Gender and birth weight as risk factors for anastomotic stricture after esophageal atresia repair: a systematic review and meta-analysis

Esophageal atresia (EA) is a rare congenital anomaly that occurs in 1:2500 to 1:4000 live-born children [1]. The survival rate has increased to up to 91–99% in the past decade [2‐5]. Excluding the immediate postoperative complications, the most frequently occurring complication affecting postoperative morbidity is the development of anastomotic strictures (AS) [6]. The rate of AS after EA repair varies with different studies, and a universal definition is lacking; however, approximately 32–59% of children are expected to require at least one dilatation during their lifetime [6].

Only a few risk factors for developing AS are known thus far, and their incidence may be affected by the type of EA. Long-gap EA, which is exposed to increased tension in the anastomosis, is considered to be more likely to form AS; in addition, recent studies confirm that anastomotic tension is an independent risk factor of AS development [7, 8]. Earlier research also suggested that AS might be influenced by gastro-esophageal reflux (GER), regardless of the presence of anastomotic tension [5]. However, recent studies have indicated that anti-reflux medication does not reduce the development of AS; nonetheless, proton pump inhibitors (PPI) are still used, possibly because they are considered to be harmless [8, 9].

Several studies have been conducted [6] regarding the incidence of AS after EA repair, and many of them have included gender and birth weight while describing the characteristics of the patients. However, the correlations between these two parameters and AS formation have not been evaluated so far. There are studies indicating that gender may play a role for length of stay after repair of esophageal atresia [10], and for overall morbidity and outcome after surgery in children [11, 12]. In the present study, we aimed to systematically review and perform a meta-analysis of the literature to analyze whether gender and birth weight are risk factors for the development of AS.

A total of 604 articles were found in the Embase, PubMed, and Cochrane database (Table 1). Fifty articles were obtained initially, after narrowing down the number of articles using the selected search terms (Fig. 1). After reviewing the patient characteristics in the chosen articles, eight articles were found to qualify for the meta-analysis; two of them belonged to the same cohort [10, 17]. Finally, the study by Stenström et al. [17] was chosen because it included more patients. Full texts of the remaining seven articles were read, and, ultimately, six articles [7, 8, 14‐17] were included in the meta-analysis (Table 1; Fig. 1).

Only one article was focused solely on EA type C [17]. The remaining five articles were also predominantly focused on type C cases (ranging between 82 and 94%), but included other Gross types as well [7, 8, 14‐16]. The age at first dilation was reported in five articles with a median age of 2 to 6 months. The number of dilations needed was presented in different time periods, mainly until 1 year of age; however, Donoso et al. reported a 5-year follow-up. In four [8, 15‐17] of the studies, the median number of dilations needed ranged between two to three. Okata et al. [7] did not report this parameter, whereas Michaud et al. [14] reported a median of seven dilatations.

All six articles [7, 8, 14‐17] analyzed the impact of gender on AS. A total of 495 (range 28 to 126 per article) patients (males, 292; females, 203) with EA were included; among them, 113 (39%) and 81 (40%) males and females, respectively, developed AS (Table 2). The summary effect measure was as follows: OR, 0.98; 95% CI, 0.67–1.43 (Fig. 2).

Four articles [8, 14, 15, 17] could be used to analyze the impact of birth weight on AS development. Thus, the total number of patients evaluated was 341, 126 (37%) of who had a birth weight of < 2500 g, while the remaining 215 (63%) had a birth weight of ≥2500 g. A total of 51 (40%) and 56 (48%) patients in the < 2500 and > 2500 g birth weight groups, respectively, developed AS (Table 2). The summary effect measure was: OR, 0.74; 95% CI, 0.47–1.15 (Fig. 3).

Although all studies (except for one [15]) were retrospective cohort studies, the overall risk of bias was considered to be low to moderate using the Newcastle-Ottawa scale for the assessment of the risk of bias. Four studies scored ≥7 stars indicating a low risk of bias and two scored 6 stars indicating a moderate risk of bias (Table 3).

In this meta-analysis, neither gender nor birth weight was found to have an impact on the risk of developing AS after EA repair.

