Perioperative Outcomes in Primary Neonatal Pullthrough versus Pullthrough in Older Children: A Systematic Review and Meta-analysis

Perioperative Outcomes in Primary Neonatal Pullthrough versus Pullthrough in Older Children: A Systematic Review and Meta-analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Perioperative Outcomes in Primary Neonatal Pullthrough versus Pullthrough in Older Children: A Systematic Review and Meta-analysis Noora Alshahwani, Amer Alsaied, Suha Tewfik, Tariq Abbas, Akshay Bangera, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7387957/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted 13 You are reading this latest preprint version Abstract Primary pullthrough for Hirschsprung disease is the current standard in most uncomplicated standard segment disease. In this review and meta-analysis, we aimed to compare perioperative outcomes and functional outcomes for pullthrough done in the neonatal period compared to that in older age (<5 year). METHODS: PubMed, Medline, Embase, CINAHL, SCOPUS, and Web of Science were searched for relevant publications in English from inception to June 29, 2024. RESULTS: Twenty studies were included in the qualitative analysis with a total 3197 patients matching the review criteria. All included studies were observational in nature, with 1 prospective cohort study, 13 retrospective cohort studies, and 6 case series. Findings suggested primary pullthrough beyond 1 month of age was superior in most outcomes, including: shorter post-operative length of stay (LOS) (MD3.11days [95%CI 95%CI 1.34, 4.87]), perioperative sepsis (OR1.76, [95%CI1.26, 2.47]), anastomotic leak (OR2.71[95%CI1.02, 7.24]), perianal excoriation upto 3 months (OR5.52[95%CI 3.07, 9.9]), post-operative HAEC at 3 months (OR5.49[95%CI 3.35, 9]), and anal senosis (OR3.04[95%CI 1.07, 8.67]). Pullthrough done in neonatal age was superior in a shorter operative time (MD-26.41min [95%CI -41.57, 11.26]). There was no significant difference in overall SSI, 30-day readmissions, and pre-operative HAEC. Functional outcomes were assessed in 8 studies showing some tendency towards constipation and incontinence in the older children, and more observed stool frequency and for longer duration post-operatively in the neonates. CONCLUSION : Older children ith Hirschprung perform better post-pullthrough and have less morbidity compared to neonates. Performing the pullthrough after 1 month is safe and likely to offer the best post-operative outcomes. This review was limited by the low level of evidence and inconsistent definitions of outcomes. Results will need to be verified with a large prospective study. Health sciences/Diseases Health sciences/Gastroenterology Health sciences/Health care Health sciences/Medical research Hirschsprung disease pullthrough procedure perioperative outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 INTRODUCTION Hirschsprung disease (HD) is a congenital disorder characterized by agangliosis of the distal gastrointestinal tract, affecting roughly 1:5000 live births [ 1 ]. Since Professor Harald Hirschsprung first described first described HD in 1886, our understanding of the disease and management have evolved significantly [ 2 ]. Initial management involved diverting the bowel, which was often insufficient. Definitive treatment was not described until the mid-twentieth century, when Swenson introduced resection of the rectosigmoid colon, and anastomosis [ 3 ]. The high mortality rate seen with early pullthrough led to the recommendation to delay repair until more than 4 months of age. The management of HD has since undergone many modifications, including the Duhamel procedure introduced in 1950s and the Soave procedure in 1960s. In the 1980s, So et. al reported the first successful primary pullthrough in HD [ 4 ]. With the introduction of laparoscopy In Pediatric surgery, Georgeson first employed a laparoscopic-assisted pullthrough approach in 1993, which later became a cornerstone of operative management [ 5 ]. Trans-anal endorectal pullthrough (TERPT) was described by De La Torre and Ortega in 1998, further minimizing the approach [ 6 ]. TERPT has since become the widely accepted approach, with or without the assistance of laparoscopy to obtain leveling biopsies. Improvements in diagnostic abilities and earlier detection of HD, as well as advancements in the pullthrough approach, have led more surgeons to favor earlier pullthrough. In 2011, a survey of European Pediatric Surgeons' Association (EUPSA) members found that 87.5% of surgeons performed TERPT before three months of age [ 7 ]. This was a significant increase from 46% in a previous survey conducted in 1998 [ 8 ]. Evidence around earlier surgery has been variable. Proponents of earlier surgery cite reduced incidence of HAEC, shorter operative time, reduced anastomotic complications [ 9 , 10 ]. Pullthrough at a later age may result in better functional outcomes and is associated with less perioperative morbidity related to infection, bleeding and anesthesia [ 9 , 11 ]. There is currently no consensus on the preferred age at pullthrough; the decision is left to the treating surgeon on a case-by-case basis. In this review, we aim to summarize the literature and compare perioperative and functional outcomes in neonatal primary pullthrough procedures compared to pullthrough done at a later age. METHODS Protocol and Registration: A study protocol was established following the PRISMA guidelines prior to commencing this systematic review. The search protocol was registered in PROSPERO before starting the review (CRD42021223769). Differences between the protocol and the review are highlighted below. Study eligibility criteria: We included comparative studies in English examining children with HD undergoing surgery as neonates (< 1 month of age) versus older (1 month – 5 years). We limited patients to age 5 years and younger, as those presenting later may be inherently different due to associated masking comorbidities or socioeconomic factors. Moreso, those with delayed diagnosis often face high morbidities related to the prolonged constipation, bowel dilation with the bowel size discrepancy faced at pullthrough. Randomized, quasi-randomized and non-randomized comparative studies were included. We later expanded our inclusion criteria to include case series with sufficient information on both age groups: neonates and older children. Abstracts and conference presentations were also sought and summarized if they included sufficient information. Case reports, commentaries, and abstracts with insufficient information were excluded. All surgical approaches (laparoscopic, open and laparoscopic-assisted) and pullthrough techniques were included. Only primary pullthrough cases were considered; cases with proximal stoma (colostomy or ileostomy) at the time of pullthrough were excluded. The primary outcome of interest was early post-operative outcomes, such as post-operative length of hospital stay (LOS), surgical site infections (SSI), anastomotic leak, and need for readmission. Our secondary outcomes of interest included the intermediate and long-term outcomes, including perianal excoriation, stricture formation, and and Hirschsprung associated enterocolitis (HAEC), and functiona outcomes such as incontinence and constipation. Constipation was defined as per the individual study. Incontinence was defined as any degree of soiling, or accidents, unintentional defecation, or through a scoring system as defined by the reporting study. Outcomes that were not included in registered protocol and were added later after viewing the papers are pre-operative HAEC, and death. Literature search: Pubmed, Medline, Embase, CINAHL, SCOPUS and Web of Science were searched for relevant publications in English language from inception (earliest being 1964) to June 29, 2024. Search terms included variations of: (Child or pediatric) AND (Hirschsprung disease or aganglionosis) AND (laparoscopy or pullthrough or surgery). The search strategy was generated by a librarian - Please refer to the appendix 1 for a detailed search strategy. Additionally, the references were screened to search for eligible articles. In order to increase comprehensiveness and reduce publication bias, we also searched the grey literature through Google scholar. The grey literature was only included if it had sufficient information on methodology and outcomes. Study selection: After removing duplicates, two independent authors (NA, AA) screened all articles by title, abstract, and full-text using the eligibility criteria. Conflicts in screening were resolved by discussion and, if necessary, by a third reviewer (NA). Risk of Bias Assessment: Two independent reviewers (NA, TA) evaluated the included studies for risk of bias. We planned to use the Cochrane Risk of Bias Tool for randomized-controlled trials, along with the Risk of Bias tool RoB 2.0 for randomized controlled trials [ 12 , 13 ], and ROBINS-I for non-randomized studies [ 14 ]. No randomized controlled trials were identified in this review, so this tool was not utilized. Each paper was assessed for the following domains in the ROBINs-i tool: bias due to confounding; bias in the selection of participants into the study; bias in classification of interventions; bias due to deviations from intended interventions; bias due to missing data; bias in measurement of the outcome; and bias in selection of the reported result. Each study received a final assessment as Low, Moderate, Serious, Critical, or No Information. Differences in opinion were resolved by discussion involving a third reviewer when needed. Data synthesis and subgroup analysis: Qualitative analysis was done by summarizing data in text and tables. Quantitative analysis was done by pooling of comparable data for all continuous and categorical outcomes when feasible, using Random effect and Quality Effect models. Odds ratio, Risk difference and number needed to treat was reported, when possible, for categorical variables. The mean, mean difference, and/or median and IQR will be reported for continuous variables. RevMan (online) was used for the statistical