Incisional hernia after surgical correction of abdominal congenital anomalies in infants: a systematic review with meta-analysis

Incisional hernia (IH) in children could result in life-threatening complications, including incarceration and bowel strangulation. The incidence and risk factors of IH in infants are scarcely reported. Since IH-correction may require extensive surgery and a long recovery program, identifying infants and birth defects at risk, may lead to a different approach during the primary surgery. Therefore, the aim of this review is to systematically review the available data on the incidence of IH following surgery for congenital anomalies in infants. All studies describing IH were considered eligible. PubMed and Embase were searched and risk of bias was assessed. Primary outcome was the incidence of IH, secondary outcomes were difference in IH occurrence between disease severity (complex vs simple) and closure method (SILO vs primary closure) in gastroschisis patients. A meta-analysis was performed to pool the reported incidences in total and per congenital anomaly separately. Subgroup analysis within gastroschisis articles was performed. The 50 included studies represent 3140 patients. The pooled proportion of IH was 0.03 (95% CI 0.02–0.05; I2 = 79%, p ≤ 0.01) all anomalies combined. Gastroschisis (GS) reported highest pooled proportion 0.10 (95% CI 0.06–0.17; n = 142/1273; I2 = 86%; p ≤ 0.01). SILO closure (OR 3.09) and simple gastroschisis, i.e. without additional anomalies, (OR 0.18) were of significant influence. This review reports the incidence of IH in infants with different congenital abdominal anomalies, of which gastroschisis reported the highest risk. In GS patients, complex GS and SILO closure are risk factors for IH development.

Incisional hernia (IH) is a dreaded complication after abdominal surgery in children. It may result in serious lifethreatening complications, including incarceration and bowel strangulation 1,2 . In addition, it is is a burden on the quality of life and may affect the development of the child 3,4 . The incidence and risk factors of IH in neonates are scarcely reported and therefore surgeons often refer to studies done in the adult population. For obvious reasons though, taking measures to prevent smoking and obesity in the infantile cohort would not aid in lowering IH rate 5 . The studies that do report IH in the paediatric population reported an incidence between 0.7 and 3.2% [6][7][8][9] . During the last decades major advancements have been made in the postnatal care of neonates with congenital anomalies. Those developments, such as extracorporeal membrane oxygenation (ECMO) and total parenteral nutrition, have increased survival of this crucial period 10 . Because more neonates survive, there has been an increase in abdominal paediatric surgery procedures 10,11 . As the total numbers of abdominal procedures rises, an increase in total accounts of IH is also to be expected.
IH correction may require extensive surgery and a long recovery program. Identifying infants and birth defects at risk, may lead to a different approach during the primary surgery. Therefore, the aim of this review is to estimate the incidence of incisional hernia following surgery for congenital anomalies in infants (less than 2 years of age) with a systematic review.
Primary and secondary outcomes. The primary endpoint was the pooled percentage of IH. Secondary endpoint included the pooled percentage per congenital anomaly and identification of possible risk factors such as surgical procedure and disease severity by means .
A Forest plot, containing the estimated overall pooled proportion of IH and the corresponding 95% CI was created using Graphpad Prism version 8. In the Forest plot we also reported the pooled proportion and CI per anomaly if; (1) IH was reported in at least three studies for the anomaly OR (2) if the total number of patients all studies on an anomaly combined was ≥ 100 patients; (3) there was at least one event of IH present all studies on a specific anomaly combined. If these criteria were not met the anomaly was reported under the forest plot as residual. These residuals were still included in the analysis for overall pooled proportions.
For all studies with multiple arms, data of both trial-arms were combined or, if only one arm matched the inclusion criteria, the appropriate arm was used. Additional extracted parameters were: author, country of conduct, year of publication, journal, study design, duration of follow-up, duration of study, number of participants, type of congenital anomaly, subdivision within anomaly, time to IH, repeat surgery because of IH, history of stoma data was extracted on. Duration of follow up was described as median with range, mean with/without standard deviation or citated text following each article's own description. Duration was either reported in month or years recalculated from the reported value if necessary.
For studies describing gastroschisis, type of closure (by SILO or primary) and severity of disease (complex or simple) was noted following definitions used by the author. Studies deemed gastroschisis complex when a patient had additional anomalies, such as intestinal atresia. If the patient only suffered from a gastroschisis, it was accepted as simple gastroschisis. Data extraction. Titles and abstracts were screened by two independent authors (LES, DN) using Rayyan.
Rayyan is an online based software that facilitates blind collaboration among reviewers. Disagreements were resolved by discussion between the two review authors. A third specialist author (JD or GM) was consulted if consensus was not reached. Afterwards the full text of the remaining articles was read to determine eligibility for inclusion (LES, DN). If the full text was not found the authors were contacted. Of the included articles the reference list was cross-checked to find any additional articles.
Validity and eligibility assessment. All included articles were assessed for the methodological quality and risk of bias using the Newcastle Ottawa quality assessment scale 13 . LES and DN did the assessment separately.
Data synthesis. For each study, a weighted average of the logit proportions of IH was determined by the use of the generic inverse variance method. The logit proportions were back transformed to the summary estimate and 95% CIs were obtained in a summary proportion representing the pooled proportion of the IH. Heterogeneity was assessed using the I 2 and χ 2 statistics. Analysis was performed using R-studio version 3.6.1 (package "meta" (Schwarzer, 2007) and "metaprop" (Viachtbauer, 2010)). The random-effects model was used for interpretation. Heterogeneity was deemed significant if the pooled data's p value was < 0.05 or χ 2 statistics were ≥ 75. Heterogeneity was interpreted as small (I 2 ≤ 0.25), medium (I 2 = 0.25-0.50) or strong (I 2 ≥ 0.50), according to Higgins 14 . The gastroschisis subgroup analysis were performed using review manager (version 5.3) to generate forest plots. In this part of the meta-analysis the odds ratio was calculated using Mantel-Haenszel statistics, using the random-effects model to interpret results.

