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BACKGROUND AND AIMS: Biliary atresia (BA) is a cholestatic, fibro-obliterative cholangiopathy of unknown etiology. BA is primarily treated by a surgical approach, i.e. the Kasai portoenterostomy (KPE), to obtain clearance of jaundice (COJ). The gut microbiota (GM) composition has been associated with the course of several cholestatic liver diseases. It is largely unknown, however, whether GM composition associates with the outcome of KPE. We compared the GM composition of BA patients and controls and assessed if GM composition before KPE was related to COJ after KPE.METHODS: We compared feces of term born BA patients before KPE and controls (patients undergoing inguinal hernia repair) by 16S rRNA sequencing. Composition and alpha diversity of the GM were compared between BA and controls before KPE and after KPE, between patients with COJ vs. without COJ (total serum bilirubin RESULTS: Alpha diversity was comparable between BA (n = 12, age 1.6[1.3-1.8]mo) and controls (n = 6, age 2.0[1.4-2.1]mo; P = 0.22). Compared to controls, BA patients had lower abundances of Bifidobacteriaceae (β=-1.98, P CONCLUSIONS: The gut microbiota of biliary atresia patients prior to Kasai portoenterostomy associates with outcome, clearance of jaundice, suggestive of predictive and mechanistic roles of the gut microbiota composition in bile homeostasis.

BACKGROUND: Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rsSO2), but solid reference values are scarce. We aimed to establish reference values of rsSO2 for preterm infants during the first week after birth, both crude and modeled based on predictors.METHODS: We included infants with gestational age (GA) RESULTS: We included 220 infants. On day 1, the mean ± SD rsSO2 value was 48.2% ± 16.6. The nadir of rsSO2 was on day 4 (38.7% ± 16.6 smoothed line) to 5 (37.4%±17.3, actual data), after which rsSO2 increased to 44.2% ± 16.6 on day 7. The final model of the reference values of rsSO2 included the following coefficients: rsSO2 = 3.2 - 7.0 × PNA + 0.8 × PNA2 - 4.0 × SGA + 1.8 × GA.CONCLUSIONS: We established reference values of rsSO2 for preterm infants during the first week after birth. GA, PNA, and SGA affect these values and need to be taken into account.IMPACT: Regional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study.

Background Pro- and anticoagulant drugs are commonly used in pediatric liver transplantation to prevent and treat thrombotic and bleeding complications. However, the combination of baseline hemostatic changes in children with liver disease and additional changes induced by transplantation makes this very challenging. This study aimed to analyze the efficacy of clinically available pro- and anticoagulant drugs in plasma from children undergoing liver transplantation. Methods In vitro effects of pro- and anticoagulant drugs on thrombin generation capacity were tested in plasma samples of 20 children (≤ 16 years) with end-stage liver disease undergoing liver transplantation, and compared with 30 age-matched healthy controls. Results Addition of pooled normal plasma had no effect in patients or controls, while 4-factor prothrombin complex concentrate increased thrombin generation in both patients and controls, with enhanced activity in patients. At start of transplantation, dabigatran and unfractionated heparin had a higher anticoagulant potency in patients, whereas 30 days after transplantation low molecular weight heparin was slightly less effective in patients. Effects of rivaroxaban were comparable between patients and controls. Conclusion This study revealed important differences in efficacy of commonly used pro- and anticoagulant drugs in children with end-stage liver disease undergoing liver transplantation. Therefore, dose adjustments of these drugs may be required. The results of this study may be helpful in the development of urgently needed protocols for strategies to prevent and treat bleeding and thrombotic complications in pediatric liver transplantation.

OBJECTIVES: The aim of the study was to determine quality of life (QoL), stress, and anxiety levels in parents of children with biliary atresia (BA), and to assess factors associated with parental QoL. METHODS: Parents of children (6-16 years) with BA were included in this cross-sectional study. We used validated questionnaires to assess parental QoL, stress, and anxiety levels. We compared the results with reference data from the general population and determined associated factors using generalized linear mixed model analysis. Results are given as mean ± SD or median [min-max]. RESULTS: We included 61 parents of 39 children (aged 11 ± 3 years). Thirty-one children (79%) had undergone a liver transplantation (LTx). Parents reported reduced family activities (88 [8-100] vs 95 [30-100], P = 0.002) and more emotional worry (83 [17-100] vs 92 [95-100], P

Introduction We aimed to assess health-related quality of life (HrQoL) in biliary atresia (BA) patients, based on original data and a literature review, and to determine factors associated with their HrQoL. Materials and Methods We reviewed available studies describing HrQoL in BA patients. We assessed HrQoL in Dutch BA patients (6–16 years) using the validated Child Health Questionnaire. We compared HrQoL scores in BA patients with healthy peers and with children who had undergone major surgery in infancy or children with chronic conditions. We determined the relationship between specific patient-related factors and HrQoL. Results Literature data indicated that HrQoL in children with BA is lower than in healthy peers. In Dutch BA patients (n = 38; age 10 ± 3 years), parent-proxy physical HrQoL (48 ± 11) was significantly lower compared with two reference groups of healthy peers (59 ± 4 and 56 ± 6, respectively, each p Conclusion Children with BA are at risk of impaired HrQoL. Special attention is warranted for children with adverse medical events and special education.

