Ripples: Towards Preventing Complications Following Abdominal Surgery in Young Children L.D. Eeftinck Schattenkerk
This thesis was prepared at the Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands. The financial support by this thesis was provided by AMC Medical Research (AMR), Department of Pediatric Surgery of the Amsterdam University Medical Center. The sponsors had no role in the design, execution, analyses, data interpretation and decisions on submitting the results. Cover design: Max Lokhorst Lay-out and Print: Ridderprint | www.ridderprint.nl Copyright (C) 2025: Laurens D. Eeftinck schattenkerk All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, by photocopying, recording, or otherwise, without the prior written permission of the author.
Ripples: Towards Preventing Complications Following Abdominal Surgery in Young Children ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus prof. dr. ir. P.P.C.C. Verbeek ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel op vrijdag 13 juni 2025, te 13.00 uur door Laurens Donald Eeftinck Schattenkerk geboren te Deventer
Promotiecommissie Promotores: prof. dr. L.W.E. van Heurn AMC-UvA prof. dr. W.J. de Jonge AMC-UvA Copromotores: prof. dr. J.P.M. Derikx AMC-UvA dr. G.D. Musters AMC-UvA Overige leden: prof. dr. E.J.M. Nieveen van Dijkum AMC-UvA prof. dr. M.A. Benninga AMC-UvA prof. dr. R.R. van Rijn AMC-UvA prof. dr. M.A. Boermeester AMC-UvA prof. dr. O.R.C. Busch AMC-UvA dr. K.C.M.J. Peeters LUMC prof. dr. J.B.F. Hulscher Rijksuniversiteit Groningen Faculteit der Geneeskunde
Table of Contents PART I INTRODUCTION 8 Chapter 1 General introduction 11 PART II INCIDENCE OF POSTOPERATIVE COMPLICATIONS BASED ON THE AVAILABLE LITERATURE 20 Chapter 2 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants: A systematic review with meta-analysis January 2021 - Journal of Pediatric Surgery 23 Chapter 3 The incidence of different forms of ileus following surgery for abdominal birth defects in infants: a systematic review with a metaanalysis method August 2021 - Innovative Surgical Sciences 61 Chapter 4 Systematic review of definitions and outcome measures for postoperative ileus and return of bowel function after abdominal surgery in children December 2020 - Scientific Reports 103 Chapter 5 Incisional hernia after surgical correction of abdominal congenital anomalies in infants: a systematic review with meta-analysis Submitted 125 PART III INCIDENCE OF- AND RISK FACTORS FOR POSTOPERATIVE COMPLICATIONS IN OUR COHORT 146 Chapter 6 Central venous catheter associated bloodstream infections and thrombosis in patients treated for gastroschisis and intestinal atresia: A retrospective cohort study of 238 patients September 2022 - European Journal of Pediatric Surgery 149 Chapter 7 Incisional hernia after abdominal surgery in infants: A retrospective analysis of incidence and risk factors February 2021 - Journal of Pediatric Surgery 169 Chapter 8 Adhesive small bowel obstruction following abdominal surgery in young children (≤ 3 years): A retrospective analysis of incidence and risk factors using multivariate cox regression January 2022 - Journal of Pediatric Surgery 187
Chapter 9 Should primary anastomosis be feared less? A retrospective analysis of anastomotic complications in young children June 2023 – World Journal of Pediatric Surgery 205 PART IV COMPLICATIONS OF- AND ENTEROSTOMY RELATED MORBIDITY 220 Chapter 10 Major stoma related morbidity in young children following stoma formation and closure; A retrospective cohort study November 2021 - Journal of Pediatric Surgery 223 Chapter 11 Impact of presence, level and closure of a stoma on growth in young children: A retrospective cohort study May 2023 – European Journal of Pediatric Surgery 239 Chapter 12 Treatment of jejunoileal atresia by primary anastomosis or enterostomy: Double the operations, double the risk of complications July 2021 - Journal of Pediatric Surgery 255 Chapter 13 Routine contrast enema prior to stoma reversal seems only required following treatment for necrotizing enterocolitis: An evaluation of the diagnostic accuracy of the contrast enema June 2022 - Journal of Pediatric Surgery 271 PART V CONCLUSIONS, GENERAL DISCUSSION AND FUTURE PERSPECTIVES. 288 Chapter 14 Conclusions, general discussion and future perspectives 291 PART VI APPENDICES 304 English summary 308 Nederlandse Samenvatting (Dutch Summary) 312 Statements (Stellingen) 316 PhD portfolio 318 List of publications 320 Acknowledgements 322 About the author 328
PART I INTRODUCTION
1
Chapter 1 General introduction
12 Chapter 1 1. A short history of abdominal surgery in young children Since the “father of pediatric surgery” doctor Ladd (1888-1967) (known for the Ladd’s procedure as a treatment for malrotation) was the first to devote his career to the surgical care of children, medicine focusing on young patients did not stop evolving. Many advancements have been made in surgical treatment as well as perioperative care for pediatric patients, especially for those born prematurely.[3] Important innovations in critical care of neonates, such as incubators, surfactant and parenteral nutrition, have resulted in a steadily increase of neonatal survival.[4-6] These innovations go hand in hand with targeted child health strategies undertaken globally by the United Nations in their Millennium Development Goals but also the interventions taken on a national level by individual countries. These actions combined have resulted in cutting in half global mortality of children aged under five years.[6] Whilst this increase in survival has simultaneously went in tandem with an increase in treatment of all surgical diseases in young children, this surge in numbers is even more profound in patients treated for congenital diseases.[4] This could be expected following an increase in the survival of premature born babies since premature birth is associated with a four-fold increased risk of having a congenital anomaly.[7] Due to these developments pediatric- and neonatal surgery now make up a significant proportion of the total surgical care in high-income countries. At the moment 6% of all children undergo an operation before the age of five years in the United States of America.[8] Whilst in Europe, a pediatric surgeon performs 202 surgeries on average per year, of which 11 procedures are on neonates.[9] Although currently surgical supply is meeting demands in high-income countries, an estimated 4.8 billion people in general do not have access to surgical care mainly in low- and middle-income countries.[1, 2] A large proportion is related to care for pediatric patients which is why the World Health Association (WHO) stated pediatric surgery in general and specifically surgery for congenital diseases as an important resolution of pediatric morbidity globally.[10] Multiple studies and programs aim to detect and address this lack of surgical care which suggests that the global number of surgeries in children will only increase in the upcoming years. 2. Complications following abdominal surgery in young children A next step in improving surgical care for children would be to detect and reduce complications of surgery. Though surgical interventions in young children are now common, there is sparse data on these complications of surgery. This is especially true in patients treated for congenital diseases, as there is limited access to databases containing large cohorts necessary for these evaluations due to the rare nature of these diseases.
