A study of the prolonged cholestasis observed in extremely low birth weight infants followed by enterostomy 

A study of the prolonged cholestasis observed in extremely low birth weight infants followed by enterostomy | 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 Research Article A study of the prolonged cholestasis observed in extremely low birth weight infants followed by enterostomy Makoto Matsukubo, Koshiro Sugita, Mitsuru Muto, Keisuke Yano, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5037072/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Dec, 2024 Read the published version in Pediatric Surgery International → Version 1 posted 9 You are reading this latest preprint version Abstract Purpose: Cholestatic liver damage is frequently observed in extremely low-birth-weight infants (ELBWIs), followed by enterostomy. We retrospectively investigated the factors related to liver damage. Methods: ELBWIs who underwent enterostomy at our institution between January 2013 and December 2022 for gastrointestinal disease during the neonatal period were reviewed. Cases presenting with direct bilirubin >2.0 mg/dl for >1 month after enterostomy were designated as the prolonged cholestatic liver (p-CL) group and compared with cases without cholestatic liver damage, the (non-CL )group. Results: Thirty-nine patients (21 in the p-CL group and 18 in the non-CL group) were included. Survival was significantly lower in the p-CL group (52.4% [11/21] vs. 88.9% [16/18]; p =0.020). Significant differences were found in the birth weight (587.8 g vs. 698.0 g, p =0.040) and small intestinal length to the enterostomy (47.6 cm vs. 72.8 cm, p =0.004). Patients in the non-CL group started enteral feeding and reached >100 ml/kg/day earlier than those in the p-CL group. There was no difference in the incidence of catheter-related bloodstream infections between the two groups( p =0.280). Conclusion : Modest differences in the birth weight and stoma site level may affect enteral feeding management and subsequently result in prolonged cholestatic liver damage in ELBWIs with high prematurity. prolonged cholestasis enterostomy extremely low birth weight infants prematurity Figures Figure 1 1. Introduction In gastrointestinal events occurring in extremely low birth weight infants (ELBWIs), creating an enterostomy is frequently selected due to the uncertainty of performing one-stage radical surgery. These cases may have prolonged cholestatic liver damage, similar to that observed in intestinal failure-associated liver disease (IFALD) or parenteral nutrition-associated liver disease (PNALD). Sometimes, such damage will continue for several months until the closure of the enterostomy. During this period, a decreased intestinal absorption capacity, immature bile secretion mechanism, effects of the tube feeding suspension period, and supplementary parenteral nutrition (PN) may contribute to the development of prolonged cholestasis [ 1 – 4 ]. The risk of prolonged cholestasis following enterostomy of ELBWIs may be reduced by improving the enterohepatic circulation and reducing PN dependence by closing the enterostomy and thereby recovering the continuity of the intestine, but it can also sometimes progress to cirrhosis complicated with portal hypertension, thus leading to a need to undergo liver transplantation [ 1 , 3 ]. Therefore, it is important to recognize the factors that affect the prolonged cholestasis seen in ELBWIs followed by enterostomy and to help prevent it, while also treating it appropriately. The aim of the present study was to clarify the factors associated with liver damage in ELBWIs who underwent enterostomy by comparing the prolonged cholestatic liver (p-CL) group and the without cholestatic liver damage (non-CL) group. 2. Patients and Methods 2.1 Study design ELBWIs who underwent enterostomy due to gastrointestinal events, such as necrotizing enterocolitis (NEC), focal intestinal perforation (FIP), meconium-related ileus (MRI), intestinal atresia (IA), and intussusception, and required PN support for > 14 days during the 10-year period from January 2013 to December 2022. Cases showing direct bilirubin > 2.0 mg/dl for > 1 month were defined as having prolonged cholestasis. Patients with prolonged cholestasis induced by congenital metabolic anomalies and neonatal hepatitis were excluded from the present study. Data on the patient’s profiles [sex, gestational age (GA), birth weight, with or without congenital heart diseases (excluding patent ductus arteriosus), gastrointestinal diseases, age at enterostomy, intestinal length from the ligament of Treitz to the enterostomy, median of direct-bilirubin (mg/dl), with or without closure of enterostomy, status at time of discharge, observation period [from neonatal intensive care unit (NICU) admission to discharge)], data on perioperative blood test [white blood count (WBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct-bilirubin, C-reactive protein (CRP), potential of Hydrogen (pH), Lactate], fasting time, time taken for enteral nutrition EN exceeding 100 ml/kg /day, with or without catheters-related blood stream infection (CRBSI), frequency of the red blood cell (RBC), fresh frozen plasma (FFP), and platelet concentrate (PC) transfusion, with or without postoperative complications (Clavien-Dindo classification > 2) regarding surgical intervention and prognosis were all retrospectively investigated. 2.2 Statistical analysis Statistical comparisons were made between the p-CL and non-CL groups. Student’s t -test, χ 2 test, log-rank test, and a Poisson regression analysis were performed. Additionally, a multivariate analysis was performed using the Cox proportional hazards regression and modified Poisson regression to identify any significant differences. These analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Statistical values of < 0.05 were considered to be significant. Data are shown as the mean ± standard deviation or median. 2.3 Ethical concern This study was performed in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Health, Labour, and Welfare of Japan in 2014. This study complied with the 1964 Declaration of Helsinki (revised in 2013) and was approved by the local ethics committee of our institution (registration number: 2023-02). Informed consent was obtained from all participants or their parents involved in this study. 3. Results 3.1 Patients’ background and characteristics before enterostomy Table 1 shown the patients’ background characteristics before enterostomy. The number of cases was 39 and they were divided into two groups as follows: 21 (53.8%) patients with prolonged cholestasis were classified as the p-CL group and 18 patients (46.1%) with non-prolonged cholestasis were classified as the non-CL group. As a result, 8 patients had NEC (20.5%), 20 patients had FIP (51.3%), 6 patients had MRI (15.4%), 2 patients had IA (5.1%), and 4 patients had intussusception (10.2%). IP was significantly more frequently observed in the non-CL group than in the p-CL group ( p =0.001). The birth weight of the p-CL group was significantly lower than that of the non-CL group ( p =0.04). There were no significant differences in sex ( p =0.75), GA ( p =0.94), congenital heart disease ( p =1.0), WBC ( p =0.11), AST ( p =0.14), ALT ( p =0.06), direct bilirubin ( p =0.31), CRP ( p =0.75), pH ( p =0.47), or lactate ( p =0.25) between the p-CL and non-CL groups. 3.2 Patients’ background and characteristics followed by enterostomy Table 2 shown the patients’ background characteristics followed by enterostomy. The mean age at enterostomy in the p-CL group (11.4 ± 7.7 days) was higher than that in the non-CL group (7.6 ± 5.2 days), but the difference was not significant ( p =0.07). The intestinal length from the ligament of Treitz to the enterostomy in the p-CL group was significantly shorter than that in the non-CL group (47.6 ± 32.0 vs.72.8 ± 18.2 cm, p =0.004). The median of direct-bilirubin after enterostomy in the p-CL group was significantly higher than that in the non-CL group (3.58 ± 3.28 vs.0.38 ± 0.33 mg/dl, p =0.01). Furthermore, the proportion of patients without a closure of the enterostomy in the p-CL group was significantly higher than that in the non-CL group (9/21 vs. 2/18, p =0.04). The proportion of patients who died at the time of discharge in p-CL group was significantly higher than in the non-CL group (10/21 vs. 2/18, p =0.02). The cause of death in the p-CL group included 3 patients with circulatory failure, 2 patients with sepsis, 2 patients with disseminated intravascular coagulation (DIC), 1 patient with pulmonary hypertension, 1 patient with heart failure, and 1 patient with intestinal failure associated with liver disease caused by short bowel syndrome (SBS) due to NEC. The causes of death in the non-CL group included one patient with pulmonary hypertension and one patient with pulmonary hypertension. There were no significant differences in the observation period between the p-CL and non-CL groups (187.1 ± 140.0 vs.190.0 ± 135.6 days, p =0.95) Figure 1 shown the cumulative survival rate between non-CL group and p-CL group. The cumulative survival rate in the p-CL group (32.4%) was significantly lower than that in the non-CL group (90.5%) ( p =0.01). 