Infant formulas for the treatment of functional gastrointestinal disorders: A position paper of the ESPGHAN Nutrition Committee.

Functional gastrointestinal disorders (FGID), such as infant regurgitation, infant colic, and functional constipation, are common and typically physiological phenomena during the early months of an infant's life and account for frequent consultations with pediatricians. Various infant formulas are marketed for their management and are frequently given by parents to infants before a medical consultation. However, the evidence supporting their effectiveness is limited and some have altered nutritional compositions when compared to standard formulas. Thus, these products should only be used under medical supervision and upon medical advice. Marketing and over-the-counter sales do not ensure proper medical guidance and supervision. The aim of this position paper is to review the current evidence regarding the safety and efficacy of formulas specifically formulated for addressing regurgitation, colic, and constipation, recognized as FGID. The objective is to provide guidance for clinical management based on the highest quality of available evidence. A wide search using Pubmed, MEDLINE, EMBASE and Cochrane Database of Systematic Reviews was performed including the MESH terms infant formula, colic, constipation, regurgitation, reflux, palmitate, lactase, lactose, magnesium, hydrolyzed protein, prebiotics or probiotics. 752 papers were identified and screened. Finally, 72 papers were included in the paper. In the absence of evidence, recommendations reflect the authors' combined expert opinion. Final consensus was obtained by multiple e-mail exchange and meetings of the Nutrition Committee. (1) For breastfed infants experiencing FGID such as regurgitation, colic, or constipation, transitioning from breastfeeding to commercial formulas is not recommended. (2) In general, whether an infant is breastfed or formula-fed, it's crucial to reassure parents that FGIDs are normal and typically do not necessitate treatment or change to a special formula. (3) Thickened formulas, often termed anti-reflux formulas, may be considered in specific cases of regurgitation. (4) The usage of specialized formulas for infants with colic is not advised due to a lack of clinical evidence. (5) In the case of constipation in infants, the use of formulas enriched with high ß-palmitate and increased magnesium content may be considered to soften the stool. Generally, there is limited evidence supporting the use of specialized formulas for FGID. Breastfeeding should never be discontinued in favor of formula feeding.

Long-term evaluation of faecal calprotectin levels in a European cohort of children with cystic fibrosis.

OBJECTIVE: Intestinal inflammation with contradictory data on faecal calprotectin (fCP) levels is documented in patients with cystic fibrosis (CF). The aim of this study was to longitudinally evaluate fCP in a cohort of children with CF and their relationship with clinical variables. DESIGN: Prospective observational study to assess evolution of fCP levels, primary aimed at improving fat absorption. Along 1.5 years of follow-up (November 2016-May 2018) with four study visits pertaining to a pilot study (two of four) and to a clinical trial (two of four), the study outcomes were measured. SETTING: Six European CF centres in the context of MyCyFAPP Project. SUBJECTS: Children with CF and pancreatic insufficiency (2-18 years old). MAIN OUTCOME MEASUREMENTS: fCP levels, pulmonary function (percentage of forced expiratory volume in 1 s (FEV1%)) and coefficient of fat absorption (CFA). Additionally, in the last two visits, gastrointestinal (GI) symptoms were evaluated through the PedsQL-GI Questionnaire. Linear mixed regression models were applied to assess association between fCP and FEV1, CFA and GI symptoms. RESULTS: Twenty-nine children with CF and pancreatic insufficiency were included. fCP levels were inversely associated with total modified specific PedsQL-GI score (p=0.04) and positively associated with diarrhoea (p=0.03), but not with CFA. Along the four study visits, fCP significantly increased (from 62 to 256 µg/g) and pulmonary function decreased (from 97% to 87%), with a significant inverse association between the two study outcomes (p<0.001). CONCLUSIONS: In children with CF, fCP levels are inversely associated with pulmonary function and thus the specificity of fCP as a marker of intestinal inflammation in paediatric patients with CF warrants further investigation.

Children with Intestinal Failure are at Risk for Psychopathology and Trauma.

