338,333 56 1.27 0.99 (0.74–1.31) 1.00 (0.75–1.33) 1.00 (0.75–1.34)
Very large 92,685 13 1.09 0.84 (0.48–1.47) 0.84 (0.48–1.47) 0.84 (0.48–1.47)
Subjects with malformations excluded, n ¼ 2,613,030
Birth weight for gestational age
Very small 70,378 17 1.75 2.07 (1.26–3.40) 1.61 (0.97–2.68) 1.59 (0.95–2.65)
Small 357,453 48 1.02 1.20 (0.88–1.65) 1.13 (0.82–1.55) 1.06 (0.76–1.47)
Appropriate 1,762,768 194 0.84 1.00 (reference) 1.00 (reference) 1.00 (reference)
Large 332,025 40 0.92 1.09 (0.78–1.54) 1.11 (0.79–1.56) 1.12 (0.79–1.57)
Very large 90,406 6 0.51 0.61 (0.27–1.37) 0.62 (0.28–1.40) 0.62 (0.27–1.40)

*Events per 100,000 person-yrs. †Model 1: adjusted for maternal age and education, subjects’ period of birth, attained age during follow-up, sex, and birth weight for
gestational age. ‡Model 2: in addition to the factors noted in model 1, also adjusted for maternal or paternal HF or ischemic heart disease.
Abbreviations as in Table 1.

In addition to the major circulatory transition that
occurs at birth, the preterm heart is often exposed to
conditions that increase cardiac workload (e.g., pat-
ent ductus arteriosus), leading to important left-to-
right shunting and bronchopulmonary disease with
the risk of pulmonary hypertension (39). A cardiac
imaging study of preterm infants found that patent
ductus arteriosus was associated with significantly
increased end-diastolic volumes and increased left
ventricular mass (19). However, it is unclear to what
extent such changes are reversed after ductal
closure.
Evidence of modulation of cardiac structure and
function has also been found in older survivors of
preterm birth. One study included 102 individuals
born preterm who underwent cardiovascular mag-
netic resonance imaging at 20 to 39 years of age;
they were compared with control subjects born at
term (20). Ventricular mass in young adulthood
increased with decreasing gestational age at birth.
Higher systolic blood pressure in preterm
dividuals could not alone explain this finding, as the
increase in ventricular mass was disproportionate
relative to any elevation in blood pressure. There
were no observable differences in left ventricular
ejection fraction between the 2 groups, but both
stroke volume and end-diastolic volume were lower
in individuals born preterm. Preterm-born
dividuals also had reduced diastolic myocardial
relaxation. Moreover, their right ventricular function
was compromised, and 6% had a right ventricular
ejection fraction below clinical reference values
(40). We speculate that such alterations of cardiac
function in preterm individuals may be a conse-
quence of the combination of interrupted normal
cardiac development and postnatal exposure to
circulatory challenges, and HF could ultimately be
an expression of this.
STUDY STRENGTHS. Strengths of the current study
include the very large cohort and the registry-based
nondifferential follow-up. Sufficient statistical po-
wer allowed us to examine the risk of HF even among
extremely preterm infants, although they only
comprised 0.18% of our cohort. Dividing gestational
age into 4 categories also enabled us to show a strong
dose–response relationship between low gestational
age at birth and later HF. We were able to control for
many confounding factors, including maternal and
pregnancy characteristics, heritability of heart dis-
ease, and birth weight for gestational age. We had
information on congenital malformations, and
in- including or excluding children with malformations
yielded essentially the same results among in-
dividuals born extremely preterm and very preterm.
The National Patient Register and Cause of Death
Register were used to ascertain HF. After excluding
subjects born with congenital malformations, we
found an incidence of 0.88 per 100,000 person-years,
in- which is almost identical to that of a British-Irish
study (0.87 per 100,000 person-years) (14). The val-
idity of the HF diagnosis is high in Swedish registers,
with a positive predictive value of 82% and even 95%
for those with a primary diagnosis of HF (41).
2640 Carr et al.
Preterm Birth and Risk of HF
C E N T R A L IL LU ST R A T I O N Risk of HF in Childhood and Young Adult Age in Relation to
Gestational Age at Birth
Carr, H. et al. J Am Coll Cardiol. 2017;69(21):2634–42.
Subjects with malformations excluded, n ¼ 2,613,030. Incidence rate ratios (95% confidence intervals) adjusted for maternal age and education,
subjects’ periods of birth, attained age during follow-up, sex, birth weight for gestational age, and maternal and paternal cardiovascular disease.
HF ¼ heart failure.
STUDY LIMITATIONS. The limitations of our study are
typical for registry-based research. Children born at
low gestational age are generally subject to closer
medical follow-up, especially during their first years of
life. Thus, we cannot rule out that surveillance bias has
influenced our results. To avoid measuring HF as a
direct complication in the neonatal period, all in-
dividuals diagnosed with HF before 1 year of age were
excluded. We were unable to investigate if and how a
hemodynamically significant patent ductus arteriosus
and its treatment relate to risk of later HF because of
the low number of HF cases in the lowest gestational
ages and the probable underreporting of patent ductus
arteriosus diagnosis in the national
compared with other prospective national cohorts
(42). The same limitation applies to the use of ante-
natal corticosteroids, diagnosis of bronchopulmonary
dysplasia, and duration of mechanical ventilation,
which may all be factors that are potential mediators of
the association between preterm birth and later risk of
HF.
HF can be difficult to diagnose in a young patient,
and reduced cardiac function may remain silent and
unreported for a long time (13,43). If this is the case,
our findings may be a late reflection of a more direct
JACC VOL. 69, NO. 21, 2017
MAY 30, 2017:2634–42
effect of prematurity. We attempted to investigate
this topic further by looking closer at age at diagnosis,
and we found that the excess incidence of HF in those
born very or extremely preterm was higher at 1 to 5
years of age compared with later. This outcome could
also be explained by those extravulnerable to disease,
having already developed HF by the time they reach
the age of the expected increase in incidence (i.e.,
depletion of susceptible effect). Another possibility is
that subjects born in earlier birth years, thus
contributing longer follow-up, are not representative
of more recent preterm births. In summary, given the
age profile of our cohort, this study captured effects
registries, of prematurity in childhood and adolescence but not
effects later in adulthood.
Our results show a strong association between
gestational age and risk of HF. However, the total
number of cases of HF in our material is small (501 cases
in >2.6 million individuals), with only 11 cases among
those born extremely preterm. Any minor change in
the number of cases would thus influence effect size.
The great risk increase for HF we have observed in the
most preterm subjects may be decreased but not easily
silenced by such alterations. Also, we have excluded
all cases of HF before 1 year of age (n ¼ 753), which
JACC VOL. 69, NO. 21, 2017 Carr et al. 2641
MAY 30, 2017:2634–42 Preterm Birth and Risk of HF