Objective: To assess long-term neurodevelopmental outcomes in school-aged children with biliary atresia. Study design: All Dutch children (6-12 years of age) diagnosed with biliary atresia were invited to participate in this study. We used validated neurodevelopmental tests to assess motor skills and cognition, and questionnaires to assess behavior. Scores were compared with the Dutch norm population, by means of 1-sample tests. Results are given as number and percentage or mean ± SD. Results: We included 46 children, with a median age of 11 years (range, 6-13 years); 36 children had undergone a liver transplantation (78%). Twelve children (26%) received special education (vs 2.4% in the norm population; P

In adults with end‐stage liver disease concurrent changes in pro‐ and antihemostatic pathways result in a rebalanced hemostasis. Children though, have a developing hemostatic system, different disease etiologies, and increased risk of thrombosis. This study aimed to assess the hemostatic state of children during and after liver transplantation. Serial blood samples were obtained from 20 children (≤16 years) undergoing primary liver transplantation (September 2017‐October 2018). Routine hemostasis tests, thrombomodulin‐modified thrombin generation, clot lysis times, and hemostatic proteins were measured. Reference values were established using an age‐matched control group of 30 children. Thrombocytopenia was present in study patients. Von Willebrand factors were doubled and ADAMTS13 levels decreased during and after transplantation up until day 30, when platelet count had normalized. Whereas prothrombin time and activated partial thromboplastin time were prolonged during transplantation, thrombin generation was within normal ranges, except during perioperative heparin administration. Fibrinogen, factor VIII levels, and clot lysis time were elevated up until day 30. In conclusion, children with end‐stage liver disease are in tight hemostatic balance. During transplantation a temporary heparin‐dependent hypocoagulable state is present, which rapidly converts to a hemostatic balance with distinct hypercoagulable features that persist until at least day 30. This hypercoagulable state may contribute to the risk of posttransplant thrombosis., This prospective exploratory study shows that children with end‐stage liver disease undergoing liver transplantation are in a fragile hemostatic balance, with a temporary heparin‐induced hypocoagulable state during transplantation, which rapidly converts to a rebalanced hemostatic state with distinct hypercoagulable features posttransplantation.

Background: While congenital choledochal malformation (CCM) is relatively well known within the pediatric surgical and pediatric gastroenterological communities, many controversies and questions remain. Methods: In this paper, we will discuss the results of an international Delphi survey among members of the European Reference Network RARE-LIVER and of the faculty of the Biliary Atresia and Related Diseases (BARD) network to identify the most common practices as well as controversies regarding diagnosis, treatment and follow-up of this still enigmatic disease. Results: Twenty-two individual respondents completed the survey. While there seems to be agreement on the definitions of CCM, preoperative workup, surgical approach and follow-up still vary considerably. The mainstay of treatment remains the removal of the entire extrahepatic biliary tract, clearance of debris both proximally and distally, followed by reconstruction with (according to 86% of respondents) a Roux-en-Y hepaticojejunostomy. Nonetheless, both laparoscopic and robotic-assisted resections are gaining ground with the suggestion that this might be facilitated by concentration of care and resources in specialized centers. However, long-term outcomes are still lacking. Conclusions: As even post-surgical CCM has to be considered as having premalignant potential, follow-up should be well-organized and continued into adulthood. This seems to be lacking in many centers. International cooperation for both benchmarking and research is paramount to improving care for this rare disease.

Biliary atresia (BA) is a rare newborn liver disease with significant morbidity and mortality, especially if not recognized and treated early in life. It is the most common cause of liver-related death in children and the leading indication for liver transplantation in the pediatric population. Timely intervention with a Kasai portoenterostomy (KPE) can significantly improve prognosis. Delayed disease recognition, late patient referral, and untimely surgery remains a worldwide problem. This article will focus on biliary atresia from a global public health perspective, including disease epidemiology, current national screening programs, and their impact on outcome, as well as new and novel BA screening initiatives. Policy challenges for the implementation of BA screening programs will also be discussed, highlighting examples from the North American, European, and Asian experience.

OBJECTIVE: To assess whether regional intestinal oxygen saturation (rintSO2) and regional cerebral oxygen saturation (rcSO2) measurements aid in estimating survival of preterm infants after surgery for NEC.SUMMARY OF BACKGROUND DATA: Predicting survival after surgery for NEC is difficult yet of the utmost importance for counseling parents.METHODS: We retrospectively studied prospectively collected data of preterm infants with surgical NEC who had available rintSO2 and rcSO2 values measured via near-infrared spectroscopy 0-24 hours preoperatively. We calculated mean rintSO2 and rcSO2 for 60-120 minutes for each infant. We analyzed whether preoperative rintSO2 and rcSO2 differed between survivors and non-survivors, determined cut-off points, and assessed the added value to clinical variables.RESULTS: We included 22 infants, median gestational age 26.9 weeks [interquartile range (IQR): 26.3-28.4], median birth weight 1088 g [IQR: 730-1178]. Eleven infants died postoperatively. Preoperative rintSO2, but not rcSO2, was higher in survivors than in non-survivors [median: 63% (IQR: 42-68) vs 29% (IQR: 21-43), P < 0.01), with odds ratio for survival 4.1 (95% confidence interval, 1.2-13.9, P = 0.02) per 10% higher rintSO2. All infants with rintSO2 values of >53% survived, whereas all infants with rintSO2 CONCLUSIONS: Measuring rintSO2, but not rcSO2, seems of added value to clinical variables in estimating survival of preterm infants after surgery for NEC. This may help clinicians in deciding whether surgery is feasible and to better counsel parents about their infants' chances of survival.

