Treatment and Outcome for Children with Esophageal Atresia from a Gender Perspective

Background Besides the incidence of esophageal atresia (EA) being higher in males, no other gender-specific differences in EA have been reported. The aim of this study was to search for gender-specific differences in EA. Methods A retrospective study was conducted at a tertiary center for pediatric surgery. The medical charts of infants born with EA were reviewed. 20 girls were identified, and 20 boys were selected as matched controls with respect to concomitant malformations. Their treatment and outcome were evaluated. Results Polyhydramnios was more common in pregnancies with boys, 40%, versus girls, 10%, with EA (p < 0.01). In total, 36 (90%) children had patent ductus arteriosus, without any gender difference (18 and 18, resp., p=1). The distribution of days at the different levels of care was not equally distributed between boys and girls. Boys with EA had significantly more postoperative days (median 5 days) in the ward than girls (median 5 and 2 days, resp., p=0.04). No other gender-specific differences in surgical treatment, complications, or symptoms at follow-up were identified. Conclusion Polyhydramnios appears to be more frequent in pregnancies with boys than girls with EA. In this study, boys have longer stays than girls at the pediatric surgery ward.


Introduction
Esophageal atresia (EA) is reported to be more common among boys than girls [1][2][3]. However, it is never reported on whether gender in praxis a ects the care or outcome of patients with EA. erefore, it is important to assess a cohort of children with EA with respect to gender, to secure equal treatment and adequate care for all. e aim of this study was therefore to investigate if there are any gender-speci c di erences in children with EA.

Study Design.
e study was a descriptive retrospective study conducted at a tertiary center for pediatric surgery.
e medical charts of all children born with EA between January 2001 and February 2016 were reviewed. Data were collected with focus on potential gender di erences with regard to (1) birth details, (2) surgical course and postoperative intervention, (3) postoperative complications, and (4) physical symptoms during the rst year. e review was carried out by one independent researcher without previous connection to the patients included in the study. Each child was followed for one year, the endpoint of the study.

Local Routines of Care.
e postoperative care during the rst day or days after esophageal reconstructive surgery is at any of the two intensive care units-the neonatal (NICU) or pediatric intensive care unit (ICU). en, the care is continued at the intermediate intensive care unit and then at the ward of pediatric surgery, before discharge. e discharge from the hospital could be either directly to home or to a local hospital.

De nitions.
Dysphagia was de ned as any reported di culty to swallow food or liquid, resulting in prolonged time and e ort to nish a meal. Gastroesophageal re ux (GER) was de ned to include symptoms such as belching, vomiting, frequent burping, and refusal to eat, or trouble eating. Both dysphagia and GER were parental reported.
Congenital cardiac shunts were de ned as heart defects at birth, including patent ductus arteriosus, patent foramen ovale, ventricular septal defects, and atrial septal defects. ese defects were only considered to be cardiac malformations when they had a hemodynamic e ect. Central venous catheter (CVC) infection was registered when treated with antibiotics. Change of drain was registered when a new drain replaced the thorax drain postoperatively, contrary to extra drain which was registered when an additional drain was received postoperatively.

Patients.
e inclusion criterion for the study was children with EA with a distal tracheoesophageal stula (TEF) (Gross type C). Excluded were children with other types of EA, children who had undergone surgery at another hospital, and children from other centers who had their esophageal reconstruction at the hospital because of concomitant cardiac malformations but later were followed at their local hospital. All girls who met these criteria were included in the study. One boy was selected as a matched control for each girl. e selection of boys was based on associated malformations only, with the intention to make the two gender groups as much alike as possible from a medical perspective. us, the female group was a cohort while the selection for pairing was performed in the male group.

Method of Operation.
All children included were operated on with the same operation technique that was unchanged over the study period. e operation was performed through a posterolateral extrapleural right-sided thoracotomy. e azygous vein was exposed and ligated. e TEF was identi ed and closed with absorbable stitches. e upper esophageal pouch was mobilized from the proximal trachea. Anastomosis with single-layer 5/0 sutures was performed, and a trans-anastomotic feeding tube (6-8 French) was used for postoperative feeding.

