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Preterm Birth and Risk of Heart Failure Up to Early Adulthood
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
medical needs of these subjects, and for developing
before term (<37 weeks of gestation) (1,2).
appropriate preventive measures.
Although prematurity is still the main cause
Results from previous studies suggest that survi-
of neonatal death globally, high-income countries
vors of preterm birth are at increased risk of hyper-
have experienced dramatic increases in survival rates
tension, stroke, and cardiovascular mortality but not
in preterm infants over the past few decades (2,3).
ischemic heart disease (4–8). To the best of our
Knowledge about how the burdens of prematurity
knowledge, the association between preterm birth
may be carried into later life in these steadily growing
and risk of heart failure (HF) has not previously been
generations of new survivors is important for
explored. HF in children and young adults is an un-
improving neonatal care, for meeting the future
usual but dangerous condition with high mortality
Listen to this manuscript’s audio summary by
From the aClinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; bDepartment of
JACC Editor-in-Chief
Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; cÖrebro University Hospital, Örebro, Sweden;
Dr. Valentin Fuster.
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.
Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
2635
Preterm Birth and Risk of HF
rates (9,10). Congenital heart disease and cardiomy-
covers all hospitalizations in Sweden from
ABBREVIATIONS
opathies, particularly idiopathic dilated cardiomyop-
1987 onward, and information on hospital-
AND ACRONYMS
athy, are the main causes of HF at young age (11–13).
based outpatient care is included from 2001.
Incidence data for pediatric HF are scarce but were
The Cause of Death Register provides infor-
estimated to be 0.87 per 100,000 person-years in a
mation on causes and dates of death in
study in the United Kingdom and Ireland of HF
Sweden from 1961 (24). The Multi-Generation
caused by cardiac muscle disease (14). Between 1987
Register was created in 2000, and it includes
and 2006, the incidence of HF among young adults in
individual index-persons born after 1932 who
Sweden increased by 50%, and the proportion of
were alive in 1961 and links them to their parents (25).
cardiomyopathies as an underlying cause of HF
Information on educational level was collected from
increased from 15% to 25% (15).
the Swedish Register of Education (26). Date of
Preterm birth entails exposure of the immature infant heart to extrauterine conditions. Evidence
CI = confidence interval HF = heart failure ICD = International Classification of Diseases
RR = relative risk
emigration was retrieved from the Register of the Total Population (27).
from animal models and small studies of preterm
EXPOSURES. Data on the main exposure (i.e., gesta-
infants shows that preterm birth interferes with
tional age at birth) were retrieved from the Medical
normal cardiac development in the neonatal period
Birth Register and categorized into 22 to 27 weeks
(16–19). In a cardiac imaging study of adults born
(extremely preterm), 28 to 31 weeks (very preterm), 32
preterm, ventricular mass in adulthood was seen to
to 36 weeks (moderately preterm), and $37 weeks
increase with lower gestational age at birth. Preterm
(term). Since the early 1990s, all pregnant women in
birth was also associated with further alterations in
Sweden are offered a diagnostic ultrasound scan in
cardiac structure and function (20).
the early second trimester, usually between weeks 17 and 20, and >96% accept (28). When no information
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.
on ultrasound dating of pregnancy was available, the last menstrual period was used for assessing gestational 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 intrauterine growth (29). Individuals were categorized as very small (<2 SD), small (2 SD to <1 SD), appro-
PATIENTS AND METHODS
priate (1 SD to 1 SD), large (>1 SD to 2 SD) or very
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,
large (>2 SD). These data were also used to statistically 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.
emigration, first diagnosis of HF or ischemic heart
OUTCOMES. The primary outcome was a diagnosis of
disease, or end of study (December 31, 2013), which-
incident HF without a previous diagnosis of ischemic
ever came first. Start of follow-up was set to 1 year of
heart disease in the National Patient Register or the
age to avoid measuring HF as an immediate compli-
Cause of Death Register. The International Classifi-
cation during neonatal care.
cation of Diseases (ICD)-9th revision (ICD-9; used
A unique personal identity number given to all
between 1987 and 1996) and 10 (ICD-10; introduced in
comprehensive
1997) were used to define HF (ICD-9 code 428 and
cross-linking with other national registries (21). The
ICD-10 code I50) and ischemic heart disease (ICD-9
caregivers are required by law to contribute informa-
codes 410 to 414 and ICD-10 codes I20 to I25).
tion to these registries. The Medical Birth Register was
OTHER VARIABLES. From the Medical Birth Register,
started in 1973 and covers >98% of all births in Sweden
we included information on maternal factors such
(22). Since 1982, it is based on copies of standardized
as age at delivery, country of birth, singleton or
clinical record forms used in all antenatal care clinics
multiple pregnancy, diagnosis of hypertension, pre-
and delivery and neonatal wards in the country, and it
eclampsia, diabetes mellitus, or gestational diabetes.
contains data on both mother and infant. The National
Data on maternal smoking in the Medical Birth
Patient Register contains data on patient diagnoses
Register were divided into 2 groups according
and medical and surgical procedures (23). The registry
to information collected at the first antenatal visit,
Swedish
residents
allows
for
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Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
Preterm Birth and Risk of HF
F I G U R E 1 Study Population
STATISTICAL ANALYSIS. The association between
preterm birth and HF was assessed in a Poisson regression analysis. Relative risks (RRs) (adjusted
Live births in Sweden 1987-2012, n=2,714,789
incidence rate ratios) and corresponding 95% confidence intervals (CIs) for each gestational age category were modeled by using log (person-years at risk) as an
Missing personal identification number, n=22,828 Missing information on gestational age, n=3,217 Missing or unreasonable birth weight, n=8,896
offset. Covariates for the adjusted models were chosen 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
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
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
Final study population, n=2,665,542
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
Flow chart of inclusions and exclusions in the study.