Background The intestinal microbiome in preterm infants differs markedly from term infants. It is unclear whether the microbiome develops over time according to infant specific factors. Methods We analysed (clinical) metadata - to identify the main factors influencing the microbiome composition development - and the first meconium and faecal samples til the 4th week via 16 S rRNA amplican sequencing. Results We included 41 infants (gestational age 25–30 weeks; birth weight 430-990 g. Birth via Caesarean section (CS) was associated with placental insufficiency during pregnancy and lower BW. In meconium samples and in samples from weeks 2 and 3 the abundance of Escherichia and Bacteroides (maternal faecal representatives) were associated with vaginal delivery while Staphylococcus (skin microbiome representative) was associated with CS. Secondly, irrespective of the week of sampling or the mode of birth, a transition was observed as children children gradually increased in weight from a microbiome dominated by Staphylococcus (Bacilli) towards a microbiome dominated by Enterobacteriaceae (Gammaproteobacteria). Conclusions Our data show that the mode of delivery affects the meconium microbiome composition. They also suggest that the weight of the infant at the time of sampling is a better predictor for the stage of progression of the intestinal microbiome development/maturation than postconceptional age as it less confounded by various infant-specific factors.

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs, University of Colorado; Baylor College of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital of Pittsburgh; St Louis Children’s Hospital; Riley Hospital for Children; Seattle Children’s Hospital; M.D./Ph.D. Scholarship from the University of Groningen; European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Networking Grant 2019; ChilDReN National Institutes of Health Grants; Ann & Robert H. Lurie Children’s Hospital; Albireo and Mirum Pharmaceuticals

BACKGROUND: We aimed to investigate whether splanchnic tissue oxygen saturation (rsSO2) measured by near-infrared spectroscopy (NIRS) could contribute to the early diagnosis of necrotizing enterocolitis (NEC).METHODS: We retrospectively included infants with suspected NEC, gestational age RESULTS: Of the 75 infants, 21 (28%) had NEC (Bell's stage ≥2). Characteristics of infants with and without NEC differed only on mechanical ventilation and nil-per-os status. RsSO2 tended to be higher and rcSO2 lower in infants with NEC. RsCoVAR (median [range]) was lower (0.11 [0.03-0.34]) vs. 0.20 [0.01-0.52], P = 0.002) and SCOR higher (0.64 [0.37-1.36]) vs. 0.47 [0.16-1.09], P = 0.004) in NEC infants. Adjusted for postnatal age, mechanical ventilation, and nil-per-os status, a 0.1 higher rsCoVAR decreased the likelihood of NEC diagnosis with likelihood ratio (LR) 0.38 (95% CI 0.18-0.78) and a 0.1 higher SCOR increased it with LR 1.28 (1.02-1.61).CONCLUSIONS: Using NIRS, high SCOR may confirm NEC and high variability of rsSO2 may rule out NEC, when suspicion arises.IMPACT: Near-infrared spectroscopy may contribute to the diagnosis of necrotizing enterocolitis.When clinical signs are present a high splanchnic-cerebral oxygenation may indicate necrotizing enterocolitis.A low splanchnic-cerebral oxygenation ratio and high variability of splanchnic tissue oxygen saturation may rule out necrotizing enterocolitis.Whether a bedside real-time availability of the splanchnic-cerebral oxygenation ratio and variability of splanchnic tissue oxygen saturation improves NEC diagnosis needs to be further investigated.

Background Anemic preterm infants may require red blood cell (RBC) transfusions to maintain sufficient oxygen supply to vital organs. Transfusion treatment, however, may have adverse intestinal effects. We aimed to investigate the short-term effects of RBC transfusions, hypothesizing to find signs of oxidative stress and intestinal injury, possibly related to levels of splanchnic (re-)oxygenation. Methods We prospectively included preterm infants (gestational age < 32 weeks). We measured urinary biomarkers for oxidative stress (8-isoprostane) and intestinal cell injury (intestinal fatty acid-binding protein, I-FABP) shortly before and after RBC transfusion. Splanchnic oxygen saturation (r(s)SO(2)) and r(s)SO(2) variability were assessed simultaneously. Results Twenty-nine preterm infants received 58 RBC transfusions at various postnatal ages. Six of them developed necrotizing enterocolitis (NEC) after transfusion. Urinary 8-isoprostane and I-FABP increased following RBC transfusion (median 282-606 pg/ml and 4732-6968 pg/ml, p < 0.01), more pronounced in infants who developed NEC. Change in I-FABP correlated with change in 8-isoprostane (rho = 0.623, p < 0.01). Lower r(s)SO(2) variability, but not higher mean r(s)SO(2) was associated with higher 8-isoprostane and I-FABP levels after transfusion. Conclusions Preterm RBC transfusions are associated with concomitant signs of oxidative stress and intestinal injury, parallel with lower variability in splanchnic oxygenation. This may represent the early pathogenetic process of transfusion-associated NEC. Impact Red blood cell (RBC) transfusions in preterm infants are associated with a near 2-fold increase in urinary biomarkers for oxidative stress (8-isoprostane) and intestinal cell injury (intestinal fatty acid-binding protein, I-FABP). Magnitude of change in I-FABP strongly correlated with the magnitude of 8-isoprostane change, suggesting a role for oxidative stress in the pathogenesis of intestinal injury. Lower splanchnic oxygen saturation variability following RBC transfusion was associated with higher 8-isoprostane and I-FABP levels. Loss of splanchnic variability after RBC transfusion may result from increased oxidative stress and its concomitant intestinal injury, possibly representing the early pathogenetic process of transfusion-associated necrotizing enterocolitis.