analysis. Heterogeneity was explored using Cochrane Q test and Higgin’s I squared value. I squared > 50% were indicative of significant heterogeneity. In case of heterogeneity, the following subgroups will be explored if feasible: type of pull-through; length of involved bowel (classic segment rectosigmoid versus long segment versus total colonic); laparoscopic versus open approach. Sensitivity analysis was done to exclude high risk of bias publications and their influence on heterogeneity. Publication bias will be assessed using a funnel plot, eggers regression and the Kendall’s Tau tests. We excluded studies from the meta-analysis where mean and standard deviation for the two study groups were not readily available. We avoided all types of computations to deduce those numbers to avoid false assumptions and false results RESULTS Overview of included studies: We screened 5041 studies after duplicates were removed (refer to Fig. 1: PRISMA flowchart). Twenty studies were included in the qualitative analysis with a total 3197 patients matching the review criteria. All included studies were observational in nature, with 1 prospective cohort study, and the rest retrospective studies. No Randomized or quasi-randomized studies were included. Six of the included studies were multi-center in nature. One of the 20 studies was a thesis sttement (see table 1 for details). Of the included 3197 patients with 1371 neonates and 1826 older children. The age cut off for neonates was 1 month (30 days) and younger. Lu et. al specified 28 to be non-neonate [25]. For the purpose of this review, we included patients up to age of 5 years only. For studies involving older patients all cases of HD were confirmed with biopsy. The length of the aganglionic segment in these cases was variable. Total colonic segment disease was seen in a total of 11 neonates and 10 older children [22,24]. Given the small number, these were included in the analysis, and later explored with sensitivity analysis. Several studies included only cases with rectal and sigmoid (classic Hirschsprung) disease [25, 30, 34]. The rest didn’t specify length of involved bowel or site of transition zone [16, 17, 19, 20, 26, 31, 32, 33]. All patients included were managed with primary pullthrough. The approach was variable, with the majority done through transanal endorectal the approach (TERPT) [17, 20, 22, 23, 27, 28, 34]. Some required both abdominal and/or perianal access [16, 19, 24, 25, 26, 30-33]. Laparoscopic assisted TERPT was utilized in some cases in 3 studies [19, 25, 30]. Yang et. al included cases done via TERPT, and excluded cases requiring laparoscopy or laparotomy [35]. Approach was not specified in 2 studies [15, 20]. Soave or modifications, was the most common technique, used in 18 studies as a unified procedure, or along with other techniques (Swenson, Duhamel) [15-17, 20-23, 25-31, 34]. Yang et. Al. excluded patients requiring laparoscopy or laparotomy [34]. The majority of studies assessed post-operative complications. This included length of hospital stay, operative time, rate of surgical site infection (overall or specified), anastomotic leak, anastomotic stricture, blood loss, perianal excoriation, anastomotic stricture/stenosis, and Hirschsprung associated enterocolitis (HAEC). Only one study had the primary outcome of assessing incidence of HAEC comparing different cut-off values in a scoring system [20]. Diagnosis of HAEC was done using a published scoring system in 4 studies [17, 25, 34]. Kastenberg et. .al 2021 defined HAEC as the need for intravenous antibiotics, rectal irrigations, or both [22]. SenthilKumar et. al excluded patients not responding to irrigations, associated life-threatening anomalies and cases with enterocolitis upon diagnosis [30]. (see table 1 for details). Functional outcomes, including constipation and/or continence and frequency were assessed in 8 studies [18, 22, 24, 29, 30, 34]. Three studies used scoring systems: Lu 2017, Senthil Kumar 2019 and Yang 2012 [25, 30, 34]. Lu et. Al utilized the Pediatric Incontinence Constipation Score system (PICSS) [25]. SenthilKumar et.al used Shanker 2000 functional scoring defined as satisfactory outcome (score 1-2), and poor outcome (3-5) [30]. Yang et al used modified Rome II criteria for the assessment of constipation, and modified Wingspread scoring system for the assessment of fecal incontinence [34]. The remaining 5 studies had arbitrary classifications with constipation, continence or both combined (see table 3 for further details). Post-operative follow-up ranged from 2 weeks to 19 years. Follow-up was not specified in 5 studies [16, 19, 24, 26, 31]. Risk of Bias: Risk of Bias assessment for 14 of the 20 included studies was done using ROBINS-I tool (Stern 2016). The remaining 6 included studies were case series, and were not eligible for risk of bias assessment using the ROBINS-I tool: Cass 1990, Mir 2001, Rintala 2004, Sowande 2006, Weidener 2003, and Yang 2012. No Randomized, or quasi-randomized studies were included. Refer to table 2 for details. Outcome assessment: A) Post-operative length of stay (LOS): Post-operative length of stay in hospital was specified in 7 studies [17, 19, 23, 28, 30, 32, 33]. Mean and standard deviation were only available in three of the seven studies: Freedman-Weiss 2019, Kim 2009, and Weidener 2003 [19, 23, 33]. and were included in the meta-analysis. LOS was 1.77 days shorter for the older age group compared to neonates (95%CI -1.55, 0.11). This was not statistically significant (p=0.25), and came with significant heterogeneity I 2 93% (see figure 2). Sensitivity analysis was done by excluding Weidener et. al (case series), resulted in a significant mean difference of 3.11 days (95%CI 1.34, 4.87) favoring the older children, with moderate heterogeneity of I 2 57%. B) Operative time: Operative time for the two groups was reported in 4 studies: Elhalaby 2014, Kim 2009, Liu 2002, and Weidener 2003 [17, 23, 24, 33]. Mean and standard deviation were available in 3, and those were included in the meta-analysis. Surgery tended to be shorter in the neonatal group compared to older children with a mean difference of -26.41 minutes (95%CI -41.57, -11.26) (see fig. 3). This was statistically significant (P<0.001), and is also clinically important. There was no significant heterogeneity with random or fixed effect models (I 2 =0%). C) SSI: Overall SSI was reported in 5 studies: Freedman-Weiss 2019, Kastenberg 2021, Liu 2002, Pratap and Sowande [19, 22, 24, 27, 32]. There were no events occurring in Kastenberg 2021 in either group [22]. There was no significant difference between the two groups with OR 0.47 (95%CI 0.15, 1.49), and with no heterogeneity (I 2 =0%) (See Fig. 4). D) Sepsis: Perioperative sepsis was reported in 2 studies: Friedman-Weiss 2019 and Huerta 2023 [19, 21]. Older children had a slightly higher odds of developing sepsis in the perioperative period compared to neonates (OR 1.76 (95%CI 1.26, 2.47) (see Fig. 5). This was statistically significant (p<0.001), and with no heterogeneity (I 2 =0%). E) Anastomotic leak: Anastomotic leak was reported by 4 studies: Lu 2017, Pratap 2007, Roy 2023 and Yang 2012 [25, 27, 29]. Anastomotic leak appeared to be lower in older children compared to neonates, with OR 2.71 (95% CI 1.02, 7.24) regardless of type of repair (see Fig. 6). This was not statistically significant (p=0.11). There was low heterogeneity (I 2 =25%), and no further sensitivity analysis was done. Deep incisional/organ space SSI, whether from undocumented leak or soiling, was reported in only one study, Freedman-Weiss 2009 [19]. The findings suggested a slightly smaller rate of infections in neonates (2/182) compared to older children (2/100) [19]. F) Readmission : Three studies captured the 30-day unplanned readmissions rate: Freedman-Weiss 2019, Huerta 2023, and Kastenberg 2021 [19, 21, 22]. Kastenberg 2021 reported no events for neonates or older children [19]. Older children tended to have a lower readmission rate (OR 1.28 (95%CI 0.93, 1.77)) (see Fig 7). This was not statistically significant. G) Perianal excoriation (PE) : The rate of perianal excoriation was reported at different times post-operatively: at or within 1 month and at 3 months post-operatively. PE at or before 1 month from surgery was reported in two studies: Rintala 2004 and Yang 2012 [28, 34]. The odds of developing perianal excoriation in neonates was almost triple that in older children (OR2.88 (95% CI 1.08, 7.72)) (see Fig. 8). This was statistically significant (p=0.04). There was no significant heterogeneity with random or fixed effect models (I 2 =0%). PE assessed at 3 months was reported by 3 studies: Lu2017, Pratap 2007, and Yang 2012 [25, 27, 34]. Similar to the pattern at 1 month, neonates were much more likely to develop perianal excoriation with OR 5.52 (95%CI 3.07, 9.90) (see fig. 9). This was statistically significant, with no heterogeneity (I 2 = 0) H) Pre-operative HAEC: Pre-operative HAEC was reported in 5 studies: Kastenberg 2021, Liu 2002, Mir 2001, Pratap 2007 and So 1998 [22, 24, 26, 27, 31]. Despite the shorter pre-operative period, neonates were slightly more likely to develop enterocolitis pre-operatively compared to older children (OR 1.90 (95% CI 0.49, 7.35)) (see Fig. 10). This was, however, not statistically significant (p=0.35), nd was associated with moderate heterogeneity (I 2 =54%). Pratap 2007 and So 1998 cited that the occurrence of HAEC directly influenced their decision for surgery [27, 31]. Sensitivity analysis excluding these two studies show that the difference in occurrence of pre-operative HAEC between neonates and older children disappeared (OR 0.75 (95%CI 0.17, 3.67)) and heterogeneity improved (I 2 =30%). I) Post-operative HAEC: Post-operative HAEC was reported at different points: at 30 days, post-operatively, 90 days post-operatively and unspecified post-operative time. The latter was labeled “overall post-operative HAEC”. Two studies reported the occurrence of HAEC at one-month post-operatively: Kastenberg 2021 and Yang 2012 [22, 34]. There was no significant difference between neonates and the older age group (OR1.13 [95% CI 