ORIGINAL RESEARCH

published: 10 January 2020

doi: 10.3389/fcvm.2019.00185

Predictors of the Need for an Atrial

Septal Defect Closure at Very Young
Age
Gustaf Tanghöj 1 , Petru Liuba 2 , Gunnar Sjöberg 3 and Estelle Naumburg 1*
1
Department of Clinical Sciences, Unit of Pediatrics, Umeå University, Umeå, Sweden, 2 Department of Cardiology, Pediatric
Heart Center, Skåne University Hospital, Lund, Sweden, 3 Department of Women’s and Children’s Health, Karolinska Institute,
Stockholm, Sweden

An asymptomatic Atrial Septal Defect (ASD) is often closed at the age of 3–5 years
using a transcatheter or surgical technique. Symptomatic ASD or ASD associated with
pulmonary hypertension (PHT) may require earlier closure, particularly in combination
with other non-cardiac risk factors for PHT, but the indications for early closure and
the potential risk for complications are largely unknown. The aim of this study was
to assess risk factors for needing ASD closure during the first and second years of
Edited by:
Oswin Grollmuss, life. This case-control study included all children treated with surgical or percutaneous
Université Paris-Sud, France ASD closure between 2000 and 2014 at two out of three pediatric heart centers in
Reviewed by: Sweden. “Cases” were children with ASD closure at ≤1 or ≤2 years of age. Clinical
Alejandro José Lopez-Magallon,
Children’s National Health System, data were retrieved from medical journals and national registries. Overall, 413 children
United States were included. Of these, 131 (32%) were ≤2 years, and 50 (12%) were ≤1 year. Risk
Ziyad M. Hijazi,
factors associated with a ≤2 years ASD closure were preterm birth, OR = 2.4 (95% CI:
Rush University, United States
1.5–3.9); additional chromosomal abnormalities, OR = 3.4 (95% CI: 1.8–6.5); pulmonary
*Correspondence:
Estelle Naumburg hypertension, OR = 5.8 (95% CI: 2.6–12.6); and additional congenital heart defects,
[email protected] OR = 2.6 (95% CI: 1.7–4.1). These risk associations remained after adjustments for
confounding factors, such as need for neonatal respiratory support, neonatal pulmonary
Specialty section:
This article was submitted to diseases, neonatal sepsis, additional congenital heart defects (CHD) and chromosomal
Pediatric Cardiology, abnormalities. ASD size:body weight ratio of 2.0, as well as a ratio of 0.8 (upper and
a section of the journal
Frontiers in Cardiovascular Medicine
lower limit of the ASD size:body weight ratios), was associated with increased risk of
Received: 09 October 2019
an early ASD closure. Risk factors such as very premature birth, very low birth weight,
Accepted: 09 December 2019 congenital, and chromosomal abnormalities, neonatal pulmonary disease and need for
Published: 10 January 2020 ventilation support, as well as pulmonary hypertension, were associated with very early
Citation: (<1 year of age) ASD closure. Several independent neonatal risk factors were associated
Tanghöj G, Liuba P, Sjöberg G and
Naumburg E (2020) Predictors of the with an increased risk of early ASD closure at 2 and at 1 year of age. An ASD size:body
Need for an Atrial Septal Defect weight ratio is a poor predictor for indications for ASD closure.
Closure at Very Young Age.
Front. Cardiovasc. Med. 6:185. Keywords: atrial septal defect, ASD, follow-up studies, heart septal defect, atrial, pediatric cardiology, pediatric
doi: 10.3389/fcvm.2019.00185 thoracic surgery, septal device occlusion

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Tanghöj et al. ASD Closure in Young Children