3.3 Risk analysis regarding the fasting period and the length of time that EN was carried out exceeding 100ml/kg /day The fasting period in the non-CL group (median 6.0 days, 95% confidence interval 5.0-9.0 days) was significantly shorter than that in the p-CL group (median 11.5 days, 95% confidence interval 6.0-12.0 days) ( p =0.006). The length of time that EN was performed exceeding 100 ml/kg /day in the non CL group (median 23.0 days, 95% confidence interval 19.0-26.0 days) was significantly shorter than that in the p-CL group (median 35.5 days, 95% confidence interval 35.5-NA days) ( p =0.006). Table 3 shows the Cox proportional hazards regression regarding the fasting period and the length of time that EN was performed exceeding 100 ml/kg /day adjusted for the birth weight and the intestinal length from the ligament of Treitz. The fasting period was not an independent risk factor for prolonged cholestasis. The p-CL group was found to be at risk of delaying the time taken to start EN compared with the non-CL group (hazard ratio 0.528, p =0.12). The time taken for EN to exceed 100 ml/kg /day showed similar results (Hazard ratio 0.547, p =0.19). 3.4 Result of the analysis regarding postoperative complications, CRBSI, and blood transfusion following enterostomy There were no significant differences in postoperative complications (estimate -0.60, standard error 1.06, p =0.57), CRBSI (estimate 0.82, standard error 0.76, p =0.28), or RBC transfusion frequency (estimate -0.16, standard error 0.20, p =0.41) between the non-CL and p-CL groups. The frequency of FFP transfusion in the p-CL group was significantly higher than that in the non-CL group (Estimate -0.418, standard error 0.188, p <0.001). PC transfusions in the p-CL group were significantly more frequent than those in the non-CL group (Estimate 0.576, standard error 0.261, p <0.027). 3.5. Risk analysis regarding prolonged cholestasis Table 4 shows the Modified Poisson regression of PC and FFP transfusion adjusted for birth weight and intestinal length from the ligament of Treitz to the enterostomy. FFP transfusion was not an independent risk factor for prolonged cholestasis and it had only a small influence as a risk factor (relative risk 0.974, p =0.06). In addition, PC transfusion had similar results (relative risk 0.974, p =0.06). 4. Discussion This study retrospectively investigated prolonged cholestasis in ELBWIs followed by enterostomies at our institution. This study aimed to clarify the causative factors of prolonged cholestasis in ELBWIs followed by enterostomy by comparing the patient backgrounds, EN status following enterostomy, postoperative complications, CRBSI, and frequency of blood transfusions. The major findings of this study were as follows: (1) the cumulative survival rate of the p-CL group was significantly lower than that of the non-CL group; (2) the birth weight of the p-CL group was significantly smaller than that of the non-CL group; (3) the intestinal length from the ligaments of Treitz to the enterostomy of the p-CL group was significantly shorter than that of the non-CL group; (4) the fasting time of the p-CL group was significantly longer than that of the non-CL group, and the length of that that EN was performed exceeding 100 ml/kg/day in the p-CL group was significantly longer than that in the non-CL group. However, neither were independent risk factors; (5) blood (FFP, PC) transfusion in the p-CL group was significantly more frequent than that in the non-CL group. These were not independent risk factors, and their influence as risk factors for prolonged cholestasis was weak. In the present study, the mortality rate of ELBWIs followed by enterostomy (30.8%) was lower than that reported in cases of gastrointestinal perforation requiring surgery in ELBWIs in Japan (41.1%) [ 4 ]. However, the survival rate was found to be significantly higher in the p-CL group than in the non-CL group. Although there was only one case of liver failure in which prolonged cholestasis was directly related to death, circulatory failure, sepsis, and DIC may have been indirectly involved. Prolonged cholestasis followed by enterostomy may contribute to multiple causes of death; therefore, its prevention and treatment may improve the survival rates. Stratification according to gastrointestinal disease showed that patients with FIP were less likely to develop prolonged cholestasis ( p = 0.001). This is thought to be because the intestinal barrier function is maintained and systemic infections are less likely to occur compared to NEC [ 5 , 6 ]. As an example of how an immature liver function contributes to prolonged cholestasis, a study reported that a birth weight 750 g in patients receiving PN for > 14 days and surviving > 28 days [ 7 ]. Cholestasis developed in 50 percent of those with a birth weight 1500–2000 g [ 8 ]. Even in the ELBWIs followed by enterostomy, the birth weight of the p-CL group was significantly lower, thus suggesting that an immature liver function is involved in the development of prolonged cholestasis. After creating an enterostomy, the available length of the intestine for EN is reduced, and EN alone is no longer able to support the patient's survival and growth, thus resulting in a pathology similar to SBS [ 3 ]. This makes it easier to develop prolonged cholestasis owing to the requirement of PN support for > 14 days [ 9 , 10 ]. The definition of SBS in newborns is not consistent in the literature, but one definition according to the Italian Society of Neonatology is that the residual intestinal length is less than 25% of the predicted length for GA [ 10 ]. It has also been reported that in a multivariate analysis related to the onset of SBS, a residual intestinal length of less than 50% of the original length was found to be independently significant [ 9 ]. Recent studies have shown that the intestinal length in normal infants is between 150 and 250 cm, but in this study, that of ELBWI at 22 to 28 weeks of GA is approximately 70 to 120 cm [ 11 ]. Based on these considerations, when it appears that EN support will be insufficient with the proximal intestine alone, alternative methods such as the practice of mucous fistula refeeding must be taken [ 12 ], such as the introduction of santulli enterostomy to maintain continuity with the distal intestinal tract [ 13 ]. Starting enteral feeding to prevent IFALD induced by IF, including SBS, is an important decision, and minimal enteral feeding should be started as soon as possible, and it should be administered aggressively to promote maximal bowel adaptation [ 14 ]. The early initiation of enteral feeding can shorten the time to full initiate feeding, reduce the dependence on PN, and reduce the incidence of CRBSI [ 14 , 15 ]. The establishment of EN should also be considered, depending on the patient's condition. Trans-pyloric feeding can be performed in patients with inadequate gastric emptying. Richardson et al. investigated a method of resupplying proximal enterostomy effluent to distal enterostomy and reported an improved weight gain [ 12 , 15 ]. However, vomiting more than three times per day or exceeding 20% of the daily enteral intake or stool volumes of > 20 mL/kg/day is likely to indicate that the amount of food cannot be sufficiently tolerated and caution is therefore required [ 14 ]. In this study, the length of time that EN was performed and the length of time that EN was performed exceeding 100 ml/kg/day was significantly lower in the non-CL group than in the p-CL group, but the difference was not significant according to a multivariate analysis adjusted for birth weight and intestinal length from the ligament of Treitz to the enterostomy. Therefore, the birth weight and intestinal length from the ligament of Treitz to the enterostomy were not independent risk factors However, both hazard ratios were low, thus indicating that they are strong risk reduction factors for prolonged cholestasis in ELBWIs followed by enterostomy. This findings of this study suggest that FFP and PC transfusions may be slightly more frequent in the p-CL group than in the non-CL group, but no previous study in the literature was found to support this as a risk factor. On the other hand, there are reports that blood transfusion for preterm infants with various comorbid illnesses such as sepsis, respiratory distress syndrome, NEC, PDA, intraventricular hemorrhage, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and anemia of prematurity was higher in infants who were < 28 weeks and 1000 g, and that the number of transfusions has been reported to be related to the incidence of NEC [ 16 , 17 ]. These comorbidities may be involved in the frequency of blood transfusions and prolonged cholestasis observed in this study; however, further investigation is required. 5. Limitation This study was a retrospective analysis, with a small number of enrolled patients and a variety of underlying diseases. Therefore, the accuracy of the multivariate analysis are not considered to be definitive. In addition, the treatment for prolonged cholestasis following enterostomy was not evaluated in this study. 6. Conclusion In this study, we retrospectively investigated the causes of prolonged cholestasis in ELBWIs followed by enterostomy at our institution. We therefore understood that modest differences in the birth weight and stoma site level may affect enteral feeding management and subsequently result in prolonged cholestasis liver damage in ELBWIs with high prematurity. Declarations Acknowledgements This study was supported by Kagoshima City Hospital Neonatal Intensive Care Unit. We thank Brian Quinn for his comments and assistance with this manuscript. Authors’ Contributions MM, KS, AN, and MM designed this study. MM, SO, KT, KY, TH, MT, and KS analyzed the data and created the Figure. TK, MM, YA, OH, YA, HA, NY, TT, and TK provided the conceptual advice. MM wrote the manuscript in consultation with MM and SI. Corresponding author: Satoshi IEIRI, M.D., Ph.D., F.A.C.S. Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University 8-35-1, Sakuragaoka, Kagoshima City, 8900075, JAPAN Tel: +81-99-275-5444, Fax: +81-99-275-2628, E-mail: [email protected] Conflict of interest The authors declare no conflicts of interest in association with the present study. References Di Dato F, Iorio R, Spagnuolo MI (2022) IFALD in children: What's new? A narrative review. Front Nutr https//. 10.3389/fnut.2022.928371 Khalaf RT, Ford SL (2022) Intestinal failure-associated liver disease in the neonatal ICU: what we know and where we're going. Curr Opin Pediatr 34:184–190. https//doi:10.1097/MOP.0000000000001105 Lee WS, Chew KS, Ng RT, Kasmi KE, Sokol RJ (2020) Intestinal failure-associated liver disease (IFALD): insights into pathogenesis and advances in management. Hepatol Int 14:305–316. https//doi:10.1007/s12072-020-10048-8 Sato M, Hamada Y, Kohno M, Ise K, Uchida K, Ogata H, Masuyama H, Morotomi Y, Yasufuku M, Wada M (2017) Neonatal gastrointestinal perforation in Japan: a nationwide survey. Pediatr Surg Int 33:33–41. https//doi:10.1007/s00383-016-3985-z Karila K, Anttila A, Iber T, Pakarinen M, Koivusalo A (2019) Intestinal failure associated cholestasis in surgical necrotizing enterocolitis and spontaneous intestinal perforation. J Pediatr Surg 54:460–464. http//doi:10.1016/j.jpedsurg.2018.10.043 Mutanen A, Pöntinen V, Gunnar R, Merras-Salmio L, Pakarinen MP (2022) Efficient achievement of enteral autonomy facilitates resolution of liver injury in necrotizing enterocolitis induced short bowel syndrome. Sci Rep 12. htto//doi:10.1038/s41598-022-22414-7 Christensen RD, Henry E, Wiedmeier SE, Burnett J, Lambert DK (2007) Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease. J Perinatol 27:284–290. http//doi:10.1038/sj.jp.7211686 Beale EF, Nelson RM, Bucciarelli RL, Donnelly WH, Eitzman DV (1979) Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics 64:342–347 Wales PW, de Silva N, Kim JH, Lecce L, Sandhu A, Moore AM (2005) Neonatal short bowel syndrome: a cohort study. J Pediatr Surg 40:755–762. http//doi:10.1016/j.jpedsurg.2005.01.037 Caporilli C, Giannì G, Grassi F, Esposito S (2023) An Overview of Short-Bowel Syndrome in Pediatric Patients: Focus on Clinical Management and Prevention of Complications. Nutrients 15. http//doi:10.3390/nu15102341 Struijs MC, Diamond IR, de Silva N, Wales PW (2009) Establishing norms for intestinal length in children. J Pediatr Surg 44:933–938. http//doi:10.1016/j.jpedsurg.2009.01.031 Richardson L, Banerjee S, Rabe H (2006) What is the evidence on the practice of mucous fistula refeeding in neonates with short bowel syndrome? J Pediatr Gastroenterol Nutr 43:67–70. http//doi:10.1097/01.mpg.0000228111.21735.02 Yue M, Yang H, Cui M, Yuan Y, Zhang N, Zhang X, Li Y (2023) The safety and effectiveness of Santulli enterostomy in neonatal intestinal conditions. Front Pediatr 10. http//doi:10.3389/fped.2022.1077346 Muto M, Kaji T, Onishi S, Yano K, Yamada W, Ieiri S (2022) An overview of the current management of short-bowel syndrome in pediatric patients. Surg Today 52:12–21. http//doi:10.1007/s00595-020-02207-z Wessel JJ, Kocoshis SA (2007) Nutritional management of infants with short bowel syndrome. Semin Perinatol 31:104–111. http//doi:10.1053/j.semperi.2007.02.009 Brubaker DB (1993) Immunopathogenic mechanisms of posttransfusion graft-vs-host disease. Proc Soc Exp Biol Med 202:122–147. http//doi:10.3181/00379727-202-43519b Garg PM, Ravisankar S, Bian H, Macgilvray S, Shekhawat PS (2015) Relationship between Packed Red Blood Cell Transfusion and Severe Form of Necrotizing Enterocolitis: A Case Control Study. Indian Pediatr 52:1041–1045. http//doi:10.1007/s13312-015-0770-3 Tables Table 1 Patients’ background characteristics before enterostomy p-CL group (n = 21) non-CL group (n = 18) p value Underlying disease NEC (5) FIP (5) MRI (3) Intussusception (2) IA (2) NEC (2) FIP (14) MRI (3) Intussusception (2) 0.42 0.001 0.59 0.64 0.49 Gestational age (week) 25.2 ± 2.3 25.2 ± 1.7 0.94 Sex (male: female) 10: 8 13: 8 0.75 Birth weight (g) 587.8 ± 157.6 698.0 ± 158.7 0.04 Congenital heart disease (with: without) 2: 16 2: 19 1.0 WBC (/ul) 10661.1 ± 8744.2 16790.5 ± 13487.2 0.11 AST (U/l) 56.9 ± 63.8 34.8 ± 18.5 0.14 ALT (U/l) 14.4 ± 22.3 4.5 ± 2.2 0.06 Direct-bilirubin (mg/dl) 0.72 ± 0.50 0.56 ± 0.48 0.31 CRP (mg/dl) 1.06 ± 1.9 0.80 ± 2.88 0.75 pH 7.29 ± 0.09 7.32 ± 0.09 0.47 Lactate (mmol/L) 3.0 ± 2.5 2.2 ± 1.5 0.25 Data are expressed as the mean ± SD NEC: necrotizing enterocolitis; FIP: focal intestinal perforation; MRI: meconium related ileus; IA: intestinal atresia Table 2 Patients’ background characteristics after enterostomy p-CL group (n = 21) non-CL group (n = 18) p -value Age at enterostomy (days) 11.4 ± 7.7 7.6 ± 5.2 0.07 Intestinal length from the ligament of Treitz to the enterostomy (cm) 47.6 ± 32.0 72.8 ± 18.2 0.004 Median of direct-bilirubin (mg/dl) followed by enterostomy 3.58 ± 3.28 0.38 ± 0.33 0.01 Closure of enterostomy (with: without) 12: 9 16: 2 0.04 Status at discharge (alive: dead) 11: 10 16: 2 0.02 Cause of death Circulatory failure 3 1 Sepsis 2 DIC 2 Heart failure 1 Pulmonary hypertension 1 1 IFALD induced by SBS 1 Observation period (days) 187.1 ± 140.0 190.0 ± 135.6 0.95 Data shown as the mean ± SD DIC: disseminated intravascular coagulation; IFALD: intestinal failure associated with liver disease; SBS: short bowel syndrome Table 3 Risk analysis regarding the fasting period and the length of time that EN was carried out exceeding 100ml/kg /day Hazard ratio 95% confidence interval p -value a) Fasting period (days) Prolonged cholestasis (without: with) 0.528 0.234–1.188 0.12 Birth weight (g) 1.002 1.002–1.005 0.04 Intestinal length from the ligament of Treitz to the enterostomy (cm) 1.009 0.996–1.021 0.17 b) Time taken EN exceeding 100ml/kg /day (days) Prolonged cholestasis (without: with) 0.547 0.222–1.352 0.19 Birth weight (g) 1.001 0.998–1.003 0.39 Intestinal length from the ligament of Treitz to the enterostomy (cm) 1.014 0.999–1.030 0.07 EN: enteral nutrition Table 4 Risk analysis regarding prolonged cholesistasis Relative risk Standard error 95% confidence interval p -value a) Prolonged cholestasis (without: with) FFP transfusion (number of time) 0.947 0.029 0.894–1.003 0.06 Birth weight (g) 0.998 0.001 0.997-1.000 0.05 Intestinal length from the ligament of Treitz to the enterostomy (cm) 0.987 0.005 0.978–0.996 0.006 b) Prolonged cholestasis (without: with) PC transfusion (number of time) 0.990 0.036 0.036–0.922 0.77 Birth weight (g) 0.999 0.001 0.997–1.001 0.26 Intestinal length from the ligament of Treitz to the enterostomy (cm) 0.989 0.005 0.979-1.000 0.004 FFP: fresh frozen plasma; PC: platelet concentrate Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 20 Dec, 2024 Read the published version in Pediatric Surgery International → Version 1 posted Editorial decision: Revision requested 09 Oct, 2024 Reviews received at journal 08 Oct, 2024 Reviews received at journal 29 Sep, 2024 Reviewers agreed at journal 29 Sep, 2024 Reviewers agreed at journal 27 Sep, 2024 Reviewers invited by journal 27 Sep, 2024 Editor assigned by journal 08 Sep, 2024 Submission checks completed at journal 06 Sep, 2024 First submitted to journal 05 Sep, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5037072","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":364016830,"identity":"70e97b09-c38c-49c0-80f6-3658360f321f","order_by":0,"name":"Makoto Matsukubo","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Makoto","middleName":"","lastName":"Matsukubo","suffix":""},{"id":364016831,"identity":"c7b35e6b-f8fb-409b-ab13-2b40baa2bbbd","order_by":1,"name":"Koshiro Sugita","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Koshiro","middleName":"","lastName":"Sugita","suffix":""},{"id":364016834,"identity":"5dc8ce1a-3a2e-4b88-b3ec-b30602c841ea","order_by":2,"name":"Mitsuru Muto","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Mitsuru","middleName":"","lastName":"Muto","suffix":""},{"id":364016836,"identity":"9ccc1371-7afa-43ae-97b5-03e55ea45f32","order_by":3,"name":"Keisuke Yano","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Keisuke","middleName":"","lastName":"Yano","suffix":""},{"id":364016840,"identity":"946eb57d-35bd-4352-a49c-f3f278c0c2b4","order_by":4,"name":"Toshio Harumatsu","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Harumatsu","suffix":""},{"id":364016844,"identity":"edefa6b9-fd23-4403-8193-5e4d8f181d83","order_by":5,"name":"Tomonori Kurimoto","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomonori","middleName":"","lastName":"Kurimoto","suffix":""},{"id":364016845,"identity":"48c29a02-44ef-4d5d-9639-572073bbd173","order_by":6,"name":"Masaya Kibe","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masaya","middleName":"","lastName":"Kibe","suffix":""},{"id":364016846,"identity":"94633b39-13d5-4ace-bf17-d28632074172","order_by":7,"name":"Asataro Yara","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Asataro","middleName":"","lastName":"Yara","suffix":""},{"id":364016847,"identity":"8a641a18-d085-45a4-bcf2-8972a977e950","order_by":8,"name":"Hiroshi Ohashi","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Ohashi","suffix":""},{"id":364016848,"identity":"38de3c10-1145-4737-adfc-a2e581f23f0e","order_by":9,"name":"Tsuyoshi Yamamoto","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tsuyoshi","middleName":"","lastName":"Yamamoto","suffix":""},{"id":364016849,"identity":"b8049a9c-d056-4433-86db-a25244e30675","order_by":10,"name":"Eiji Hirakawa","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eiji","middleName":"","lastName":"Hirakawa","suffix":""},{"id":364016850,"identity":"fd927410-65bf-4cc3-bcd0-23437d090f35","order_by":11,"name":"Yoshiki