0.23, 5.57]) (see Fig. 11, A). There was moderate heterogeneity with the finding (I 2 =57%). This risk of post-operative HAEC at three months was reported in three studies: Lu 2017, Pratap 2007, and Yang 2012 [25, 27, 34]. There was a statistically significant higher risk of HAEC in the neonates compared to older children with OR 5.49 (95% CI 3.35, 9.00) (see Fig. 11, B). There was no significant heterogeneity with random or fixed effect models (I 2 =0%). This outcome remains significant after excluding Yang 2012 as a case series with no ROB assessment (OR 5.47[95%CI 3.54, 10.06]). Overall post-operative HAEC was reported in 12 studies: Bokova 2024, Cass1990, Feung 2024, Gunadi 2021, Huerta 2023, Kim 2019, Liu 2002, Lu 2017, Mir 2001, Rintala 2004, Roy 2023, and Yang 2012 [15, 16, 18, 20, 21, 23, 24, 25, 26, 28, 29, 34]. Of those, Yang 2012 specified that period was 6 months post op [34], and Cass 1990 was at a maximum of 9 months post op [16], and the rest with no specified post-operative period. Overall, there was no significant difference in post-operative HAEC between neonates and older (OR 1.38 [95% CI 0.69, 2.76]) (see Fig. 11, C). There was significant heterogeneity (I 2 75%), that could potentially be due to the different procedure types, and different times of assessment. Three studies, Cass 1990, Liu 2002, and Roy 2023, favored neonates [16, 24, 29]. The rest either favored older children or showed no difference. Sensitivity analysis excluding case series or studies with unknown post-operative point of assessment did not improve the heterogeneity. Subgroup analysis according to quality: low/moderate ROB vs serious ROB or no ROB assessed (case series) showed no difference amongst the two groups in outcome or heterogeneity. J) Anal stenosis / anastomotic stricture (AS): Anastomotic stricture was reported in 6 studies: Kastenberg 2021, Lu 2017, Pratap 2007, Roy 2023, SenthilKumar 2009, and Yang 2012 [22, 25, 27, 29, 30, 34]. There were no reported events in either group in Kastenberg 2021 [22]. Overall AS was higher in the neonates’ group with OR 3.04 (95%CI 1.07, 8.67) (see Fig. 12). This was statistically significant (p=0.04), and was associated with moderate heterogeneity (I 2 =57%) To explore the heterogeneity, subgroup analysis according to time of assessment was done. Yang 2012 was the only study reporting AS at 1 month at 1/28 for neonates and 1/90 for older children [34]. At 3 months, AS was reported by Lu 2017, Pratap 2007 and Yang 2012 [25, 27, 34]. The odds of developing anastomotic stricture at 3 months post-operative was significantly higher in neonates than in older children, with OR 8.47 (95%CI 3.30, 21.71). This showed no heterogeneity, and remained the same even after excluding studies with serious ROB or case series [34]. Only 1 study, Pratap 2007, assessed AS at 6 months and found it to be similar in neonates and older children (1/30 and 0/35 respectively) [27]. The remaining 3 studies - Kastenberg 2021, Roy 2023, and SenthilKumar 2009- didn’t specify the time of assessment of AS [22, 269, 30]. There were no events to report for either group on Kastenberg 2021 [22]. For this subgroup, there was no difference in AS between neonates and older children (OR 0.88 [95%CI 0.22, 3.48]). There was low/moderate heterogeneity (I 2 =40%). Functional outcomes: Functional results including constipation, continence, and stool frequency were reported in 8 studies: Cass 1990, Kastenberg 2021, Kim 2009, Liu 2002, Lu 2017, Senthil Kumar 2009, Roy 2022, and Yang 2012, [16, 22, 23, 24, 25, 30, 29, 34]. Outcomes were measured using different tools, preventing a quantitative analysis. Below is a summary of the results (refer to table 3 for details). Constipation was assessed mostly subjectively as present or absent in three studies, or as needing intervention or not in 5 studies: Cass 1990, Kastenberg 2021, Liu 2002, SenthilKumar 2009, and Yang 2012 [16, 22, 24, 30, 34]. The PICSS was used in Lu 2017 [25]. Outcomes for constipation were superior or marginally better in neonates in all the studies. Follow-up duration was mentioned in 4 of 5 studies, and ranged from 5 months to >=3.5 years. Continence was reported in 6 studies: Cass 1990, Kastenberg 2021, Liu 2002, Lu 2017, Roy 2024 and Yang 2021 [15, 22, 24, 25, 29, 34]. PICCS was used in Lu 2017 and fecal Continence Assessment was used in Roy 2023 [25, 29]. Yang 2012 utilized the Wingspread functional score, showing an overall excellent to good continence achieved in 85.4 % of patients (82 of 96 patients), and a trend of improved outcomes with time, with no information on age at surgery [34]. Subjective assessment was utilized in the remaining 3 studies. Three of the six showed superior outcomes for continence in neonates: Kastenberg 2021, Lu 2017, and Roy 2024 [22, 25, 29]. There was no difference to report in Cass 1990 and Liu 2002 [16, 24]. Stool frequency was listed per patient in Cass 1990, with no clear difference across the two groups [16]. Kim 2009 reported this outcome as time to normal frequency or “stabilization period,” showing that longer time was needed following pullthrough in the neonatal period compared to older age (11.3 ± 6.9 weeks in neonates vs 7.3 ± 4.6 weeks in older children, P= 0.016) [23]. Discussion Current management of HD depends on multiple factors, including age, length of aganglionic segment, experience of center and comfort with certain techniques as well as with laparoscopy. The majority of dedicated pediatric centers worldwide have adopted the practice of primary pullthrough for classic segment HD. In an online survey of the Australian and New Zealand association of Pediatric Surgeons (ANZAPS), 49/56 (88%) of the participants were comfortable with primary pullthrough in a clinically stable neonate with recto-sigmoid HD [ 35 ]. The majority (82%) would perform this in < 3 months of age, and 100% would do it by 6 months of age [ 35 ]. The majority of the published literature compared pullthrough at or before 3 months of age, and that above 3 months of age. Data is generally conflicted with some supporting earlier pullthrough, some showing no difference and some supporting pullthrough at later ages. Proponents of earlier pullthrough argue that this may prevent episodes of pre-operative enterocolitis. Zhang et. al found that a significant reduction in HAEC incidence was observed among individuals under 3 months of age who underwent earlier surgery (69.1% pre-surgery vs. 30.9% post-surgery, p < 0.001) [ 36 ]. In our meta-analysis, there was an initial trend showing higher pre-operative HAEC in neonates. After excluding the studies where pre-operative HAEC was an indication for earlier surgery, there was no difference in the two groups (OR 0.79 [95%CI 0.17, 3.67]). This points out a potential selection bias influencing the outcomes. Post-operative HAEC seems to be influenced by age of repair, with a significant higher risk for neonatal pullthrough. Our meta-analysis suggested that this trend is present at 1-month post-operative, 3-months post-operative and longer. We didn’t explore the influence of pre-operative HAEC on the occurrence of post-operative HAEC. A large retospective cohort study showed showed an association between pre- and post-operative HAEC (37). This could be due to the altered gut microbacteria [ 37 ]. The latest studies indicated that pullthrough done below 3 months of age had a shorter surgery and shorter length of stay [ 36 , 38 ]. Our meta-analysis suggested better outcomes with pullthrough when done beyond 1 month of age, regardless of the approach or technique; neonates had a shorter operative time with a cumulative mean difference of -26.41 minutes (95%CI -41.57, -11.26), while having a longer length of stay with mean difference of 3.11 days (95%CI 1.34, 4.87) compared to older children. This is consistent with the other literature suggesting ease of dissection in neonates as a potential reason [ 39 ]. Neonates are often thought to need longer to recover from post-operative ileus and to achieve full feed [ 40 ]. This might be due to physiologic immaturity of the enteric nervous system [ 39 ]. It could also be due to the general practice of slower introduction of feeds in the younger population, despite recent advances and guidelines around ERAS in neonates [ 41 ]. Other contributing factors to longer length of stay are the higher rate perioperative SSI and sepsis in neonate seen in the literature and consistent with the findings in our meta-analysis [ 19 , 21 , 42 , 43 ]. It is possible that the fact that the neonatal group is sicker due to selection bias may contribute to this finding. More so, the immaturity of the immune system in neonates is a potential factor contributing to a higher risk of sepsis as well. Westfal et. al shared that anastomotic leak was significantly higher in infants < 2.5 months of age undergoing Soave pullthrough compared to older (5.5% vs 1.3%) [ 44 ]. This agreed with the finding in our meta-analysis, showing the higher odds of anastomotic leak in neonates (OR 2.71 (95% CI 1.02, 7.24)) regardless of type of repair. It has been suggested that impaired immunity, poor tissue tolerance and tension on anastomosis may contribute to the higher risk of leak in neonates [ 25 ]. It is worth mentioning that the evidence of pullthrough in older children > 3 years of age shows higher anastomotic leak, potentially secondary to the presence of chronic dilation, chronic inflammation or both [ 45 ]. Our meta-analysis suggested that the course for neonates after discharge is more difficult, especially in the first few months after surgery. Neonates had a higher rate of perianal excoriation up to 3 months post-operatively (OR5.52), as well as anastomotic stricture (OR8.47), and post-operative HAEC (OR up to 5.43) compared to older children. There is some evidence that this corrects by 6 months after surgery. It is possible that the need for stretching of a small surgical field and the and the weaker connective tissue in the neonates as well as the immature immune system all contribute to the more aggressive healing reaction and higher stenosis in the future. The long-term functional outcomes following