In total, six articles [7, 8, 14‐17] were found to match our criteria for analysis of the impact of gender on AS development. The pooled OR was approximately 1, which suggests no significant difference between males and females with regard to the risk of developing AS. The rate of AS was higher in females in four [8, 14, 16, 17] out of six articles, ranging between 3 to 8 percentage points compared to males. On combining the data from all six studies, [7, 8, 14‐17] an overall rate of 40% in females and 39% in males was observed.

Furthermore, the pooled OR for AS, based on birth weight, did not differ significantly. Only four articles [8, 14, 15, 17] were suitable for birth weight analysis. Difficulties in analyzing this parameter were encountered due to diverse cut-offs on birth weight in the different articles. In one article [14], manual conversion from nominal to categorical data was performed based on the normal distribution. This may have compromised the accuracy of the original data. In three [8, 15, 16] out of the four articles, the rate of AS was higher (range, 5–17%) in patients with ≥2500 g birth weight compared to those with < 2500 g birth weight.

Thus, neither birth weight nor gender seemed to impact the development of AS. It is worth noting that the included studies were mainly retrospective and single-cohort studies. However, the risk of bias was considered to be low to moderate when assessed with the Newcastle-Ottawa scale. There was also the risk of type II error due to the low number of articles included. Follow-up time is an important parameter that needs to be considered while evaluating the rate of AS. Two of the selected articles [14, 16] failed to report the follow-up time. The remaining four [7, 8, 15, 17] had a follow-up period of 1 year after the EA repair. Of the six articles, only one [7] did not present the age at first dilatation or the number of dilations required in the cohort. The wide variations in these two parameters in the remaining articles might indicate the differences in the criteria for requiring dilation and the definition of AS. As noted in the introduction, the definition of AS is not universal. The articles chosen in the current study presented different definitions, which may confound the results. In addition, it might explain the wide range in AS rate in the included studies. Most studies primarily relied on symptoms that were confirmed with an esophagram. Michaud et al. [14] included failure to thrive in their definition of AS. Thus, a universal definition of AS will be of great value in the future.

AS is one of the main causes of morbidity after EA reconstruction. Therefore, it is important to explore the risk factors for the underlying mechanism. The ability to predict the development of AS after EA repair might prove useful for a safe postoperative follow-up and high-quality parental information. Identification of risk factors and an improved understanding of the pathogenesis of AS could aid in the development of preventative therapies.

The main strength of this study is that it explored a field that has not been researched in detail or reviewed systematically, so far. Most of the articles included in this meta-analysis were recently published, except for one [14]. The latter provides a current depiction of this particular research field and its upcoming challenges. Another strength of our study was that all the articles selected were from different countries. This gives a worldwide perspective of the EA and AS rates based on the gender and birth weights of the patients. It also manifests the differences in the definitions of AS, which is a topic of discussion in several published studies [6].

Our study had various limitations. First, the number of patients in all the selected articles was low. EA is an uncommon congenital malformation and thus, understandably, most studies are small cohort studies. Second, based on the method used in our study, selection bias may be a confounder. In general, the articles found during the first selection did not tabulate the patients’ characteristics in a detailed manner, based on our requirements. This may have excluded articles that could potentially have had added to the raw data in the current study. We tried to contact the authors in order to receive more elaborate raw data but were only successful with two authors [8, 17]. Third, the data from the selected articles were predominantly based on EA Gross type C but not in full effect. It was also impossible to adjust for age at surgery; hence, possibly later repair due to long gap often have more tension in the anastomosis and consequently have higher risk of anastomotic stricture. Although randomized control trials were not applicable in this meta-analysis, all articles, except one, were single-center retrospective cohort studies. Further research using a different approach, such as generating a multi-centered database on patient characteristics and focusing on specific types of EA, may be useful. A larger database could then lead to less selection bias and a better chance of evaluating the impact of gender and birth weight on the development of AS.

This meta-analysis studied esophageal AS, the main complication after EA reconstruction. Although males are more likely to develop EA, they do not have a higher risk of AS. Furthermore, birth weight does not seem to be a risk factor for developing AS after reconstruction of EA. Further studies with larger sample sizes are required to analyze these two parameters in detail, which may potentially aid in the early detection of children who are at risk of developing AS.