13 General introduction Chapter 1 This thesis will show that complications following abdominal surgery in young children are not as rare as some might think. This insight is important because of the consequences of postoperative complications. These consequences have a wide- and unpredictable range. They can be tedious, limiting quality of life without being directly life-threatening, such as feeding difficulties, impaired growth and postoperative ileus. Aside from being harmful to patients and parents, these common complications increase hospital stay with conjoined increase in medical costs. However, there are also more grave complications which could necessitate redo-surgery, for example following anastomotic stenosis. These complications too are frequent, as our results will show. The necessity of redo-surgery not only gives rise to repeated risk of postoperative complications, but also repeated surgery at a young age seems to impair neurodevelopment later on in life.[11] The gravest of postoperative complications, mortality, is rare but does occur following postoperative complications. It can occur both relatively quick following surgery (e.g. following anastomotic leakage) as well as later during follow-up (e.g. following bowel ischemia caused by adhesions) the incidence of which warrants further research. Information on incidences of- and risk factors for different postoperative complications could provide context for clinical decision making as well as be of use when informing parents on the expected course of disease. By objectifying which diseases or even more specifically which patients have highest incidence of these complications provides a basis for future research into interventions aiming to minimize these risks in the future of pediatric surgery. From here onwards there will be a brief introduction of common complications following surgery in young children including central catheter associated infections/thrombosis, incisional hernia, obstructive complications, intestinal anastomotic complications and complications following enterostomy formation. 3. Postoperative complications 3.1. Central venous catheter associated infection/thrombosis Total parenteral nutrition via a central venous catheter is essential in case the intestinal tract can’t be used due to severe infections or intestinal blockage (e.g. atresias). Without it, severe malnutrition would be unavoidable. However, central venous catheters themselves can be a cause of severe complications such as central venous catheter associated infections or thrombosis. Since the catheter is directly inserted into a central vein, translocation of bacteria, fungi or viruses via the catheter can cause bloodstream infections causing a systemic inflammatory response. Specifically in neonates, these
14 Chapter 1 bloodstream infections are a major contributor to morbidity and mortality within neonatal intensive care units.[12] The cause of catheter related thrombosis is diverse. A combination of factors, including the insertion of the catheter, reduction of flow through the central vein caused by the catheter and ongoing micro damage caused by movement of the catheter, will active the coagulation cascade resulting in blood clots. These can in turn cause blockage of flow through the vein leading to thrombosis which might necessitate treatment with anticoagulants. The catheters used to administer total parenteral nutrition differ in the mode of insertion, either tunnelled subcutaneously before the vein is entered or non-tunnelled, and the type of vein used, either a small peripheral or a large central vein. The decision between these options is based on a trade-off between the up- and downsides of both options mostly interchanging the chances of the occurrence of thrombosis or infection. Because of this, there is variation in standard of practice between different centres which demands further research into this topic. 3.2. Fecal Obstructive complications Fecal obstructive complications following abdominal surgery can either occur shortly after surgery or later during follow-up. Shortly after surgery, prolonged intestinal paralysis can lead to ileus; a clinical diagnosis characterized by intolerance to oral feeding, nausea and the lack of stool. This complication, mostly resolving by itself in time, is responsible for one-in-five of the unplanned readmissions in the first month following surgery in children in the United States.[13] Later during follow-up, mechanical obstruction caused by adhesions can necessitate redo-surgery for adhesion removal. These adhesions are, partly, an unavoidable reaction to abdominal surgery occurring as part of the natural healing process of intra-abdominal scarring. However, insights into the pathophysiology of adhesions have shown that certain factors, such as intestinal tissue handling and mediation of inflammation might decrease the amount of adhesion formation. This could be seen as an explanation why fewer adhesive obstructions seem to occur following laparoscopies compared to laparotomies.[14] Still, in both treatment options, adhesive obstructions do occur and can necessitate surgery even years after the primary operation. 3.3. Incisional hernia An incisional hernia is a protrusion of tissue at the sight of a surgical scar. This complication is extensively studied in adults but less so in young children. There are two previous studies focussing on these complications in children which suggested that incisional hernias occur between one and three percent when taking all pediatric patients
15 General introduction Chapter 1 (age rang 0-18 years) into account.[15, 16] These studies suggested that patients treated for necrotizing enterocolitis and infantile hypertrophic pyloric stenosis seem relatively most at risk of developing an incisional hernia. Additionally, having a history of enterostomy formation or surgery during the neonatal phase are suggested to be risk factors for hernia development. The strength of these conclusions is questionable because of low statistical power due to the inclusion of between 7 and 21 children with an incisional hernia. Additionally, most studies excluded laparoscopic surgeries, even though trocar site hernias in young children have been reported to complicate these procedures.[17] Furthermore, these studies included operation performed in children of wide age ranges extending from neonatal age up to 15 years of age, which decreases the generalizability of these results leaving room for speculation. 3.4. Intestinal anastomotic complications Aside from adhesions, mechanical obstructions are potentially caused by anastomotic stenosis occurring in newly formed intestinal anastomosis. This stenosis can occur shortly following surgery in case of technical error or tissue oedema, whereas strictures that form later during follow-up seem to be caused by chronic inflammation causing anastomotic scarring.[18] In both cases redo-surgery with redo-anastomosis is necessary in most patients. Currently, there is no uniformity in the technique used to create an intestinal anastomosis in order to minimize the risk of these complications.