pullthrough were more difficult to discern. Previous studies comparing early pullthrough before 3 months of age and that after 3 months suggest worse constipation and persistent soiling with the younger group [ 36 , 37 ]. similarly, Westfal et. al. found that constipation and soiling were both worse in 2.5 months (10% and 25.9% vs 7.1% and 11.4% respectively) [ 44 ]. The narrative review of functional outcomes in our study suggested that older children are more susceptible to constipation in the long-term, and potentially have worse continence. The latter is counter intuitive, since a general understanding that the younger the patient, the more likely the stretch of the field will cause disruption to the sphincter complex, leading to an element of incontinence. It was also suggested that neonates tend to have more frequent stools, and need longer to reach status quo [ 23 ]. The findings suggest that those who are operated at a younger age have a different functional portfolio than those who are operated at an older age. On the one hand, neonatal pullthough may result in less constipation, have a more frequent stool, and yet this is compensated with better continence later. On the other hand, the older children have less frequent stooling initially, less excoriation and a shorter stabilization period (period to normal frequency of stooling), yet worse continence. Due to the great subjectivity of the findings, this is hard to generalize. Limitations: This review covered a vast literature for pullthrough procedures extending from 1990 to 2024. The changes in admission protocols, antibiotics, techniques, etc. create multiple factors that are difficult to assess or control. This, however, contributes positively to the applicability of the findings across different settings and for the different procedures. The population included some with long segment/total colonic HD patients. On some occasions, we were not able to quantify this subgroup. The variable and unclear definitions of the outcome, such as HAEC, strictures, anastomotic leaks, also posed as a great source of heterogeneity. Functional outcomes were mainly assessed subjectively and at variable points from surgery, limiting our ability to combine the results. Additionally, the literature involved in this review is observational, and mainly retrospective in nature, subjecting it to recall and attrition bias. It is however, currently, the best available literature informing the decision regarding timing of pullthrough. Future Research: Large cohort studies allowing for age break down as a continuous variable would help verify the findings in this meta-analysis. Long-term follow-up of these patients with consideration for functional outcomes, both continence and constipation, would be necessary to make a more accurate recommendation. Furthermore, long-term need for additional procedures, such as repeat biopsy, Botox injection, redo-pullthrough, need for diversion, are all unaddressed areas in this review Conclusion Despite several limitations, this review and meta-analysis shows at least some evidence that pullthrough for Hirschsprung done after the neonatal period offers superior post-operative outcomes, regardless of the approach or the technique used. 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15:27:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14625,"visible":true,"origin":"","legend":"","description":"","filename":"APPENDIX1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7387957/v1/b2f73e7b0a1de97d2e38f697.docx"},{"id":92277053,"identity":"64680c95-dad9-496d-9a2b-6aa85353c5af","added_by":"auto","created_at":"2025-09-26 15:35:30","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":275482,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMA2020checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7387957/v1/732f42d1ff1b0c3bc1da9e55.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Perioperative Outcomes in Primary Neonatal Pullthrough versus Pullthrough in Older Children: A Systematic Review and Meta-analysis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHirschsprung disease (HD) is a congenital disorder characterized by agangliosis of the distal gastrointestinal tract, affecting roughly 1:5000 live births [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Since Professor Harald Hirschsprung first described first described HD in 1886, our understanding of the disease and management have evolved significantly [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Initial management involved diverting the bowel, which was often insufficient. Definitive treatment was not described until the mid-twentieth century, when Swenson introduced resection of the rectosigmoid colon, and anastomosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The high mortality rate seen with early pullthrough led to the recommendation to delay repair until more than 4 months of age. The management of HD has since undergone many modifications, including the Duhamel procedure introduced in 1950s and the Soave procedure in 1960s. In the 1980s, So et. al reported the first successful primary pullthrough in HD [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. With the introduction of laparoscopy In Pediatric surgery, Georgeson first employed a laparoscopic-assisted pullthrough approach in 1993, which later became a cornerstone of operative management [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Trans-anal endorectal pullthrough (TERPT) was described by De La Torre and Ortega in 1998, further minimizing the approach [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. TERPT has since become the widely accepted approach, with or without the assistance of laparoscopy to obtain leveling biopsies.\u003c/p\u003e\u003cp\u003eImprovements in diagnostic abilities and earlier detection of HD, as well as advancements in the pullthrough approach, have led more surgeons to favor earlier pullthrough. In 2011, a survey of European Pediatric Surgeons' Association (EUPSA) members found that 87.5% of surgeons performed TERPT before three months of age [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This was a significant increase from 46% in a previous survey conducted in 1998 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Evidence around earlier surgery has been variable. Proponents of earlier surgery cite reduced incidence of HAEC, shorter operative time, reduced anastomotic complications [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Pullthrough at a later age may result in better functional outcomes and is associated with less perioperative morbidity related to infection, bleeding and anesthesia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. There is currently no consensus on the preferred age at pullthrough; the decision is left to the treating surgeon on a case-by-case basis.\u003c/p\u003e\u003cp\u003eIn this review, we aim to summarize the literature and compare perioperative and functional outcomes in neonatal primary pullthrough procedures compared to pullthrough done at a later age.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eProtocol and Registration:\u003c/h2\u003e\u003cp\u003e A study protocol was established following the PRISMA guidelines prior to commencing this systematic review. The search protocol was registered in PROSPERO before starting the review (CRD42021223769). Differences between the protocol and the review are highlighted below.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy eligibility criteria:\u003c/h3\u003e\n\u003cp\u003eWe included comparative studies in English examining children with HD undergoing surgery as neonates (\u0026lt;\u0026thinsp;1 month of age) versus older (1 month \u0026ndash; 5 years). We limited patients to age 5 years and younger, as those presenting later may be inherently different due to associated masking comorbidities or socioeconomic factors. Moreso, those with delayed diagnosis often face high morbidities related to the prolonged constipation, bowel dilation with the bowel size discrepancy faced at pullthrough.\u003c/p\u003e\u003cp\u003eRandomized, quasi-randomized and non-randomized comparative studies were included. We later expanded our inclusion criteria to include case series with sufficient information on both age groups: neonates and older children. Abstracts and conference presentations were also sought and summarized if they included sufficient information. Case reports, commentaries, and abstracts with insufficient information were excluded.\u003c/p\u003e\u003cp\u003eAll surgical approaches (laparoscopic, open and laparoscopic-assisted) and pullthrough techniques were included. Only primary pullthrough cases were considered; cases with proximal stoma (colostomy or ileostomy) at the time of pullthrough were excluded.\u003c/p\u003e\u003cp\u003eThe primary outcome of interest was early post-operative outcomes, such as post-operative length of hospital stay (LOS), surgical site infections (SSI), anastomotic leak, and need for readmission.\u003c/p\u003e\u003cp\u003eOur secondary outcomes of interest included the intermediate and long-term outcomes, including perianal excoriation, stricture formation, and and Hirschsprung associated enterocolitis (HAEC), and functiona outcomes such as incontinence and constipation. Constipation was defined as per the individual study. Incontinence was defined as any degree of soiling, or accidents, unintentional defecation, or through a scoring system as defined by the reporting study. Outcomes that were not included in registered protocol and were added later after viewing the papers are pre-operative HAEC, and death.\u003c/p\u003e\n\u003ch3\u003eLiterature search:\u003c/h3\u003e\n\u003cp\u003ePubmed, Medline, Embase, CINAHL, SCOPUS and Web of Science were searched for relevant publications in English language from inception (earliest being 1964) to June 29, 2024. Search terms included variations of: (Child or pediatric) AND (Hirschsprung disease or aganglionosis) AND (laparoscopy or pullthrough or surgery). The search strategy was generated by a librarian - Please refer to the appendix 1 for a detailed search strategy. Additionally, the references were screened to search for eligible articles. In order to increase comprehensiveness and reduce publication bias, we also searched the grey literature through Google scholar. The grey literature was only included if it had sufficient information on methodology and outcomes.