Naito","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoshiki","middleName":"","lastName":"Naito","suffix":""},{"id":364016851,"identity":"a21aaf2b-07e2-41ff-829a-57e07d2978ad","order_by":12,"name":"Ayaka Nagano","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Ayaka","middleName":"","lastName":"Nagano","suffix":""},{"id":364016852,"identity":"4c98fc55-f953-4c36-a8df-71c15a204a0b","order_by":13,"name":"Masakazu Murakami","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Masakazu","middleName":"","lastName":"Murakami","suffix":""},{"id":364016853,"identity":"45b26aa9-6172-4408-8503-b70d7847d4a6","order_by":14,"name":"Shun Onishi","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Shun","middleName":"","lastName":"Onishi","suffix":""},{"id":364016854,"identity":"8b8c422e-7e7c-4456-8fe2-69da57e0ac10","order_by":15,"name":"Takafumi Kawano","email":"","orcid":"","institution":"Kagoshima University","correspondingAuthor":false,"prefix":"","firstName":"Takafumi","middleName":"","lastName":"Kawano","suffix":""},{"id":364016855,"identity":"96aaf3d0-72db-4002-8c85-dd83d036b7f4","order_by":16,"name":"Motofumi Torikai","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Motofumi","middleName":"","lastName":"Torikai","suffix":""},{"id":364016856,"identity":"a73b82c9-a88c-4b0a-a8b8-10ccaca00731","order_by":17,"name":"Takuya Tokuhisa","email":"","orcid":"","institution":"Kagoshima City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takuya","middleName":"","lastName":"Tokuhisa","suffix":""},{"id":364016857,"identity":"85d9e90e-c170-45d1-b7ee-0469c9e9760b","order_by":18,"name":"Satoshi Ieiri","email":"data:image/png;base64,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","orcid":"","institution":"Kagoshima University","correspondingAuthor":true,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Ieiri","suffix":""}],"badges":[],"createdAt":"2024-09-05 09:37:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5037072/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5037072/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00383-024-05946-z","type":"published","date":"2024-12-20T15:58:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":67196862,"identity":"840ce719-8d4c-4683-abb2-f3127b9ca196","added_by":"auto","created_at":"2024-10-22 09:15:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":29192,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA Kaplan-Meier plot and log-rank test analysis of the cumulative survival rates in groups stratified by cholestasis prolongation in ELBWIs with enterostomy.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe observation period was from neonatal intensive care unit (NICU) admission to discharge and was censored at death.\u003c/p\u003e","description":"","filename":"4Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5037072/v1/bd988cfc5afd624d7f308fc8.png"},{"id":72202667,"identity":"bbd921e0-6a6a-44b7-bf10-73a1af71d3ff","added_by":"auto","created_at":"2024-12-23 16:15:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":731215,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5037072/v1/b9a3fb01-9e19-4145-b33a-5ddbd3aa97d0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A study of the prolonged cholestasis observed in extremely low birth weight infants followed by enterostomy ","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eIn gastrointestinal events occurring in extremely low birth weight infants (ELBWIs), creating an enterostomy is frequently selected due to the uncertainty of performing one-stage radical surgery.\u003c/p\u003e \u003cp\u003eThese cases may have prolonged cholestatic liver damage, similar to that observed in intestinal failure-associated liver disease (IFALD) or parenteral nutrition-associated liver disease (PNALD). Sometimes, such damage will continue for several months until the closure of the enterostomy. During this period, a decreased intestinal absorption capacity, immature bile secretion mechanism, effects of the tube feeding suspension period, and supplementary parenteral nutrition (PN) may contribute to the development of prolonged cholestasis [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The risk of prolonged cholestasis following enterostomy of ELBWIs may be reduced by improving the enterohepatic circulation and reducing PN dependence by closing the enterostomy and thereby recovering the continuity of the intestine, but it can also sometimes progress to cirrhosis complicated with portal hypertension, thus leading to a need to undergo liver transplantation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Therefore, it is important to recognize the factors that affect the prolonged cholestasis seen in ELBWIs followed by enterostomy and to help prevent it, while also treating it appropriately.\u003c/p\u003e \u003cp\u003eThe aim of the present study was to clarify the factors associated with liver damage in ELBWIs who underwent enterostomy by comparing the prolonged cholestatic liver (p-CL) group and the without cholestatic liver damage (non-CL) group.\u003c/p\u003e"},{"header":"2. Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design\u003c/h2\u003e \u003cp\u003eELBWIs who underwent enterostomy due to gastrointestinal events, such as necrotizing enterocolitis (NEC), focal intestinal perforation (FIP), meconium-related ileus (MRI), intestinal atresia (IA), and intussusception, and required PN support for \u0026gt;\u0026thinsp;14 days during the 10-year period from January 2013 to December 2022. Cases showing direct bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;2.0 mg/dl for \u0026gt;\u0026thinsp;1 month were defined as having prolonged cholestasis. Patients with prolonged cholestasis induced by congenital metabolic anomalies and neonatal hepatitis were excluded from the present study.\u003c/p\u003e \u003cp\u003eData on the patient\u0026rsquo;s profiles [sex, gestational age (GA), birth weight, with or without congenital heart diseases (excluding patent ductus arteriosus), gastrointestinal diseases, age at enterostomy, intestinal length from the ligament of Treitz to the enterostomy, median of direct-bilirubin (mg/dl), with or without closure of enterostomy, status at time of discharge, observation period [from neonatal intensive care unit (NICU) admission to discharge)], data on perioperative blood test [white blood count (WBC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), direct-bilirubin, C-reactive protein (CRP), potential of Hydrogen (pH), Lactate], fasting time, time taken for enteral nutrition EN exceeding 100 ml/kg /day, with or without catheters-related blood stream infection (CRBSI), frequency of the red blood cell (RBC), fresh frozen plasma (FFP), and platelet concentrate (PC) transfusion, with or without postoperative complications (Clavien-Dindo classification\u0026thinsp;\u0026gt;\u0026thinsp;2) regarding surgical intervention and prognosis were all retrospectively investigated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Statistical analysis\u003c/h2\u003e \u003cp\u003eStatistical comparisons were made between the p-CL and non-CL groups. Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test, χ\u003csup\u003e2\u003c/sup\u003e test, log-rank test, and a Poisson regression analysis were performed. Additionally, a multivariate analysis was performed using the Cox proportional hazards regression and modified Poisson regression to identify any significant differences. These analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). Statistical values of \u0026lt;\u0026thinsp;0.05 were considered to be significant. Data are shown as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Ethical concern\u003c/h2\u003e \u003cp\u003e This study was performed in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Health, Labour, and Welfare of Japan in 2014.\u003c/p\u003e \u003cp\u003e This study complied with the 1964 Declaration of Helsinki (revised in 2013) and was approved by the local ethics committee of our institution (registration number: 2023-02). Informed consent was obtained from all participants or their parents involved in this study.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003e3.1 Patients\u0026rsquo; background and characteristics before enterostomy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 shown the patients\u0026rsquo; background characteristics before enterostomy. The number of cases was 39 and they were divided into two groups as follows: 21 (53.8%) patients with prolonged cholestasis were classified as the p-CL group and 18 patients (46.1%) with non-prolonged cholestasis were classified as the non-CL group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs a result, 8 patients had NEC (20.5%), 20 patients had FIP (51.3%), 6 patients had MRI (15.4%), 2 patients had IA (5.1%),\u0026nbsp;and 4 patients had\u0026nbsp;intussusception (10.2%). IP was significantly more frequently observed in\u0026nbsp;the\u0026nbsp;non-CL group than in\u0026nbsp;the p-CL group\u0026nbsp;(\u003cem\u003ep\u003c/em\u003e=0.001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe birth weight of the p-CL group was significantly lower than that of\u0026nbsp;the\u0026nbsp;non-CL group (\u003cem\u003ep\u003c/em\u003e=0.04). There were no significant differences in sex (\u003cem\u003ep\u003c/em\u003e=0.75), GA (\u003cem\u003ep\u003c/em\u003e=0.94), congenital heart disease (\u003cem\u003ep\u003c/em\u003e=1.0), WBC (\u003cem\u003ep\u003c/em\u003e=0.11), AST (\u003cem\u003ep\u003c/em\u003e=0.14), ALT (\u003cem\u003ep\u003c/em\u003e=0.06), direct bilirubin (\u003cem\u003ep\u003c/em\u003e=0.31), CRP (\u003cem\u003ep\u003c/em\u003e=0.75), pH (\u003cem\u003ep\u003c/em\u003e=0.47),\u0026nbsp;or\u0026nbsp;lactate (\u003cem\u003ep\u003c/em\u003e=0.25) between the p-CL and non-CL groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003e3.2 Patients\u0026rsquo; background and characteristics followed by enterostomy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 shown the patients\u0026rsquo; background characteristics followed by enterostomy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;mean age\u0026nbsp;at enterostomy in\u0026nbsp;the p-CL group (11.4 \u0026plusmn; 7.7 days)\u0026nbsp;was higher than that in\u0026nbsp;the non-CL group (7.6 \u0026plusmn; 5.2 days), but the\u0026nbsp;difference was not significant\u0026nbsp;(\u003cem\u003ep\u003c/em\u003e=0.07). The intestinal length from the ligament of Treitz to the enterostomy in the p-CL group was significantly shorter than that in the non-CL group (47.6 \u0026plusmn; 32.0 vs.72.8 \u0026plusmn; 18.2 cm, \u003cem\u003ep\u003c/em\u003e=0.004). The median of direct-bilirubin after enterostomy in the p-CL group was significantly higher than that in the non-CL group (3.58 \u0026plusmn; 3.28 vs.0.38 \u0026plusmn; 0.33 mg/dl, \u003cem\u003ep\u003c/em\u003e=0.01). Furthermore, the proportion of patients without a closure of the enterostomy in the p-CL group was significantly higher than that in the non-CL group (9/21 vs. 2/18, \u003cem\u003ep\u003c/em\u003e=0.04). The proportion of patients who died at the time of discharge in p-CL group was significantly higher than in the non-CL group (10/21 vs. 2/18, \u003cem\u003ep\u003c/em\u003e=0.02). The cause of death in the p-CL group included 3 patients with circulatory failure, 2 patients with sepsis, 2 patients with disseminated intravascular coagulation (DIC), 1 patient with pulmonary hypertension, 1 patient with heart failure, and 1 patient with intestinal failure associated with liver disease caused by short bowel syndrome (SBS) due to NEC. The causes of death in the non-CL group included one patient with pulmonary hypertension and one patient with pulmonary hypertension. There were no significant differences in the observation period between the p-CL and non-CL groups (187.1 \u0026plusmn; 140.0 vs.190.0 \u0026plusmn; 135.6 days, \u003cem\u003ep\u003c/em\u003e=0.95)\u003c/p\u003e\n\u003cp\u003eFigure 1 shown the cumulative survival rate between non-CL group and p-CL group. The cumulative survival rate in the p-CL group (32.4%) was significantly lower than that in the non-CL group (90.5%) (\u003cem\u003ep\u003c/em\u003e=0.01).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.3 Risk analysis regarding the fasting period and the length of time that EN was carried out exceeding 100ml/kg /day\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe fasting period in the non-CL group (median 6.0 days, 95% confidence interval 5.0-9.0 days) was significantly shorter than that in the p-CL group (median 11.5 days, 95% confidence interval 6.0-12.0 days) (\u003cem\u003ep\u003c/em\u003e=0.006). The\u0026nbsp;length of time that EN was performed exceeding 100 ml/kg /day\u0026nbsp;in the non CL group (median 23.0 days, 95% confidence interval 19.0-26.0 days) was significantly shorter than that in\u0026nbsp;the p-CL\u0026nbsp;group (median 35.5 days, 95% confidence interval 35.5-NA days) (\u003cem\u003ep\u003c/em\u003e=0.006).\u003c/p\u003e\n\u003cp\u003eTable 3 shows\u0026nbsp;the\u0026nbsp;Cox proportional hazards regression regarding the fasting period and the length of time that\u0026nbsp;EN was performed exceeding 100\u0026nbsp;ml/kg /day adjusted for the birth weight and the intestinal length from the ligament of Treitz.\u003c/p\u003e\n\u003cp\u003eThe fasting period was not an independent risk factor for prolonged cholestasis. The p-CL group was found to be at risk of delaying the time taken to start EN compared with the non-CL group (hazard ratio 0.528, \u003cem\u003ep\u003c/em\u003e=0.12). The time taken for EN to exceed 100 ml/kg /day showed similar results (Hazard ratio 0.547, \u003cem\u003ep\u003c/em\u003e=0.19).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.4 Result of the analysis regarding postoperative complications, CRBSI, and blood transfusion following enterostomy\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no significant differences in postoperative complications (estimate -0.60, standard error 1.06, \u003cem\u003ep\u003c/em\u003e=0.57), CRBSI (estimate 0.82, standard error 0.76, \u003cem\u003ep\u003c/em\u003e=0.28), or RBC transfusion frequency (estimate -0.16, standard error 0.20, \u003cem\u003ep\u003c/em\u003e=0.41) between the non-CL and p-CL groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe\u0026nbsp;frequency of FFP transfusion\u0026nbsp;in\u0026nbsp;the p-CL group\u0026nbsp;was significantly higher than that in\u0026nbsp;the non-CL group (Estimate -0.418, standard error 0.188,\u003cem\u003e\u0026nbsp;p\u003c/em\u003e\u0026lt;0.001). PC transfusions in the p-CL group were significantly more frequent than those in the non-CL group (Estimate 0.576, standard error 0.261, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.027).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u003cem\u003e3.5. Risk analysis regarding prolonged cholestasis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 4 shows the Modified Poisson regression of PC and FFP transfusion adjusted for birth weight and intestinal length from the ligament of Treitz to the enterostomy. FFP transfusion was not an independent risk factor for prolonged cholestasis and it had only a small influence as a risk factor (relative risk 0.974, \u003cem\u003ep\u003c/em\u003e=0.06). In addition, PC transfusion had similar results (relative risk 0.974, \u003cem\u003ep\u003c/em\u003e=0.06).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study retrospectively investigated prolonged cholestasis in ELBWIs followed by enterostomies at our institution. This study aimed to clarify the causative factors of prolonged cholestasis in ELBWIs followed by enterostomy by comparing the patient backgrounds, EN status following enterostomy, postoperative complications, CRBSI, and frequency of blood transfusions.\u003c/p\u003e \u003cp\u003eThe major findings of this study were as follows: (1) the cumulative survival rate of the p-CL group was significantly lower than that of the non-CL group; (2) the birth weight of the p-CL group was significantly smaller than that of the non-CL group; (3) the intestinal length from the ligaments of Treitz to the enterostomy of the p-CL group was significantly shorter than that of the non-CL group; (4) the fasting time of the p-CL group was significantly longer than that of the non-CL group, and the length of that that EN was performed exceeding 100 ml/kg/day in the p-CL group was significantly longer than that in the non-CL group. However, neither were independent risk factors; (5) blood (FFP, PC) transfusion in the p-CL group was significantly more frequent than that in the non-CL group. These were not independent risk factors, and their influence as risk factors for prolonged cholestasis was weak.\u003c/p\u003e \u003cp\u003eIn the present study, the mortality rate of ELBWIs followed by enterostomy (30.8%) was lower than that reported in cases of gastrointestinal perforation requiring surgery in ELBWIs in Japan (41.1%) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, the survival rate was found to be significantly higher in the p-CL group than in the non-CL group. Although there was only one case of liver failure in which prolonged cholestasis was directly related to death, circulatory failure, sepsis, and DIC may have been indirectly involved. Prolonged cholestasis followed by enterostomy may contribute to multiple causes of death; therefore, its prevention and treatment may improve the survival rates. Stratification according to gastrointestinal disease showed that patients with FIP were less likely to develop prolonged cholestasis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). This is thought to be because the intestinal barrier function is maintained and systemic infections are less likely to occur compared to NEC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAs an example of how an immature liver function contributes to prolonged cholestasis, a study reported that a birth weight\u0026thinsp;\u0026lt;\u0026thinsp;500 g was associated with a 30-fold increase in the risk of PNALD compared with a birth weight\u0026thinsp;\u0026gt;\u0026thinsp;750 g in patients receiving PN for \u0026gt;\u0026thinsp;14 days and surviving\u0026thinsp;\u0026gt;\u0026thinsp;28 days [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Cholestasis developed in 50 percent of those with a birth weight\u0026thinsp;\u0026lt;\u0026thinsp;1000 g, but only in 7 percent of those with a birth weight\u0026thinsp;\u0026gt;\u0026thinsp;1500\u0026ndash;2000 g [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Even in the ELBWIs followed by enterostomy, the birth weight of the p-CL group was significantly lower, thus suggesting that an immature liver function is involved in the development of prolonged cholestasis.