OBJECTIVES: The objective of this study is to assess the psychopathology and medical traumatic stress in children with intestinal failure (IF) and identify associated risk factors. METHODS: Two-center study, performed from September 2019 until April 2022 (partly during COVID-19 pandemic), including children (1.5-17 years) with IF, dependent on parenteral nutrition (PN) or weaned off PN, treated by a multidisciplinary IF-team. Psychopathology in children was evaluated with a semi-structured interview assessing psychiatric classifications and validated questionnaires assessing emotional (internalizing) and behavioral (externalizing) problems. Medical traumatic stress was assessed with a validated questionnaire. Problem scores were compared with normative data. Associations between clinical characteristics and outcomes were analyzed with linear regression analyses. RESULTS: Forty-one (of 111 eligible) children were included [median age 8.9 years (interquartile range, IQR 5.5-11.8), 54% female, 73% born preterm]. Median PN-duration was 17.3 months (IQR 6.9-54.0); 17 children (41%) were still PN-dependent. One third of the children met criteria for at least 1 psychiatric classification (compared with 14% in age-matched general population). Anxiety disorders and attention deficit hyperactivity disorder were most common. In school-aged children (n = 29, 6-17 years), significantly increased emotional problems were consistently reported by children ( P = 0.011), parents ( P < 0.001), and teachers ( P = 0.004). In preschool children (n = 12, 1.5-5 years), no significant differences with normative data were found. Subclinical or clinical emotional problems were reported in 19 children (46%). Medical traumatic stress was present in 14%, and 22% of children had received psychological help for trauma before. Lower gastrointestinal related quality of life was associated with more emotional problems, but not PN-duration. CONCLUSIONS: Children with IF, particularly school-aged children, are at risk for psychological problems which is reflected by the high rate of received psychotherapy and the high rate of emotional problems and psychiatric classifications.

Gastrointestinal Biomarkers and Their Association with Feeding in the First Five Days of Pediatric Critical Illness.

OBJECTIVES: Predicting the patients' tolerance to enteral nutrition (EN) would help clinicians optimize individual nutritional intake. This study investigated the course of several gastrointestinal (GI) biomarkers and their association with EN advancement (ENA) longitudinally during pediatric intensive care unit (PICU) admission. METHODS: This is a secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric Intensive Care Unit randomized controlled trial. EN was started early and increased gradually. The cholecystokinin (CCK), leptin, glucagon, intestinal fatty acid-binding protein 2 (I-FABP2), and citrulline plasma concentrations were measured upon PICU admission, day 3 and day 5. ENA was defined as kcal EN provided as % of predicted resting energy expenditure. The course of the biomarkers and ENA was examined in patients with samples on all time points using Friedman and Wilcoxon signed-rank tests. The association of ENA with the biomarkers was examined using a 2-part mixed-effects model with data of the complete population, adjusted for possible confounders. RESULTS: For 172 patients, median age 8.6 years (first quartile; third quartile: 4.2; 13.4), samples were available, of which 55 had samples on all time points. The median ENA was 0 (0; 0) on admission, 14.5 (0.0; 43.8) on day 3, and 28.0 (7.6; 94.8) on day 5. During PICU stay, CCK and I-FABP2 concentrations decreased significantly, whereas glucagon concentrations increased significantly, and leptin and citrulline remained stable. None of the biomarkers was longitudinally associated with ENA. CONCLUSIONS: Based on the current evidence, CCK, leptin, glucagon, I-FABP2, and citrulline appear to have no added value in predicting ENA in the first 5 days of pediatric critical illness.

Challenges in body composition assessment using air-displacement plethysmography by BOD POD in pediatric and young adult patients.

BACKGROUND & AIMS: Air-Displacement-Plethysmography (ADP) by BOD POD is widely used for body fat assessment in children. Although validated in healthy subjects, studies about use in pediatric patients are lacking. We evaluated user experience and usability of ADP measurements with the BOD POD system in healthy children and pediatric and young adult patients. METHODS: Using the experiences of seven cohort studies, which included healthy children and patients aged 2-22 years, we retrospectively evaluated the user experience with the User Experience Questionnaire (UEQ) (n = 13) and interviews (n = 7). Technical performance was studied using the quality control data collected by the ADP-system. RESULTS: From 2016 to 2022, 1606 measurements were scheduled. BOD POD was mostly rated 'user-friendly', with a generally neutral evaluation on all scales of the UEQ. However, questionable reliability and validity of the results were frequently (86%) reported. We found a high technical failure-rate of the device, predominantly in stability (17%) and accuracy of the measurement (12%), especially in the 'pediatric option' for children aged <6 years. Measurement failure-rate was 38%, mostly due to subject's fear or device failure, especially in young and lean children, and in children with physical and/or intellectual disabilities. CONCLUSION: We conclude that ADP by BOD POD in children and young adults is non-invasive and user-friendly. However, in specific pediatric populations, BOD POD has several limitations and high (technical) failure-rates, especially in young children with aberrant body composition. We recommend caution when interpreting body composition results of pediatric patients as assessed with BOD POD using the current default settings.

Enteral Nutrition in Preterm Infants (2022): A Position Paper From the ESPGHAN Committee on Nutrition and Invited Experts.