[18, 19] This is in one bit because studies evaluating different technical factors are lacking. The only advancement made in the recent years has shown that a single layer of sutures compared to a double layer seems to decrease the incidence of short-term stenosis without increasing the risks of leakage, leaving many other technical factors open for discussion.[20] Leakage of a newly formed intestinal anastomosis is seen as a grave complication which necessitates emergency surgery in most cases and could even result in mortality. Many surgeons believe this risk to be too high to safely create a primary anastomosis in young children with intestinal diseases. However, there is a lack of knowledge concerning the incidence of- and risk factors for anastomotic leakage as well as the rate of mortality associated to this complication. 4. Complications associated to enterostomy formation The creation of an enterostomy can be essential and lifesaving in young children with life threatening morbidity such as bowel perforations. [1, 2] Creation of an enterostomy is thought to be a relatively safe method to give the abdomen rest to recover. After recovery, when the inflammatory response has cooled off or after other congenital defects have settled, another operation is necessary to perform a secondary anastomosis. As stated
16 Chapter 1 previously, many believe that by doing so the risk of anastomotic leakage is limited which seems one of the main arguments to pick stoma formation over primary anastomosis. In this view however, the stoma associated morbidity and the risk of complications following stoma reversal are mostly left out of the discussion. A reason for this blind spot might be the lack of studies published on this subject; over the last 30 years, only a few studies have focussed on young children with a stoma.(29, 30) 4.1. Stoma related growth impairment Whilst enterostomys can be lifesaving, it seems that having a stoma has a negative impact on a childs growth.[21] This growth impairment at young age in turn seems to have a negative impact on long-term development as well as increase the risk of stoma related complications.[22, 23] Having a stoma will cause loss of nutrients and sodium to some extend. If these losses result in sodium depletion, it can result in a failure to thrive. [24] This impaired growth in combination with sodium depeletion seems to occur even in children with adequate caloric intake.(31, 32) Following this insight, the suppletion of sodium in young children is now common practice at many institutions including ours. Yet adqueate guidelines are lacking resulting in differences in basic practice.(33) Since growth is such a multifactorial process it might well be that other patient specific factors are associated to growth impairment, however studies into this topic are lacking. 4.2. Major stoma related morbidity Set aside growth impairment, direct stoma related morbidity can occur during the time patients have the enterostomy. Examples are stoma necrosis, stenosis, prolapse or parastomal hernias, all of which could necessitate redo-surgery.[3] Moreover, stoma creation demands a timed reversal in most patients; which is mostly performed within 2-4 months following stoma creations. Stoma reversal, in some centres like ours, is commonly preceded by a contrast loopogram to evaluate the presence of distal strictures. Therefore, treatment by stoma demands at least two operations of a patient at a very young age as well as repeated exposure to radiation. When debating risks of primary anastomosis versus stoma formation, these risk are mostly left out. This is flawed since it is known that complications such as anastomotic leakage do also occur following stoma reversal. [2, 3, 6] In order to have an informed discussion about the best surgical treatment options for young children with intestinal defects it is important to approximate the true incidence of these stoma related complications as well as to identify risk factors. This could provide a basis for preventative strategies in the future, or might lead to changes in surgical approaches. Opening-up this discussion might result in a choice of treatment more suited to a specific patient rather than certain diseases in fear of complications.
17 General introduction Chapter 1 Aims of this thesis This thesis has aimed to close a knowledge gap on the occurrence of different types of complications following abdominal surgery in young children as well as the occurrence of the complications following treatment by stoma in the same cohort of patients This thesis aims to close a knowledge gap on the occurrence of different types of complications and their risk factors following abdominal surgery in young children as well as the occurrence of the complications following treatment by stoma in the same cohort of patients. This information may provide a basis for research and decision making into changes in surgical practice aiming to decrease the occurrence of these complications. Thesis outline Though surgical interventions in young children are now common, limited knowledge exists on the rate of postoperative complications. For this reason, we aggregated the available literature on three different overarching types of complications, namely infectious, obstructive and incisional hernias. This resulted in three separate systematic reviews showing the incidences of different types of complications, which are all provided in Part II. From here onwards we separately evaluated complications in our manually created database including all patients who underwent abdominal surgery in the two recently merged university hospitals of Amsterdam now called the Amsterdam UMC. This resulted in Part III in which the incidence of- and risk factors for short term complications such as central catheter associated infection/thrombosis or complications of primary anastomosis are evaluated. Likewise, this is done for long-term complications such as incisional hernia and adhesive bowel obstruction. Moreover, by providing an overview of the outcome measures used in the literature to describe pediatric postoperative ileus, this chapter builds one of the findings of Part 1 suggesting high variation in definitions as well as outcome measures. This is the start of the path towards a core-outcome set. Part IV focusses specifically on young children treated with an enterostomy. It shows the risks related to having an enterostomy at a young age. These risks entail the risk of growth impairment but also enterostomy related morbidity. Moreover, this chapter will show that it seems unwise to perform a routine contrast enema prior to enterostomy reversal except following treatment for necrotizing enterocolitis. Taking into account these risks as well as the risks of primary anastomosis provided in Chapter III, this chapter closes by summarising the aggregated risks of complications following both enterostomy formation and reversal to primary anastomosis in patients treated for jejunoileal atresia.