\u003c/p\u003e \u003cp\u003eAfter creating an enterostomy, the available length of the intestine for EN is reduced, and EN alone is no longer able to support the patient's survival and growth, thus resulting in a pathology similar to SBS [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This makes it easier to develop prolonged cholestasis owing to the requirement of PN support for \u0026gt;\u0026thinsp;14 days [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The definition of SBS in newborns is not consistent in the literature, but one definition according to the Italian Society of Neonatology is that the residual intestinal length is less than 25% of the predicted length for GA [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. It has also been reported that in a multivariate analysis related to the onset of SBS, a residual intestinal length of less than 50% of the original length was found to be independently significant [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recent studies have shown that the intestinal length in normal infants is between 150 and 250 cm, but in this study, that of ELBWI at 22 to 28 weeks of GA is approximately 70 to 120 cm [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Based on these considerations, when it appears that EN support will be insufficient with the proximal intestine alone, alternative methods such as the practice of mucous fistula refeeding must be taken [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], such as the introduction of santulli enterostomy to maintain continuity with the distal intestinal tract [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStarting enteral feeding to prevent IFALD induced by IF, including SBS, is an important decision, and minimal enteral feeding should be started as soon as possible, and it should be administered aggressively to promote maximal bowel adaptation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The early initiation of enteral feeding can shorten the time to full initiate feeding, reduce the dependence on PN, and reduce the incidence of CRBSI [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The establishment of EN should also be considered, depending on the patient's condition. Trans-pyloric feeding can be performed in patients with inadequate gastric emptying. Richardson et al. investigated a method of resupplying proximal enterostomy effluent to distal enterostomy and reported an improved weight gain [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, vomiting more than three times per day or exceeding 20% of the daily enteral intake or stool volumes of \u0026gt;\u0026thinsp;20 mL/kg/day is likely to indicate that the amount of food cannot be sufficiently tolerated and caution is therefore required [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, the length of time that EN was performed and the length of time that EN was performed exceeding 100 ml/kg/day was significantly lower in the non-CL group than in the p-CL group, but the difference was not significant according to a multivariate analysis adjusted for birth weight and intestinal length from the ligament of Treitz to the enterostomy. Therefore, the birth weight and intestinal length from the ligament of Treitz to the enterostomy were not independent risk factors However, both hazard ratios were low, thus indicating that they are strong risk reduction factors for prolonged cholestasis in ELBWIs followed by enterostomy.\u003c/p\u003e \u003cp\u003eThis findings of this study suggest that FFP and PC transfusions may be slightly more frequent in the p-CL group than in the non-CL group, but no previous study in the literature was found to support this as a risk factor. On the other hand, there are reports that blood transfusion for preterm infants with various comorbid illnesses such as sepsis, respiratory distress syndrome, NEC, PDA, intraventricular hemorrhage, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and anemia of prematurity was higher in infants who were \u0026lt;\u0026thinsp;28 weeks and 1000 g, and that the number of transfusions has been reported to be related to the incidence of NEC [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These comorbidities may be involved in the frequency of blood transfusions and prolonged cholestasis observed in this study; however, further investigation is required.\u003c/p\u003e"},{"header":"5. Limitation","content":"\u003cp\u003eThis study was a retrospective analysis, with a small number of enrolled patients and a variety of underlying diseases. Therefore, the accuracy of the multivariate analysis are not considered to be definitive. In addition, the treatment for prolonged cholestasis following enterostomy was not evaluated in this study.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eIn this study, we retrospectively investigated the causes of prolonged cholestasis in ELBWIs followed by enterostomy at our institution. We therefore understood that modest differences in the birth weight and stoma site level may affect enteral feeding management and subsequently result in prolonged cholestasis liver damage in ELBWIs with high prematurity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Kagoshima City Hospital Neonatal Intensive Care Unit. We thank Brian Quinn for his comments and assistance with this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMM, KS, AN,\u0026nbsp;and MM designed this study. MM, SO, KT, KY, TH, MT,\u0026nbsp;and KS analyzed the data and created the Figure. TK, MM, YA, OH, YA, HA, NY, TT,\u0026nbsp;and TK provided\u0026nbsp;the conceptual advice. MM\u0026nbsp;wrote the manuscript in consultation with MM and SI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author:\u003c/strong\u003e \u003cstrong\u003eSatoshi IEIRI, M.D., Ph.D., F.A.C.S.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Pediatric Surgery, Research Field in Medical and Health Sciences,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMedical and Dental Area, Research and Education Assembly, Kagoshima University\u003c/p\u003e\n\u003cp\u003e8-35-1, Sakuragaoka, Kagoshima City, 8900075, JAPAN\u003c/p\u003e\n\u003cp\u003eTel: +81-99-275-5444, Fax: +81-99-275-2628,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eE-mail: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest in association with the present study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDi Dato F, Iorio R, Spagnuolo MI (2022) IFALD in children: What's new? A narrative review. Front Nutr https//. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fnut.2022.928371\u003c/span\u003e\u003cspan address=\"10.3389/fnut.2022.928371\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhalaf RT, Ford SL (2022) Intestinal failure-associated liver disease in the neonatal ICU: what we know and where we're going. Curr Opin Pediatr 34:184\u0026ndash;190. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps//doi:10.1097/MOP.0000000000001105\u003c/span\u003e\u003cspan address=\"https://doi:10.1097/MOP.0000000000001105\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee WS, Chew KS, Ng RT, Kasmi KE, Sokol RJ (2020) Intestinal failure-associated liver disease (IFALD): insights into pathogenesis and advances in management. Hepatol Int 14:305\u0026ndash;316. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps//doi:10.1007/s12072-020-10048-8\u003c/span\u003e\u003cspan address=\"https://doi:10.1007/s12072-020-10048-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSato M, Hamada Y, Kohno M, Ise K, Uchida K, Ogata H, Masuyama H, Morotomi Y, Yasufuku M, Wada M (2017) Neonatal gastrointestinal perforation in Japan: a nationwide survey. Pediatr Surg Int 33:33\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps//doi:10.1007/s00383-016-3985-z\u003c/span\u003e\u003cspan address=\"https://doi:10.1007/s00383-016-3985-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarila K, Anttila A, Iber T, Pakarinen M, Koivusalo A (2019) Intestinal failure associated cholestasis in surgical necrotizing enterocolitis and spontaneous intestinal perforation. J Pediatr Surg 54:460\u0026ndash;464. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1016/j.jpedsurg.2018.10.043\u003c/span\u003e\u003cspan address=\"http://doi:10.1016/j.jpedsurg.2018.10.043\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMutanen A, P\u0026ouml;ntinen V, Gunnar R, Merras-Salmio L, Pakarinen MP (2022) Efficient achievement of enteral autonomy facilitates resolution of liver injury in necrotizing enterocolitis induced short bowel syndrome. Sci Rep 12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehtto//doi:10.1038/s41598-022-22414-7\u003c/span\u003e\u003cspan address=\"htto//doi:10.1038/s41598-022-22414-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChristensen RD, Henry E, Wiedmeier SE, Burnett J, Lambert DK (2007) Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease. J Perinatol 27:284\u0026ndash;290. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1038/sj.jp.7211686\u003c/span\u003e\u003cspan address=\"http://doi:10.1038/sj.jp.7211686\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeale EF, Nelson RM, Bucciarelli RL, Donnelly WH, Eitzman DV (1979) Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics 64:342\u0026ndash;347\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWales PW, de Silva N, Kim JH, Lecce L, Sandhu A, Moore AM (2005) Neonatal short bowel syndrome: a cohort study. J Pediatr Surg 40:755\u0026ndash;762. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1016/j.jpedsurg.2005.01.037\u003c/span\u003e\u003cspan address=\"http://doi:10.1016/j.jpedsurg.2005.01.037\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCaporilli C, Giann\u0026igrave; G, Grassi F, Esposito S (2023) An Overview of Short-Bowel Syndrome in Pediatric Patients: Focus on Clinical Management and Prevention of Complications. Nutrients 15. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.3390/nu15102341\u003c/span\u003e\u003cspan address=\"http://doi:10.3390/nu15102341\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStruijs MC, Diamond IR, de Silva N, Wales PW (2009) Establishing norms for intestinal length in children. J Pediatr Surg 44:933\u0026ndash;938. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1016/j.jpedsurg.2009.01.031\u003c/span\u003e\u003cspan address=\"http://doi:10.1016/j.jpedsurg.2009.01.031\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichardson L, Banerjee S, Rabe H (2006) What is the evidence on the practice of mucous fistula refeeding in neonates with short bowel syndrome? J Pediatr Gastroenterol Nutr 43:67\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1097/01.mpg.0000228111.21735.02\u003c/span\u003e\u003cspan address=\"http://doi:10.1097/01.mpg.0000228111.21735.02\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYue M, Yang H, Cui M, Yuan Y, Zhang N, Zhang X, Li Y (2023) The safety and effectiveness of Santulli enterostomy in neonatal intestinal conditions. Front Pediatr 10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.3389/fped.2022.1077346\u003c/span\u003e\u003cspan address=\"http://doi:10.3389/fped.2022.1077346\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMuto M, Kaji T, Onishi S, Yano K, Yamada W, Ieiri S (2022) An overview of the current management of short-bowel syndrome in pediatric patients. Surg Today 52:12\u0026ndash;21. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1007/s00595-020-02207-z\u003c/span\u003e\u003cspan address=\"http://doi:10.1007/s00595-020-02207-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWessel JJ, Kocoshis SA (2007) Nutritional management of infants with short bowel syndrome. Semin Perinatol 31:104\u0026ndash;111. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1053/j.semperi.2007.02.009\u003c/span\u003e\u003cspan address=\"http://doi:10.1053/j.semperi.2007.02.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrubaker DB (1993) Immunopathogenic mechanisms of posttransfusion graft-vs-host disease. Proc Soc Exp Biol Med 202:122\u0026ndash;147. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.3181/00379727-202-43519b\u003c/span\u003e\u003cspan address=\"http://doi:10.3181/00379727-202-43519b\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarg PM, Ravisankar S, Bian H, Macgilvray S, Shekhawat PS (2015) Relationship between Packed Red Blood Cell Transfusion and Severe Form of Necrotizing Enterocolitis: A Case Control Study. Indian Pediatr 52:1041\u0026ndash;1045. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp//doi:10.1007/s13312-015-0770-3\u003c/span\u003e\u003cspan address=\"http://doi:10.1007/s13312-015-0770-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients\u0026rsquo; background characteristics before enterostomy\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ep-CL group\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e(n\u0026thinsp;=\u0026thinsp;21)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003enon-CL group\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e(n\u0026thinsp;=\u0026thinsp;18)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Italic\"\u003ep\u003c/span\u003e value\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eUnderlying disease\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNEC (5)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eFIP (5)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eMRI (3)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eIntussusception (2)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eIA (2)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eNEC (2)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eFIP (14)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eMRI (3)\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003eIntussusception (2)\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.42\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.001\u003c/span\u003e\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.59\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.64\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.49\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eGestational age (week)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e25.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e25.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.94\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eSex (male: female)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e10: 8\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e13: 8\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.75\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eBirth weight (g)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e587.8\u0026thinsp;\u0026plusmn;\u0026thinsp;157.6\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e698.0\u0026thinsp;\u0026plusmn;\u0026thinsp;158.7\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.04\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eCongenital heart disease (with: without)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2: 16\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2: 19\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1.0\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eWBC (/ul)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e10661.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8744.2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e16790.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13487.2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.11\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eAST (U/l)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e56.9\u0026thinsp;\u0026plusmn;\u0026thinsp;63.8\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e34.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.14\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eALT (U/l)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;22.3\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.06\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eDirect-bilirubin (mg/dl)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.72\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.31\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eCRP (mg/dl)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.80\u0026thinsp;\u0026plusmn;\u0026thinsp;2.88\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.75\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003epH\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e7.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e7.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.09\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.47\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eLactate (mmol/L)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.25\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eData are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eNEC: necrotizing enterocolitis; FIP: focal intestinal perforation; MRI: meconium related ileus; IA: intestinal atresia\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ePatients\u0026rsquo; background characteristics after enterostomy\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ep-CL group\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e(n\u0026thinsp;=\u0026thinsp;21)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003enon-CL group\u003c/div\u003e\n \u003cdiv class=\"SimplePara\"\u003e(n\u0026thinsp;=\u0026thinsp;18)\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Italic\"\u003ep\u003c/span\u003e-value\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eAge at enterostomy (days)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e11.4\u0026thinsp;\u0026plusmn;\u0026thinsp;7.7\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e7.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.07\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eIntestinal length from the ligament of Treitz to the enterostomy (cm)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e47.6\u0026thinsp;\u0026plusmn;\u0026thinsp;32.0\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e72.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.004\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eMedian of direct-bilirubin (mg/dl) followed by enterostomy\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3.58\u0026thinsp;\u0026plusmn;\u0026thinsp;3.28\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.33\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.01\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eClosure of enterostomy (with: without)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e12: 9\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e16: 2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.04\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eStatus at discharge (alive: dead)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e11: 10\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e16: 2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.02\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eCause of death\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eCirculatory failure\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e3\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eSepsis\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eDIC\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e2\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eHeart failure\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003ePulmonary hypertension\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eIFALD induced by SBS\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eObservation period (days)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e187.1\u0026thinsp;\u0026plusmn;\u0026thinsp;140.0\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e190.0\u0026thinsp;\u0026plusmn;\u0026thinsp;135.6\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.95\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eData