Risk factors for isolated atrial septal defect secundum morbidity

Atrial septal defect secundum is a common type of congenital heart defect and even more common among children born premature. The aim of this study was to assess premature birth as a potential associated risk factors for cardiac morbidity in children with isolated ASD II. In this retrospective national registry-based case–control study all children born in Sweden between 2010 and 2015 with an isolated ASD II diagnosis were included. Association between premature birth and cardiac morbidity in children with isolated ASD II was assessed by different outcomes-models using conditional logistic regression and adjustments were made for confounding factors. Overall, 11% of children with an isolated ASD II received treatment for heart failure. Down syndrome was the only independent risk factors for associated with cardiac morbidity in children with ASD II (OR = 2.25 (95%CI 1.25–4.07). Preterm birth in children was not associated with an increased risk of ASD II cardiac morbidity.


Demographics
This study included 762 children diagnosed with isolated ASD II.Among these, 81 (11%) children were prescribed a drug for heart failure, and 193 (26%) had more than five outpatient visits.The mean number of outpatient visits was 3.7 (± 3.1) and median age at the first visit was 64 days (IQR: 131 days).Further demographic data are presented in Table 1.
The potential mediators BPD (bronchopulmonary dysplasia), PPHN (persistent pulmonary hypertension of the newborn), and Down syndrome were evaluated.BPD was significantly more common among children born preterm than among term-born children.However, children with PPHN or Down syndrome were equally distributed among children born preterm and term born children (Table 2).No significant differences in number

Risk factors
Children with drug treatment for heart failure treatment were more often diagnosed with PPHN than children without treatment (6% vs. 2% p = 0.03) and were younger at first visit (64.0 days 131.0 iqr vs. 109.5days 278.0 iqr, p < 0.01) compared to children with no drug treatment for heart failure .Children with more than five outpatient visits were younger (67.0 days 161.0 iqr vs. 119 days 285.0 iqr, p < 0.01) at their first visit than children with fewer than five outpatient visits.Down syndrome was significantly more common among those with more than five outpatient visits (Table 3).
Children with drug treatment for heart failure had more outpatient visits (8.4 days ± 4.7 std vs. 3.1days ± 2.2 std, p < 0.01) than children without drug treatment.Further data on risk factors for drug treatment are provided in Table 3.
There was no independent risk factor for cardiac morbidity due to ASD II among children born preterm (Table 4).Down syndrome was associated with an increased risk of ASD II morbidity described as more than five outpatient visits (Table 4).

Discussion
In this national case-control study we assessed the association between premature birth and risk of increased cardiac morbidity in children with secundum atrial septal defect (ASD II).Cardiac morbidity due to ASD II was not independently associated with premature birth, although persistent pulmonary hypertension and BPD was more common among children born preterm.Down syndrome was independently associated with increased morbidity due to ASD in our study.
Allover 11% of children with an isolated ASD II in this study, received treatment for heart failure, which is in line with previous findings 22,23 .Preterm birth, which includes several mediators for overall morbidity has not been assessed previously in relation to ASD II morbidity.We did not include PPHN in our regression analyses, as it may be classified as a mediator of morbidity in children born preterm and is linked to premature birth as well as to Down syndrome 12,24,25 .Altered pulmonary vascular resistance and delayed normalization of the pulmonary circulation, high pulmonary pressure, along with the intolerance to pulmonary overflow, can indicate that there might be a need of cardiac drug treatment in children with ASDII and maybe especially those with Down syndrome 26 .We choose to define cardiac morbidity by an increased number of outpatient visits to a pediatric In contrast to our hypothesis, being born preterm was not an independent risk factor for cardiac morbidity.An increasing number of studies indicates children born preterm are at risk of an early ASD II closure and of heart failure and pulmonary hypertension throughout the entire childhood and even during adulthood 12,13,15,27 .Assessing the benefits of early ASD II closure can be difficult, as clinical improvement of ASD II in a pretermborn patient may also be part of a normalization of the pulmonary vascular resistance as a child grows 28 .Premature birth was not associated with an increased risk of cardiac morbidity in our study, which contrasts with results from other studies 12,29 .We believe that the number of children lost to follow up is limited in our study and cannot explain these difference.An intervention was made in 16% of the term born children and 18% of the preterm born children (p-value: 0.08) and further studies on the risk of an early intervention in children born preterm is needed.Pre-interventional ASD II-associated morbidity, shown by others, may be associated with other, yet unknown factors.
The number of outpatient visits has previously been used in other studies to assess health care resource utilization and as a measure of morbidity 30 .Setting a cut-off number of outpatient visits to identify morbidity is sensitive, as a low number can hamper the analysis and the interpretation of the results.A low value may introduce low specificity while a high value may result in low sensitivity 21 .We used the third interquartile range of outpatient visits as a cut-off proxy measurement of isolated ASD II morbidity 21 .However, more than five visits may be influenced other factors, such as local traditions.By the national approach we believe this study has ruled out the risk of a such skewed outcome measures.
ASD II diagnosis may be confused with PFO and it is of great importance to separate these diagnosis when assessing morbidity in children with ASD II.The SWEDCON register is based on the EPCC coding for diagnosis and will distinguish between ASD (EPCC) 05.04.02) and PFO (EPCC code 05.03.03) diagnosis 19 .All cardiac diagnoses in SWEDCON are set by a pediatric cardiologist or an echo-trained pediatrician and diagnosis in SWEDCON is always based on echo cardiac findings.Thus, the risk of selection bias or misclassification in in this study must be regarded as low.Small ASD II may not be recorded in the SWEDCON register.This must be regarded as equal for all children, and we believe the risk of selection bias due to small ASD II is low.The validity of ASD II diagnoses in SWEDCON has a good coherence between medical records and registered data 31 .Missing information on birth is low, and 98.1% of all births are registered in the Medical Birth Register 32 .This reduces the risk of missing data and increases the validity of retrieved data.
All children with isolated ASD II in Sweden were included in this study.The well documented high national coverage of SWEDCON and the large number of included children strengthens the study.The use of well-known risk factors and a well-defined outcome variable, along with the documented good coherence and validation of data in the registries, are other factors that strengths to the study.
The retrospective approach may limit the study through the risk of selection, recall, and attribution bias.However, by combining two national registries, which both are validated with good agreement with other sources, strengthens the reliability of the collected data and decreases the risk of biases.
The SWEDCON register do not include information type of drug which is a limitation.However, information on drugs used for a clinical condition such as heart failure (the intention to treat) is registered and is used as a proxy for heart failure.Growth retardation, clinical and echo cardiac signs of heart failure, along with frequent infections are known signs of morbidity due to an open ASD II, but not registered in SWEDCON.By using two different proxies to assess ASD II morbidity; medicines for heart failure and number of outpatient visits, we used other ways to assess cardiac morbidity.

Table 3 .
Distribution of risk factors in each group.BPD, Bronchopulmonary dysplasia; PPHN, Persistent pulmonary hypertension.

Table 4 .
Adjusted risk for heart failure drug treatment and risk factors for making more than five outpatient visits.