INTRODUCTION after the neonatal period and into adulthood, the morphology
of both the ventricles as well as the function is impaired or
Asymptomatic Atrial Septal Defects (ASD) are preferably closed altered (6–10). Being born prematurely, prior to 37 gestational
when the children have reached the age of 3–5 years (1, 2). weeks, accounts for 6% of all newborns in Sweden (11). Advances
A significant ASD causes a left to right shunt leading to in perinatal care over the last 30 years have led to significant
volume overload, enlargement of the right atrium and ventricle improvements in survival rates, but the risk of early death and
and altered myocardial structure and function (3). Preterm pulmonary, neurological, cognitive and cardiovascular morbidity
children may be three times as common among children remains (12).
with percutaneous device closure than in the general Swedish We hypothesize that preterm birth is a risk factor for an early
population (4). ASD closure (surgical or percutaneous device closure) compared
The myocardium of the preterm child has irreversible to term children, due to the complex comorbidity, often large
morphological and global structural alterations (5–8). Even long ASD size in relation to low bodyweight and cardiac alterations.

FIGURE 1 | Study-group.

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Tanghöj et al. ASD Closure in Young Children

TABLE 1 | Demographic data for ASD closure at 2 years of age or younger.

Percutaneous device ASD-closure Surgical ASD-closure All types of ASD closure

Children <2 Children >2 P-value Children <2 Children >2 P-value Children <2 Children >2 P-value
years years years years years years

Total number 68 194 63 88 131 282

Weight at closure (kg) 9.6 (±2.4) 24.3 (±16.0) <0.001 8.1 (±2.5) 21.0 (±11.8) <0.001 8.9 (±2.5) 23.3 (±14.8) <0.001
Age at closure (years) 1.3 (±0.4) 6.2 (±1.0) <0.001 1.0 (±0.5) 5.6 (±3.3) <0.001 1.2 (±0.5) 6.0 (±3.8) <0.001
Gestational age (weeks) 36.9 (±4.0) 38.0 (±3.1) 0.021 36.5 (±4.3) 38.1 (±3.6) 0.018 36.7 (±4.5) 38.0 (±3.2) 0.002
ASD size (mm) 11.4 (±3.3) 13.7 (±5.0 0.001 13.0 (±4.2) 14.7 (±6.5) 0.07 12.1 (±3.8) 14.9 (±5.5) 0.001
ASD size:body weight 1.2 (±0.4) 0.7 (±0.4) <0.001 1.7 (±0.7) 0.8 (±0.4) <0.001 1.4 (±0.6) 0.7 (±0.4) 0.0001