excluding individuals with malformations. Because of the large number of missing data on maternal smoking among preterm individuals, we adjusted for
usually in weeks 8 to 12 of pregnancy. This informa-
maternal smoking habits in a separate model,
tion has been routinely collected since 1983, but data
including individuals with complete data on all
are sometimes missing, particularly for mothers of
covariates.
preterm individuals. Information on highest attained
Incidence rates for HF were also calculated on the
level of maternal education was retrieved from the
basis of gestational age at birth and attained age at
Education Register and was categorized as #9 years,
time of diagnosis (Online Table 1). Using a Poisson
10 to 12 years, or $13 years of education.
regression model, we estimated unadjusted incidence
Individuals born with malformations that could
rate ratios for the same age intervals, also presented
possibly correlate with risk of HF were identified by
in Online Table 1. All data were analyzed by using SAS
searching the Medical Birth Register and the National
version 9.4 software (SAS Institute, Inc., Cary, North
Patient Register for 1 of the following ICD-9 or ICD-10
Carolina).
diagnoses: malformations of the circulatory system
ETHICS. Ethical
(745.0 to 747.9 or Q20 to Q28), congenital malforma-
the Regional Ethical Vetting Board in Stockholm
tion syndromes due to known exogenous causes not
(Etikprövningsnämnden)
classified elsewhere (759.8 or Q86), other specified
number 2011/195-31/2.
permission
was
with
obtained the
from
registration
congenital malformation syndromes affecting multiple organ systems (743.0/755/756.0/756.7/756.8/757.1/
RESULTS
758.6/759.8 or Q87), other congenital malformations not classified elsewhere (759.0 to 759.9 or Q89), or
Among 2,665,542 individuals included in the study,
chromosomal abnormalities (758.0 to 758.9 or Q90 to
156,879 (5.9%) were born preterm; 5.14% were
Q99). Children with a diagnosis of patent ductus
moderately preterm, 0.56% very preterm, and 0.18%
arteriosus (747A or Q25.0) were not excluded from
extremely
our analysis because this condition is very common
individuals were more often low birth weight for
after preterm birth and is a possible mediator of HF.
gestational age than individuals born at term.
By using the Multi-Generation Register, it was
Mothers of preterm individuals were more likely to be
possible to trace the registered father for almost 99% of
younger (#19 years of age) or older ($35 years of age),
individuals in the cohort. This approach enabled a
to have lower levels of education, to be smokers, and
search for both maternal and paternal diagnoses of HF
of non-Nordic origin. Maternal pregnancy complica-
or ischemic heart disease or death from HF or ischemic
tions and multiple pregnancies were more common in
heart disease in the National Patient Register and Cause
women with preterm births.
preterm
(Online
Table
2).
Preterm
of Death Register, using the aforementioned ICD-9
During follow-up (beginning at 1 year of age),
and ICD-10 codes plus the earlier ICD version 8 codes
there were 501 cases of HF. Three of these cases were
for HF (428) and ischemic heart disease (410 to 414).
deaths caused by HF. Total time of follow-up was
Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
34.8 million person-years, yielding an incidence of 1.4 per 100,000 person-years. After exclusion of
2637
Preterm Birth and Risk of HF
T A B L E 1 Cohort Characteristics in Relation to Outcome: Children Born in Sweden
1987–2012, Follow-Up From 1 Yr of Age
52,512 individuals born with malformations (as specified in the Patients and Methods section), there were 305 cases of HF in 34.2 million person-years of
Total
follow-up (incidence 0.89 per 100,000 person-years).
All subjects
The median individual time of follow-up for all
Subject characteristics
subjects was 13.1 years (IQR: 6.1 to 20.1 years). Cohort characteristics in relation to outcome are presented in Table 1. Individuals diagnosed with HF
%
2,665,542 100.0
No. of Incidence Cases Rate*
501
Unadjusted IRR (95% CI) for HF
1.44
–
Sex Female
1,296,690 48.6
Male
1,368,852
211
1.25
1.00 (reference)
51.4
290
1.62
1.30 (1.09–1.56)
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)
2004–2012
944,564
35.4
43
1.03
1.00 (reference)
52,512
1.98
196
30.7
34.5 (28.8–41.2)
2,613,030 98.0
305
0.89
1.00 (reference)
more often smokers and had lower levels of education. Maternal and paternal HF or ischemic heart disease was also more frequent in subjects with HF. PRETERM BIRTH AND RISK OF HF. Numbers and
Malformations Yes No 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. Preterm birth was associated with an increased risk
Maternal and pregnancy characteristics 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)
increased with decreasing gestational age.
20–24 yrs
389,956
14.6
85
1.46
0.95 (0.73–1.22)
25–29 yrs
861,936
32.3
187
1.55
1.00 (reference)
ital malformations and adjustment for maternal
30–34 yrs
868,124
32.6
143
1.34
0.87 (0.70–1.08)
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) 1.75 (1.34–2.29)
After exclusion of individuals with major congen-
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
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)
with subjects born at term (Table 2). Additional
$13 yrs
1,174,185
44.5
176
1.24
1.00 (reference)
–
–
adjustment for parental cardiovascular disease only minimally attenuated relative risks for HF. Adjusting
Missing data Nonsmoker
for maternal smoking habits did not alter the
Smoker
described associations (Online Table 3). There was no
Missing data
significant increase in risk of HF for subjects born
Country of birth
moderately preterm in the adjusted models. The median age at diagnosis of HF was 16.5 years (IQR: 5.2 to 19.7 years). Online Table 1 displays agespecific incidence rates for HF in relation to gestational age at birth. Incidence rates dropped after the first 5 years of life and then rose again after 16 years of age. Subjects born before 32 weeks of gestation had
24,166
4
Smoking habits (at first antenatal visit)
Sweden Other Nordic country Other Missing data
2,152,861
85.5
361
1.36
1.00 (reference)
366,709
14.6
102
1.66
1.22 (0.98–1.52)
38
–
– 1.00 (reference)
145,972 2,194,530
82.7
418
1.41
71,440
2.69
19
1.75
1.11 (0.85–1.44)
387,934
14.6
62
1.56
1.23 (0.78–1.95)
–
–
11,638
2
Hypertensive disease No
2,572,282
96.5
484
1.44
1.00 (reference)
Hypertension
16,310
0.61
2
1.02
0.71 (0.18–2.83)
Preeclampsia
76,950
2.89
15
1.54
1.07 (0.64–1.79)
2,630,853
the highest incidence rates of HF across all age cate-
Diabetes
gories. The same pattern was seen after excluding
No
98.7
498
1.45
1.00 (reference)
subjects born with malformations.