OBJECTIVES The aim of the study was to assess the neurological status in infants with biliary atresia (BA) at time of diagnosis, using Prechtl's validated General Movement Assessment. METHODS Infants diagnosed with BA were prospectively included in a nationwide cohort study. From birth to approximately 46 weeks of postmenstrual age (PMA), general movements (GMs) are defined as "writhing movements." At 46 to 49 weeks PMA, "'fidgety movements" emerge. The infant's early motor repertoire was recorded on video before Kasai portoenterostomy. We scored GM optimality scores (min-max 5-42) or motor optimality scores (MOS, min-max 5-28) as appropriate. We defined GM optimality scores

Background: Epigenetic changes, such as DNA methylation, may contribute to an increased susceptibility for developing necrotizing enterocolitis (NEC) in preterm infants. We assessed DNA methylation in five NEC-associated genes, selected from literature: EPO, VEGFA, ENOS, DEFA5, and TLR4 in infants with NEC and controls.Methods: Observational cohort study including 24 preterm infants who developed NEC (≥Bell Stage IIA) and 45 matched controls. DNA was isolated from stool samples and methylation measured using pyrosequencing. We investigated differences in methylation prior to NEC compared with controls. Next, in NEC infants, we investigated methylation patterns long before, a short time before NEC onset, and after NEC.Results: Prior to NEC, only TLR4 CpG 2 methylation was increased in NEC infants (median = 75.4%, IQR = 71.3–83.8%) versus controls (median = 69.0%, IQR = 64.5–77.4%, p = 0.025). In NEC infants, VEGFA CpG 3 methylation was 0.8% long before NEC, increasing to 1.8% a short time before NEC and 2.0% after NEC (p = 0.011; p = 0.021, respectively). A similar pattern was found in DEFA5 CpG 1, which increased from 75.4 to 81.4% and remained 85.3% (p = 0.027; p = 0.019, respectively). These changes were not present for EPO, ENOS, and TLR4.Conclusion: Epigenetic changes of TLR4, VEGFA, and DEFA5 are present in NEC infants and can differ in relation to the time of NEC onset. Differences in DNA methylation of TLR4, VEGFA, and DEFA5 may influence gene expression and increase the risk for developing NEC. This study also demonstrates the use of human DNA extraction from stool samples as a novel non-invasive method for exploring the bowel of preterm infants and which can also be used for necrotizing enterocolitis patients.

BACKGROUND: Necrotizing enterocolitis (NEC) is a neonatal disease associated with necrosis and perforation of the bowel. We investigated the association between blood group and NEC outcomes and the potential contribution of fetal-maternal blood group incompatibility.METHODS: Retrospective study including all preterm-born infants with NEC (≥ Bell's stage IIa) admitted to our NICU between January 2008 and October 2019. We analyzed the association between infants' blood groups and fetal-maternal blood group incompatibility with Bell stage severity, need for surgery, and mortality due to NEC.RESULTS: We included 237 NEC patients. In univariable analyses both AB blood group and fetal-maternal blood group incompatibility increased infants' risk of severe outcomes, with odds ratios (OR) ranging from 6.57 to 12.06 and 1.97 to 2.38, respectively. When adjusted for gestational age only AB blood group remained significant with OR 7.47 (95% confidence interval, 1.95-28.53, P = 0.003), 12.37 (2.63-58.20, P = 0.001), and 8.16 (2.28-29.14, P = 0.001) for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively. Blood group incompatibility adjusted for gestational age was not related to worse outcomes with OR 1.84 (0.87-3.89, P = 0.11, 2.08 (0.98-4.41, P = 0.06) 1.52 (0.68-3.42, P = 0.31), for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively.CONCLUSION: Our data confirm an association between blood group AB and worse outcomes in NEC infants, but this is not based on fetal-maternal blood group incompatibility.

Objectives Environmental factors may be involved in the pathogenesis of biliary atresia (BA). This epidemiological study aimed to analyze the relationships between the incidence of BA, the incidence of confirmed viral or bacterial infections and population density, and geographical and temporal clustering of BA in the Netherlands. Study design Correlations between the monthly incidence of BA and the number of confirmed infections were assessed. BA incidence per province was calculated and compared to the province with highest population density. Birthplaces were classified as rural or urban. Temporal clustering of month of birth and month of conception were analyzed. We performed analyses for isolated BA (IBA) and syndromic BA (SBA) separately. Chi2, logistic regression, and Walter and Elwood test were used. Results A total of 262 IBA and 49 SBA patients, born between 1987 and 2018, were included. IBA incidence correlated to the number of confirmed infections of, for example, Chlamydia trachomatis (R = 0.14; P = 0.02) and adenovirus (R = 0.22; P = 0.005). We observed a higher incidence of IBA (0.75/10,000; odds ratio [OR] = 1.86; P = 0.04) and SBA (0.27/10,000; OR = 6.91; P = 0.001) in Groningen and a higher incidence of SBA in Gelderland (0.13/10,000; OR = 3.35; P = 0.03). IBA incidence was 68% higher in rural (0.67/10,000) versus urban areas (0.40/10,000) (P = 0.02). The estimated month of conception of patients with SBA clustered in November (85% increase compared to average SBA incidence [0.09/10,000; P = 0.04]). Conclusions IBA incidence correlated weakly with national confirmed infections. IBA and SBA incidence varied geographically in the Netherlands. IBA incidence was higher in rural than in urban areas, which may be explained decreased exposure to pathogens. Our results provide support for a role of environmental factors in the pathogenesis of IBA.