ASD size:body weight = 2 6 (9%) 1 (1%) 0.001 17 (27%) 1 (1%) <0.001 23 (17%) 2 (1%) <0.001
ASD size:body weight = 0.8 56 (82%) 60 (30%) <0.001 52 (60%) 39 (44%) <0.001 108 (82%) 99 (35%) <0.001
Birthweight (gram) 2,821.9 3,148.5 0.006 2,695.5 3,226.0 <0.001 2,762.7 3,179.5 <0.001
(±902.0) (±785.6) (±896.5) (±822.0) (±898.2) (±796.3)
Gender (girls/boys) 45/23 116/78 0.135 32/31 55/33 0.151 77/52 171/111 0.328
Preterm birth < 37 gestational 23 (39%) 45 (22%) 0.010 21 (33%) 13 (14.8%) 0.007 44 (34%) 49 (17%) <0.001
weeks
Late preterm birth: 32–37 GW 15 (22%) 27 (14%) 0.115 12 (19%) 9 (10%) 0.122 27 (21%) 36 (13%) 0.039
Very preterm birth: 28–32 GW 6 (9%) 4 (2%) 0.012 5 (8%) 0 (0%) 0.011 11 (8%) 4 (1%) <0.001
Extremely preterm birth: <28 2 (3%) 5 (3%) 0.837 4 (6%) 4 (4%) 0.626 9 (3%) 6 (5%) 0.483
GW
Preterm birth: < 32 gestational 8 (12%) 9 (5%) 0.040 10 (16%) 6 (7%) 0.075 20 (15%) 16 (6%) 0.001
weeks
Very low birth weight 7 (10%) 9 (5%) 0.094 7 (12%) 5 (6%) 0.217 14 (11%) 14 (5%) 0.039
Extremely low birth weight 3 (4%) 4 (2%) 0.301 4 (7%) 4 (5%) 0.616 7 (6%) 8 (3%) 0.198
Chromosomal abnormalities 15 (22%) 14 (7%) <0.001 11 (18%) 5 (6%) 0.020 26 (20%) 19 (7%) <0.001
Other congenital heart defects 17 (25%) 43 (22%) 0.632 36% (57%) 15 (17%) <0.001 53 (41%) 58 (21%) <0.001
Arrhythmias prior to closure 3 (4%) 5 (3%) 0.437 2 (3%) 5 (6%) 0.470 5 (4%) 10 (4%) 0.884
Infant respiratory distress 6 (9%) 12 (6%) 0.459 6 (10%) 2 (2%) 0.069 12 (9%) 14 (5%) 0.104
syndrome
Bronchopulmonary dysplasia 3 (4%) 7 (4%) 0.766 5 (8%) 2 (2%) 0.131 8 (6%) 9 (3%) 0.168
Neonatal ventilator support 6 (9%) 5 (3%) 0.029 5 (8%) 5 (6%) 0.596 11 (8%) 10 (4%) 0.040
Neonatal CPAP* 12 (18%) 17 (9%) 0.048 15 (24%) 6 (7%) 0.003 27 (21%) 23 (8%) <0.001
Neonatal sepsis 7 (10%) 8 (4%) 0.061 7 (11%) 2 (2%) 0.033 14 (11%) 10 (4%) 0.004
Neonatal pulmonary 12 (18%) 8 (4%) <0.001 11 (18%) 2 (2%) 0.001 23 (18%) 10 (4%) <0.001
hypertension
Symptomatic ASD 39 (30%) 9 (3%) <0.001 26 (41%) 2 (2%) <0.001 13 (19%) 7 (3%) <0.001
Right ventricular or atrial enlargement as indication for closure 90 (74%) 212 (79%) 0.216
QP:QS > 1.5 as indication for closure 26 (21%) 52 (20%) 0.659
Pulmonary hypertension as indication for closure 14 (12%) 4 (2%) <0.001

