Risk Factors for Recoarctation and Mortality in Infants Submitted to Aortic Coarctation Repair: A Systematic Review

Aortic coarctation is a common congenital heart defect that often requires correction at a young age. Currently, success is defined by the achievement of a durable repair with low morbidity and mortality. We sought to systematically review the literature on risk factors for recoarctation and mortality in infants submitted to aortic arch coarctation repair under 1 year of age. PubMed and Scopus were searched for studies reporting risk factors for recoarctation and mortality from January 1989 to August 2019. Among the 1038 retrieved articles, 18 met the inclusion criteria, with a total of 2891 patients. The extracted risk factors for recoarctation were comprehensively summarized in the following categories: demographic variables, associated anomalies, clinical and repair variables, and morphometric variables. Younger age and lower weight were weak determinants of need for reintervention, while smaller aortic arch was a strong predictor of recoarctation. While balloon angioplasty is a clear risk factor for arch restenosis, the chosen surgical technique is not a strong risk factor. Associated minor cardiac anomalies and lower weight at surgery were important risk factors for death. Younger and smaller infants are at increased risk for adverse outcomes when submitted to aortic arch coarctation repair. This is particularly important when associated with smaller arch morphology. Strategies to improve the management of these patients may play a key role in improving their outcomes. Notably, surgical technique was not a strong predictor of recoarctation and mortality, suggesting that the choice of one over the other should be tailored.


Introduction
Coarctation of the aorta is a common congenital heart defect typically characterized by narrowing of the aortic isthmus near the ductus arteriosus. It can range from a discrete coarctation to a long segment of arch hypoplasia [1]. Aortic coarctation can occur as an isolated defect, but frequently it appears associated with other cardiac malformations [2].
Patients that present for initial aortic coarctation repair are often very young (frequently under 1 year of age) and can have critical clinical conditions [3]. With advances in surgical strategies, this defect is commonly repaired at diagnosis at this early age, with good short-term and long-term outcomes [4][5][6][7][8]. Different surgical techniques have been defined [1], and some centers have also described percutaneous interventions for infants with native coarctation [9][10][11]. In young patients with native aortic coarctation not associated with other major cardiac defects, end-to-end anastomosis and extended end-to-end anastomosis are the most frequently used techniques [3]. Regardless of the technique used, nowadays, surgery success is defined by the achievement of a durable repair with low morbidity [12].
There have been several studies evaluating risk factors for adverse outcomes after surgical intervention, including recoarctation, although the literature is often conflicting and inconclusive, especially regarding the influence of child weight and surgical strategy on the rate of reinterventions [7,8,13,14]. Other possible risk factors identified in individual studies include anatomical and morphological characteristics of the aortic arch, preoperative care, and age at time of the intervention [12,14,15]. Nevertheless, a comprehensive analysis of the evidence to determine the risk factors conclusively lacks in the literature. Conducting a systematic review is a paramount method to summarize and aggregate findings from individual studies, and, in clinical settings, it is vital for the assessment of risk factors that influence the decision-making process.
In this study, we aim to pool available data and attempt a large-scale examination of the existing studies to define the risk factors associated with recoarctation and mortality after surgical repair of coarctation of the aorta in neonates and infants until 1 year of age.

Search Strategy
We conducted a systematic literature review that followed the PRISMA guidelines [16]. PubMed and Scopus electronic databases were searched for articles published between January 1989 and August 2019 using the following query: (

Eligibility Criteria
The databases were searched independently by two authors that evaluated identified studies for inclusion based on Title and Abstract, according to the eligibility criteria.
When a study could not be excluded on this basis or in case of disagreement, the full text was reviewed, and the two independent reviewers discussed it until a consensus was reached.
The study was eligible for inclusion if it examined risk factors for recoarctation or mortality and met the following criteria: (1) patients were submitted to surgical or percutaneous repair of aortic coarctation until 1 year of age, and (2) patients with isolated aortic coarctation or associated with minor congenital heart defects, without associated complex congenital heart defects. The outcome of interest was the occurrence of recoarctation, reintervention for recurrent arch obstruction, or related mortality. Articles published more than 30 years ago were excluded considering the great technical advances recognized in pediatric cardiac surgery. Also, reviews, letters, conference papers, editorials, and nonhuman studies were excluded.