Diabetes mellitus
10,666 0.40
1
0.71
0.49 (0.12–1.95)
Gestational diabetes
24,023 0.90
2
0.76
0.53 (0.07–3.76)
17
1.88
1.32 (0.81–2.14)
BIRTH WEIGHT FOR GESTATIONAL AGE AND RISK OF HF. We also found an association between low
Multiple pregnancy
71,997
Maternal or paternal HF or ischemic heart disease
birth weight for gestational age and increased risk of
Maternal
HF (Table 3). Compared with infants born with
Paternal
65,682
appropriate birth weight for gestational age, those
Missing data
21,058
born very small for gestational age (>2 SDs below the mean) had a 3-fold risk of subsequent HF in the unadjusted analysis. After excluding subjects with
2.70
17,981 0.67 2.47
16
4.61
3.28 (1.99–5.40)
24
1.90
1.34 (0.89–2.03)
–
–
–
*Events per 100,000 person-yrs. CI ¼ confidence interval; HF ¼ heart failure; IRR ¼ incidence rate ratio.
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Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
Preterm Birth and Risk of HF
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
N
No. of Events
Incidence Rate*
Unadjusted IRR (95% CI)
Adjusted Model 1: IRR (95%CI)†
Adjusted Model 2: IRR (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)
137,083
42
2.32
1.73 (1.26–2.38)
1.54 (1.11–2.12)
1.54 (1.11–2.12)
2,508,663
439
1.34
1.00 (reference)
1.00 (reference)
1.00 (reference)
17.0 (7.96–36.3)
32–36 weeks $37 weeks
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)
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)
2,463,328
271
0.84
1.00 (reference)
1.00 (reference)
1.00 (reference)
$37 weeks
*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
pressure may cause organ damage such as left ven-
and gestational age into account in the adjusted
tricular hypertrophy (31). Thus, it is plausible that an
models, this association was weakened and no longer
elevation of blood pressure may contribute to the
significant. There was no indication of confounding
increased risk of HF observed in preterm individuals
by parental cardiovascular disease.
in our study.
DISCUSSION
adults (32) but comprises a very small proportion of
Ischemic heart disease is a major cause of HF in HF in children and adolescents (15,33). Thus far, there
PRINCIPAL
FINDINGS. This
registry-based cohort
study of >2.6 million children and young adults
have been no data confirming a link between preterm birth and ischemic heart disease (6,34,35). In the
found that preterm birth was associated with an
present study, individuals with ischemic heart dis-
increased risk of incident HF, also after adjustment
ease as first event were censored and no longer
for birth weight for gestational age and potential
contributed risk time in the study. Thus, ischemic
confounders. The RR was inversely related to gesta-
heart disease is an unlikely explanation for the
tional age at birth (Central Illustration). Individuals
observed association between preterm birth and HF.
born extremely preterm and very preterm faced a 17-
Instead, cardiomyopathies, including the diagnosti-
fold and >3-fold increased risk of HF, respectively; corresponding risk was not significantly increased for
cally broad “idiopathic dilated,” are considered a principal cause of HF in the younger population
those born moderately preterm. A very low birth
(15,33). In individuals born preterm, such heart mus-
weight for gestational age (>2 SDs below the mean)
cle disease could be the result of cardiac remodeling
was also associated with an increased risk of HF, but
after preterm birth.
this risk increase was not significant after adjustment for potential confounding factors. POTENTIAL
MECHANISMS. The
The current understanding of cardiac development is that cardiomyocytes proliferate until late
by
gestation and switch to an adult hypertrophic
which preterm birth may influence subsequent risk of
mechanisms
growth mode shortly after birth (36–38). Animal
HF in childhood and young adulthood remain elusive.
models show that the immature cardiomyocytes of
A review of existing evidence concluded that in-
the preterm heart adapt to extrauterine conditions
dividuals born preterm have slightly higher resting
through structural remodeling, which may have an
systolic blood pressure in early adulthood, which may
impact on future cardiac function (16,17). In a small
increase their risk of developing hypertension (4,5).
echocardiographic study of preterm infants, there
Hypertension is, in turn, 1 of the most important
were signs of delay in maturation of the myocardium
risk factors for developing HF in adults, also in
at 28 days of age (18). The same study found signs of
the
absence of ischemic heart disease (30,31).
left ventricular diastolic dysfunction and greater
In childhood, even mild, untreated elevation of blood
dependence on atrial contraction in preterm infants.
Carr et al.