ICU/NICU Strategies.
According to the ICU/NICU strategies, the children stayed in ICU/NICU as long as they needed respiratory and/or circulatory support. is strategy did not change over the study period.  [4]. e following background for power calculation was calculated on by a statistician: clinically signi cant relevance for the examined parameters was considered as a di erence of 30%. e study matched case and control sets (1 matched control per case). Preliminary data indicated that the probability of exposure among controls was 0.5, and the correlation coe cient for exposure between matched cases and controls was 0.1. If the true odds ratio for positive nding in exposed subjects with respect to unexposed subjects was 0.1, then we would need to examine 19 case patients with 1 matched control per case to reject the null hypothesis that the odds ratio equals 1 with probability (power) of 0.8. e type I error probability associated with the test of this null hypothesis is 0.05.
All data were compiled using Microsoft Excel, and all statistical analyses were performed using the Social Science Statistics site (http://www.socscistatistics.com) [5]. Fisher's two-tailed exact test was used for comparison of dichotomous data, and the Mann-Whitney U test was used for comparison of continuous data, to compute statistical signi cance. A p value < 0.05 was considered statistically signi cant.

Ethical Considerations.
is study was executed according to the Helsinki Declaration and approved by the Regional Ethical Review Board (registration number 2010/49). Data were anonymized before analyses, and the presentation method precludes participant identi cation.
e study did not a ect the care given to each patient. All patients were treated per the standard care for patients with EA at the pediatric surgical center and according to national guidelines.

Results
During the selected study period of 15 years, there were a total of 77 live births of infants with EA in the region corresponding to 5 newborns each year with an insigni cant slight increase in the number of patients yearly during the period studied. e mortality was zero. e female : male ratio was 1 : 4 during this period.
In total, seven ( ve boys and two girls) were excluded according to the exclusion criteria: patients with Gross type A (n � 3) and Gross type B (n � 1) and those who belonged to other hospitals (n � 3). e medical charts of the remaining 70 patients were reviewed. Out of these patients, 20 were girls. All girls were included in the study and matched with 20 boys with respect to concomitant malformations.

Birth Parameters and Concomitant Malformations.
Polyhydramnios was present in 25% of all pregnancies and turned out to be more common in pregnancies with boys (40%) than girls (10%) with EA (p < 0.01). No gender-speci c di erences were detected with respect to birth weight, gestation age, or prenatal suspected diagnosis (Table 1). One or more concomitant malformations were present in 35% of the girls and in 30% of the boys. e most common abnormality was vertebral malformation, which was present in 25% of girls with EA. All children had cardiac examinations performed before surgery. Patent ductus arteriosus was identi ed in 18 girls and 18 boys, corresponding to a total of 90%. Manifest cardiac malformations with hemodynamic in uences were found in four patients, and three of them had cardiac surgery and one was planned for it at the time of the study ( Table 2). No children had any detected chromosomal abnormalities.

Medical Care and Treatment.
e time to surgery from birth did not signi cantly di er between girls and boys with EA (median 1 day for both genders), nor did the percentage of patients receiving oral feeding before diagnosis of EA 2 Surgery Research and Practice (25% and 35%, resp.). Furthermore, no signi cant di erences in frequencies of thorax drain placement during surgery or postoperative complications within 30 days were detected (Table 3). e time until the rst tube feeding was median 2 days for both girls and boys, and the time until oral feeding was median 9 days for girls and 10 days for boys, without any statistical di erence. Frequency, as well as type of postoperative complications, did not di er between boys and girls. In analyses regarding need of postoperative care at di erent care levels (children intensive care, neonatal intensive care, and pediatric surgery ward), signi cantly longer postoperative stays at the pediatric surgery ward were registered for boys than girls with EA, while there was no signi cant di erence in time needed at the intensive care departments or in the total stay (Table 4).

Outcome at ree-Month Control and at One-Year Follow-Up.
In the three-month control, there were no gender-speci c di erences in anastomotic stricture or prestenosis dilatation, or any di erence in reported symptoms (Table 5). During the whole rst year, there were no genderspeci c di erences in the time to rst dilatation of the anastomotic strictures in esophagus, or in dilatation frequencies (Table 6). e one-year follow-up still included 20 boys and 20 girls with EA. One girl had surgery during her rst year of life due to severe tracheomalacia. Also during the rst year, one girl (out of two) and two boys (out of two) with associated heart conditions had cardiac surgery. e most frequently reported symptoms during the year after surgery were dysphagia, vomiting, and asthma/coughing for girls and dysphagia and tracheomalacia for boys ( Figure 1).