*Continuous Positive Airway Pressure.

The aim of this study was to assess risk factors for an early in Stockholm, Sweden. This cohort was studied in a previous
ASD closure, taking into account several potential confounding study on adverse events after ASD closure (13). Cases were
factors, including the ASD size: bodyweight ratio. children aged 2 years or younger at the time of ASD closure.
Controls were children of an older age.
In a second analysis, cases were defined as children of 1 year
MATERIALS AND METHODS of age and younger and controls were children older than 1 year
of age at the time of ASD closure.
Material
The study included all children born in Sweden who were
treated with an ASD closure, surgically or percutaneously, Exposure Information and Risk Factors
before the age of 18, between January 2000 and December Data were retrieved from medical records and the Swedish
2014 at Skåne University Hospital in Lund and the Astrid National Birth Register (MFR) (14). Gestational age was
Lindgren Children’s Hospital at Karolinska University Hospital estimated from the antenatal determination of gestational

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Tanghöj et al. ASD Closure in Young Children

TABLE 2 | Demographic information on children with ASD closure at 1 year of age or less.

Percutaneous device ASD closure Surgical ASD closure All types of ASD closure

Cases Cases Cases Controls p-value

Total number 16 (32%) 34 (68%) 50 363 <0.001

Weight at closure (kg) 6.8 (±1.7) 6.6 (±1.8) 6.6 (±1.7) 20.3 (±14.1) <0.001
Age at closure (years) 0.7 (±0.2) 0.6 (±0.2) 0.7 (±0.2) 4.9 (±3.8) <0.001
Gestational age (weeks) 34.0 (±5.5) 35.5 (±5.0) 35.0 (±5.2) 38.0 (±3.2) <0.001
Birthweight (gram) 1,652.3 (±1070.7) 2,525.5 (±927.0) 2,427.8 (±975.7) 3,138.3 (±796.2) 0.591
Sex (girls/boys) 10/6 13/17 27/23 221/141 <0.001
ASD size 11.1 (±3.2) 12.7 (±3.9) 12.2 (±3.8) 13.6 (±4.2) 0.09
Mean ASD size:bodyweight 1.7 (±0.5) 2.0 (±0.7) 1.9 (±0.7) 0.8 (±0.4) <0.001
Preterm 8 (50%) 14 (41%) 22 (44%) 71 (20%) 0.876
Late preterm 2 (13%) 6 (18%) 8 (16%) 55 (15%) <0.001
Very preterm 4 (25%) 4 (12%) 8 (16%) 7 (2%) 0.001
Extremely preterm: < 28 gestational weeks 2 (13%) 4 (12%) 6 (12%) 9 (3%) <0.001
Preterm birth: < 32 gestational weeks 6 (37%) 8 (24%) 15 (30%) 21 (6%) <0.001
Very low birthweight 6 (37%) 5 (15%) 11 (22%) 17 (5%) 0.001
Extremely low birthweight 2 (13%) 4 (12%) 6 (12%) 9 (3%) <0.001
Chromosomal abnormalities 5 (31%) 8 (23%) 12 (26%) 32 (9%) <0.001
Other congenital heart defects 7 (44%) 22 (65%) 29 (58%) 82 (23%) 0.351
Arrhythmias before closure 1 (6%) 2 (6%) 3 (6%) 12 (3%) <0.001
Infant respiratory distress syndrome 4 (25%) 5 (15%) 9 (18%) 17 (5%) 0.003
Bronchopulmonary dysplasia 2 (13%) 4 (12%) 6 (12%) 11 (3.0%) <0.001
Neonatal ventilator support 4 (25%) 5 (15%) 9 (18%) 12 (3%) <0.001
Neonatal CPAP* 6 (37%) 13 (39%) 19 (38%) 31 (9%) <0.001
Neonatal sepsis 4 (25%) 6 (18%) 10 (20%) 14 (4%) <0.001
Pulmonary hypertension 7 (44%) 10 (29%) 17 (34%) 16 (4%) <0.001
Symptomatic ASD 5 (31%) 20 (59%) 25 (50%) 23 (6%) <0.001*

*Continuous Positive Airway Pressure.

age by ultrasound and retrieved from MFR. Premature Statistical Analyses

birth was considered to be birth prior to 37 completed Depending on the type of data, mean (std.) or percentage (%) was
gestational weeks and was stratified according to gestational calculated. Student’s t-test was used for parametrically distributed
age at birth: late, 32 to <37 weeks; very premature, 28 variables (unpaired two-sided) and Person’s χ2 for categorical
to < 32 weeks; and extremely premature, <28 weeks. data. A p < 0.05 was considered significant.
Analyses were also made for children born prior to 32 Conditional logistic regression was performed to evaluate
completed gestational weeks as a group (i.e., very and extremely the association between ASD closure at an age of 2 years or
premature children). younger and all significant potential risk factors (p ≤ 0.05)
The largest diameter of the ASD was measured using with a substantial number of exposed cases and controls.
transesophageal echocardiography (TEE) images, expressed in Maximum-likelihood estimates of the odds ratio (OR) and 95%
millimeters and retrieved from stored videotapes and digital confidence interval (CI) were obtained, taking into account
examinations. A ratio for ASD size (mm):bodyweight (kg) potential confounding factors. Regression models were not used
was calculated and the upper and lower limit of the standard to analyze ASD closure in children below 1 year of age, due to
deviation distribution, (0.8–2.0), was used for cut-off limits in the small numbers.
multivariate model. Univariate and multivariate conditional logistic regression
Potential risk factors, such as the need for neonatal respiratory was performed for early ASD closure for three groups:
support, neonatal pulmonary diseases, neonatal sepsis, additional • All types of methods for ASD closure
congenital heart defects (CHD) and chromosomal abnormalities, • Percutaneous device closure
were retrieved from MFR and medical records. Factors • Surgical closure
such as symptoms from volume overload or pulmonary
hypertension prior ASD closure were retrieved from The IBM SPSS Statistics, Version 25 software (IBM Corporation,
medical records. New York, USA) was used.