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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
N
No. of Events
Incidence Rate*
Unadjusted IRR (95% CI)
Adjusted Model 1: IRR (95% CI)†
Adjusted Model 2: IRR (95% CI)‡
All subjects, N ¼ 2,665,542 Birth weight for gestational age Very small Small Appropriate Large Very large
73,937
44
4.33
3.36 (2.45–4.61)
2.69 (1.94–3.73)
2.66 (1.92–3.70)
366,036
87
1.80
1.40 (1.10–1.78)
1.31 (1.03–1.67)
1.25 (0.98–1.60)
1,794,551
301
1.29
1.00 (reference)
1.00 (reference)
1.00 (reference)
338,333
56
1.27
0.99 (0.74–1.31)
1.00 (0.75–1.33)
1.00 (0.75–1.34)
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)
357,453
48
1.02
1.20 (0.88–1.65)
1.13 (0.82–1.55)
1.06 (0.76–1.47)
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)
Small Appropriate
*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
(40). We speculate that such alterations of cardiac
occurs at birth, the preterm heart is often exposed to
function in preterm individuals may be a conse-
conditions that increase cardiac workload (e.g., pat-
quence of the combination of interrupted normal
ent ductus arteriosus), leading to important left-to-
cardiac development and postnatal exposure to
right shunting and bronchopulmonary disease with
circulatory challenges, and HF could ultimately be
the risk of pulmonary hypertension (39). A cardiac
an expression of this.
imaging study of preterm infants found that patent ductus arteriosus was associated with significantly
STUDY STRENGTHS. Strengths of the current study
increased end-diastolic volumes and increased left
include the very large cohort and the registry-based
ventricular mass (19). However, it is unclear to what
nondifferential follow-up. Sufficient statistical po-
extent such changes are reversed after ductal
wer allowed us to examine the risk of HF even among
closure.
extremely
preterm
infants,
although
they
only
Evidence of modulation of cardiac structure and
comprised 0.18% of our cohort. Dividing gestational
function has also been found in older survivors of
age into 4 categories also enabled us to show a strong
preterm birth. One study included 102 individuals
dose–response relationship between low gestational
born preterm who underwent cardiovascular mag-
age at birth and later HF. We were able to control for
netic resonance imaging at 20 to 39 years of age;
many confounding factors, including maternal and
they were compared with control subjects born at
pregnancy characteristics, heritability of heart dis-
term (20). Ventricular mass in young adulthood
ease, and birth weight for gestational age. We had
increased with decreasing gestational age at birth.
information
Higher
in-
including or excluding children with malformations
dividuals could not alone explain this finding, as the
yielded essentially the same results among in-
increase in ventricular mass was disproportionate
dividuals born extremely preterm and very preterm.
relative to any elevation in blood pressure. There
The National Patient Register and Cause of Death
were no observable differences in left ventricular
Register were used to ascertain HF. After excluding
ejection fraction between the 2 groups, but both
subjects born with congenital malformations, we
stroke volume and end-diastolic volume were lower
found an incidence of 0.88 per 100,000 person-years,
in
in-
which is almost identical to that of a British-Irish
dividuals also had reduced diastolic myocardial
study (0.87 per 100,000 person-years) (14). The val-
relaxation. Moreover, their right ventricular function
idity of the HF diagnosis is high in Swedish registers,
was compromised, and 6% had a right ventricular
with a positive predictive value of 82% and even 95%
ejection fraction below clinical reference values
for those with a primary diagnosis of HF (41).
systolic
individuals
blood
born
pressure
preterm.
in
preterm
Preterm-born
on
congenital
malformations,
and
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2640
Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
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
effect of prematurity. We attempted to investigate
typical for registry-based research. Children born at
this topic further by looking closer at age at diagnosis,
low gestational age are generally subject to closer
and we found that the excess incidence of HF in those
medical follow-up, especially during their first years of
born very or extremely preterm was higher at 1 to 5
life. Thus, we cannot rule out that surveillance bias has
years of age compared with later. This outcome could
influenced our results. To avoid measuring HF as a
also be explained by those extravulnerable to disease,
direct complication in the neonatal period, all in-
having already developed HF by the time they reach
dividuals diagnosed with HF before 1 year of age were
the age of the expected increase in incidence (i.e.,
excluded. We were unable to investigate if and how a
depletion of susceptible effect). Another possibility is
hemodynamically significant patent ductus arteriosus
that subjects born in earlier birth years, thus
and its treatment relate to risk of later HF because of
contributing longer follow-up, are not representative
the low number of HF cases in the lowest gestational
of more recent preterm births. In summary, given the
ages and the probable underreporting of patent ductus
age profile of our cohort, this study captured effects
arteriosus
of prematurity in childhood and adolescence but not
diagnosis
in
the
national
registries,
compared with other prospective national cohorts
effects later in adulthood.
(42). The same limitation applies to the use of ante-
Our results show a strong association between
natal corticosteroids, diagnosis of bronchopulmonary
gestational age and risk of HF. However, the total
dysplasia, and duration of mechanical ventilation,
number of cases of HF in our material is small (501 cases
which may all be factors that are potential mediators of
in >2.6 million individuals), with only 11 cases among
the association between preterm birth and later risk of
those born extremely preterm. Any minor change in
HF.
the number of cases would thus influence effect size.
HF can be difficult to diagnose in a young patient,
The great risk increase for HF we have observed in the
and reduced cardiac function may remain silent and
most preterm subjects may be decreased but not easily
unreported for a long time (13,43). If this is the case,
silenced by such alterations. Also, we have excluded
our findings may be a late reflection of a more direct
all cases of HF before 1 year of age (n ¼ 753), which
Carr et al.
JACC VOL. 69, NO. 21, 2017 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,
[email protected].
which further limited our possibility of observing patients over time or investigating underlying causes
PERSPECTIVES
of HF in this particular cohort (23).
CONCLUSIONS
COMPETENCY IN MEDICAL KNOWLEDGE: Survivors of
This study found a strong association between
cardiovascular mortality in young adulthood than those born at
preterm birth and risk of incident HF in children and
term. The relationship between gestational age also applies to the
young adults. The increase in risk was inversely
risk of developing HF.
preterm birth are at higher risk of developing hypertension and
related to gestational age at birth, although absolute risks were low. Considering the rising number of individuals surviving preterm birth and the potential consequences of early onset of reduced cardiac function, the problem may grow with time. There
TRANSLATIONAL OUTLOOK: Further research is needed to elucidate the mechanisms compromising cardiac function after preterm birth and evaluate interventions to improve long-term cardiovascular health in these individuals.
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.