18 Chapter 1 References Part I: Introduction 1. Nakayama DK. Vignettes from the history of pediatric surgery. Journal of pediatric surgery. 2020;55s:137. 2. Battaglia JD. Neonatal surgery: Changing patterns 1972–1980. Journal of pediatric surgery. 1982;17(5):666-9. 3. Patel RM, Rysavy MA, Bell EF, Tyson JE. Survival of Infants Born at Periviable Gestational Ages. Clin Perinatol. 2017;44(2):287-303. 4. Glinianaia SV, Morris JK, Best KE, Santoro M, Coi A, Armaroli A, et al. Long-term survival of children born with congenital anomalies: A systematic review and meta-analysis of population-based studies. PLOS Medicine. 2020;17(9):e1003356. 5. Mohangoo A, Lanting C, Gravenhorst BJ, Verloove-Vanhorick P, Buitendijk S. 457 Contribution of Congenital Anomalies to Preterm Birth Risk in the Netherlands. Pediatric Research. 2010;68(1):234-5. 6. Rabbitts JA, Groenewald CB. Epidemiology of Pediatric Surgery in the United States. Paediatric anaesthesia. 2020;30(10):1083-90. 7. Parigi GB, Czauderna P, Rolle U, Zachariou Z. European Census on Pediatric Surgery. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery [et al] = Zeitschrift fur Kinderchirurgie. 2018;28(3):227-37. 8. Meara JG, Greenberg SL. The Lancet Commission on Global Surgery Global surgery 2030: Evidence and solutions for achieving health, welfare and economic development. Surgery.. 9. Sitkin NA, Farmer DL. Congenital anomalies in the context of global surgery. Seminars in Pediatric Surgery. 2016;25(1):15-8. 10. Murray CJL, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet. 2012;380(9859):2197-223. 11. Roorda D, Königs M, Eeftinck Schattenkerk L, van der Steeg L, van Heurn E, Oosterlaan J. Neurodevelopmental outcome of patients with congenital gastrointestinal malformations: a systematic review and meta-analysis. Archives of disease in childhood Fetal and neonatal edition. 2021;106(6):63542. 12. Hadfield BR, Cantey JB. Neonatal bloodstream infections. Current opinion in infectious diseases. 2021;34(5):533-7. 13. Kulaylat AN, Rocourt DV, Tsai AY, Martin KL, Engbrecht BW, et al. Understanding readmissions in children undergoing surgery: A pediatric NSQIP analysis. Journal of pediatric surgery. 2018. 14. Molinaro F, Kaselas C, Lacreuse I, Moog R, Becmeur F. Postoperative intestinal obstruction after laparoscopic versus open surgery in the pediatric population: A 15-year review. European journal of pediatric surgery : official journal of Austrian Association of Pediatric Surgery [et al] = Zeitschrift fur Kinderchirurgie. 2009;19(3):160-2. 15. Mullassery D, Pedersen A, Robb A, Smith N. Incisional hernia in pediatric surgery - experience at a single UK tertiary centre. Journal of pediatric surgery. 2016;51(11):1791-4. 16. Tanaka K, Misawa T, Ashizuka S, Yoshizawa J, Akiba T, Ohki T. Risk Factors for Incisional Hernia in Children. World journal of surgery. 2018;42(7):2265-8. 17. Paya K, Wurm J, Fakhari M, Felder-Puig R. Trocar-site hernia as a typical postoperative complication of minimally invasive surgery among preschool children. Surgical endoscopy. 18. Guyton KL, Hyman NH, Alverdy JC. Prevention of Perioperative Anastomotic Healing Complications: Anastomotic Stricture and Anastomotic Leak. Advances in surgery. 2016;50(1):129-41. 19. Boscarelli A. Intestinal anastomosis in children: it's time for a general consensus. Transl Pediatr. 2017;6(1):76-7.
19 General introduction Chapter 1 20. Ordorica-Flores RM, Bracho-Blanchet E, Nieto-Zermeño J, Reyes-Retana R, Tovilla-Mercado JM, LeonVillanueva V, et al. Intestinal anastomosis in children: a comparative study between two different techniques. Journal of pediatric surgery. 1998;33(12):1757-9. 21. Bethell G, Kenny S, Corbett H. Enterostomy-related complications and growth following reversal in infants. Arch Dis Child Fetal Neonatal Ed. 2017;102(3):F230-f4. 22. Homan GJ. Failure to Thrive: A Practical Guide. Am Fam Physician. 2016;94(4):295-9. 23. Corbett SS, Drewett RF. To what extent is failure to thrive in infancy associated with poorer cognitive development? A review and meta-analysis. J Child Psychol Psychiatry. 2004;45(3):641-54. 24. Trautmann T, Bang C, Franke A, Vincent D, Reinshagen K, Boettcher M. The Impact of Oral Sodium Chloride Supplementation on Thrive and the Intestinal Microbiome in Neonates With Small Bowel Ostomies: A Prospective Cohort Study. Frontiers in immunology. 2020;11:1421.
PART II INCIDENCE OF POSTOPERATIVE COMPLICATIONS BASED ON THE AVAILABLE LITERATURE
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Chapter 2 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants: A systematic review with meta-analysis Laurens D. Eeftinck Schattenkerk a,b, Gijsbert D. Musters a , David J. Nijssen a , Wouter J. de Jonge b,c , Ralph de Vries d , L.W. Ernest van Heurn a,b , Joep P.M. Derikx a,b Affiliations: a: Department of Paediatric Surgery, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, and Vrije Universiteit Amsterdam, Meibergdreef 9, 1005 AZ Amsterdam, the Netherlands; b:Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; c: Department of General, Visceral, Thoracic, and Vascular Surgery, University Hospital Bonn, Bonn, Germany d Medical Library, Vrije Universiteit, Amsterdam, the Netherlands
24 Chapter 2 Abstract Background: Surgical site infections (SSI) are a frequent and significant problem understudied in infants operated for abdominal birth defects. Different forms of SSIs exist, namely wound infection, wound dehiscence, anastomotic leakage, post-operative peritonitis and fistula development. These complications can extend hospital stay, surge medical costs and increase mortality. If the incidence was known, it would provide context for clinical decision making and aid future research. Therefore, this review aims to aggregate the available literature on the incidence of different SSIs forms in infants who needed surgery for abdominal birth defects. Method: The electronic databases Pubmed, EMBASE, and Cochrane library were searched in February 2020. Studies describing infectious complications in infants (under three years of age) were considered eligible. Primary outcome was the incidence of SSIs in infants. SSIs were categorized in wound infection, wound dehiscence, anastomotic leakage, postoperative peritonitis, and fistula development. Secondary outcome was the incidence of different forms of SSIs depending on the type of birth defect. Meta-analysis was performed pooling reported incidences in total and per birth defect separately. Results: 154 studies, representing 11,786 patients were included. The overall pooled percentage of wound infections after abdominal birth defect surgery was 6% (95%- CI:0.05–0.07) ranging from 1% (95% CI:0.00-0.05) for choledochal cyst surgery to 10% (95%-CI:0.06-0.15) after gastroschisis surgery. Wound dehiscence occurred in 4% (95%-CI:0.03 – 0.07) of the infants, ranging from 1% (95%-CI:0.00-0.03) after surgery for duodenal obstruction to 6% (95%-CI:0.04-0.08) after surgery for gastroschisis. Anastomotic leakage had an overall pooled percentage of 3% (95%-CI:0.02–0.05), ranging from 1% (95%-CI:0.00-0.04) after surgery for duodenal obstruction to 14% (95% CI:0.060.27) after colon atresia surgery. Postoperative peritonitis and fistula development could not be specified per birth defect and had an overall pooled percentage of 3% (95%-CI:0.01– 0.09) and 2% (95%-CI:0.01–0.04). Conclusions: This review has systematically shown that SSIs are common after correction for abdominal birth defects and that the distribution of SSI differs between birth defects.