Introduction Studies report contradicting results on the incidence of infantile hypertrophic pyloric stenosis (IHPS) and its association with seasons. We aim to assess the IHPS incidence in the Netherlands and to determine whether seasonal variation is present in a nationwide cohort. Materials and Methods All infants with IHPS hospitalized in the Netherlands between 2007 and 2017 were included in this retrospective cohort study. Incidence rates per 1,000 livebirths (LB) were calculated using total number of LB during the matched month, season, or year, respectively. Seasonal variation based on month of birth and month of surgery was analyzed using linear mixed model and one-way ANOVA, respectively. Results A total of 2,479 infants were included, of which the majority was male (75.9%). Median (interquartile range) age at surgery was 34 (18) days. The average IHPS incidence rate was 1.28 per 1,000 LB (variation: 1.09–1.47 per 1,000 LB). We did not find a conclusive trend over time in IHPS incidence. Differences in incidence between season of birth and season of surgery were not significant (p = 0.677 and p = 0.206, respectively). Conclusion We found an average IHPS incidence of 1.28 per 1,000 LB in the Netherlands. Our results showed no changing trend in incidence and no seasonal variation.

BackgroundNecrotizing enterocolitis (NEC) is a devastating disease that is relatively frequently diagnosed in term infants with congenital heart disease (CHD), compared with term infants without CHD, in whom NEC is rare. The exact pathogenesis of NEC in term infants with CHD is unknown, but it is hypothesized that ischemia of the intestines plays a pivotal role. We aimed to explore whether (near) term CHD infants, who develop NEC, exhibit more clinical signs of hypoxia/ischemia and low body perfusion directly after birth and during the first 48 hours after admission to the neonatal intensive care unit, when compared with (near) term CHD infants who did not develop NEC.Methods956 infants with CHD born after ≥ 35 weeks of gestational age were retrospectively reviewed for this case-control study between January 1999 and February 2020. We included infants with radiographically confirmed pneumatosis intestinalis and controls matched by type of CHD. Seven infants were diagnosed with transposition of the great arteries, six with left and four with right ventricular outflow tract obstruction. Several parameters suggestive of (relative) hypoxia/ischemia were used for analyses.ResultsWe included sixteen CHD infants with NEC and selected sixteen controls. There were no significant demographic differences between both groups. Apgar score at one and five minutes (median [IQR]) were lower in infants who developed NEC compared with control infants (8 [7-8]) vs. (9 [8-9],P = .011) and (8 [8-9]) vs. (9 [9-10],P = .009). A higher proportion of infants with NEC required respiratory support in the delivery room (11(69) vs. 2(13),P = .001). The (median [IQR]) diastolic blood pressure on the second day after admission (39 mmHg [34–42], vs. 43 mmHg [37–51],P = .112) and lowest (median [IQR]) pH in the 48 hours after admission (7.24 [7.17–7.35] vs. 7.38 ([7.27–7.43],P = .157) were not significantly lower in NEC infants but both demonstrated a similar direction towards (relative) hypoxia/ischemia in NEC infants.ConclusionsOur clinical results support a hypoxic/ischemic pathophysiology of NEC in (near) term CHD infants, with lower Apgar scores, more respiratory support in the delivery room and a tendency towards a lower diastolic blood pressure and pH in CHD infants who develop NEC.

BACKGROUND: Anemia is associated with decreased tissue oxygenation in preterm infants and may contribute to developing necrotizing enterocolitis (NEC). We aimed to investigate whether hemoglobin level is associated with intestinal injury, by comparing anemic infants 10 days prior to red blood cell (RBC) transfusion with non-anemic controls.METHODS: A nested case-control study in which we matched anemic preterms (gestational age (GA) < 32 weeks) with non-anemic controls (1:1), based on GA, birth weight (BW), and postnatal age. We measured urinary intestinal fatty acid-binding protein, I-FABP, marker for intestinal injury, twice weekly. Simultaneously, we assessed splanchnic oxygen saturation (rsSO2) and rsSO2 variability.RESULTS: Thirty-six cases and 36 controls were included (median GA 27.6 weeks, BW 1020 grams). Median I-FABP level was higher in cases from 6 days to 24-h before transfusion (median ranging: 4749-8064 pg/ml versus 2194-3751 pg/ml). RsSO2 and rsSO2 variability were lower in cases than controls shortly before transfusion. Hemoglobin levels correlated negatively with rsSO2 and rsSO2 variability in cases, and negatively with I-FABP in cases and controls together.CONCLUSIONS: Urinary I-FABP levels were higher in anemic infants before RBC transfusion than in non-anemic matched controls, suggesting intestinal injury associated with anemia. This may predispose to NEC in some anemic preterm infants.IMPACT: Anemia is a common comorbidity in preterm infants and may lead to impaired splanchnic oxygen saturation and intestinal tissue hypoxia, a proposed mechanism for NEC. Lower hemoglobin level is associated with higher urinary I-FABP levels, a marker for intestinal injury, both in anemic preterm infants and in cases and controls together. Lower splanchnic oxygen saturation and reduction of its variability are associated with higher urinary I-FABP levels in anemic preterm infants before their first RBC transfusion. These results support the hypothesis that anemia in very preterm infants results in intestinal cell injury, which may precede NEC development in some.

Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/β-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-α while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future.

Background Intra-abdominal hypertension is frequently present in critically ill patients and is an independent predictor for mortality. Risk factors for intra-abdominal hypertension and abdominal compartment syndrome have been widely investigated. However, data are lacking on prevalence and outcome in high-risk patients. Our objectives in this study were to investigate prevalence and outcome of intra-abdominal hypertension and abdominal compartment syndrome in high-risk patients in a prospective, observational, single-center cohort study. Results Between March 2014 and March 2016, we included 503 patients, 307 males (61%) and 196 females (39%). Patients admitted to the intensive care unit with a diagnosis of pancreatitis, elective or emergency open abdominal aorta surgery, orthotopic liver transplantation, other elective or emergency major abdominal surgery and trauma were enrolled. One hundred and sixty four (33%) patients developed intra-abdominal hypertension and 18 (3.6%) patients developed abdominal compartment syndrome. Highest prevalence of abdominal compartment syndrome occurred in pancreatitis (57%) followed by orthotopic liver transplantation (7%) and abdominal aorta surgery (5%). Length of intensive care stay increased by a factor 4 in patients with intra-abdominal hypertension and a factor 9 in abdominal compartment syndrome, compared to patients with normal intra-abdominal pressure. Rate of renal replacement therapy was higher in abdominal compartment syndrome (38.9%) and intra-abdominal hypertension (8.2%) compared to patients with normal intra-abdominal pressure (1.2%). Both intensive care mortality and 90-day mortality were significantly higher in intra-abdominal hypertension (4.8% and 15.2%) and abdominal compartment syndrome (16.7% and 38.9%) compared to normal intra-abdominal pressure (1.2% and 7.1%). Body mass index (odds ratio 1.08, 95% confidence interval 1.03–1.13), mechanical ventilation at admission (OR 3.52, 95% CI 2.08–5.96) and Apache IV score (OR 1.03, 95% CI 1.02–1.04) were independent risk factors for the development of intra-abdominal hypertension or abdominal compartment syndrome. Conclusions The prevalence of abdominal compartment syndrome was 3.6% and the prevalence of intra-abdominal hypertension was 33% in this cohort of high-risk patients. Morbidity and mortality increased when intra-abdominal hypertension or abdominal compartment syndrome was present. The patient most at risk of IAH or ACS in this high-risk cohort has a BMI > 30 kg/m2 and was admitted to the ICU after emergency abdominal surgery or with a diagnosis of pancreatitis.

Much about the aetiology, pathophysiology, natural course and optimal treatment of choledochal malformation remains under debate. Surgeons continuously strive to optimize their roles in the management of choledochal malformation. Nowadays the standard treatment is complete cyst excision followed by Rouxen-Y hepaticojejunostomy, be it via a laparotomy, laparoscopy or robot-assisted procedure. Whatever surgical endeavor is undertaken, it will be a major operation, with significant morbidity. It is important to realize that especially in asymptomatic cases, this is considered prophylactic surgery, aimed at preventing symptoms but even more important the development of malignancy later in life. A clear overview of long-term outcomes is therefore necessary. This paper aims to review the long-term outcomes after surgery for choledochal malformation. We will focus on biliary complications such as cholangitis, the development of malignancy and quality of life. We will try and identify factors related to a worse outcome. Finally, we make a plea for a large scale study into quality and course of life after resection of a choledochal malformation, to help patients, parents and their treating physicians to come to a well-balanced decision regarding the treatment of a choledochal malformation. (C) 2020 The Authors. Published by Elsevier Inc.

Nutrient requirements of preterm neonates may be substantial, to support growth and maturation processes in the presence of challenging post-natal circumstances. This may be accompanied by substantial intestinal oxygen requirements. Preterm neonates may not be able to meet these oxygen requirements, due to a developmental delay in intestinal oxygenation regulation mechanisms. This review summarizes the available literature on post-natal maturation of intestinal oxygenation mechanisms and translates these changes into clinical observations and potential implications for preterm neonates. The different mechanisms that may be involved in regulation of intestinal oxygenation, regardless of post-natal age, are first discussed. The contribution of these mechanisms to intestinal oxygenation regulation is then evaluated in newborn and mature intestine. Finally, the course of clinical observations is used to translate these findings to potential implications for preterm neonates.

Near-infrared spectroscopy is used in the assessment of regional splanchnic oxygen saturation (rWe included infants with gestational age (GA)32 weeks and/or birth weight1200 g. We excluded infants who developed necrotizing enterocolitis or sepsis or who died. In the first week after birth, we determined a daily 2-h mean of rWe included 220 infants. On day 1, the mean ± SD rWe established reference values of rRegional splanchnic oxygen saturation is lower in infants with a lower gestational age and in small-for-gestational age infants. Regional splanchnic oxygen saturation decreases with a higher postnatal age until day 4 after birth and then increases until day 7 after birth. Gestational age, postnatal age, and small-for-gestational age status affect regional splanchnic oxygen saturation and need to be taken into account when interpreting regional splanchnic oxygen saturations using NIRS. Reference values for infant regional splanchnic oxygen saturation can be computed with a formula based on these variables, as provided by this study.