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
medical needs of these subjects, and for developing
before term (<37 weeks of gestation) (1,2).
appropriate preventive measures.
Although prematurity is still the main cause
Results from previous studies suggest that survi-
of neonatal death globally, high-income countries
vors of preterm birth are at increased risk of hyper-
have experienced dramatic increases in survival rates
tension, stroke, and cardiovascular mortality but not
in preterm infants over the past few decades (2,3).
ischemic heart disease (4–8). To the best of our
Knowledge about how the burdens of prematurity
knowledge, the association between preterm birth
may be carried into later life in these steadily growing
and risk of heart failure (HF) has not previously been
generations of new survivors is important for
explored. HF in children and young adults is an un-
improving neonatal care, for meeting the future
usual but dangerous condition with high mortality
Listen to this manuscript’s audio summary by
From the aClinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; bDepartment of
JACC Editor-in-Chief
Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; cÖrebro University Hospital, Örebro, Sweden;
Dr. Valentin Fuster.
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.
Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
2635
Preterm Birth and Risk of HF
rates (9,10). Congenital heart disease and cardiomy-
covers all hospitalizations in Sweden from
ABBREVIATIONS
opathies, particularly idiopathic dilated cardiomyop-
1987 onward, and information on hospital-
AND ACRONYMS
athy, are the main causes of HF at young age (11–13).
based outpatient care is included from 2001.
Incidence data for pediatric HF are scarce but were
The Cause of Death Register provides infor-
estimated to be 0.87 per 100,000 person-years in a
mation on causes and dates of death in
study in the United Kingdom and Ireland of HF
Sweden from 1961 (24). The Multi-Generation
caused by cardiac muscle disease (14). Between 1987
Register was created in 2000, and it includes
and 2006, the incidence of HF among young adults in
individual index-persons born after 1932 who
Sweden increased by 50%, and the proportion of
were alive in 1961 and links them to their parents (25).
cardiomyopathies as an underlying cause of HF
Information on educational level was collected from
increased from 15% to 25% (15).
the Swedish Register of Education (26). Date of
Preterm birth entails exposure of the immature infant heart to extrauterine conditions. Evidence
CI = confidence interval HF = heart failure ICD = International Classification of Diseases
RR = relative risk
emigration was retrieved from the Register of the Total Population (27).
from animal models and small studies of preterm
EXPOSURES. Data on the main exposure (i.e., gesta-
infants shows that preterm birth interferes with
tional age at birth) were retrieved from the Medical
normal cardiac development in the neonatal period
Birth Register and categorized into 22 to 27 weeks
(16–19). In a cardiac imaging study of adults born
(extremely preterm), 28 to 31 weeks (very preterm), 32
preterm, ventricular mass in adulthood was seen to
to 36 weeks (moderately preterm), and $37 weeks
increase with lower gestational age at birth. Preterm
(term). Since the early 1990s, all pregnant women in
birth was also associated with further alterations in
Sweden are offered a diagnostic ultrasound scan in
cardiac structure and function (20).
the early second trimester, usually between weeks 17 and 20, and >96% accept (28). When no information
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.
on ultrasound dating of pregnancy was available, the last menstrual period was used for assessing gestational 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 intrauterine growth (29). Individuals were categorized as very small (<2 SD), small (2 SD to <1 SD), appro-
PATIENTS AND METHODS
priate (1 SD to 1 SD), large (>1 SD to 2 SD) or very
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,
large (>2 SD). These data were also used to statistically 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.
emigration, first diagnosis of HF or ischemic heart
OUTCOMES. The primary outcome was a diagnosis of
disease, or end of study (December 31, 2013), which-
incident HF without a previous diagnosis of ischemic
ever came first. Start of follow-up was set to 1 year of
heart disease in the National Patient Register or the
age to avoid measuring HF as an immediate compli-
Cause of Death Register. The International Classifi-
cation during neonatal care.
cation of Diseases (ICD)-9th revision (ICD-9; used
A unique personal identity number given to all
between 1987 and 1996) and 10 (ICD-10; introduced in
comprehensive
1997) were used to define HF (ICD-9 code 428 and
cross-linking with other national registries (21). The
ICD-10 code I50) and ischemic heart disease (ICD-9
caregivers are required by law to contribute informa-
codes 410 to 414 and ICD-10 codes I20 to I25).
tion to these registries. The Medical Birth Register was
OTHER VARIABLES. From the Medical Birth Register,
started in 1973 and covers >98% of all births in Sweden
we included information on maternal factors such
(22). Since 1982, it is based on copies of standardized
as age at delivery, country of birth, singleton or
clinical record forms used in all antenatal care clinics
multiple pregnancy, diagnosis of hypertension, pre-
and delivery and neonatal wards in the country, and it
eclampsia, diabetes mellitus, or gestational diabetes.
contains data on both mother and infant. The National
Data on maternal smoking in the Medical Birth
Patient Register contains data on patient diagnoses
Register were divided into 2 groups according
and medical and surgical procedures (23). The registry
to information collected at the first antenatal visit,
Swedish
residents
allows
for
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JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
Preterm Birth and Risk of HF
F I G U R E 1 Study Population
STATISTICAL ANALYSIS. The association between
preterm birth and HF was assessed in a Poisson regression analysis. Relative risks (RRs) (adjusted
Live births in Sweden 1987-2012, n=2,714,789
incidence rate ratios) and corresponding 95% confidence intervals (CIs) for each gestational age category were modeled by using log (person-years at risk) as an
Missing personal identification number, n=22,828 Missing information on gestational age, n=3,217 Missing or unreasonable birth weight, n=8,896
offset. Covariates for the adjusted models were chosen 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
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
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
Final study population, n=2,665,542
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
Flow chart of inclusions and exclusions in the study.
excluding individuals with malformations. Because of the large number of missing data on maternal smoking among preterm individuals, we adjusted for
usually in weeks 8 to 12 of pregnancy. This informa-
maternal smoking habits in a separate model,
tion has been routinely collected since 1983, but data
including individuals with complete data on all
are sometimes missing, particularly for mothers of
covariates.