25 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants Chapter 2 Introduction Surgical site infection (SSI) following abdominal birth defect surgery are a frequent and significant clinical problem which has been understudied in infants (under three years of age) who have been operated because of abdominal birth defects. Different forms of SSIs exist, namely wound infection, wound dehiscence, anastomotic leakage, post-operative peritonitis and fistula development. These complications may lead to longer hospital stay, increased medical costs, affect the quality of life and increase mortality rates.[25-28] Operations during the infantile years might lead to an increase in SSI risk.[29, 30] However, due to the rarity of most birth defects, the incidences of the different forms of SSI are not well known. Increased knowledge on the incidence of SSI would provide context for clinical decision-making and could serve as a starting point for future research. Determining which birth defects have the highest incidence of these SSIs might, for instance, allow targeted prophylactic antibiotics in order to minimize these risks. Therefore, this review aims to determine the incidence of the different surgical site infections for each abdominal birth defect surgery in infants by means of a meta-analysis. Methods Studies were selected using the criteria described below. They are based on the PRISMA Guidelines.[31] We registered our protocol in the International Prospective Register of Systematic Reviews (PROSPERO) on 7 March 2019 (registration number: CRD42019119268). Participants All studies reporting on SSIs after abdominal surgery of birth defect in infants operated within three years of age were considered eligible for this review. Studies done in animals, in vitro, non-English, conference abstracts and studies containing less than ten cases were excluded. Search strategy To identify all relevant publications, we conducted systematic searches in the bibliographic databases PubMed and Embase from inception up to February 2020 using both simple search terms as well as hierarchical family forms (e.g. MESH). Our institutions clinical data expert (RV) helped design the search strategy. This search combined four groups of search terms and their equivalents: (1) terms related to the age at the moment of surgery (e.g. neonate); (2) terms related to the location of surgery (e.g. intestinal surgery); (3) terms related to congenital abdominal defects (e.g. anorectal malformations); (4) terms related
26 Chapter 2 to infectious complications (e.g. wound infection). We provided MESH and search terms used in PubMed in Appendix 1. Appendix 1 – Search strategy PUBMED Search block title Search terms used in PUBMED Age group "Infant"[Mesh] OR "Intensive Care, Neonatal"[Mesh] OR "Intensive Care Units, Neonatal"[Mesh] OR "Neonatal Nursing"[Mesh] OR infant*[tiab] OR newborn*[tiab] OR neonat*[tiab] OR prematur*[tiab] OR preterm*[tiab] Location of surgery "Abdomen/surgery"[Mesh] OR "Intestines/surgery"[Mesh] OR "Lower Gastrointestinal Tract/surgery"[Mesh] OR "Upper Gastrointestinal Tract/surgery"[Mesh:NoExp] OR "Duodenum/surgery "[Mesh] OR "Stomach/surgery "[Mesh] OR Abdominal surg*[tiab] OR Abdomen surg*[tiab] OR intestinal surg*[tiab] OR (Lower Gastrointestinal Tract*[tiab] AND surger*[tiab]) OR (Upper Gastrointestinal Tract*[tiab] AND surger*[tiab]) OR Duodenal surg*[tiab] OR Stomach surg*[tiab] OR gastric surg*[tiab] OR "Laparotomy"[Mesh] OR Laparotom*[tiab] OR "Laparoscopy"[Mesh] OR laparoscop*[tiab] Congenital anomaly "Congenital Abnormalities/surgery"[Mesh:NoExp] OR "Abnormalities, Multiple/surgery"[Mesh] OR "Digestive System Abnormalities/ surgery"[Mesh] OR "Hernias, Diaphragmatic, Congenital"[Mesh] OR "Urinary Fistula/congenital"[Mesh] OR "Urachus/surgery"[Mesh] OR "Gastroschisis/surgery"[Mesh] OR "Hernia, Umbilical/surgery"[Mesh] OR "Teratoma/surgery"[Mesh] OR diaphragmatic hernia*[tiab] OR Morgagni*[tiab] OR Bochdalek*[tiab] OR ((imperforated anus[tiab] OR anus atresia[tiab] OR anal atresia*[tiab] OR anorectal malformat*[tiab] OR ano-rectal malformat*[tiab] OR intestinal atresi*[tiab] OR duodenal atresi*[tiab] OR jejunal atresi*[tiab] OR ileal atresi*[tiab] OR colonic atresi*[tiab] OR choledochal cyst*[tiab] OR Hirschsprung*[tiab] OR congenital megacolon*[tiab] OR Meckel*[tiab] OR gastroschis*[tiab] OR omphalocel*[tiab] OR urachus[tiab] OR biliary atresi*[tiab] OR teratoma*[tiab] OR teratoid*[tiab] OR dermoid*[tiab]) AND (surgery[tiab] OR surgical[tiab])) OR intestinal malrotation*[tiab] Post-operative infectious complication "Postoperative Complications"[Mesh:NoExp] OR "Anastomotic Leak"[Mesh] OR "Surgical Wound Dehiscence"[Mesh] OR "Surgical Wound Infection"[Mesh] OR "Surgical Procedures, Operative/ complications"[Mesh:NoExp] OR "Digestive System Surgical Procedures/ complications"[Mesh] OR anastomotic leak*[tiab] OR anastomosis leak*[tiab] OR stenos*[tiab] OR postoperative periton*[tiab] OR postoperative periton*[tiab] OR postoperative fistula*[tiab] OR post-operative fistula*[tiab] OR complication*[tiab] OR infection*[tiab]