\u003c/p\u003e\n\u003ch3\u003eStudy selection:\u003c/h3\u003e\n\u003cp\u003eAfter removing duplicates, two independent authors (NA, AA) screened all articles by title, abstract, and full-text using the eligibility criteria. Conflicts in screening were resolved by discussion and, if necessary, by a third reviewer (NA).\u003c/p\u003e\n\u003ch3\u003eRisk of Bias Assessment:\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers (NA, TA) evaluated the included studies for risk of bias. We planned to use the Cochrane Risk of Bias Tool for randomized-controlled trials, along with the Risk of Bias tool RoB 2.0 for randomized controlled trials [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and ROBINS-I for non-randomized studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. No randomized controlled trials were identified in this review, so this tool was not utilized. Each paper was assessed for the following domains in the ROBINs-i tool: bias due to confounding; bias in the selection of participants into the study; bias in classification of interventions; bias due to deviations from intended interventions; bias due to missing data; bias in measurement of the outcome; and bias in selection of the reported result.\u003c/p\u003e\u003cp\u003eEach study received a final assessment as Low, Moderate, Serious, Critical, or No Information. Differences in opinion were resolved by discussion involving a third reviewer when needed.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eData synthesis and subgroup analysis:\u003c/h2\u003e\u003cp\u003eQualitative analysis was done by summarizing data in text and tables. Quantitative analysis was done by pooling of comparable data for all continuous and categorical outcomes when feasible, using Random effect and Quality Effect models. Odds ratio, Risk difference and number needed to treat was reported, when possible, for categorical variables. The mean, mean difference, and/or median and IQR will be reported for continuous variables. RevMan (online) was used for the statistical analysis.\u003c/p\u003e\u003cp\u003eHeterogeneity was explored using Cochrane Q test and Higgin\u0026rsquo;s I squared value. I squared\u0026thinsp;\u0026gt;\u0026thinsp;50% were indicative of significant heterogeneity. In case of heterogeneity, the following subgroups will be explored if feasible: type of pull-through; length of involved bowel (classic segment rectosigmoid versus long segment versus total colonic); laparoscopic versus open approach. Sensitivity analysis was done to exclude high risk of bias publications and their influence on heterogeneity. Publication bias will be assessed using a funnel plot, eggers regression and the Kendall\u0026rsquo;s Tau tests. We excluded studies from the meta-analysis where mean and standard deviation for the two study groups were not readily available. We avoided all types of computations to deduce those numbers to avoid false assumptions and false results\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eOverview of included studies:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe screened 5041 studies after duplicates were removed (refer to Fig. 1: PRISMA flowchart). Twenty studies were included in the qualitative analysis with a total 3197 patients matching the review criteria. All included studies were observational in nature, with 1 prospective cohort study, and the rest retrospective studies. No Randomized or quasi-randomized studies were included. Six of the included studies were multi-center in nature. One of the 20 studies was a thesis sttement (see table 1 for details).\u003c/p\u003e\n\u003cp\u003eOf the included 3197 patients with 1371 neonates and 1826 older children. The age cut off for neonates was 1 month (30 days) and younger. Lu et. al specified \u0026lt;=28 to be neonate, \u0026gt;28 to be non-neonate [25]. For the purpose of this review, we included patients up to age of 5 years only. For studies involving older patients all cases of HD were confirmed with biopsy. The length of the aganglionic segment in these cases was variable. Total colonic segment disease was seen in a total of 11 neonates and 10 older children [22,24]. Given the small number, these were included in the analysis, and later explored with sensitivity analysis. Several studies included only cases with rectal and sigmoid (classic Hirschsprung) disease [25, 30, 34]. The rest didn’t specify length of involved bowel or site of transition zone [16, 17, 19, 20, 26, 31, 32, 33].\u003c/p\u003e\n\u003cp\u003eAll patients included were managed with primary pullthrough. The approach was variable, with the majority done through transanal endorectal the approach (TERPT) [17, 20, 22, 23, 27, 28, 34]. Some required both abdominal and/or perianal access [16, 19, 24, 25, 26, 30-33]. Laparoscopic assisted TERPT was utilized in some cases in 3 studies [19, 25, 30]. Yang et. al included cases done via TERPT, and excluded cases requiring laparoscopy or laparotomy [35]. Approach was not specified in 2 studies [15, 20]. Soave or modifications, was the most common technique, used in 18 studies as a unified procedure, or along with other techniques (Swenson, Duhamel) [15-17, 20-23, 25-31, 34]. Yang et. Al. excluded patients requiring laparoscopy or laparotomy [34].\u003c/p\u003e\n\u003cp\u003eThe majority of studies assessed post-operative complications. This included length of hospital stay, operative time, rate of surgical site infection (overall or specified), anastomotic leak, anastomotic stricture, blood loss, perianal excoriation, anastomotic stricture/stenosis, and Hirschsprung associated enterocolitis (HAEC). Only one study had the primary outcome of assessing incidence of HAEC comparing different cut-off values in a scoring system [20]. Diagnosis of HAEC was done using a published scoring system in 4 studies [17, 25, 34]. Kastenberg et. .al 2021 defined HAEC as the need for intravenous antibiotics, rectal irrigations, or both [22]. SenthilKumar et. al excluded patients not responding to irrigations, associated life-threatening anomalies and cases with enterocolitis upon diagnosis [30]. (see table 1 for details). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunctional outcomes, including constipation and/or continence and frequency were assessed in 8 studies [18, 22, 24, 29, 30, 34]. Three studies used scoring systems: Lu 2017, Senthil Kumar 2019 and Yang 2012 [25, 30, 34]. Lu et. Al utilized the Pediatric Incontinence Constipation Score system (PICSS) [25]. SenthilKumar et.al used\u0026nbsp;Shanker 2000 functional scoring defined as satisfactory outcome (score 1-2), and poor outcome (3-5) [30]. Yang et al used modified Rome II criteria for the assessment of constipation, and modified Wingspread scoring system for the assessment of fecal incontinence [34]. The remaining 5 studies had arbitrary classifications with constipation, continence or both combined (see table 3 for further details).\u003c/p\u003e\n\u003cp\u003ePost-operative follow-up ranged from 2 weeks to 19 years. Follow-up was not specified in 5 studies [16, 19, 24, 26, 31].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of Bias:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRisk of Bias assessment for 14 of the 20 included studies was done using ROBINS-I tool (Stern 2016). The remaining 6 included studies were case series, and were not eligible for risk of bias assessment using the ROBINS-I tool: Cass 1990, Mir 2001, Rintala 2004, Sowande 2006, Weidener 2003, and Yang 2012. No Randomized, or quasi-randomized studies were included. Refer to table 2 for details.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome assessment:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA) \u003cu\u003ePost-operative length of stay (LOS):\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePost-operative length of stay in hospital was specified in 7 studies [17, 19, 23, 28, 30, 32, 33]. Mean and standard deviation were only available in three of the seven studies: Freedman-Weiss 2019, Kim 2009, and Weidener 2003 [19, 23, 33]. and were included in the meta-analysis. LOS was 1.77 days shorter for the older age group compared to neonates (95%CI -1.55, 0.11). This was not statistically significant (p=0.25), and came with significant heterogeneity I\u003csup\u003e2\u003c/sup\u003e 93% (see figure 2). Sensitivity analysis was done by excluding Weidener et. al (case series), resulted in a significant mean difference of 3.11 days (95%CI 1.34, 4.87) favoring the older children, with moderate heterogeneity of I\u003csup\u003e2\u003c/sup\u003e 57%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB) \u003cu\u003eOperative time:\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOperative time for the two groups was reported in 4 studies: Elhalaby 2014, Kim 2009, Liu 2002, and Weidener 2003 [17, 23, 24, 33]. Mean and standard deviation were available in 3, and those were included in the meta-analysis. Surgery tended to be shorter in the neonatal group compared to older children with a mean difference of -26.41 minutes (95%CI -41.57, -11.26) (see fig. 3). This was statistically significant (P\u0026lt;0.001), and is also clinically important. There was no significant heterogeneity with random or fixed effect models (I\u003csup\u003e2\u003c/sup\u003e=0%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC) \u003cu\u003eSSI:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOverall SSI was reported in 5 studies: Freedman-Weiss 2019, Kastenberg 2021, Liu 2002, Pratap and Sowande [19, 22, 24, 27, 32]. There were no events occurring in Kastenberg 2021 in either group [22]. There was no significant difference between the two groups with OR 0.47 (95%CI 0.15, 1.49), and with no heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=0%) (See Fig. 4). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eD) \u003cu\u003eSepsis:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePerioperative sepsis was reported in 2 studies: Friedman-Weiss 2019 and Huerta 2023 [19, 21]. Older children had a slightly higher odds of developing sepsis in the perioperative period compared to neonates (OR 1.76 (95%CI 1.26, 2.47) (see Fig. 5). This was statistically significant (p\u0026lt;0.001), and with no heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=0%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eE) \u003cu\u003eAnastomotic leak:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnastomotic leak was reported by 4 studies: Lu 2017, Pratap 2007, Roy 2023 and Yang 2012 [25, 27, 29]. Anastomotic leak appeared to be lower in older children compared to neonates, with OR 2.71 (95% CI 1.02, 7.24) regardless of type of repair (see Fig. 6). This was not statistically significant (p=0.11). There was low heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=25%), and no further sensitivity analysis was done.\u003c/p\u003e\n\u003cp\u003eDeep incisional/organ space SSI, whether from undocumented leak or soiling, was reported in only one study, Freedman-Weiss 2009 [19]. The findings suggested a slightly smaller rate of infections in neonates (2/182) compared to older children (2/100) [19].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eF) \u003cu\u003eReadmission\u003c/u\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree studies captured the 30-day unplanned readmissions rate: Freedman-Weiss 2019, Huerta 2023, and Kastenberg 2021 [19, 21, 22]. Kastenberg 2021 reported no events for neonates or older children [19]. Older children tended to have a lower readmission rate (OR 1.28 (95%CI 0.93, 1.77)) (see Fig 7). This was not statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eG) \u003cu\u003ePerianal excoriation (PE)\u003c/u\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe rate of perianal excoriation was reported at different times post-operatively: at or within 1 month and at 3 months post-operatively.\u003c/p\u003e\n\u003cp\u003ePE at or before 1 month from surgery was reported in two studies: Rintala 2004 and Yang 2012 [28, 34]. The odds of developing perianal excoriation in neonates was almost triple that in older children (OR2.88 (95% CI 1.08, 7.72)) (see Fig. 8). This was statistically significant (p=0.04). There was no significant heterogeneity with random or fixed effect models (I\u003csup\u003e2\u003c/sup\u003e=0%).\u003c/p\u003e\n\u003cp\u003ePE assessed at 3 months \u0026nbsp;was reported by 3 studies: Lu2017, Pratap 2007, and Yang 2012 [25, 27, 34]. Similar to the pattern at 1 month, neonates were much more likely to develop perianal excoriation with OR 5.52 (95%CI 3.07, 9.90) (see fig. 9). This was statistically significant, with no heterogeneity (I\u003csup\u003e2\u003c/sup\u003e= 0)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eH) \u003cu\u003ePre-operative HAEC:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePre-operative HAEC was reported in 5 studies: Kastenberg 2021, Liu 2002, Mir 2001, Pratap 2007 and So 1998 [22, 24, 26, 27, 31]. Despite the shorter pre-operative period, neonates were slightly more likely to develop enterocolitis pre-operatively compared to older children (OR 1.90 (95% CI 0.49, 7.35)) (see Fig. 10). This was, however, not statistically significant (p=0.35), nd was associated with moderate heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=54%). Pratap 2007 and So 1998 cited that the occurrence of HAEC directly influenced their decision for surgery [27, 31]. Sensitivity analysis excluding these two studies show that the difference in occurrence of pre-operative HAEC between neonates and older children disappeared (OR 0.75 (95%CI 0.17, 3.67)) and heterogeneity improved (I\u003csup\u003e2\u003c/sup\u003e=30%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eI) \u003cu\u003ePost-operative HAEC:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePost-operative HAEC was reported at different points: at 30 days, post-operatively, 90 days post-operatively and unspecified post-operative time. The latter was labeled “overall post-operative HAEC”.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo studies reported the occurrence of HAEC at one-month post-operatively: Kastenberg 2021 and Yang 2012 [22, 34]. There was no significant difference between neonates and the older age group (OR1.13 [95% CI 0.23, 5.57]) (see Fig. 11, A). There was moderate heterogeneity with the finding (I\u003csup\u003e2\u003c/sup\u003e=57%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis risk of post-operative HAEC at three months was reported in three studies: Lu 2017, Pratap 2007, and Yang 2012 [25, 27, 34]. There was a statistically significant higher risk of HAEC in the neonates compared to older children with OR 5.49 (95% CI 3.35, 9.00) (see Fig. 11, B). There was no significant heterogeneity with random or fixed effect models (I\u003csup\u003e2\u003c/sup\u003e=0%). This outcome remains significant after excluding Yang 2012 as a case series with no ROB assessment (OR 5.47[95%CI 3.54, 10.06]).\u003c/p\u003e\n\u003cp\u003eOverall post-operative HAEC was reported in 12 studies: Bokova 2024, Cass1990, Feung 2024, Gunadi 2021, Huerta 2023, Kim 2019, Liu 2002, Lu 2017, Mir 2001, Rintala 2004, Roy 2023, and Yang 2012 [15, 16, 18, 20, 21, 23, 24, 25, 26, 28, 29, 34]. Of those, Yang 2012 specified that period was 6 months post op [34], and Cass 1990 was at a maximum of 9 months post op [16], and the rest with no specified post-operative period. Overall, there was no significant difference in post-operative HAEC between neonates and older (OR 1.38 [95% CI 0.69, 2.76]) (see Fig. 11, C). There was significant heterogeneity (I\u003csup\u003e2\u003c/sup\u003e 75%), that could potentially be due to the different procedure types, and different times of assessment. Three studies, Cass 1990, Liu 2002, and Roy 2023, favored neonates [16, 24, 29]. The rest either favored older children or showed no difference. Sensitivity analysis excluding case series or studies with unknown post-operative point of assessment did not improve the heterogeneity. Subgroup analysis according to quality: low/moderate ROB vs serious ROB or no ROB assessed (case series) showed no difference amongst the two groups in outcome or heterogeneity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJ) \u003cu\u003eAnal stenosis / anastomotic stricture (AS):\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnastomotic stricture was reported in 6 studies: Kastenberg 2021, Lu 2017, Pratap 2007, Roy 2023, SenthilKumar 2009, and Yang 2012 [22, 25, 27, 29, 30, 34]. There were no reported events in either group in Kastenberg 2021 [22]. Overall AS was higher in the neonates’ group with OR 3.04 (95%CI 1.07, 8.67) (see Fig. 12). This was statistically significant (p=0.04), and was associated with moderate heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=57%)\u003c/p\u003e\n\u003cp\u003eTo explore the heterogeneity, subgroup analysis according to time of assessment was done. Yang 2012 was the only study reporting AS at 1 month at 1/28 for neonates and 1/90 for older children [34].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt 3 months, AS was reported by Lu 2017, Pratap 2007 and Yang 2012 [25, 27, 34]. The odds of developing anastomotic stricture at 3 months post-operative was significantly higher in neonates than in older children, with OR 8.47 (95%CI 3.30, 21.71). This showed no heterogeneity, and remained the same even after excluding studies with serious ROB or case series [34].\u003c/p\u003e\n\u003cp\u003eOnly 1 study, Pratap 2007, assessed AS at 6 months and found it to be similar in neonates and older children (1/30 and 0/35 respectively) [27].\u003c/p\u003e\n\u003cp\u003eThe remaining 3 studies - Kastenberg 2021, Roy 2023, and SenthilKumar 2009- didn’t specify the time of assessment of AS [22, 269, 30]. There were no events to report for either group on Kastenberg 2021 [22]. For this subgroup, there was no difference in AS between neonates and older children (OR 0.88 [95%CI 0.22, 3.48]). There was low/moderate heterogeneity (I\u003csup\u003e2\u003c/sup\u003e=40%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFunctional outcomes:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunctional results including constipation, continence, and stool frequency were reported in 8 studies: Cass 1990, Kastenberg 2021, Kim 2009, Liu 2002, Lu 2017, Senthil Kumar 2009, Roy 2022, and Yang 2012, [16, 22, 23, 24, 25, 30, 29, 34]. Outcomes were measured using different tools, preventing a quantitative analysis. Below is a summary of the results (refer to table 3 for details).\u003c/p\u003e\n\u003cp\u003eConstipation was assessed mostly subjectively as present or absent in three studies, or as needing intervention or not in 5 studies: Cass 1990, Kastenberg 2021, Liu 2002, SenthilKumar 2009, and Yang 2012 [16, 22, 24, 30, 34]. The PICSS was used in Lu 2017 [25]. \u0026nbsp;Outcomes for constipation were superior or marginally better in neonates in all the studies. Follow-up duration was mentioned in 4 of 5 studies, and ranged from 5 months to \u0026gt;=3.5 years.\u003c/p\u003e\n\u003cp\u003eContinence was reported in 6 studies: Cass 1990, Kastenberg 2021, Liu 2002, Lu 2017, Roy 2024 and Yang 2021 [15, 22, 24, 25, 29, 34]. PICCS was used in Lu 2017 and fecal Continence Assessment was used in Roy 2023 [25, 29]. Yang 2012 utilized the Wingspread functional score, showing an overall excellent to good continence achieved in 85.4 % of patients (82 of 96 patients), and a trend of improved outcomes with time, with no information on age at surgery [34]. Subjective assessment was utilized in the remaining 3 studies. \u0026nbsp;Three of the six showed superior outcomes for continence in neonates: Kastenberg 2021, Lu 2017, and Roy 2024 [22, 25, 29]. There was no difference to report in Cass 1990 and Liu 2002 [16, 24].