preterm individuals. Information on highest attained
Incidence rates for HF were also calculated on the
level of maternal education was retrieved from the
basis of gestational age at birth and attained age at
Education Register and was categorized as #9 years,
time of diagnosis (Online Table 1). Using a Poisson
10 to 12 years, or $13 years of education.
regression model, we estimated unadjusted incidence
Individuals born with malformations that could
rate ratios for the same age intervals, also presented
possibly correlate with risk of HF were identified by
in Online Table 1. All data were analyzed by using SAS
searching the Medical Birth Register and the National
version 9.4 software (SAS Institute, Inc., Cary, North
Patient Register for 1 of the following ICD-9 or ICD-10
Carolina).
diagnoses: malformations of the circulatory system
ETHICS. Ethical
(745.0 to 747.9 or Q20 to Q28), congenital malforma-
the Regional Ethical Vetting Board in Stockholm
tion syndromes due to known exogenous causes not
(Etikprövningsnämnden)
classified elsewhere (759.8 or Q86), other specified
number 2011/195-31/2.
permission
was
with
obtained the
from
registration
congenital malformation syndromes affecting multiple organ systems (743.0/755/756.0/756.7/756.8/757.1/
RESULTS
758.6/759.8 or Q87), other congenital malformations not classified elsewhere (759.0 to 759.9 or Q89), or
Among 2,665,542 individuals included in the study,
chromosomal abnormalities (758.0 to 758.9 or Q90 to
156,879 (5.9%) were born preterm; 5.14% were
Q99). Children with a diagnosis of patent ductus
moderately preterm, 0.56% very preterm, and 0.18%
arteriosus (747A or Q25.0) were not excluded from
extremely
our analysis because this condition is very common
individuals were more often low birth weight for
after preterm birth and is a possible mediator of HF.
gestational age than individuals born at term.
By using the Multi-Generation Register, it was
Mothers of preterm individuals were more likely to be
possible to trace the registered father for almost 99% of
younger (#19 years of age) or older ($35 years of age),
individuals in the cohort. This approach enabled a
to have lower levels of education, to be smokers, and
search for both maternal and paternal diagnoses of HF
of non-Nordic origin. Maternal pregnancy complica-
or ischemic heart disease or death from HF or ischemic
tions and multiple pregnancies were more common in
heart disease in the National Patient Register and Cause
women with preterm births.
preterm
(Online
Table
2).
Preterm
of Death Register, using the aforementioned ICD-9
During follow-up (beginning at 1 year of age),
and ICD-10 codes plus the earlier ICD version 8 codes
there were 501 cases of HF. Three of these cases were
for HF (428) and ischemic heart disease (410 to 414).
deaths caused by HF. Total time of follow-up was
Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
34.8 million person-years, yielding an incidence of 1.4 per 100,000 person-years. After exclusion of
2637
Preterm Birth and Risk of HF
T A B L E 1 Cohort Characteristics in Relation to Outcome: Children Born in Sweden
1987–2012, Follow-Up From 1 Yr of Age
52,512 individuals born with malformations (as specified in the Patients and Methods section), there were 305 cases of HF in 34.2 million person-years of
Total
follow-up (incidence 0.89 per 100,000 person-years).
All subjects
The median individual time of follow-up for all
Subject characteristics
subjects was 13.1 years (IQR: 6.1 to 20.1 years). Cohort characteristics in relation to outcome are presented in Table 1. Individuals diagnosed with HF
%
2,665,542 100.0
No. of Incidence Cases Rate*
501
Unadjusted IRR (95% CI) for HF
1.44
–
Sex Female
1,296,690 48.6
Male
1,368,852
211
1.25
1.00 (reference)
51.4
290
1.62
1.30 (1.09–1.56)
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)
2004–2012
944,564
35.4
43
1.03
1.00 (reference)
52,512
1.98
196
30.7
34.5 (28.8–41.2)
2,613,030 98.0
305
0.89
1.00 (reference)
more often smokers and had lower levels of education. Maternal and paternal HF or ischemic heart disease was also more frequent in subjects with HF. PRETERM BIRTH AND RISK OF HF. Numbers and
Malformations Yes No 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. Preterm birth was associated with an increased risk
Maternal and pregnancy characteristics 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)
increased with decreasing gestational age.
20–24 yrs
389,956
14.6
85
1.46
0.95 (0.73–1.22)
25–29 yrs
861,936
32.3
187
1.55
1.00 (reference)
ital malformations and adjustment for maternal
30–34 yrs
868,124
32.6
143
1.34
0.87 (0.70–1.08)
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) 1.75 (1.34–2.29)
After exclusion of individuals with major congen-
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
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)
with subjects born at term (Table 2). Additional
$13 yrs
1,174,185
44.5
176
1.24
1.00 (reference)
–
–
adjustment for parental cardiovascular disease only minimally attenuated relative risks for HF. Adjusting
Missing data Nonsmoker
for maternal smoking habits did not alter the
Smoker
described associations (Online Table 3). There was no
Missing data
significant increase in risk of HF for subjects born
Country of birth
moderately preterm in the adjusted models. The median age at diagnosis of HF was 16.5 years (IQR: 5.2 to 19.7 years). Online Table 1 displays agespecific incidence rates for HF in relation to gestational age at birth. Incidence rates dropped after the first 5 years of life and then rose again after 16 years of age. Subjects born before 32 weeks of gestation had
24,166
4
Smoking habits (at first antenatal visit)
Sweden Other Nordic country Other Missing data
2,152,861
85.5
361
1.36
1.00 (reference)
366,709
14.6
102
1.66
1.22 (0.98–1.52)
38
–
– 1.00 (reference)
145,972 2,194,530
82.7
418
1.41
71,440
2.69
19
1.75
1.11 (0.85–1.44)
387,934
14.6
62
1.56
1.23 (0.78–1.95)
–
–
11,638
2
Hypertensive disease No
2,572,282
96.5
484
1.44
1.00 (reference)
Hypertension
16,310
0.61
2
1.02
0.71 (0.18–2.83)
Preeclampsia
76,950
2.89
15
1.54
1.07 (0.64–1.79)
2,630,853
the highest incidence rates of HF across all age cate-
Diabetes
gories. The same pattern was seen after excluding
No
98.7
498
1.45
1.00 (reference)
subjects born with malformations.