27 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants Chapter 2 Figure 1 Flowchart article selection Primary and secondary outcomes Primary outcome was the pooled percentage of the different forms of SSI namely wound infection, wound dehiscence, anastomotic leakage, post-operative peritonitis and fistula development. Definitions used in the articles were followed, no further specification on complication definition was applied. Secondary endpoint was the pooled percentage of SSI per birth defect. These outcomes are presented in separate Forest plots for each
28 Chapter 2 complication. It contains the estimated overall pooled proportion of a complication and the corresponding 95%-CI. If the total case rate of the specific complication was above 50, the pooled proportion and CI per birth defect was showed IF; (1) the complication was reported in at least three studies for the specific birth defect OR (2) if the total number of patients all studies on an birth defect combined was ≥ 100 patients; AND (3) there was at least one event of the complication present within all studies on a specific birth defect. Anomalies that did not met these criteria were reported under the forest plot as residual. These residuals were still included in the calculation of 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. Further 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 birth defect Data extraction Rayyan was used by two independent authors (LES, DN) for title and abstract screening. Rayyan is an online based software facilitating blind screening for reviewers. Disagreements were resolved by discussion. If consensus was not reached a specialist (JD, GM) was consulted. Then, full text of the remaining articles was assessed for inclusion eligibility (LES, DN). Authors were contacted if full texts were not available online. 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. [32] For randomized controlled trials this was done using the Jadad scoring system.[33] The assessment was done by LES and DN separately. Data synthesis For each study, a weighted average of the logit proportions 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 I2 and χ2 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 χ2 statistics were ≥75. Heterogeneity was interpreted as small (I2≤0.25), medium (I2=0.25 – 0.50) or strong (I2≥0.50), according to Higgins.[34]
29 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants Chapter 2 Results Study characteristics We identified 5784 records of which 3909 records were left for title and abstract screening after automated removal of duplicates. Of the 3909 records, 722 were included and assessed for full text. Following full text evaluation 154 studies were included for quantitative analysis (Figure 1). One-hundred-eighteen of these studies were retrospective cohorts, twenty-seven prospective cohorts, five were retrospective multicentre cohort studies, two were randomized controlled trials, one was a retrospective matched case-control study and one was a study that combined a prospective and retrospective cohort. Studies were conducted in 33 different countries. Asian countries were most prominent with 62 studies, European studies represented 36 studies, North- & South-America represented 42 studies, Africa represented 7 studies and the Middle-East also 7 studies. Oceania represented no studies. Of the 154 studies, 75 (48%) reported a follow-up of at least half a year. This systematic review and meta-analysis represents 11,786 patients described in 154 studies (Appendix 2) [35-188]. Among these patients, the congenital conditions were divided as follows: Hirschsprung’s disease (N=3843); gastroschisis (N=2598); anorectal malformations (N=1876); duodenal obstruction (N=1055); small intestinal atresia (N=741); biliary atresia (N=641); congenital diaphragmatic hernia (N=411); omphalocele (N=255); choledochal cyst (N=156); Meckel diverticula (N=46); meconium ileus (N=44); colonic atresia (N=44); teratoma (N=42); malrotation (N=33); duplication cyst (N=1). Risk of bias was assessed and is shown in Appendix 3; most studies reported medium quality.
30 Chapter 2 Appendix 2 – Study characteristics Author Year Journal Country Design *1 Study duration FU > 0.5y Anomaly WI WD AL PoP FD H. Stollman 2008 Journal of Pediatric Surgery Netherlands RCS 1971-2004 No Small intestinal atresia 4 / 110 X 8 / 110 X X C.B. Guo 2010 Transplantation Proceedings China RCS 2006-2009 No Biliary atresia X X X 0 / 22 X J. Zhu 2012 Hepatobiliary Pancreat Dis Int China RCS 2006-2010 Yes Biliary atresia 3 / 43 3 / 43 X X X S. H. Lee 2012 Pediatric Surgery International South Korea RCS 2001-2010 No Small intestinal atresia 1 / 11 X X X X S. G. Cox 2005 Pediatric Surgery International South Africa RCS 1966-2004 Yes Colonic atresia X X 2 / 14 X X A. Bianchi 1998 Journal of Pediatric Surgery United kingdom PCS 1994-1997 Yes Gastroschisis 2 / 14 X X X X S. Festen 2002 Journal of Pediatric surgery Netherlands Multicentre RCS 1980-1992 Yes Small intestinal atresia X X 2 / 14 X X M.A. Escobar 2005 Journal of Pediatric Surgery USA RCS 1972-2004 Yes Hirschsprung's disease 4 / 33 X X X X M. Pacilli 2005 Journal of Pediatric Surgery United kingdom RCS 1997-2004 Yes Omphalocele 5 / 9 5 / 9 X X X L. B. Chirdan 2008 Pediatric Surgery International Nigeria RCS 2001-2004 No ARM 12 / 63 X X X X J. Yan 2017 Biomedical Research China PCS 2011-2014 Yes Hirschsprung's disease 2 / 38 X 0 / 37 X X R. K. Schlueter 2014 Journal of Pediatric Surgery USA RCS 2001-2013 Yes Gastroschisis 11 / 129 X X 1 / 129 X D. Mitanchez 2010 Journal of Pediatric Surgery France RCS 2001-2006 Yes Omphalocele 4 / 14 X X X X A. Mirshemirani 2007 Acta medica Iranica Iran PCS 1993-2003 Yes ARM 3 / 30 0 / 30 X X X A. Dariel 2015 European Journal of Pediatric Surgery Canada RCS 2006-2010 Yes Gastroschisis 30 / 63 X X X X S. MendezMartinez 2016 European Journal of General Medicine Mexico PCS 2008-2013 No Gastroschisis 7 / 42 4 / 42 X 4 / 42 X