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Tanghöj et al. ASD Closure in Young Children

TABLE 3 | Risk factors for ASD closure at 2 years of age or younger.

Percutaneous device closure Surgery All ASD interventions

Univariate Adjusted Univariate Adjusted Univariate Adjusted

0R 95% C.I. 0R 95% C.I. 0R 95% C.I. 0R 95% C.I. 0R 95% C.I. 0R 95% C.I.

Gender (female) 0.8 0.4–1.4 − − 1.6 0.8–3.1 1.1 0.7–1.7

Preterm 2.2 1.2–4.2 2.1 0.9–4.6 2.9 1.3–6.3 1.8 0.5–6.8 2.4 1.5–3.9 1.7 0.9–3.3
Late preterm 1.8 0.9–3.5 − − 2.1 0.8–5.3 1.8 1.0–3.1
Very Preterm 4.6 1.2–16.8 − − x x 6.4 2.0–20.4
Extremely preterm 1.1 0.2–6.0 − − 1.4 0.3–5.9 1.5 0.5–4.2
< 32 gestational weeks 1.0 1.0–7.4 4.2 0.3–61.0 2.6 0.8–7.5 0.5 0.1–9.3 3.0 1.5–6.0 2.0 0.5–9.0
Very low birthweight 2.4 0.8–6.6 0.2 0.1–3.0 2.1 0.6–6.9 1.6 0.1–32.7 2.3 1.1–5.0 0.4 0.1–1.9
Extremely low birthweight 2.2 0.5–10.1 − − 1.4 0.3–6.0 2.0 0.7–5.5
Chromosomal abnormalities 3.6 1.7–8.0 3.2 1.4–7.5 3.5 1.2–10.7 2.1 0.5–9.5 3.4 1.8–6.5 2.7 1.4–5.4
Other CHD 1.2 0.6–2.2 0.8 0.4–1.7 6.5 3.1–13.7 4.4 1.9–10.5 2.6 1.7–4.1 1.9 1.1–3.2
Arrhythmias before closure 1.8 0.4–7.6 0.5 0.1–2.9 1.1 0.4–3.2
Infant respiratory distress 1.4 0.5–4.1 4.5 0.9–22.9 1.9 0.9–4.3
syndrome
Bronchopulmonary dysplasia 1.2 0.3–4.9 3.7 0.7–20.0 1.9 0.7–5.2
Neonatal ventilatory support 3.6 1.1–12.2 1.3 0.2–7.9 1.4 0.4–5.1 0.1 0.1–0.4 2.5 1.0–5.9 0.3 0.1–1.3
Neonatal CPAP* 2.2 0.9–4.9 0.8 0.2–3.0 4.2 1.5–11.6 4.4 0.6–33.3 2.9 1.6–5.3 1.6 0.6–3.9
Neonatal sepsis 2.7 0.9–7.6 1.7 0.5–6.0 5.5 1.1–27.3 12.5 0.6–264 3.3 1.4–7.6 2.4 0.8–7.1
Pulmonary hypertension 5.0 1.9–13.0 3.9 1.2–12.1 9.1 1.9–42.66 13.2 1.2–143 5.8 2.6–12.6 3.7 1.5–9.2

Univariate analysis.
*Continuous Positive Airway Pressure.

