The short-term effects of RBC transfusions on intestinal injury in preterm infants.

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 (rsSO2) and rsSO2 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 rsSO2 variability, but not higher mean rsSO2 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.

Gene expression in the intestine of newborn piglets after hypoxia-reoxygenation.

BACKGROUND: In preterm infants, intestinal hypoxia may partly contribute to the pathophysiology of necrotizing enterocolitis through changes in gene expression. Splanchnic hypoxia can be detected with monitoring of regional splanchnic oxygen saturation (rsSO2). Using a piglet model of asphyxia, we aimed to correlate changes in rsSO2 to gene expression. METHODS: Forty-two newborn piglets were randomized to control or intervention groups. Intervention groups were subjected to hypoxia until they were acidotic and hypotensive. Next, they were reoxygenated for 30 min according to randomization, i.e., 21% O2, 100% O2, or 100% O2 for 3 min followed by 21% O2, and observed for 9 h. We continuously measured rsSO2 and calculated mean rsSO2 and variability of rsSO2 (rsCoVar = SD/mean). Samples of terminal ileum were analyzed for mRNA expression of selected genes related to inflammation, erythropoiesis, fatty acid metabolism, and apoptosis. RESULTS: The expression of selected genes was not significantly different between control and intervention groups. No associations between mean rsSO2 and gene expression were observed. However, lower rsCoVar was associated with the upregulation of apoptotic genes and the downregulation of inflammatory genes (P < 0.05). CONCLUSION: Our study suggests that hypoxia and reoxygenation cause reduced vascular adaptability, which seems to be associated with the upregulation of apoptosis and downregulation of inflammation. IMPACT: Our results provide important insight into the (patho)physiological significance of changes in the variability of rsSO2. Our findings may advance future research and clinical practice regarding resuscitation strategies of preterm infants.

Intestinal Oxygenation and Survival After Surgery for Necrotizing Enterocolitis: An Observational Cohort Study.

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 <35% died. Median C-reactive protein [138 mg/L (IQR: 83-179) vs 73 mg/L (IQR: 12-98), P < 0.01), lactate [1.1 mmol/L (IQR: 1.0-1.6) vs 4.6 mmol/L (IQR: 2.8-8.0), P < 0.01], and fraction of inspired oxygen [25% (IQR: 21-31) vs 42% (IQR: 30-80), P < 0.01] differed between survivors and non-survivors. Only rintSO2 remained significant in the multiple regression model. 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.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. 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 insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: 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 PPTMs), 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 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Neonatal anemia relates to intestinal injury in preterm infants.

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.

Prevalence of inflicted and neglectful femur shaft fractures in young children in national level I trauma centers.

BACKGROUND: The prevalence of inflicted femur fractures in young children varies (1.5-35.2%), but these data are based on small retrospective studies with high heterogeneity. Age and mobility of the child seem to be indicators of inflicted trauma. OBJECTIVE: This study describes other factors associated with inflicted and neglectful trauma that can be used to distinguish inflicted and neglectful from accidental femur fractures. MATERIALS AND METHODS: This retrospective study included children (0-6 years) who presented with an isolated femur fracture at 1 of the 11 level I trauma centers in the Netherlands between January 2010 and January 2016. Outcomes were classified based on the conclusions of the Child Abuse and Neglect teams or the court. Cases in which conclusions were unavailable and there was no clear accidental cause were reviewed by an expert panel. RESULTS: The study included 328 children; 295 (89.9%) cases were classified as accidental trauma. Inflicted trauma was found in 14 (4.3%), while 19 (5.8%) were cases of neglect. Indicators of inflicted trauma were age 0-5 months (29%, positive likelihood ratio [LR +] 8.35), 6-12 months (18%, LR + 5.98) and 18-23 months (14%, LR + 3.74). Indicators of neglect were age 6-11 months (18%, LR + 4.41) and age 18-23 months (8%, LR + 1.65). There was no difference in fracture morphology among groups. CONCLUSION: It is unlikely that an isolated femur fracture in ambulatory children age > 24 months is caused by inflicted trauma/neglect. Caution is advised in children younger than 24 months because that age is the main factor associated with inflicted trauma/neglect and inflicted femur fractures.

Weight shapes the intestinal microbiome in preterm infants: results of a prospective observational study.

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.

Near-infrared spectroscopy as a diagnostic tool for necrotizing enterocolitis in preterm infants.

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 <32 weeks and/or birth weight <1200 g in the first 3 weeks after birth. We calculated mean rsSO2, cerebral tissue oxygen saturation (rcSO2), variability of rsSO2 (coefficients of variation [rsCoVAR] = SD/mean), and splanchnic-cerebral oxygenation ratio ([SCOR] = rsSO2/rcSO2) in the period around the abdominal radiograph to confirm or reject NEC. 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.

Regional splanchnic oxygen saturation for preterm infants in the first week after birth: reference values.

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) <32 weeks and/or birth weight <1200 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 rsSO2 to assess its associations with sex, GA, postnatal age (PNA), small-for-gestational age (SGA) status, patent ductus arteriosus, hemoglobin, nutrition, and head circumference at birth and translated those into a prediction model. 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.

Early Motor Repertoire in Infants With Biliary Atresia: A Nationwide Prospective Cohort Study.