shown as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eDIC: disseminated intravascular coagulation; IFALD: intestinal failure associated with liver disease; SBS: short bowel syndrome\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab7\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eRisk analysis regarding the fasting period and the length of time that EN was carried out exceeding 100ml/kg /day\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eHazard ratio\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e95% confidence interval\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Italic\"\u003ep\u003c/span\u003e-value\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth colspan=\"4\" align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ea) Fasting period (days)\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eProlonged cholestasis (without: with)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.528\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.234\u0026ndash;1.188\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.12\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eBirth weight (g)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1.002\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1.002\u0026ndash;1.005\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.04\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eIntestinal length from the ligament of Treitz to the enterostomy (cm)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1.009\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.996\u0026ndash;1.021\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.17\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eb) Time taken EN exceeding 100ml/kg /day (days)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eProlonged cholestasis (without: with)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.547\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.222\u0026ndash;1.352\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.19\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eBirth weight (g)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1.001\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.998\u0026ndash;1.003\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.39\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eIntestinal length from the ligament of Treitz to the enterostomy (cm)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e1.014\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.999\u0026ndash;1.030\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.07\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eEN: enteral nutrition\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab8\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eRisk analysis regarding prolonged cholesistasis\u003c/div\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eRelative risk\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003eStandard error\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e95% confidence interval\u003c/div\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Italic\"\u003ep\u003c/span\u003e-value\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth colspan=\"5\" align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003ea) Prolonged cholestasis (without: with)\u003c/div\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eFFP transfusion (number of time)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.947\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.029\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.894\u0026ndash;1.003\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.06\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eBirth weight (g)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.998\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.001\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.997-1.000\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.05\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eIntestinal length from the ligament of Treitz to the enterostomy (cm)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.987\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.005\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.978\u0026ndash;0.996\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.006\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eb) Prolonged cholestasis (without: with)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003ePC transfusion (number of time)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.990\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.036\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.036\u0026ndash;0.922\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.77\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eBirth weight (g)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.999\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.001\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.997\u0026ndash;1.001\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.26\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003eIntestinal length from the ligament of Treitz to the enterostomy (cm)\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.989\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.005\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e0.979-1.000\u003c/div\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cdiv class=\"SimplePara\"\u003e\u003cspan class=\"Bold\"\u003e0.004\u003c/span\u003e\u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eFFP: fresh frozen plasma; PC: platelet concentrate\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\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":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"prolonged cholestasis, enterostomy, extremely low birth weight infants, prematurity","lastPublishedDoi":"10.21203/rs.3.rs-5037072/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5037072/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eCholestatic liver damage is frequently observed in extremely low-birth-weight infants (ELBWIs), followed by enterostomy. We retrospectively investigated the factors related to liver damage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eELBWIs who underwent enterostomy at our institution between January 2013 and December 2022 for gastrointestinal disease during the neonatal period were reviewed. Cases presenting with direct bilirubin \u0026gt;2.0 mg/dl for \u0026gt;1 month after enterostomy were designated as the prolonged cholestatic liver (p-CL) group and compared with cases without cholestatic liver damage, the (non-CL )group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Thirty-nine patients (21 in the p-CL group and 18 in the non-CL group) were included. Survival was significantly lower in the p-CL group (52.4% [11/21] vs. 88.9% [16/18]; \u003cem\u003ep\u003c/em\u003e=0.020). Significant differences were found in the birth weight (587.8 g vs. 698.0 g, \u003cem\u003ep\u003c/em\u003e=0.040) and small intestinal length to the enterostomy (47.6 cm vs. 72.8 cm, \u003cem\u003ep\u003c/em\u003e=0.004). Patients in the non-CL group started enteral feeding and reached \u0026gt;100 ml/kg/day earlier than those in the p-CL group. There was no difference in the incidence of catheter-related bloodstream infections between the two groups(\u003cem\u003ep\u003c/em\u003e=0.280).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Modest differences in the birth weight and stoma site level may affect enteral feeding management and subsequently result in prolonged cholestatic liver damage in ELBWIs with high prematurity.\u003c/p\u003e","manuscriptTitle":"A study of the prolonged cholestasis observed in extremely low birth weight infants followed by enterostomy ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-22 09:15:04","doi":"10.21203/rs.3.rs-5037072/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-09T08:57:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-08T22:42:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-30T03:59:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9651411456311442349666979891155115423","date":"2024-09-29T18:12:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"228829074348530170332645455493091955855","date":"2024-09-27T11:42:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-27T07:34:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-08T09:16:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-06T13:58:40+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Surgery International","date":"2024-09-05T09:35:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"69b337b1-eb5a-49e4-b6a0-7405a85544ef","owner":[],"postedDate":"October 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:08:37+00:00","versionOfRecord":{"articleIdentity":"rs-5037072","link":"https://doi.org/10.1007/s00383-024-05946-z","journal":{"identity":"pediatric-surgery-international","isVorOnly":false,"title":"Pediatric Surgery International"},"publishedOn":"2024-12-20 15:58:12","publishedOnDateReadable":"December 20th, 2024"},"versionCreatedAt":"2024-10-22 09:15:04","video":"","vorDoi":"10.1007/s00383-024-05946-z","vorDoiUrl":"https://doi.org/10.1007/s00383-024-05946-z","workflowStages":[]},"version":"v1","identity":"rs-5037072","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5037072","identity":"rs-5037072","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}