Data Collection and Quality Assessment
Data from studies were extracted independently to a previously prepared spreadsheet, and both reviewers discussed the data for consistency. The retrieved data were summarized in the following: first author's name, year of publication, study design, sample size, sample characteristics (sex, age, weight, associated anomalies), repair strategy, follow-up time, reintervention or recoarctation rate, mortality rate, reported endpoints, risk factors identified and respective adjusted effect size, confidence interval, p value, and method of analysis. When data were missing from the articles, the corresponding authors were contacted to retrieve more information.
Considering that this review was based mainly on observational studies, we used the Quality Assessment Tools, developed by the National Heart, Lung and Blood Institute from the National Institute of Health, to assess the quality of the included articles [17]. Although not entirely validated, this 14-criteria form has been widely used to evaluate the internal validity and risk of bias of observational studies in systematic reviews and meta-analysis. Two of the reviewers assessed all studies and evaluated the 14 criteria independently. The quality of the studies was then graded as "Good," "Fair," or "Poor," according to the potential for bias and the ability of the study to accurately assess an association between exposure and outcome. If there were discrepancies between the two authors, the data were discussed to reach a consensus.

Study Characteristics
The studies characteristics and clinical parameters, along with the main results of the included studies, are summarized in Tables 1, 2, 3, 4. Thirteen [9, 12-14, 19-22, 24-27, 29] of the included studies were rated as "Good" and five studies [18,23,28,30,31] as "Fair" according to the Quality Assessment Tools (this evaluation is summarized in Online Resource 1). We included 18 studies that recruited a total of 2891 patients from eight different countries. The follow-up duration ranged from 0 to 360 months.
Around 61% of patients were male. The weight of the patients at the intervention ranged between 0.8 and 10.4 kg, and approximately 34.4% had a ventricular septal defect associated. Other associated minor anomalies, such as bicuspid aortic valve, were also reported in some of the studies in variable percentages Table 2.
The most common surgery strategies were the following: end-to-end anastomosis in 27.8%; extended end-toend anastomosis in 25.6%; subclavian flap aortoplasty in 7.8%; balloon angioplasty in 6.2%; patch aortoplasty in 4.8%; combined surgical strategies were used in 3.4%, and less than 1% of patients had another type of repair performed. Regarding surgical strategy, a thoracotomy was performed in 70% of patients, with only 21.7% being submitted to a sternotomy; the remaining 8% had a percutaneous approach to perform angioplasty.
Crude rates of reintervention for recoarctation of the aorta in the included studies were calculated by dividing the number of patients requiring the reintervention by the total number of patients included and ranged from 5.9 to 46.6% in 16 of the studies. The rate of procedure-related mortality was calculated by dividing the number of deaths by the total number of patients included in the 18 studies and ranged from 0 to 22.4%. Patients lost to follow-up were excluded from these calculations. The total recoarctation rate in the combined population of this study was 11.9% and the procedure-related mortality was 3.8%. Full-text arƟcles excluded (n=59) due to:   Table 2 Baseline characteristics of study participants, including age, weight, associated anomalies, and surgical repair approach

Associated Anomalies
A positive association between recoarctation and aortic arch hypoplasia was shown in only two studies: OR 2.864 (p = 0.001) [22] and OR 1.31 (p = 0.0047) [18]; interestingly, Gorbatykh et al. [18] found that the arch hypoplasia was not a significant risk factor for recoarctation when Remarkably, the presence of other cardiac defects was not proven to be statistically related with the occurrence of recoarctation [12,14,19,31].

Clinical and Intervention Variables
Prostaglandins infusion prior to surgery was assessed in three studies [12][13][14], with only Lehnert et al. [12] establishing a significantly positive relation with recoarctation: Exp(B) = 1.53 (p = 0.0043). Conversely, no study found a documented patent arterial duct to be a significant risk factor [12,13,20,24]. The need for inotropes prior to surgery and the type of suture used were also associated with recoarctation [13,29].
The type of coarctation repair strategy were evaluated in eight articles [9, 12, 18-20, 25, 27, 30]: two positively associated patch aortoplasty [19,25], while Gorbatykh et al. [18] established in a multivariable model both direct endto-end anastomosis and oblique anastomosis as risk factors for recoarctation, but not reverse aortoplasty: OR = 2.82 (p < 0.001), OR = 1.42 (p = 0.045), and OR = 0.66 (p = 0.36), respectively. Also, extended end-to-end repair anastomosis was found to be risk factors in the analysis by Truong et al. [29] Particularly, repair performed by balloon angioplasty was a significant risk factor for recoarctation in the three studies that explored this type of repair [9,20,27].
Postoperative peak doppler velocity, post-intervention systolic gradient and residual coarctation on the pre-discharge echocardiography were also identified as significantly associated risk factors for recoarctation in three studies [19,24,27,29].