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 <36 and MOS <26 as atypical, and compared the results with 2 reference groups of healthy peers. RESULTS: We assessed GMs in 35 infants with BA (11/35 boys, gestational age 40 weeks [36-42], birth weight 3370 g [2015-4285]). At time of diagnosis (PMA 47 weeks [42-60]), 16 infants (46%) showed atypical GMs. The proportion of infants with atypical GMs was significantly higher in BA (46%) than in 2 reference groups of healthy infants (vs 10%, P < 0.001; vs 18%, P < 0.001). Total and direct bilirubin levels were 165 µmol/L (87-364) and 134 µmol/L (72-334), respectively, height z score was 0.05 (-2.90, 1.75), weight z score -0.52 ([-2.50, -0.20) and mean upper arm circumference z score -1.80 (-2.50, -0.20). We found no statistically significant relation between atypical GMs and clinical variables. CONCLUSIONS: Almost half of the infants with BA showed atypical GMs at time of diagnosis, suggesting neurological impairment. Close monitoring of these infants is warranted to determine their individual neurodevelopmental trajectories.

A Higher Incidence of Isolated Biliary Atresia in Rural Areas: Results From an Epidemiological Study in The Netherlands.

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.

High prevalence of non-accidental trauma among deceased children presenting at Level I trauma centers in the Netherlands.

PURPOSE: Between 0.1-3% of injured children who present at a hospital emergency department ultimately die as a result of their injuries. These events are typically reported as unnatural causes of death and may result from either accidental or non-accidental trauma (NAT). Examples of the latter include trauma that is inflicted directly or resulting from neglect. Although consultation with a forensic physician is mandatory for all deceased children, the prevalence of fatal inflicted trauma or neglect among children is currently unclear. METHODS: This is a retrospective study that included children (0-18 years) who presented and died at one of the 11 Level I trauma centers in the Netherlands between January 1, 2014, and January 1, 2019. Outcomes were classified based on the conclusions of the Child Abuse and Neglect team or those of forensic pathologists and/or the court in cases referred for legally mandated autopsies. Cases in which conclusions were unavailable and there was no clear accidental cause of death were reviewed by an expert panel. RESULTS: The study included 175 cases of childhood death. Seventeen (9.7%) of these children died due to inflicted trauma (9.7%), 18 (10.3%) due to neglect, and 140 (80%) due to accidents. Preschool children (< 5 years old) were significantly more likely to present with injuries due to inflicted trauma and neglect compared to older children (44% versus 6%, p < 0.001, odds ratio [OR] 5.80, 95% confidence interval [CI] 2.66-12.65). Drowning accounted for 14 of the 18 (78%) pediatric deaths due to neglect, representing 8% of the total cases. Postmortem radiological studies and autopsies were performed on 37 (21%) of all cases of childhood death. CONCLUSION: One of every five pediatric deaths in our nationwide Level I trauma center study was attributed to NAT; 44% of these deaths were the result of trauma experienced by preschool-aged children. A remarkable number of fatal drownings were due to neglect. Postmortem radiological studies and autopsies were performed in only one-fifth of all deceased children. The limited use of postmortem investigations may have resulted in missed cases of NAT, which will result in an overall underestimation of fatal NAT experienced by children.

Evidence for a rebalanced hemostatic system in pediatric liver transplantation: A prospective cohort study.

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.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Long-Term Neurodevelopmental Outcomes in Children with Biliary Atresia.

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 < .01). Motor outcomes were significantly affected compared with the norm population (P < .01), with 25% normal (vs 85%), 25% borderline (vs 10%), and 50% low scores (vs 5%). Total IQ was lower in patients with biliary atresia, compared with the norm population (91 ± 18 vs 100 ± 15; P < .01). There were no significant differences in test scores between children with native liver and after liver transplantation. CONCLUSIONS: School-aged children with biliary atresia show neurodevelopmental impairments compared with the norm population, especially in motor skills. Our data strongly warrant evaluation of neurodevelopmental intervention programs to assess whether long-term outcomes could be improved.

Choledochal malformations in adults in the Netherlands: Results from a nationwide retrospective cohort study.

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%).

Predicting intestinal recovery after necrotizing enterocolitis in preterm infants.

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.

Quality of Life in Parents of Children With Biliary Atresia.

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 ±â€ŠSD or median [min-max]. RESULTS: We included 61 parents of 39 children (aged 11 ±â€Š3 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 < 0.001) compared with reference data, but a stronger family cohesion (85 [30-100] vs 60 [30-100], P = 0.05). Scores on parental QoL, anxiety and stress were similar to reference data. Fathers (16.0 [11-19]) and mothers (15.4 ±â€Š1.4) scored higher on the psychological domain compared with reference data (vs 14.7 ±â€Š2.2, P < 0.01). There was no significant difference in QoL of parents with children with native liver or those who had undergone LTx. Older age and high anxiety trait in parents were adversely associated with physical QoL. Household income below &OV0556;35 000/year and high anxiety trait were adversely associated with environmental QoL. CONCLUSIONS: QoL in parents of school-aged children with BA appears to be unaffected. Parents with high-anxiety personality trait, older age, and low household income are at increased risk of impaired QoL.

Hypoxic/ischemic hits predispose to necrotizing enterocolitis in (near) term infants with congenital heart disease: a case control study.

BACKGROUND: Necrotizing 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. METHODS: 956 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. RESULTS: We 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. CONCLUSIONS: Our 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.