31 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants Chapter 2 Author Year Journal Country Design *1 Study duration FU > 0.5y Anomaly WI WD AL PoP FD M. Levy 2017 Ann. Intensive Care France PCS 2009-2015 Yes Congenital diafragmatic hernia 1 / 42 X X X X I. Segal 2013 Journal of Pediatric Surgery Canada RCS 2004-2009 Yes Congenital diafragmatic hernia 2 / 36 X X X X I. Segal 2013 Journal of Pediatric Surgery Canada RCS 2004-2009 No Gastroschisis 8 / 62 X X X X A. Owen 2010 Journal of Pediatric Surgery United kingdom RCS 2006-2008 Yes Gastroschisis 10 / 336 16 / 336 X X X R. Werbeck 2010 Journal of Pediatric Surgery USA RCS 1991-2010 Yes Gastroschisis 0 / 13 X X X X B. Demirogullari 2011 Pediatric Surgery International Turkey RCS 1998-2011 No ARM 5 / 112 1 / 157 X X X S. Li 2017 European Review for Medical and Pharmacological Sciences China RCS 2006-2013 Yes Hirschsprung's disease 0 / 15 X 0 / 15 X X Q. Chen 2014 World J. Pediatric Surgery China RCS 2003-2012 Yes Duodenal obstruction 7 / 287 3 / 287 2 / 287 X X A. Bianchi 1998 Seminars in Pediatric Surgery United kingdom RCS 1984-1997 Yes Hirschsprung's disease 2 / 13 1 / 13 3 / 13 X X G. Mattioli 1998 Journal of Pediatric Surgery Italy RCS 1993-1996 No Hirschsprung's disease 0/8 0/8 0/8 X X D. Teitelbaum 1998 Seminars in Pediatric Surgery USA RCS X Yes Hirschsprung's disease 4 / 24 X X X X S. Demirbilek 1999 Pediatric Surgery International Turkey RCS 1987-1997 Yes ARM 0 / 31 1 / 31 X X X M. Santos 1999 Journal of Pediatric Surgery USA RCS 1988-1999 No Hirschsprung's disease 1 / 65 X 4 / 65 X X S. Hay 2000 Journal of Pediatric Surgery Egypt RCS X No Biliary atresia 3 / 21 X X 1 / 21 X
32 Chapter 2 Author Year Journal Country Design *1 Study duration FU > 0.5y Anomaly WI WD AL PoP FD J. Langer 2000 Journal of Pediatric Surgery USA PCS X No Hirschsprung's disease 4 / 22 X X 4 / 22 X I. Karnak 2000 Pediatric Surgery International Turkey RCS 1977-1998 No Colonic atresia X X 4 / 18 X X E. Mir 2001 Pediatrics International Turkey PCS 1996-2000 No Hirschsprung's disease 4 / 10 2 / 10 X X X N. Patwardhan 2001 Journal of Pediatric Surgery United kingdom RCS 1994-1999 Yes ARM X 3 / 49 X X X S. Namasivayam 2002 Pediatric Surgery International India PCS 1995-2000 Yes Small intestinal atresia X X 3 / 19 X X A. Saxena 2001 Pediatric Surgery International Germany PCS 1984-1998 Yes Gastroschisis 2 / 70 X X X X A. Önen 2003 Pediatric Surgery International Turkey PCS combined with RCS 1990-2000 No Meckel's diverticulum 3 / 34 2 / 34 X X X A. Shah 2003 Journal of Pediatric Surgery India PCS X Yes ARM X 1 / 12 X X X B. Weidner 2003 Journal of Pediatric Surgery USA RCS 1998-2001 No Hirschsprung's disease 0 / 15 X 0 / 15 X X D. Bittencourt 2004 Pediatric Surgery International Brazil PCS 1993-2001 Yes Duodenal obstruction 1 / 23 X X X X M. Escobar 2004 Journal of Pediatric Surgery USA RCS 1972-2001 Yes Duodenal obstruction X X 2 / 169 X X T. Wester 2004 Journal of Pediatric Surgery Finland RCS 2000-2003 No Hirschsprung's disease 0 / 15 X 0 / 15 X X F. Majid 2015 Pakistan Pediatric Journal Pakistan PCS X Yes Duodenal obstruction 2 / 27 X 2 / 27 X X M. Olesevich 2005 Journal of Pediatric Surgery USA RCS 1992-2004 No Gastroschisis 2 / 42 X X X X C. Sauer 2005 Journal of Pediatric Surgery Canada RCS 1999-2003 No Hirschsprung's disease 2 / 24 X X X X S. Zhang 2005 Journal of Pediatric Surgery China RCS 1999 -2002 Yes Hirschsprung's disease X X 0 / 43 X X
33 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants Chapter 2 Author Year Journal Country Design *1 Study duration FU > 0.5y Anomaly WI WD AL PoP FD S. Lee 2006 Journal of Pediatric Surgery USA RCS 1981-2002 Yes Omphalocele 0 / 20 X X X X A. Li 2006 Chinese Medical Journal China RCS 1999-2004 Yes Hirschsprung's disease X X 2 / 252 X X N. Liem 2006 Asian Journal of Surgery Vietnam PCS 2002-2004 Yes Hirschsprung's disease X X 0 / 53 X X R. Lindley 2006 Acta Pediatrica United kingdom RCS 1994-2004 No ARM X 3 / 75 X X X J. Maksoud-Filho 2006 Pediatric Surgery International Brazil RCS 1998-2005 No Gastroschisis 2 / 43 X X X 1 / 43 A. Owen 2006 Journal of Pediatric Surgery United kingdom RCS 1990-2004 No Gastroschisis 9 / 48 X X X X B. Anupama 2007 Journal of Pediatric Surgery China PCS 1996-2005 No Hirschsprung's disease 4 / 25 X 3 / 25 X X G. Aspelund 2007 Journal of Pediatric Surgery Canada RCS 2000-2006 Yes Biliary atresia 1 / 29 X X 1 / 29 X B. Banieghbal 2007 Journal of Pediatric Surgery South Africa PCS 2002-2005 Yes Small intestinal atresia 1 / 16 X X X X S. Dutta 2007 Journal of laparoendoscopy USA RCS 2002-2005 No Biliary atresia 1 / 10 X X X X P. Menon 2007 Journal of Pediatric Surgery India PCS 1997-2005 Yes ARM 5 / 46 0 / 46 X X 0 / 46 K. Riehle 2007 Journal of Pediatric Surgery USA RCS 1993-2004 No Congenital diafragmatic hernia 0 / 46 X X X 0 / 46 M. Stringer 2007 Journal of Pediatric Surgery United kingdom PCS 1994-2006 Yes Biliary atresia X X X X X M. Baglaj 2007 European Journal of Pediatric Surgery United Kingdom RCS 1986-2006 No Small intestinal atresia X X 2 / 26 X X K. Henrich 2007 Pediatric Surgery International Germany PCS 1994-2004 No Omphalocele 4 / 26 X X X X M. Shinall 2008 Journal of Pediatric Surgery USA RCS 1997-2001 No Hirschsprung's disease 5 / 60 X X X X T. Spilde 2008 Journal of Pediatric Surgery USA RCS 2003-2007 No Duodenal obstruction X X 0 / 29 X X