Discussion
e results of this study indicate that polyhydramnios was more common in pregnancies with boys than girls with EA, and the distribution of days spent at di erent care levels after reconstruction turned out to be skewed since the boys had signi cantly more days in the pediatric surgery ward. No other gender-speci c di erences were detected for patient characteristics, care, or outcome. e nding that polyhydramnios was more common in pregnancies with boys than girls with EA has not, to the authors' best knowledge, been assessed or reported in any previous study. However, the overall prevalence of polyhydramnios was 25% in our cohort, which is low compared to previous studies where polyhydramnios in EA pregnancies has been reported to be 55% without any gender analysis made [6,7]. One reason for di erences in prevalence could be that polyhydramnios is de ned di erently or registered di erently with regard to pregnancy length or by di erent routines. Also, polyhydramnios is not speci cally correlated with EA; it also occurs as an idiopathic condition [8].
e gender distribution in studies reporting on idiopathic polyhydramnios reports a gender distribution of 7 boys : 3 girls [9], which is in line with our results. Polyhydramnios could also be associated with other malformations, and in our study, the frequency of concomitant malformations (25%) is lower than in some previous reports on EA (50-55%) [1,6,7].
is may be re ected in the lower frequency of polyhydramnios found in our study. e reason for the gender di erence in the frequency of polyhydramnios is not clear and cannot be explained by any physiological factors related to EA. e nding cannot be related to any other pathology prenatally diagnosed, since this has not been studied before by our group. In a recent publication about idiopathic polyhydramnios, a similar gender di erence was found [9]. us, it seems that EA on its own has no signi cance and impact for gender di erences in polyhydramnios, and our nding can probably not be dened as speci c for this selected group of patients. is is  especially with regard to the limited numbers of children included in our study. At our hospital, boys with EA spent a longer time in the pediatric surgery ward after surgical reconstruction and before discharge than the girls did. e question could be raised, if the result mirrors a true gender di erence in care or if it is caused by that several care levels are involved in the analysis which might blur the picture. e total number of days spent in the hospital did not di er between the genders, nor did the time at any of the intensive care units, but the girls were discharged from the surgical ward earlier than the boys. Although there was a lack of signi cant gender di erences in birth weight and SGA, it cannot be excluded that those parameters still might in uence the time in the ward. However, it might also be explained by geographical reasons such as if the girls came from places closer to the hospital. en, days at the ward might have been substituted with extra controls in the outpatient clinic after discharge. However, this parameter was not included in analyses. In a previous study, our group presented gender analysis on children with Hirschsprung disease [10]. In that study, the length of hospital stays did not di er between girls and boys, but the boys had more emergency admissions during the rst postoperative year.

Surgery Research and Practice
Some results provide novel insights and raise new questions regarding children born with EA and concomitant cardiac ndings. A great majority (90%) of the included children had patent ductus arteriosus. We did not detect signi cant gender-speci c di erences with respect to the incidence of these heart defects, but the frequency overall appears to be higher in children with EA. Previous research have suggested that patent ductus arteriosus and patent foramen ovale are present in 45% and 62% of full-term babies during their rst 60 hours of life [11]. e nding is therefore going to be further studied. e strength of the study was that all included patients had followed the same standard of care per the local strict care and follow-up programs. e sta at the center routinely conducted detailed and continual documentation in the medical records, which made it possible to collect essentially all needed data, although it was a retrospective study. Another strength was that the two groups could be considered comparable out from a balance of other concomitant malformations, which otherwise could have in uenced physical outcome and/or time of care. e obvious limitations of the study are the retrospective design and small numbers of patients. us, the results only present a hypothesis.
Also, it cannot be excluded that the information about polyhydramnios may be weak, since it is based on the information documented in the children's medical charts, and not the mothers', although per the local routines, this should be documented correctly also for the child. e small study population reduces the chance to prove any signi cance and increases the risk of making a type II error. erefore, one should be aware that the lack of signi cance does not mean gender equality or that the genders were equally treated.
In previous studies on EA, several evaluations similar to ours have been made, but none have presented gender analyses in EA. No signi cant and important gender-speci c di erences have been detected and caused important changes in our clinical routines. It is important to consider that both biological and social di erences in girls and boys, or attitudes among care personnel, could constitute potential determinants of outcome also in pediatric surgery, and therefore   Surgery Research and Practice gender aspects should be enlightened so that the care can be improved in the best way for all children.

Conclusion
e results of this study suggest that polyhydramnios is more frequent in pregnancies with boys than girls with EA. In the study, boys spend more days in the pediatric surgery ward than girls, before being discharged, which cannot be explained by di erences in birth characteristics or concomitant malformations.
It is important to continue research and investigating gender-speci c aspects of EA and to perform future studies with larger patient cohorts. is is since gender analysis of biological parameters in EA, medical care, and outcome will help optimizing care and the nal outcome for all children born with EA.

Conflicts of Interest
When this work was being performed, there were no external in uences or con icts of interest.
Disclosure e abstract of this manuscript was presented at the 18th European Pediatric Surgeons' Association Congress 2017.