We aimed to investigate whether splanchnic tissue oxygen saturation (rWe retrospectively included infants with suspected NEC, gestational age32 weeks and/or birth weight1200 g in the first 3 weeks after birth. We calculated mean rOf the 75 infants, 21 (28%) had NEC (Bell's stage ≥2). Characteristics of infants with and without NEC differed only on mechanical ventilation and nil-per-os status. RUsing NIRS, high SCOR may confirm NEC and high variability of rNear-infrared spectroscopy may contribute to the diagnosis of necrotizing enterocolitis. When clinical signs are present a high splanchnic-cerebral oxygenation may indicate necrotizing enterocolitis. A low splanchnic-cerebral oxygenation ratio and high variability of splanchnic tissue oxygen saturation may rule out necrotizing enterocolitis. Whether a bedside real-time availability of the splanchnic-cerebral oxygenation ratio and variability of splanchnic tissue oxygen saturation improves NEC diagnosis needs to be further investigated.

Background: Intestinal recovery after NEC is difficult to predict in individuals. We evaluated whether several biomarkers predict intestinal recovery after NEC in preterm infants. Methods: We measured intestinal tissue oxygen saturation (rintSO2) and collected urinary intestinal-fatty acid binding protein (I-FABPu) levels 0–24 h and 24–48 h after NEC onset, and before and after the first re-feed. We assessed intestinal recovery in two ways: time to full enteral feeding (FEFt; below or equal/above group’s median) and development of post-NEC complications (recurrent NEC/post-NEC stricture). We determined whether the rintSO2, its range, and I-FABPu differed between groups. Results: We included 27 preterm infants who survived NEC (Bell’s stage ≥ 2). Median FEFt was 14 [IQR: 12–23] days. Biomarkers only predicted intestinal recovery after the first re-feed. Mean rintSO2 ≥ 53% combined with mean rintSO2range ≥ 50% predicted FEFt < 14 days with OR 16.7 (CI: 2.3–122.2). The rintSO2range was smaller (33% vs. 51%, p < 0.01) and I-FABPu was higher (92.4 vs. 25.5 ng/mL, p = 0.03) in case of post-NEC stricture, but not different in case of recurrent NEC, compared with infants without complications. Conclusion: The rintSO2, its range, and I-FABPu after the first re-feed after NEC predicted intestinal recovery. These biomarkers have potential value in individualizing feeding regimens after NEC.

Contains fulltext : 229851.pdf (Publisher’s version ) (Open Access) BACKGROUND AND AIMS: Patients with a choledochal malformation, formerly described as cysts, are at increased risk of developing a cholangiocarcinoma and resection is recommended. Given the low incidence of choledochal malformation (CM) in Western countries, the incidence in these countries is unclear. Our aim was to assess the incidence of malignancy in CM patients and to assess postoperative outcome. METHODS: In a nationwide, retrospective study, all adult patients who underwent surgery for CM between 1990 and 2016 were included. Patients were identified through the Dutch Pathology Registry and local patient records and were analysed to determine the incidence of malignancy, as well as postoperative mortality and morbidity. RESULTS: A total of 123 patients with a CM were included in the study (Todani Type I, n = 71; Type II, n = 10; Type III, n = 3; Type IV, n = 27; unknown, n = 12). Median age was 40 years (range 18-70) and 81% were female. The majority of patients (99/123) underwent extrahepatic bile duct resection, with additional liver parenchyma resections in eight patients, only exploration in two, and a local cyst resection in eight patients. Postoperative 30-day mortality was 2% (2/123) and limited to patients who underwent liver resection. Severe morbidity occurred in 24%. In 14 of the 123 patients (11%), a malignancy was found in the resected specimen. One patient developed a periampullary malignancy 7 years later. CONCLUSIONS: In a large Western series of CM patients, 11% were found to have a malignancy. This justifies resection in these patients, despite the risk of morbidity (24%) and mortality (2%).

Objective To assess intestinal and cerebral oxygenation during and after red blood cell (RBC) transfusions in preterms with or without subsequent transfusion-associated necrotizing enterocolitis (TANEC). Study Design In preterms of Results In TANEC infants, rcSO2 was lower during and after RBC transfusions than in controls, median (interquartile range) 55% (50–62) versus 72% (65–75), p Conclusion In preterm infants lower rcSO2, but not rintSO2, values during and after RBC transfusions are associated with TANEC. Lower rintSO2 and rcSO2 variabilities after RBC transfusions may represent a diminished capacity for vascular adaptation, possibly leading to TANEC.

BACKGROUND: Preterm infants requiring surgery are at risk of impaired neurocognitive development caused, possibly, by cerebral ischemia associated with impaired cerebrovascular autoregulation (CAR). We evaluated CAR before, during, and after laparotomy.STUDY DESIGN: This was a hypothesis generating prospective observational cohort study.SUBJECTS: We included preterm infants requiring surgery for necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). Before, during, and after surgery we measured cerebral oxygen saturation using NIRS and calculated cerebral fractional tissue oxygen extraction (cFTOE).OUTCOME MEASURES: Impaired CAR was defined if correlation coefficients (rho) between mean cFTOE and mean arterial blood pressure values were ≤-0.30 with P RESULTS: Nineteen infants with median (IQR) GA 27.6 weeks (26.6-31.0), birth weight 1090 g (924-1430), and postnatal age 9 days (7-12) were included. CAR was impaired more often during surgery than before (12 versus 3, P = .02) or after (12 versus 0, P CONCLUSIONS: More than half of preterm infants with NEC or SIP displayed evidence of impaired CAR during laparotomy. Further research should focus on mechanisms contributing to impaired CAR in preterm infants during surgery.