Morphometric Variables
Three studies [14,19,24] assessed the risk of the diameter of the coarctation, with two [19,24] of them showing a positive correlation between smaller diameter and the occurrence of restenosis of the aortic arch.
The morphometric variables of the aorta were analyzed in seven studies [13,14,18,19,24,26,29]. Notably, McElhinney et al. [14] found that while ascending aortic arch diameter was a risk factor for restenosis, when indexed to weight, this relation diminished. Contrarily, a smaller transverse arch diameter remained a risk factor even when indexed to weight: OR = 3.0 (p = 0.001) and OR = 7.9 (p = 0.04), respectively. Moreover, Burch et al. [13] also demonstrated that the risk of recoarctation decreased per 1-mm increase in transverse aortic arch diameter: RR = 0.57 (p = 0.04).
Truong et al. [29] also established the increase in the descending aorta diameter, indexed to weight, as a protective factor: HR = 0.14 (p = 0.04).
The remaining studies [18,24,26] were unable to demonstrate arch morphometry as a significant risk factor for recoarctation of the aorta.

Factors Associated with Mortality
The risk factors for mortality were assessed in four of the included studies [12,21,23,25]. Table 6 illustrates the summarized results. The effect of weight was studied in three studies [12,21,23] but only Lehnert et al. [12] and Curzon et al. [21] found a positive association between weight < 2.5 kg and the risk of intervention-related or cardiac death.
One particular study [25] focused on associated cardiac anomalies as potential factors that increased mortality. In fact, Quaegebeur et al. [25] showed that the presence of ventricular septal defects, concomitant with the type of aortic arch repair, was a significant risk factor for death. Furthermore, Lehnert et al. [12] established the presence of ventricular septal defects as a risk factor for mortality in these patients (in this study, death occurred in five patients that had concomitant closure of the septal defect and coarctation repair and in one patient requiring pulmonary banding).