Diabetes mellitus
10,666 0.40
1
0.71
0.49 (0.12–1.95)
Gestational diabetes
24,023 0.90
2
0.76
0.53 (0.07–3.76)
17
1.88
1.32 (0.81–2.14)
BIRTH WEIGHT FOR GESTATIONAL AGE AND RISK OF HF. We also found an association between low
Multiple pregnancy
71,997
Maternal or paternal HF or ischemic heart disease
birth weight for gestational age and increased risk of
Maternal
HF (Table 3). Compared with infants born with
Paternal
65,682
appropriate birth weight for gestational age, those
Missing data
21,058
born very small for gestational age (>2 SDs below the mean) had a 3-fold risk of subsequent HF in the unadjusted analysis. After excluding subjects with
2.70
17,981 0.67 2.47
16
4.61
3.28 (1.99–5.40)
24
1.90
1.34 (0.89–2.03)
–
–
–
*Events per 100,000 person-yrs. CI ¼ confidence interval; HF ¼ heart failure; IRR ¼ incidence rate ratio.
2638
Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
Preterm Birth and Risk of HF
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
N
No. of Events
Incidence Rate*
Unadjusted IRR (95% CI)
Adjusted Model 1: IRR (95%CI)†
Adjusted Model 2: IRR (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)
137,083
42
2.32
1.73 (1.26–2.38)
1.54 (1.11–2.12)
1.54 (1.11–2.12)
2,508,663
439
1.34
1.00 (reference)
1.00 (reference)
1.00 (reference)
17.0 (7.96–36.3)
32–36 weeks $37 weeks
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)
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)
2,463,328
271
0.84
1.00 (reference)
1.00 (reference)
1.00 (reference)
$37 weeks
*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
pressure may cause organ damage such as left ven-
and gestational age into account in the adjusted
tricular hypertrophy (31). Thus, it is plausible that an
models, this association was weakened and no longer
elevation of blood pressure may contribute to the
significant. There was no indication of confounding
increased risk of HF observed in preterm individuals
by parental cardiovascular disease.
in our study.
DISCUSSION
adults (32) but comprises a very small proportion of
Ischemic heart disease is a major cause of HF in HF in children and adolescents (15,33). Thus far, there
PRINCIPAL
FINDINGS. This
registry-based cohort
study of >2.6 million children and young adults
have been no data confirming a link between preterm birth and ischemic heart disease (6,34,35). In the
found that preterm birth was associated with an
present study, individuals with ischemic heart dis-
increased risk of incident HF, also after adjustment
ease as first event were censored and no longer
for birth weight for gestational age and potential
contributed risk time in the study. Thus, ischemic
confounders. The RR was inversely related to gesta-
heart disease is an unlikely explanation for the
tional age at birth (Central Illustration). Individuals
observed association between preterm birth and HF.
born extremely preterm and very preterm faced a 17-
Instead, cardiomyopathies, including the diagnosti-
fold and >3-fold increased risk of HF, respectively; corresponding risk was not significantly increased for
cally broad “idiopathic dilated,” are considered a principal cause of HF in the younger population
those born moderately preterm. A very low birth
(15,33). In individuals born preterm, such heart mus-
weight for gestational age (>2 SDs below the mean)
cle disease could be the result of cardiac remodeling
was also associated with an increased risk of HF, but
after preterm birth.
this risk increase was not significant after adjustment for potential confounding factors. POTENTIAL
MECHANISMS. The
The current understanding of cardiac development is that cardiomyocytes proliferate until late
by
gestation and switch to an adult hypertrophic
which preterm birth may influence subsequent risk of
mechanisms
growth mode shortly after birth (36–38). Animal
HF in childhood and young adulthood remain elusive.
models show that the immature cardiomyocytes of
A review of existing evidence concluded that in-
the preterm heart adapt to extrauterine conditions
dividuals born preterm have slightly higher resting
through structural remodeling, which may have an
systolic blood pressure in early adulthood, which may
impact on future cardiac function (16,17). In a small
increase their risk of developing hypertension (4,5).
echocardiographic study of preterm infants, there
Hypertension is, in turn, 1 of the most important
were signs of delay in maturation of the myocardium
risk factors for developing HF in adults, also in
at 28 days of age (18). The same study found signs of
the
absence of ischemic heart disease (30,31).
left ventricular diastolic dysfunction and greater
In childhood, even mild, untreated elevation of blood
dependence on atrial contraction in preterm infants.
Carr et al.