RESULTS TABLE 4 | Risk factors for ASD closure at 1 year of age or younger.
Study Population All ASD closures
Of a total of 513 children treated with an ASD closure, 98 were
excluded due to invalid identification number (n = 8), being born 0R 95% C.I.
abroad (n = 55), or due to refusing consent to participate (n =
Late preterm 1.1 0.5–2.4
33). Thus, 413 children were included in the study population for
Very preterm 9.7 3.3–28.1
analysis (Figure 1).
Extremely preterm 5.4 1.8–15.8
A total of 131 (32%) cases were 2 years of age or younger at
< 32 gestational weeks 6.9 3.3–14.8
the time of ASD closure. Device closure was more common than
surgical closure among controls (n = 194 vs. n = 88), while type Very low birthweight 5.8 2.5–13.3

of closure was equally distributed among cases (n = 68 vs. n = Extremely low birthweight 5.4 1.8–15.9

63). Cases below 2 years of age were born at an earlier gestational Chromosomal abnormalities 3.6 1.7–7.5

age, with a lighter birth weight, and more commonly with Other congenital heart defect 4.7 2.6–8.7

comorbidities, such as chromosomal abnormalities, other types Infant respiratory distress syndrome 4.5 1.9–10.6
of CHD, and required neonatal respiratory support (Table 1). Bronchopulmonary dysplasia 4.4 1.5–12.3
A large ASD size in relation to bodyweight (ASD Neonatal ventilatory support 6.3 2.5–16.0
size:bodyweight = 2), as well as a smaller ASD size in relation Neonatal CPAP* 6.5 3.3–12.8
to bodyweight (ASD size:bodyweight = 0.8) was more common Neonatal sepsis 6.4 2.7–15.3
among cases of 2 years of age or younger (Table 1). Pulmonary hypertension 11.1 5.1–24.0
Pulmonary hypertension being stated as the indication for Univariate analysis.
closure was more common among cases aged 2 years or *Continuous Positive Airway Pressure.
younger (Table 1).
Overall, 50 (12%) cases were 1 year of age or younger at the
time of ASD closure and, of these, 32% had an ASD device closure Risk Factors
and 68% a surgical closure (Table 2). Most neonatal and pre- Being born prematurely was associated with the risk of an ASD
interventional factors were more common among these young closure at 2 years of age and younger, OR = 2.4 (95% CI:
cases (Table 2). 1.5–3.9) for all used ASD closure methods, and even more for

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TABLE 5 | Adjusted risk factors for early closure in relation to ASD size and body weight ratio.

Percutaneous device closure Surgical closure All ASD interventions

0R 95% C.I. 0R 95% C.I. 0R 95% C.I.

ASD size: body weight ratio = 2.0

ASD size:body weight ratio = 2.0 9.9 1.0–95.5 21.4 1.9–236.0 21.0 4.31–102.0
Preterm birth (<37GW) 6.1 0.7–53.0 1.3 0.1–31.4 1.9 1.0–3.7
Chromosomal abnormalities 2.0 1.3–7.5 1.8 0.4–8.7 2.4 1.2–5.0
Other congenital heart defects 0.8 0.4–1.8 4.6 1.9–11.3 1.9 1.1–3.2
Pulmonary hypertension 3.1 0.9–10.3 6.1 0.5–68.3 2.7 1.0–7.2
ASD size:body weight ratio = 0.8
ASD size:body weight ratio = 0.8 8.9 4.3–18.5 5.4 2.0–14.3 7.06 4.39–13.18
Preterm birth (<37GW) 1.5 0.6–3.7 3.4 0.8–14.0 1.7 0.8–3.6
Chromosomal abnormalities 2.9 1.1–7.5 1.1 0.2–5.7 2.0 0.9–4.4
Other congenital heart defects 0.9 0.4–2.2 4.0 1.6–9.9 1.9 1.1–3.3
Pulmonary hypertension 4.1 1.1–15.1 11.5 1.0–129.4 4.1 1.5–11.3

Multivariate analysis.