Introduction Portal hypertension often occurs in biliary atresia (BA). The subsequent development of esophageal varices and bleeding from these varices are a well-known complication. We aim to describe the incidence and severity of variceal bleeding in patients with BA. In addition, we describe the characteristics of patients who experienced variceal bleeds. Materials and Methods We included all infants treated for BA at our center between March 1987 and August 2015. Variceal bleeding was defined as hematemesis and/or melena with presence of varices at endoscopy. Findings at endoscopy and ultrasound, laboratory tests, clearance of jaundice, fibrosis-grade at Kasai portoenterostomy, and several varices prediction scores were documented. Routine endoscopies were not performed. Results In this study, 74 patients were included. During follow-up, 18 out of 74 patients (24%) developed variceal bleeding at an age of 9 months (range, 4–111). Twelve patients were listed for liver transplantation at the time of bleeding. Patients who did not clear their jaundice developed variceal bleeds more often and earlier in life. Bleeds were treated with sclerotherapy, banding, or octreotide. Four patients did not receive treatment. No bleeding-related mortality occurred. Conclusion One-fourth of the children diagnosed with BA experience variceal bleeds during follow-up. Most of these children are younger than 1 year and often already listed for transplantation. Major complications did not occur after variceal bleeding.

Background The factors that determine the effect of enteral feeding on intestinal perfusion after preterm birth remain largely unknown. We aimed to determine the effect of enteral feeding on intestinal oxygen saturation (rintSO2) in preterm infants and evaluated whether this effect depended on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. We also evaluated whether changes in postprandial rintSO2 affected cerebral oxygen saturation (rcSO2). Methods In a longitudinal observational pilot study using near-infrared spectroscopy we measured rintSO2 and rcSO2 continuously for two hours on postnatal Days 2 to 5, 8, 15, 22, 29, and 36. We compared preprandial with postprandial values over time using multi-level analyses. To assess the effect of PNA, PMA, and feeding volumes, we performed Wilcoxon signed-rank tests or logistic regression analyses. To evaluate the effect on rcSO2, we also used logistic regression analyses. Results We included 29 infants: median (range) gestational age 28.1 weeks (25.1–30.7) and birth weight 1025 g (580–1495). On Day 5, rintSO2 values decreased postprandially: mean (SE) 44% (10) versus 35% (7), P = .01. On Day 29, rintSO2 values increased: 44% (11) versus 54% (7), P = .01. Infants with a PMA ≥ 32 weeks showed a rintSO2 increase after feeding (37% versus 51%, P = .04) whereas infants with a PMA intSO2 (per 10 mL/kg: OR 1.63, 95% CI, 1.02–2.59). We did not find an effect on rcSO2 when rintSO2 increased postprandially. Conclusions Our study suggests that postprandial rintSO2 increases in preterm infants only from the fifth week after birth, particularly at PMA ≥ 32 weeks when greater volumes of enteral feeding are tolerated. We speculate that at young gestational and postmenstrual ages preterm infants are still unable to increase intestinal oxygen saturation after feeding, which might be essential to meet metabolic demands. Trial registration For this prospective longitudinal pilot study we derived patients from a larger observational cohort study: CALIFORNIA-Trial, Dutch Trial Registry NTR4153.

Intestinal recovery after NEC is difficult to predict in individuals. We evaluated whether several biomarkers predict intestinal recovery after NEC in preterm infants.We measured intestinal tissue oxygen saturation (rWe included 27 preterm infants who survived NEC (Bell's stage ≥ 2). Median FEFt was 14 [IQR: 12-23] days. Biomarkers only predicted intestinal recovery after the first re-feed. Mean rThe r

Background and aim: Predicting necrotizing enterocolitis (NEC) might help in preventing its devastating consequences. We aimed to investigate whether early cerebral and intestinal tissue oxygen saturation (rSO(2)) and fractional tissue oxygen extraction (FTOE) predict the onset of NEC.Study design: Prospective observational case-control study.Subjects: Infants with gestational age (GA) Outcome measures: Cerebral oxygenation and intestinal oxygenation were prospectively monitored two-hours daily during the first five days after birth and once a week thereafter until five weeks after birth or until NEC developed. We used Kaplan-Meier analyses to determine the ability of near-infrared spectroscopy (NIRS) measurements, including their variability, to predict the development of NEC.Results: We included ten infants (median (range) GA 27.1 (24.6-29.4) weeks, BW 903 (560-1630) grams) who developed NEC at median postnatal day 13 (range: 4-43 days), and 20 matched controls. Infants with cerebral rSO(2) = 70% (odds ratio 9.00 (95% CI 1.33-61.14). Intestinal FTOE was higher in infants who developed NEC compared to controls during the last NIRS measurement at median 2 days (range: 1-7) before NEC onset (median 0.65 vs. 0.44).Conclusions: Cerebral oxygenation monitoring early after birth might be valuable in the risk assessment of NEC development. Additionally, our results suggest that intestinal oxygenation is impaired before the onset of clinical NEC.