could have influenced the association between pre- cardiac health in survivors of extremely and very
term birth and HF. Longitudinal follow-up would bring preterm birth.
us closer to the true nature of this relationship, but as
most survivors of extremely preterm birth are still ADDRESS FOR CORRESPONDENCE: Dr. Hanna Carr,
young, this scenario will not be possible for some time Clinical Epidemiology Unit, T2, Karolinska University
yet. Furthermore, the outpatient section of the Na- Hospital, Solna, 171 76 Stockholm, Sweden. E-mail:
tional Patient Register was not established until 2001, hanna.carr@ki.se.
which further limited our possibility of observing
patients over time or investigating underlying causes PERSPECTIVES
of HF in this particular cohort (23).
COMPETENCY IN MEDICAL KNOWLEDGE: Survivors of
CONCLUSIONS
preterm birth are at higher risk of developing hypertension and
cardiovascular mortality in young adulthood than those born at
This study found a strong association between
term. The relationship between gestational age also applies to the
preterm birth and risk of incident HF in children and
risk of developing HF.
young adults. The increase in risk was inversely
related to gestational age at birth, although absolute
TRANSLATIONAL OUTLOOK: Further research is needed to
risks were low. Considering the rising number of
elucidate the mechanisms compromising cardiac function after
individuals surviving preterm birth and the potential
preterm birth and evaluate interventions to improve long-term
consequences of early onset of reduced cardiac
cardiovascular health in these individuals.
function, the problem may grow with time. There
may be a need for closer follow-up and assessment of

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KEY WORDS cardiovascular disease,
epidemiology, neonatology, pediatrics, risk
factor
A PPE NDI X For supplemental tables, please
see the online version of this article.