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStool frequency was listed per patient in Cass 1990, with no clear difference across the two groups [16]. Kim 2009 reported this outcome as time to normal frequency or “stabilization period,” showing that longer time was needed following pullthrough in the neonatal period compared to older age (11.3 ± 6.9 weeks in neonates vs 7.3 ± 4.6 weeks in older children, P= 0.016) [23].\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCurrent management of HD depends on multiple factors, including age, length of aganglionic segment, experience of center and comfort with certain techniques as well as with laparoscopy. The majority of dedicated pediatric centers worldwide have adopted the practice of primary pullthrough for classic segment HD. In an online survey of the Australian and New Zealand association of Pediatric Surgeons (ANZAPS), 49/56 (88%) of the participants were comfortable with primary pullthrough in a clinically stable neonate with recto-sigmoid HD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The majority (82%) would perform this in \u0026lt;\u0026thinsp;3 months of age, and 100% would do it by 6 months of age [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe majority of the published literature compared pullthrough at or before 3 months of age, and that above 3 months of age. Data is generally conflicted with some supporting earlier pullthrough, some showing no difference and some supporting pullthrough at later ages.\u003c/p\u003e\u003cp\u003eProponents of earlier pullthrough argue that this may prevent episodes of pre-operative enterocolitis. Zhang et. al found that a significant reduction in HAEC incidence was observed among individuals under 3 months of age who underwent earlier surgery (69.1% pre-surgery vs. 30.9% post-surgery, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. In our meta-analysis, there was an initial trend showing higher pre-operative HAEC in neonates. After excluding the studies where pre-operative HAEC was an indication for earlier surgery, there was no difference in the two groups (OR 0.79 [95%CI 0.17, 3.67]). This points out a potential selection bias influencing the outcomes. Post-operative HAEC seems to be influenced by age of repair, with a significant higher risk for neonatal pullthrough. Our meta-analysis suggested that this trend is present at 1-month post-operative, 3-months post-operative and longer. We didn\u0026rsquo;t explore the influence of pre-operative HAEC on the occurrence of post-operative HAEC. A large retospective cohort study showed showed an association between pre- and post-operative HAEC (37). This could be due to the altered gut microbacteria [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe latest studies indicated that pullthrough done below 3 months of age had a shorter surgery and shorter length of stay [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Our meta-analysis suggested better outcomes with pullthrough when done beyond 1 month of age, regardless of the approach or technique; neonates had a shorter operative time with a cumulative mean difference of -26.41 minutes (95%CI -41.57, -11.26), while having a longer length of stay with mean difference of 3.11 days (95%CI 1.34, 4.87) compared to older children. This is consistent with the other literature suggesting ease of dissection in neonates as a potential reason [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Neonates are often thought to need longer to recover from post-operative ileus and to achieve full feed [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. This might be due to physiologic immaturity of the enteric nervous system [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. It could also be due to the general practice of slower introduction of feeds in the younger population, despite recent advances and guidelines around ERAS in neonates [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Other contributing factors to longer length of stay are the higher rate perioperative SSI and sepsis in neonate seen in the literature and consistent with the findings in our meta-analysis [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. It is possible that the fact that the neonatal group is sicker due to selection bias may contribute to this finding. More so, the immaturity of the immune system in neonates is a potential factor contributing to a higher risk of sepsis as well.\u003c/p\u003e\u003cp\u003eWestfal et. al shared that anastomotic leak was significantly higher in infants\u0026thinsp;\u0026lt;\u0026thinsp;2.5 months of age undergoing Soave pullthrough compared to older (5.5% vs 1.3%) [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. This agreed with the finding in our meta-analysis, showing the higher odds of anastomotic leak in neonates (OR 2.71 (95% CI 1.02, 7.24)) regardless of type of repair. It has been suggested that impaired immunity, poor tissue tolerance and tension on anastomosis may contribute to the higher risk of leak in neonates [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. It is worth mentioning that the evidence of pullthrough in older children\u0026thinsp;\u0026gt;\u0026thinsp;3 years of age shows higher anastomotic leak, potentially secondary to the presence of chronic dilation, chronic inflammation or both [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur meta-analysis suggested that the course for neonates after discharge is more difficult, especially in the first few months after surgery. Neonates had a higher rate of perianal excoriation up to 3 months post-operatively (OR5.52), as well as anastomotic stricture (OR8.47), and post-operative HAEC (OR up to 5.43) compared to older children. There is some evidence that this corrects by 6 months after surgery. It is possible that the need for stretching of a small surgical field and the and the weaker connective tissue in the neonates as well as the immature immune system all contribute to the more aggressive healing reaction and higher stenosis in the future.\u003c/p\u003e\u003cp\u003eThe long-term functional outcomes following pullthrough were more difficult to discern. Previous studies comparing early pullthrough before 3 months of age and that after 3 months suggest worse constipation and persistent soiling with the younger group [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. similarly, Westfal et. al. found that constipation and soiling were both worse in \u0026lt;\u0026thinsp;2.5months compared to \u0026gt;\u0026thinsp;2.5 months (10% and 25.9% vs 7.1% and 11.4% respectively) [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. The narrative review of functional outcomes in our study suggested that older children are more susceptible to constipation in the long-term, and potentially have worse continence. The latter is counter intuitive, since a general understanding that the younger the patient, the more likely the stretch of the field will cause disruption to the sphincter complex, leading to an element of incontinence. It was also suggested that neonates tend to have more frequent stools, and need longer to reach status quo [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The findings suggest that those who are operated at a younger age have a different functional portfolio than those who are operated at an older age. On the one hand, neonatal pullthough may result in less constipation, have a more frequent stool, and yet this is compensated with better continence later. On the other hand, the older children have less frequent stooling initially, less excoriation and a shorter stabilization period (period to normal frequency of stooling), yet worse continence. Due to the great subjectivity of the findings, this is hard to generalize.\u003c/p\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003eLimitations:\u003c/h2\u003e\u003cp\u003e This review covered a vast literature for pullthrough procedures extending from 1990 to 2024. The changes in admission protocols, antibiotics, techniques, etc. create multiple factors that are difficult to assess or control. This, however, contributes positively to the applicability of the findings across different settings and for the different procedures. The population included some with long segment/total colonic HD patients. On some occasions, we were not able to quantify this subgroup. The variable and unclear definitions of the outcome, such as HAEC, strictures, anastomotic leaks, also posed as a great source of heterogeneity. Functional outcomes were mainly assessed subjectively and at variable points from surgery, limiting our ability to combine the results. Additionally, the literature involved in this review is observational, and mainly retrospective in nature, subjecting it to recall and attrition bias. It is however, currently, the best available literature informing the decision regarding timing of pullthrough.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003eFuture Research:\u003c/h2\u003e\u003cp\u003eLarge cohort studies allowing for age break down as a continuous variable would help verify the findings in this meta-analysis. Long-term follow-up of these patients with consideration for functional outcomes, both continence and constipation, would be necessary to make a more accurate recommendation. Furthermore, long-term need for additional procedures, such as repeat biopsy, Botox injection, redo-pullthrough, need for diversion, are all unaddressed areas in this review\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDespite several limitations, this review and meta-analysis shows at least some evidence that pullthrough for Hirschsprung done after the neonatal period offers superior post-operative outcomes, regardless of the approach or the technique used. Literature on long-term functional outcomes in relation to age at pullthrough is lacking, and doesn\u0026rsquo;t allow for any meaningful conclusions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFinancial disclosure: This paper received no financial support\u003c/p\u003e\n\u003cp\u003eAuthors have no conflicts of interest to disclose\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Acknowledgment: We would like to thank Sa\u0026rsquo;ad Laws from the Weil Cornell Medical College in Qatar library in his assistance with the search strategy and paper sourcing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eHaricharan RN, Georgeson KE. Hirschsprung disease. \u003cem\u003eSemin Pediatr Surg\u003c/em\u003e. 2008;17(4):266-275. doi:10.1053/j.sempedsurg.2008.07.005. PMID: 19019295.