Discussion
The present systematic review was based mainly on observational studies and explored the risk factors for recoarctation and mortality in infants submitted to repair of coarctation of the aorta under 1 year of age. This large qualitative study included 2891 individuals retrieved from 18 different studies. A broad range of risk factors was analyzed, including demographics, morphometric, clinical, and intervention variables, as well as associated cardiovascular anomalies.
Younger age, lower weight, and prematurity have been thought as risk factors for adverse outcomes in these patients. In this review, six studies [12-14, 18, 19, 24] analyzed the effect of age as a potential risk factor for recoarctation, but only two studies [12,14] showed that younger age at repair minimally increased the risk of restenosis of the aorta in multivariable analysis. These findings suggest that age at repair may not be a strong determinant of recoarctation or death as previously assumed. Of the eight studies [12-14, 18, 19, 24, 28, 29] addressing weight as a possible risk factor, only two [18,28] demonstrated that lower weight at repair was a risk factor for recoarctation, and Gorbatykh et al. [18] noted that this was not a significant factor when adjusting for surgical strategy. However, two studies [12,21] have found an association of weight at repair < 2.5 kg with up to a 2.65-fold increase [21] in mortality. Low weight at intervention is classically viewed as a potential risk factor. This is reinforced by our systematic review, which showed that weight < 2.5 kg is indeed a risk factor for mortality and recoarctation, although the evidence supporting the former is weak. Regarding prematurity, five studies [12-14, 19, 29] addressed this as a potential risk factor, but none was able to demonstrate a significant association with recoarctation. Also, smaller length [22] and lower birth weight [29] were pointed as risk factors in two individual studies, but no other study addressed these factors. Notably, no study found a relationship between time of diagnosis-prenatal or postnatal-and adverse outcomes, even though some literature had previously suggested that a prenatal diagnosis improved outcome, with lower required doses of prostaglandins and decreased mortality rates [32,33].
Seven studies [12-14, 18, 19, 26, 29] evaluated the association between recoarctation and aortic arch morphometry. Two studies [18,22] showed that the hypoplastic aortic arch was a significant risk factor but presented conflicting results. Hager et al. [22] showed that the odds of developing recoarctation or death when hypoplastic arch is present are 2.9 to 1, whereas Gorbatykh et al. [18] demonstrated that this was not a determinant factor when added to a multivariable regression model with the different types of surgical strategy. Interestingly, McElhinney et al. [14] found that a smaller transverse arch diameter was related to increased recoarctation, and its effect increased when indexed to weight. Moreover, Burch et al. [13] concluded that per 1-mm increase in the transverse arch diameter the risk for recoarctation diminished 43%. This evidence supports the assumption that hypoplastic aortic arch is an important risk factor for the reintervention and should be taken into account when choosing the repair strategy.
On the other hand, possible residual arch obstruction, ascertain by postoperative peak doppler velocity flow [27,29], or increased discharge systolic blood pressure gradient [19] were significant risk factors for recoarctation. This residual obstruction of the aortic arch, while possibly related to a technical failure to address the obstruction, may also be associated with underappreciated arch hypoplasia.
Minor associated cardiac defects, such as small ventricular defects, bicuspid aortic valve, and left superior vena cava, were addressed as potential risk factors in seven studies [12-14, 19, 20, 24, 31], but none found a significant increase in recoarctation rates, although Quaegebeur et al. [25] demonstrated that the presence of ventricular septal defects or aortic valve stenosis was associated with increased mortality.
Lehnert et al. [12] was the only study that found a positive relation between recoarctation and prostaglandin infusion before surgery. Moreover, it was also noted that, in patients receiving prostaglandins, extended end-to-end anastomosis led to fewer reinterventions compared to end-to-end anastomosis. This might be explained by difficult in ascertain the margins to be resected, which results from changes in morphology of the aortic isthmus with the reopening of the ductus arteriosus. In fact, although the exact etiology of the recoarctation is yet to be fully understood, the role played by residual ductal tissue seems to be crucial [34].
Regarding surgical technique, the literature has pointed to extended end-to-end anastomosis as the better alternative to avoid recoarctation due to a more extensive resection, preservation of the subclavian artery and oblique anastomosis [4,6,35]. However, the results of this systematic review are somewhat conflicting. Six studies [12,14,18,19,25,30] addressed the type of surgery strategy with future need for reintervention, but only two [19,25] of those associated patch aortoplasty with recurrent coarctation and Gorbatykh et al. [18] even assessed an increased risk when an oblique anastomosis was performed. Although several studies have been conducted to compare different surgical strategies [4,[6][7][8]36], these findings suggest that none is universally superior to another, and the choice of one over the other should be tailored.
The three studies that compared coarctation repair by percutaneous balloon angioplasty to surgical repair [9,20,27] agreed that this technique significantly increased the risk for recoarctation and need for reintervention. Usually, this technique is viewed as a palliative treatment in low-weight newborns with immature systems and organs because it allows stabilization and growth until surgery [37]. Balloon angioplasty with stenting is the repair strategy of choice in adults [1], but in younger individuals, it brings an important challenge: the placement of a stent is usually not feasible due to the continuous somatic growth of the vessels at this age. Recently, some studies have investigated the prospect of introducing breakable stents in infants: introduced at a small diameter, the stents have properties that allow subsequent unlimited expansions in line with arch growth, which may reduce the incidence of restenosis and favor this technique in selected patients [11,38,39].
This systematic review has several strengths. It is the first systematic review to comprehensively explore risk factors for recoarctation of the aorta and mortality in infants submitted to coarctation repair under 1 year of age. A strict search strategy was followed, using PRISMA guidelines to screen two databases, PubMed and Scopus. Moreover, based on the Quality Assessment Tools developed by the National Heart, Lung and Blood Institute from the National Institute of Health, all the included studies were rated as "Good" or "Fair," which suggested a low risk of bias. Finally, the included publications involved different populations and cardiothoracic surgery departments from eight countries across the world to warrant the applicability the findings and to investigate an extensive range of risk factors for recoarctation and mortality in young infants.
However, there are some important limitations to our systematic review. First, the retrieved studies were heterogeneous regarding the definition of the potential risk factors, adjusted covariates, and sample size; as such, the comparison of the studies was challenging. However, although we did not acquire sufficient studies to perform a meta-analysis for the relationship between the different risk factors for recoarctation and mortality due to heterogeneity of methodology, we still managed to identify key factors. Second, considering the limited number of studies that analyzed some risk factors, the accuracy and validity of the relationship between these factors and the outcome may also be questionable. Importantly, while most studies were rated as "Good" using the Quality Assessment Tools, indicating a low risk of bias and good ability to draw associative conclusions about the effects of the exposure, significant publication bias was noted in most of the included studies. Most studies did not report all nonsignificant results or reported only the associated p-values. Additionally, the included studies were mostly observational, retrospective and monocentric, with only one clinical trial and one prospective multicentric observational cohort. Hence, the conclusions of this review are subjected to observational bias, and the body of evidence should be taken accordingly.
In conclusion, this study analyzed and identified the risk factors for recoarctation and mortality in infants under 1 year of age submitted to coarctation repair. Notably, we demonstrated that the most determining factors for recoarctation were related to smaller aortic arch and balloon angioplasty, while mortality was strongly associated with lower weight at repair. Moreover, this systematic review established the ambiguity of the methodology in this field, which greatly influences the comparability of findings and condensation of the scientific evidence.
In the future, more extensive, prospective and multicentric cohorts are required for a clear understanding of the many involved factors, which is vital for patient's management.
Author Contributions MD and JM designed the study. MD and JM worked equally in study selection, data collection and assessed the quality of included studies. MD drafted the manuscript. MD, JM, ALM, and AB revised the manuscript. All authors reviewed and approved the final manuscript.
Funding This research did not receive any funding or financial support.