JACC VOL. 69, NO. 21, 2017 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
N
No. of Events
Incidence Rate*
Unadjusted IRR (95% CI)
Adjusted Model 1: IRR (95% CI)†
Adjusted Model 2: IRR (95% CI)‡
All subjects, N ¼ 2,665,542 Birth weight for gestational age Very small Small Appropriate Large Very large
73,937
44
4.33
3.36 (2.45–4.61)
2.69 (1.94–3.73)
2.66 (1.92–3.70)
366,036
87
1.80
1.40 (1.10–1.78)
1.31 (1.03–1.67)
1.25 (0.98–1.60)
1,794,551
301
1.29
1.00 (reference)
1.00 (reference)
1.00 (reference)
338,333
56
1.27
0.99 (0.74–1.31)
1.00 (0.75–1.33)
1.00 (0.75–1.34)
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)
357,453
48
1.02
1.20 (0.88–1.65)
1.13 (0.82–1.55)
1.06 (0.76–1.47)
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)
Small Appropriate
*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
(40). We speculate that such alterations of cardiac
occurs at birth, the preterm heart is often exposed to
function in preterm individuals may be a conse-
conditions that increase cardiac workload (e.g., pat-
quence of the combination of interrupted normal
ent ductus arteriosus), leading to important left-to-
cardiac development and postnatal exposure to
right shunting and bronchopulmonary disease with
circulatory challenges, and HF could ultimately be
the risk of pulmonary hypertension (39). A cardiac
an expression of this.
imaging study of preterm infants found that patent ductus arteriosus was associated with significantly
STUDY STRENGTHS. Strengths of the current study
increased end-diastolic volumes and increased left
include the very large cohort and the registry-based
ventricular mass (19). However, it is unclear to what
nondifferential follow-up. Sufficient statistical po-
extent such changes are reversed after ductal
wer allowed us to examine the risk of HF even among
closure.
extremely
preterm
infants,
although
they
only
Evidence of modulation of cardiac structure and
comprised 0.18% of our cohort. Dividing gestational
function has also been found in older survivors of
age into 4 categories also enabled us to show a strong
preterm birth. One study included 102 individuals
dose–response relationship between low gestational
born preterm who underwent cardiovascular mag-
age at birth and later HF. We were able to control for
netic resonance imaging at 20 to 39 years of age;
many confounding factors, including maternal and
they were compared with control subjects born at
pregnancy characteristics, heritability of heart dis-
term (20). Ventricular mass in young adulthood
ease, and birth weight for gestational age. We had
increased with decreasing gestational age at birth.
information
Higher
in-
including or excluding children with malformations
dividuals could not alone explain this finding, as the
yielded essentially the same results among in-
increase in ventricular mass was disproportionate
dividuals born extremely preterm and very preterm.
relative to any elevation in blood pressure. There
The National Patient Register and Cause of Death
were no observable differences in left ventricular
Register were used to ascertain HF. After excluding
ejection fraction between the 2 groups, but both
subjects born with congenital malformations, we
stroke volume and end-diastolic volume were lower
found an incidence of 0.88 per 100,000 person-years,
in
in-
which is almost identical to that of a British-Irish
dividuals also had reduced diastolic myocardial
study (0.87 per 100,000 person-years) (14). The val-
relaxation. Moreover, their right ventricular function
idity of the HF diagnosis is high in Swedish registers,
was compromised, and 6% had a right ventricular
with a positive predictive value of 82% and even 95%
ejection fraction below clinical reference values
for those with a primary diagnosis of HF (41).
systolic
individuals
blood
born
pressure
preterm.
in
preterm
Preterm-born
on
congenital
malformations,
and
2639
2640
Carr et al.
JACC VOL. 69, NO. 21, 2017 MAY 30, 2017:2634–42
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
effect of prematurity. We attempted to investigate
typical for registry-based research. Children born at
this topic further by looking closer at age at diagnosis,
low gestational age are generally subject to closer
and we found that the excess incidence of HF in those
medical follow-up, especially during their first years of
born very or extremely preterm was higher at 1 to 5
life. Thus, we cannot rule out that surveillance bias has
years of age compared with later. This outcome could
influenced our results. To avoid measuring HF as a
also be explained by those extravulnerable to disease,
direct complication in the neonatal period, all in-
having already developed HF by the time they reach
dividuals diagnosed with HF before 1 year of age were
the age of the expected increase in incidence (i.e.,
excluded. We were unable to investigate if and how a
depletion of susceptible effect). Another possibility is
hemodynamically significant patent ductus arteriosus
that subjects born in earlier birth years, thus
and its treatment relate to risk of later HF because of
contributing longer follow-up, are not representative
the low number of HF cases in the lowest gestational
of more recent preterm births. In summary, given the
ages and the probable underreporting of patent ductus
age profile of our cohort, this study captured effects
arteriosus
of prematurity in childhood and adolescence but not
diagnosis
in
the
national
registries,
compared with other prospective national cohorts
effects later in adulthood.
(42). The same limitation applies to the use of ante-
Our results show a strong association between
natal corticosteroids, diagnosis of bronchopulmonary
gestational age and risk of HF. However, the total
dysplasia, and duration of mechanical ventilation,
number of cases of HF in our material is small (501 cases
which may all be factors that are potential mediators of
in >2.6 million individuals), with only 11 cases among
the association between preterm birth and later risk of
those born extremely preterm. Any minor change in
HF.
the number of cases would thus influence effect size.
HF can be difficult to diagnose in a young patient,
The great risk increase for HF we have observed in the
and reduced cardiac function may remain silent and
most preterm subjects may be decreased but not easily
unreported for a long time (13,43). If this is the case,
silenced by such alterations. Also, we have excluded
our findings may be a late reflection of a more direct
all cases of HF before 1 year of age (n ¼ 753), which
Carr et al.
JACC VOL. 69, NO. 21, 2017 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,
[email protected].
which further limited our possibility of observing patients over time or investigating underlying causes
PERSPECTIVES
of HF in this particular cohort (23).
CONCLUSIONS
COMPETENCY IN MEDICAL KNOWLEDGE: Survivors of
This study found a strong association between
cardiovascular mortality in young adulthood than those born at
preterm birth and risk of incident HF in children and
term. The relationship between gestational age also applies to the
young adults. The increase in risk was inversely
risk of developing HF.
preterm birth are at higher risk of developing hypertension and
related to gestational age at birth, although absolute risks were low. Considering the rising number of individuals surviving preterm birth and the potential consequences of early onset of reduced cardiac function, the problem may grow with time. There
TRANSLATIONAL OUTLOOK: Further research is needed to elucidate the mechanisms compromising cardiac function after preterm birth and evaluate interventions to improve long-term cardiovascular health in these individuals.
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.