Results
Study characteristics. During the search 5794 records were identified. Automated removal of duplicates left 3909 records for title and abstract screening. Of these 3909 records, 722 met the criteria for full text assessment. One article was included after screening references of included articles. Full text evaluation resulted in 50 studies, which were included for quantitative analysis (Fig. 1). These 50 studies represent 3140 patients ( Table 1). www.nature.com/scientificreports/ Six were prospective cohort studies, one combined a prospective-with a retrospective cohort, four were multicentre retrospective cohort studies, thirty-eight were retrospective cohort studies and one was a matched case-control study. None of the studies had a randomized design. Nineteen of the studies were conducted in North America, sixteen in Europe, eleven in Asia, three in Africa and one in the Middle-East. Follow up was at least half a year in 24 (48%) of all studies.

History of stoma.
All studies that reported on the history of stoma were articles describing anorectal malformations (ARM). Together, these studies contained four hernias. Two of which were not at the stoma site, but were reported as port-site hernia following laparoscopic assisted anorectoplasty 22 . The other two were seen at the site of stoma 23 . There were two articles describing ARM treatment without a stoma, no hernias occurred in these cohorts 26,62 . Gastroschisis. Subgroup analysis within the GS studies showed a reduced risk of IH for simple gastroschisis compared to complex (Fig. 3); Odds ratio 0.18 (95% CI 0.03-0.94; p = 0.04; I 2 = 0%). Also, an increased risk of IH was present when SILO closure was performed compared to primary closure ( Fig. 4) with an odds ratio of 3.09 (95% CI 1. 63-5.87; p ≤ 0.01; I 2 = 27%).