34 Chapter 2 Author Year Journal Country Design *1 Study duration FU > 0.5y Anomaly WI WD AL PoP FD A. Tongsin 2008 Journal of Medical Association of Thailand Thailand RCS 1988-2007 No Small intestinal atresia X X 10 / 142 X X S. Zheng 2008 Pediatric Surgery International China RCS 2004 -2007 No ARM 11 / 38 X X X X M. Dassinger 2009 Pediatric Surgery International USA RCS 1993-2008 No Colonic atresia X X 0 / 12 X X C. Ferreira 2009 Surgical endoscopy France PCS X No Congenital diafragmatic hernia X X X 1 / 30 X D. Gourlay 2008 Journal of Pediatric Surgery USA RCS 1993-2003 Yes Congenital diafragmatic hernia 2 / 38 X X X X M. Hua 2009 Ghang Gung Medical Journal Taiwan RCS 1991-2006 Yes Choledochal cyst 1 / 30 X X X X S. Kay 2009 Journal of Pediatric Surgery USA RCS 2004 -2008 No Duodenal obstruction X X 0 / 19 X X C. Shen 2009 Journal of Pediatric Surgery China RCS 2001 -2008 No Hirschsprung's disease 5 / 29 X 2 / 29 X X A. Gunnarsdottir 2009 Eurpean Journal of pediatric Surgery Sweden PCS 2000-2007 Yes Hirschsprung's disease X 2 / 29 2 / 29 X X L. Hong 2010 European journal of Obstetrics & Gynecology China PCS 2004-2008 Yes Gastroschisis 4 / 17 X X X X Y. Takahashi 2010 Pediatric surgery International Japan PCS 2001-2009 No Duodenal obstruction 1 / 18 X 1 / 18 X X C. de Vos 2011 South African Journal of Science South Africa RCS 2000-2009 Yes ARM 2 / 39 2 / 39 X X X S. Hill 2011 Journal of laparoendoscopy USA RCS 2001-2010 No Duodenal obstruction X X 1 / 58 X X A. Karimi 2011 Pediatric Surgery International Netherlands RCS 1984-2007 No Meconium Ileus 2 / 34 X 5 / 34 X X
35 The incidence of abdominal surgical site infections after abdominal birth defects surgery in infants Chapter 2 Author Year Journal Country Design *1 Study duration FU > 0.5y Anomaly WI WD AL PoP FD Y. Kozlov 2010 European Journal of Surgery Russia RCS 2005 -2009 No Duodenal obstruction 0 / 27 X 0 / 27 X X Q. Na 2011 Journal of International Medical research China PCS 2008-2011 No Omphalocele 1 / 16 X X X X D. van der Zee 2011 World J. Surgery Netherlands RCS 2000-2010 Yes Duodenal obstruction X X 5 / 28 X X B. Li 2012 Pediatric surgery International China RCS 2009-2012 No Small intestinal atresia X X 1 / 35 X X K. Sato 2012 Pediatric surgery International Japan RCS 2005-2011 No Small intestinal atresia 1 / 14 X 2 / 14 X X K. Sato 2012 Pediatric surgery International Japan RCS 2005-2011 No ARM 3 / 13 X X X X M. Diao 2012 Surgical innovation China RCS 2011-2017 No Choledochal cyst 0 / 21 X X X X M. Diao 2012 Surgical innovation China RCS X No Biliary atresia 0 / 11 X X X X N. Ghaffarpour 2013 Journal of Pediatric Surgery Sweden RCS X No Duodenal obstruction 2 / 28 0 / 28 X X X A. Jensen 2013 Journal of laparoendoscopy USA RCS 2005 -2011 No Duodenal obstruction 1 / 66 X X X X K. Chan 2014 Journal of Pediatric Surgery Hong Kong RCS 2002-2013 Yes ARM 0 / 32 0 / 32 X X X M. Diao 2014 International Journal of Surgery China RCS 2011-2013 Yes Choledochal cyst 0 / 27 X X X X M. Diao 2014 Journal of Pediatric Surgery China RCS 2011-2012 Yes ARM 0 / 31 X X X X P. Kuradusenge 2014 East African Medical Journal Kenya PCS 2011-2013 No ARM 3 / 42 2 / 42 X X X A. Ming 2014 Journal of Pediatric Surgery China RCS 1992-2012 Yes ARM 4 / 66 4 / 66 X X X A. Nasr 2014 Journal of Pediatric Surgery Canada MCCS 2000-2010 No Hirschsprung's disease 2 / 54 X 0 / 54 X X
36 Chapter 2 Author Year Journal Country Design *1 Study duration FU > 0.5y Anomaly WI WD AL PoP FD M. Shrestha 2014 Journal Nepal Paediatric Society Nepal PCS 2008 -2013 Yes Hirschsprung's disease X X 0 / 15 0 / 15 X J. Sulkowski 2014 Journal of Pediatric Surgery USA Multicentre RCS 1999-2009 Yes Hirschsprung's disease 65 / 1555 X 65 / 1555 X X H. Versteegh 2014 Journal of Pediatric Surgery Netherlands RCS 1985-2009 Yes ARM X 5 / 12 X X X L. Yang 2014 Journal of Pediatric Surgery China RCS 2011-2013 No ARM 1 / 20 X X X X C. Emami 2015 Journal of Pediatric Surgery Canada RCS 2005 -2011 No Gastroschisis 38 / 344 X X X X X. Shangjie 2014 Cell Biochemical Biophysiology China PCS 2009-2014 No Hirschsprung's disease 22 / 281 X 17 / 281 X X E. Tarca 2015 Chirurgia Romania RCS 1990-2012 No Gastroschisis X X X X X Y. Wang 2015 Pediatrics and Neonatology Taiwan RCS 2009-2011 No Congenital diafragmatic hernia 0 / 25 X X X X O. Almosallam 2016 Ann Saudi Medicine Saudi Arabia RCS 2000-2014 No ARM 7 / 104 X X X 2 / 104 T. Altokhais 2015 American Journal of Perinatology Saudi Arabia RCS 1997-2013 No Congenital diafragmatic hernia X 1 / 11 X X 1 / 11 J. Guerra 2016 Journal of Pediatric Surgery Canada RCS 1995-2014 No Hirschsprung's disease X X 0 / 36 X X W. Jiang 2016 Journal of Pediatric Surgery China RCS 2008-2014 No Omphalocele 5 / 24 X X X X S. Chiarenza 2017 BioMed Research international Italy RCS 2004-2015 Yes Duodenal obstruction X X X X X M. Diao 2017 Surgical endoscopy China RCS 2013-2016 No ARM X 0 / 15 X X X C. Dingemann 2017 European Journal of Pediatric Surgery Germany Multicentre RCS 2007-2012 No Gastroschisis 0 / 39 X X X X
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