surgical ASD closure, OR = 2.9 (95% CI: 1.3–6.3) (Table 3). An Qp:Qs >1.5, as well as right heart enlargement, was equally
Severe neonatal morbidities, such as sepsis and the need for common among cases and controls, indicating that the risk of
neonatal ventilation support of any kind, were associated with overtreatment among cases is limited in our study. The risk of
increased risk of an early ASD closure, and especially for surgical selection bias due overtreatment of young children in our study
closure (Table 3). was thus limited.
In a univariate analysis, very and extremely premature birth
were also associated with the risk of an even earlier ASD closure, Premature Birth
at 1 year of age and younger, for all used ASD closure methods Children born prior to a gestational age of 37 weeks (premature),
(Table 4). All neonatal morbidities and medical support, as well have an altered myocardium compared to term-born children
as additional congenital and chromosomal abnormalities, were (5–7, 21). These alterations, as described in echocardiographic
associated with ASD closure at 1 year of age or younger (Table 4). and magnetic resonance imaging studies, are present even long
The risk of requiring early ASD percutaneous device closure after the neonatal period (6–10, 21). Preterm birth (prior to 32
was associated with additional chromosomal abnormalities, OR gestational weeks), as well an extremely preterm birth (prior to
= 3.2 (95% CI: 1.4–7.5); pulmonary hypertension, OR = 3.9 (95% 28 gestational weeks), was more common among children with
CI:1.2–12.1); additional CHD, OR = 4.4 (95% CI: 1.9–10.5); and an early closure before 2 years of age, as well as for closure
pulmonary hypertension, OR = 13.2 (95% CI: 1.2–143), after before 1 year of age. However, the association between an early
adjustments were made for confounding factors (Table 5). An closure and premature birth was only present when adjustments
ASD size:body weight ratio of 2.0, as well as a ratio of 0.8, was for confounding factors were made, including ASD size:body
associated with increased risk of an early ASD closure, even after weight ratio = 2. Thus, children with a low bodyweight at
adjustments for confounding factors were made (Table 5). closure, as is common in preterm children, and with a larger
ASD size, have an increased risk of ASD closure at young age.
DISCUSSION The myocardial impairment recently found in prematurely born
children, perhaps along with smaller heart volumes, can have an
An atrial septal defect (ASD) allows the shunting of blood from impact on this risk.
the systemic and pulmonary circulation and causes right heart
volume overload (15). Spontaneous closure has been described Surgical Repair
for small or moderate sized ASD (16–18). In children with an Spontaneous closure has been described in ASDs of 5 mm or
asymptomatic ASD, guidelines recommend elective ASD closure less. However, some ASDs may enlarge over time (18, 19).
at 3to 5 years old (15). Closure of ASD has been suggested when Numerous studies have described the safety and efficacy of ASD
there is clinical evidence of volume overload with pulmonary to closure, and it is suggested that the percutaneous approach is
systemic blood flow (Qp:Qs) >1.5 and right heart enlargement. preferable to surgery in most patients (20, 22, 23). In our study,
ASD-related symptoms, such as failure to thrive and impaired the presence of other congenital heart defects was associated with
exercise tolerance, pulmonary hypertension and failure to wean an increased risk of ASD closure. This risk was, not surprisingly,
from respiratory support may lead to early ASD closure (1, 15, 19, greater among the surgical closures (OR = 4.4 (95% CI 1.9–
20). In our study, persistent pulmonary hypertension after birth 10.5), and can be explained by the ASD being closed at the same
was linked to an increased risk of early closure, especially when time as other, more severe heart defects, were repaired. This
the ASD size: weight ratio was low. Thus, recommendations for risk remained unaltered even after adjustments, as well as for
closure, such as pulmonary hypertension, were met in our study. children with an ASD size:body weight ratio = 2 and especially

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Tanghöj et al. ASD Closure in Young Children