\u003c/li\u003e\n \u003cli\u003eSergi C. 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Early outcome of transanal endorectal pull-through with a short muscle cuff during the neonatal period. \u003cem\u003eJ Pediatr Surg\u003c/em\u003e. 2004;39(2):157-160. doi:10.1016/j.jpedsurg.2003.10.007. PMID: 14966731.\u003c/li\u003e\n \u003cli\u003eRoy C, Jaffray B. Pull through for Hirschsprung disease without planned rectal decompression is safe. \u003cem\u003eJ Pediatr Surg\u003c/em\u003e. 2023;58(2):231-235. doi:10.1016/j.jpedsurg.2022.10.027. PMID: 36402590.\u003c/li\u003e\n \u003cli\u003eSenthil Kumar L. \u003cem\u003eSingle Stage Transanal Endorectal Pull-Through (TEPT) for Hirschsprung Disease\u003c/em\u003e [MD thesis]. Coimbatore: Coimbatore Medical College; 2009.\u003c/li\u003e\n \u003cli\u003eSo HB, Becker JM, Schwartz DL, Kutin ND. Eighteen years\u0026apos; experience with neonatal Hirschsprung disease treated by endorectal pull-through without colostomy. \u003cem\u003eJ Pediatr Surg\u003c/em\u003e. 1998;33(5):673-675. doi:10.1016/s0022-3468(98)90185-3. PMID: 9607466.\u003c/li\u003e\n \u003cli\u003eSowande OA, Adejuyigbe O, Ademuyiwa O, Usang UE, Bakare TI. Primary Swenson pull-through in infants less than 4-months: a preliminary report. \u003cem\u003eAfr J Paediatr Surg\u003c/em\u003e. 2006;3(2):57-60.\u003c/li\u003e\n \u003cli\u003eWeidner BC, Waldhausen JH. Swenson revisited: a one-stage, transanal pull-through procedure for Hirschsprung disease. \u003cem\u003eJ Pediatr Surg\u003c/em\u003e. 2003;38(8):1208-1211. doi:10.1016/s0022-3468(03)00269-0. PMID: 12891494.\u003c/li\u003e\n \u003cli\u003eYang L, Tang ST, Cao GQ, et al. Transanal endorectal pull-through for Hirschsprung disease using long cuff dissection and short V-shaped partially resected cuff anastomosis: early and late outcomes. \u003cem\u003ePediatr Surg Int\u003c/em\u003e. 2012;28(5):515-521. doi:10.1007/s00383-012-3071-0. PMID: 22426598.\u003c/li\u003e\n \u003cli\u003eNataraja RM, Ferguson P, King S, Lynch A, Pacilli M. Management of Hirschsprung disease in Australia and New Zealand: a survey of the Australian and New Zealand Association of Paediatric Surgeons (ANZAPS). \u003cem\u003ePediatr Surg Int\u003c/em\u003e. 2019;35(4):419-423. doi:10.1007/s00383-018-04432-7. PMID: 30607542.\u003c/li\u003e\n \u003cli\u003eZhang Y, Xiang X, Li X, Feng W, Guo Z. Early intervention in Hirschsprung disease: effects on enterocolitis and surgical outcomes. \u003cem\u003eBMC Pediatr\u003c/em\u003e. 2024;24(1):476. doi:10.1186/s12887-024-04956-z. PMID: 39061020; PMCID: PMC11282594.\u003c/li\u003e\n \u003cli\u003eXie C, Yan J, Zhang Z, Kai W, Wang Z, Chen Y. Risk factors for Hirschsprung-associated enterocolitis following Soave: a retrospective study over a decade. \u003cem\u003eBMC Pediatr\u003c/em\u003e. 2022;22(1):654. Published 2022 Nov 10. doi:10.1186/s12887-022-03692-6\u003c/li\u003e\n \u003cli\u003eXiao S, Yang W, Yuan L, et al. [Timing investigation of single-stage definitive surgery for newborn with Hirschsprung disease]. \u003cem\u003eZhonghua Wei Chang Wai Ke Za Zhi\u003c/em\u003e. 2016;19(10):1160-1164. PMID: 27781255.\u003c/li\u003e\n \u003cli\u003eTeitelbaum DH, Cilley RE, Sherman NJ, et al. A decade of experience with the primary pull-through for Hirschsprung disease in the newborn period: a multicenter analysis of outcomes. \u003cem\u003eAnn Surg\u003c/em\u003e. 2000;232(3):372-380. doi:10.1097/00000658-200009000-00009. PMID: 10973387; PMCID: PMC1421142.\u003c/li\u003e\n \u003cli\u003eMannava S, Vogler A, Markel T. Pathophysiology and management of postoperative ileus in adults and neonates: a review. \u003cem\u003eJ Surg Res\u003c/em\u003e. 2024;297:9-17. doi:10.1016/j.jss.2024.02.001. PMID: 38428262.\u003c/li\u003e\n \u003cli\u003eLu C, Sun X, Geng Q, Tang W. Early oral feeding following intestinal anastomosis surgery in infants: a multicenter real world study. \u003cem\u003eFront Nutr\u003c/em\u003e. 2023;10:1185876. doi:10.3389/fnut.2023.1185876. PMID: 37545580; PMCID: PMC10399449.\u003c/li\u003e\n \u003cli\u003eVu LT, Vittinghoff E, Nobuhara KK, Farmer DL, Lee H. Surgical site infections in neonates and infants: is antibiotic prophylaxis needed for longer than 24 h? \u003cem\u003ePediatr Surg Int\u003c/em\u003e. 2014;30(6):587-592. doi:10.1007/s00383-014-3506-x. PMID: 24805114.\u003c/li\u003e\n \u003cli\u003eDuque-Estrada EO, Duarte MR, Rodrigues DM, Raphael MD. Wound infections in pediatric surgery: a study of 575 patients in a university hospital. \u003cem\u003ePediatr Surg Int\u003c/em\u003e. 2003;19(6):436-438. doi:10.1007/s00383-002-0735-1. PMID: 12883851.\u003c/li\u003e\n \u003cli\u003eWestfal ML, Okiemy O, Chung PHY, et al. Optimal timing for Soave primary pull-through in short-segment Hirschsprung disease: a meta-analysis. \u003cem\u003eJ Pediatr Surg\u003c/em\u003e. 2022;57(4):719-725. doi:10.1016/j.jpedsurg.2021.07.007. PMID: 34330420; PMCID: PMC8776908.\u003c/li\u003e\n \u003cli\u003ePeng CH, Chen YJ, Pang WB, et al. STROBE-anastomotic leakage after pull-through procedure for Hirschsprung disease. \u003cem\u003eMedicine (Baltimore)\u003c/em\u003e. 2018;97(46):e13140. doi:10.1097/MD.0000000000013140. PMID: 30431584; PMCID: PMC6257430.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hirschsprung disease, pullthrough procedure, perioperative outcomes","lastPublishedDoi":"10.21203/rs.3.rs-7387957/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7387957/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePrimary pullthrough for Hirschsprung disease is the current standard in most uncomplicated standard segment disease. In this review and meta-analysis, we aimed to compare perioperative outcomes and functional outcomes for pullthrough done in the neonatal period compared to that in older age (\u0026lt;5 year).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMETHODS: \u003c/strong\u003ePubMed, Medline, Embase, CINAHL, SCOPUS, and Web of Science were searched for relevant publications in English from inception to June 29, 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRESULTS: \u003c/strong\u003eTwenty studies were included in the qualitative analysis with a total 3197 patients matching the review criteria. All included studies were observational in nature, with 1 prospective cohort study, 13 retrospective cohort studies, and 6 case series. Findings suggested primary pullthrough beyond 1 month of age was superior in most outcomes, including: shorter post-operative length of stay (LOS) (MD3.11days [95%CI 95%CI 1.34, 4.87]), perioperative sepsis (OR1.76, [95%CI1.26, 2.47]), anastomotic leak (OR2.71[95%CI1.02, 7.24]), perianal excoriation upto 3 months (OR5.52[95%CI 3.07, 9.9]), post-operative HAEC at 3 months (OR5.49[95%CI 3.35, 9]), and anal senosis (OR3.04[95%CI 1.07, 8.67]). Pullthrough done in neonatal age was superior in a shorter operative time (MD-26.41min [95%CI -41.57, 11.26]). There was no significant difference in overall SSI, 30-day readmissions, and pre-operative HAEC. Functional outcomes were assessed in 8 studies showing some tendency towards constipation and incontinence in the older children, and more observed stool frequency and for longer duration post-operatively in the neonates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONCLUSION\u003c/strong\u003e: Older children ith Hirschprung perform better post-pullthrough and have less morbidity compared to neonates. Performing the pullthrough after 1 month is safe and likely to offer the best post-operative outcomes. This review was limited by the low level of evidence and inconsistent definitions of outcomes. Results will need to be verified with a large prospective study.\u003c/p\u003e","manuscriptTitle":"Perioperative Outcomes in Primary Neonatal Pullthrough versus Pullthrough in Older Children: A Systematic Review and Meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-26 15:03:26","doi":"10.21203/rs.3.rs-7387957/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-30T15:32:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-24T14:06:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-24T08:16:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141287075046298534142042643929994941861","date":"2025-10-01T08:09:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"333458977790645774783316982627456465090","date":"2025-09-27T02:41:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"213405459747610560214293835360851984757","date":"2025-09-22T10:05:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-18T23:06:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"68222999365758078939446289844552182688","date":"2025-09-18T00:26:15+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-17T09:47:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-17T07:27:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-26T10:03:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-21T18:32:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-21T18:28:43+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"87c14665-fc09-4dd5-aa30-98299cea0bf5","owner":[],"postedDate":"September 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55319759,"name":"Health sciences/Diseases"},{"id":55319760,"name":"Health sciences/Gastroenterology"},{"id":55319761,"name":"Health sciences/Health care"},{"id":55319762,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-02-09T16:02:07+00:00","versionOfRecord":{"articleIdentity":"rs-7387957","link":"https://doi.org/10.1038/s41598-026-35690-4","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-02-02 15:58:48","publishedOnDateReadable":"February 2nd, 2026"},"versionCreatedAt":"2025-09-26 15:03:26","video":"","vorDoi":"10.1038/s41598-026-35690-4","vorDoiUrl":"https://doi.org/10.1038/s41598-026-35690-4","workflowStages":[]},"version":"v1","identity":"rs-7387957","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7387957","identity":"rs-7387957","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}