Discussion
This systematic review pooled the reported proportions on incisional hernia following abdominal surgery for congenital anomalies in infants. These proportions approximate the incidences of these complications. Therefore, our reported approximation of the incidence of IH was 3%. Within the different congenital anomalies gastroschisis patients are most at risk with an approximated incidence of 10%. In subgroup analysis complex gastroschisis (patients with GS and additional anomalies) and SILO closure were identified as risk factors for IH.
Studies reporting on laparoscopy and laparotomy seem to have similar incidences of IH although, due to the design of included studies, we were not able to compare studies. Still, this seems to be in line with previous cohort studies that focused on incisional hernia specifically in pediatric patients. These studies opted that the  www.nature.com/scientificreports/ occurrence of IH seems to be more related to specific diagnosis instead of mode of surgery 6,7 . Within the included studies type of incision was only scarcely reported. Out of those that did, none reported the use of a midline incision. Transverse incision was the most reported type of incision. The use of this incision in infants provides a surgeon the best exposure to the abdominal cavity in neonates. The abdominal cavity of infants resembles a horizontal ellipsoid. With age and growth this ellipsoid changes into vertical position 65 . Thus, the younger the child the better visualization is obtained by using a transverse incision. Transverse incisions have been shown to have a lower incidence of IH compared to midline incision in adults 66,67 .
Previous studies suggested that the acquired newborn abdominal diseases necrotizing enterocolitis and pyloromyotomy are at higher risk for the development of IH 7,68 . Our review shows that the congenital abdominal wall defects gastroschisis and omphalocele should be added to this list.
Gastroschisis and omphalocele showed highest incidences of IH compared to the other congenital abdominal anomalies. Both anomalies are characterized by an abdominal wall defect with protruding viscera. In omphalocele, the viscera are covered with a membrane whilst in gastroschisis cases the viscera are not covered and thus more susceptible to infection. In order to surgically repair the defect, the viscera have to be reduced intraabdominally. The primary goal of surgical repair is to close the defect as soon as possible, as to decrease the risk of infection, whilst simultaneously minimizing the risk of ischemic injury to the viscera due to increased intra-abdominal pressure (IAP) [69][70][71][72] . An increase of pressure between 0-15 mmHg is accepted because of the low risk of abdominal compartment syndrome 70 . However, even this increased outwards abdominal pressure during the wound healing process increases fascial tension, which could cause the increased incidence of IH 34 . Since 2004 an alternative method for a select group of patients named sutureless closure was proposed by methods of primary reduction and covering of the gastroschisis defect by watertight dressing and the umbilical cord 73 . This technique supposedly minimizes IAP and allows for spontaneous closure 74 . It is reported that this technique increases the risk of umbilical hernias compared to sutured closure. Still these hernias seem to resolve, not requiring redo surgery and sutureless closure seems to overall entail less complications 58,75,76 . This also might be the case for sutured closure. Out of six included studies that reported on redo surgery only 17 of the 31 hernias needed reoperation. It must be noted that most studies did not report on redo surgery.
Most gastroschisis cases are isolated conditions, but in 10% associated anomalies like intestinal atresias or necrotizing enterocolitis occur resulting in complex gastroschisis 72 . Our results show that simple gastroschisis has an odds-ratio of 0.18 to develop an IH compared to complex gastroschisis. In general, complex cases are associated with both longer parental nutrition and length of hospital stay 77 . This combination of impaired nutritional status and multiple anomalies could accumulate to a multifactorial cause of increased IH incidence.
We have shown that SILO closure increases the risk of IH compared to primary closure. SILO placement is mostly considered when the viscera cannot be reduced into the abdominal cavity because of bowel oedema. This oedema might result in higher IAP leading to an increase in the chances of IH. In a study comparing primary closure with SILO closure it was shown that the incidence of IH increased with longer duration of SILO reduction 34 .
Since the incidence in incisional hernia in the pediatric population is low, most cohort studies only describe limited numbers of patients with an incisional hernia. Still, in most of these studies thorough statistical analysis is done, often by chi-square or regression analysis. However, both analyses demand a sufficient amount of hernia cases ensuring the least expected count to be five for chi-squared statistics and a minimum of ten hernias per one controlling variable (events per variable (EPV)) for any form of regression analysis 78,79 . Not abiding these statistical rules can lead to inaccurate results causing conclusions to be, to some extent, unsupported or deceptive. Future research should ensure statistical power with a sufficiently large cohort. The incidence provided by this review can aid in power size calculations.
This review was limited because none of the included studies used a specific classification for incisional hernias or described the way they were diagnosed. Moreover, many studies did not report on duration of follow-up or had a follow up of less than a year, possibly resulting in missed incisional hernias. Also, different surgical approaches and disease severities were included. These differences dissolve when combining the study results into proportional meta-analysis, which could have influenced our results. The broad inclusion criteria, resulting in differences between compared studies, can partly explain the broad confidence intervals of gastroschisis and omphalocele. In adults, consensus has been reached that an incisional hernia should be classified by its location, length and width 80 . Whilst infantile incisional hernias might differ from adults, it seems advisable for prospective studies to include these characteristics as well as to describe the diagnostic modality as to aid in the generalizability of the interpretations. Using any form of diagnostic imaging will increase the total amount of detected IHs. Yet, this increase will be accompanied with disagreement between observers, as is the case in adults, making www.nature.com/scientificreports/ the IHs less generalizable which is why we suggest physical examination could be sufficient 81 . In our opinion, the clinical significance of IHs in infants undetectable by physical examination is doubtful. Smaller hernias have been reported to close without necessitating surgery, as is also the case in congenital umbilical hernias 7 . Since most IHs develop within a year after surgery it is desirable to plan an extra repeat visit at least a year after surgery as part of the research protocol 6 . Another limitation of our study is that most included studies did not describe the incisional hernia cases in detail. Often, just the total number was noted without describing further case characteristics. This withheld us from thoroughly analyzing indications for redo-surgery or known risk factors such as having a history of stoma or surgical site infection. However, for gastroschisis specifically, though these finding are based on nonrandomized retrospective cohort studies, our results suggest that SILO closure and complex cases are more at risk of IH. The high overall heterogeneity seems to be fairly explained by the spread in IH proportions within gastroschisis studies. This spread in its turn could be explained by differences in distribution of the described risk factors. Other anomalies showed moderate to low heterogeneity.

Conclusion
This systematic review shows that the incidence of incisional hernia is 3% all studies on surgical correction of abdominal congenital anomalies in infants are combined. Overall the incidences seem comparable between studies reporting on laparoscopies and laparotomies. Gastroschisis patients are most at risk for developing IH with an approximated incidence of 10%. In subgroup analysis complex gastroschisis and SILO closure were identified as significant risk factors for IH.

Data availability
Data available on request.