an ASD size:body weight ratio = 0.8. Therefore, in cases where is limited through using several sources. The registries have
a surgical repair was needed for other cardiac diseases, the ASD been validated, with good coherence between the registries and
was closed even when the ASD size was small and bodyweight medical records (33, 34). Two out of three Swedish heart centers
increased (ASD size:body weight ratio = 0.8). The surgeons are that perform percutaneous device closure of ASD and one of
thus not likely to leave an ASD even if there could be a chance of two operating centers in Sweden contributed data to our study.
spontaneous closure. This reduces selection bias and increases the number of included
patients, which increases the power of the study (35).
ASD Size:Bodyweight Ratio
According to current guidelines, a hemodynamically significant
CONCLUSIONS
ASD with enlarged right side heart structures should be closed
electively once the diagnosis is confirmed (1). Factors such An increased risk of an early ASD closure is associated
as increased ASD size:bodyweight ratio have previously been with additional chromosomal abnormalities and pulmonary
described as predicting the risk of complications following ASD hypertension. A larger ASD size in relation to lighter bodyweight
device closure (24, 25). An ASD size:bodyweight ratio = 1.2 (ratio = 2), or smaller ASD size in relation to a heavier
or less has been considered optimal for percutaneous device bodyweight (ratio = 0.8) were associated with increased risk of an
closure (24–26). In our study, the risk of an early ASD closure early ASD closure. The ratio between ASD size and bodyweight
was associated with estimated ASD size:bodyweight ratio of 0.8 has a wide range when it comes to predicting an early ASD
and of 2.0, even after adjustments for potential confounders. In closure and might not be the best indicator of the need for
a previous study, we did not find an increased risk of adverse ASD closure.
events following ASD closure for children with large or small
ASD size:bodyweight ratios (13). This indicates that the ASD
DATA AVAILABILITY STATEMENT
size:bodyweight ratio cannot be the only predictor of the need
for an early closure nor for the risk of adverse events. The datasets generated for this study are available on request to
the corresponding author.
Risk Factors for Early Closure
It is well-known that congenital heart defects are more
common among children with chromosomal abnormalities. ETHICS STATEMENT
Down syndrome is known to increase the risk of pulmonary
The authors assert that all procedures contributing to this
hypertension, as well as symptoms of volume overload and heart
work comply with the ethical standards of the Helsinki
failure in the presence of shunt defects (27–29). Chromosomal
Declaration of 1975, as revised in 2008. This study was
abnormalities were associated with an increased risk of an early
approved by the Ethics Committee for Human Research
ASD closure in our study, OR = 3.2 (95% CI: 1.4–7.5). This risk
at the Umeå University (D-nr 2015-10-31M alteration
was present for surgical, as well as device, closure, even when
2015-88-32M), and informed consent was obtained by
other factors were accounted for. Several studies have shown ASD
everyone in the study population or each guardian for the
repair in children with Down syndrome to be beneficial and safe
included children.
(28, 30). Children with chromosomal abnormalities may have
earlier signs of enlarged right side heart structures and symptoms
caused by volume overload. This study indicates that children AUTHOR CONTRIBUTIONS
with chromosomal abnormalities might be more sensitive to
volume overload. GT performed the data analysis. GT, PL, and GS participated
The cases in our study, children at 2 years of age or younger in the analytical framework and contributed to the
at closure, as well as 1 year of age and younger, obviously writing of the manuscript. EN had primary responsibility
had a lower bodyweight than the controls of an older age. for study, protocol development, patient enrolment,
The benefits of ASD closure are well studied, and complete outcome assessment, participated in the analytical
resolution of right ventricular enlargements have been described framework, and had the primary responsibility for writing
(31, 32). The risk of adverse effects during and following ASD the manuscript.
closures has also been studied for small children, even those
born prematurely, and it is considered safe and effective (2, 4,
23). A relationship between an improved myocardial function FUNDING
and an early closure of an atrial septal defect, especially in
This study was funded by the Unit of Research, Education and
prematurely born children, has yet to be studied. The indications
Development, Östersund Hospital, Region Jämtland Härjedalen.
and predictors of an early closure have to be considered in these
future studies.
ACKNOWLEDGMENTS
Limitations and Strengths
This case-control study used medical records, as well as national We thank Annica Maxedius, Skåne University Hospital in Lund,
registries to retrieve data. The risk of selection and recall bias for her substantial support in retrieving medical journals.

Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 January 2020 | Volume 6 | Article 185

Tanghöj et al. ASD Closure in Young Children

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Natural history of growth of secundum atrial septal defects and implications terms.

Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 January 2020 | Volume 6 | Article 185