OBJECTIVES: To review the current literature and develop consensus conclusions and recommendations on nutrient intakes and nutritional practice in preterm infants with birthweight <1800 g. METHODS: The European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee of Nutrition (CoN) led a process that included CoN members and invited experts. Invited experts with specific expertise were chosen to represent as broad a geographical spread as possible. A list of topics was developed, and individual leads were assigned to topics along with other members, who reviewed the current literature. A single face-to-face meeting was held in February 2020. Provisional conclusions and recommendations were developed between 2020 and 2021, and these were voted on electronically by all members of the working group between 2021 and 2022. Where >90% consensus was not achieved, online discussion meetings were held, along with further voting until agreement was reached. RESULTS: In general, there is a lack of strong evidence for most nutrients and topics. The summary paper is supported by additional supplementary digital content that provide a fuller explanation of the literature and relevant physiology: introduction and overview; human milk reference data; intakes of water, protein, energy, lipid, carbohydrate, electrolytes, minerals, trace elements, water soluble vitamins, and fat soluble vitamins; feeding mode including mineral enteral feeding, feed advancement, management of gastric residuals, gastric tube placement and bolus or continuous feeding; growth; breastmilk buccal colostrum, donor human milk, and risks of cytomegalovirus infection; hydrolyzed protein and osmolality; supplemental bionutrients; and use of breastmilk fortifier. CONCLUSIONS: We provide updated ESPGHAN CoN consensus-based conclusions and recommendations on nutrient intakes and nutritional management for preterm infants.

The Use of Blended Diets in Children With Enteral Feeding Tubes: A Joint Position Paper of the ESPGHAN Committees of Allied Health Professionals and Nutrition.

OBJECTIVES: This joint position paper of the Committees of Allied Health Professionals (CAHP) and Nutrition (CON) of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) provides a comprehensive guide for health professionals to manage blended diets in children via gastrostomy tubes. METHODS: A systematic literature search was performed from 1992 to 2021 using Pubmed, MEDLINE, and Cochrane Database of Systematic Reviews and recent guidelines reviewed. In the absence of evidence, recommendations reflect the authors' expert opinion. Final consensus was obtained by multiple e-mail exchange and virtual meetings of the CAHP and CON. RESULTS: Reported benefits of blended diets include reduced GERD and infections, improved defecation, level of alertness and attention span, skin conditions, and appearance of hair and nails. Families report a sense of greater normality. Small case series, cross-sectional surveys, questionnaire-based small case studies, reports of personal experience, and single-center pilot studies are available in the medical literature. A total of 20 recommendations for practice were made based on the results and consensus process. CONCLUSIONS: There is little evidence published to formally inform about the potential health benefits or risks of this practice and how to use it in the best way. This leaves health professionals caring for such patients in a relative vacuum regarding what to consider when providing a duty of care to patients and carers who wish to pursue this method of feeding. This article provides guidelines for safe and appropriate use of a BD, but more research is needed.

TFAP2B Haploinsufficiency Impacts Gastrointestinal Function and Leads to Pediatric Intestinal Pseudo-obstruction.

Background: Pediatric Intestinal Pseudo-obstruction (PIPO) is a congenital enteric disorder characterized by severe gastrointestinal (GI) dysmotility, without mechanical obstruction. Although several genes have been described to cause this disease, most patients do not receive a genetic diagnosis. Here, we aim to identify the genetic cause of PIPO in a patient diagnosed with severe intestinal dysmotility shortly after birth. Methods: Whole exome sequencing (WES) was performed in the patient and unaffected parents, in a diagnostic setting. After identification of the potential disease-causing variant, its functional consequences were determined in vitro and in vivo. For this, expression constructs with and without the causing variant, were overexpressed in HEK293 cells. To investigate the role of the candidate gene in GI development and function, a zebrafish model was generated where its expression was disrupted using CRISPR/Cas9 editing. Results: WES analysis identified a de novo heterozygous deletion in TFAP2B (NM_003221.4:c.602-5_606delTCTAGTTCCA), classified as a variant of unknown significance. In vitro studies showed that this deletion affects RNA splicing and results in loss of exon 4, leading to the appearance of a premature stop codon and absence of TFAP2B protein. Disruption of tfap2b in zebrafish led to decreased enteric neuronal numbers and delayed transit time. However, no defects in neuronal differentiation were detected. tfap2b crispants also showed decreased levels of ednrbb mRNA, a downstream target of tfap2b. Conclusion: We showed that TFAP2B haploinsufficiency leads to reduced neuronal numbers and GI dysmotility, suggesting for the first time, that this gene is involved in PIPO pathogenesis.

Ghrelin Levels in Children With Intestinal Failure Receiving Long-Term Parenteral Nutrition.

Background: Children with intestinal failure (IF) require parenteral nutrition (PN). Transition to oral and enteral nutrition (EN) can be difficult also due to abnormal gastrointestinal motility. The gut hormone ghrelin is increased in states of negative energy balance, functioning to preserve euglycemia, and also has appetite stimulating and prokinetic properties. We aimed to evaluate and compare ghrelin levels in children with IF, and to assess the relationship with PN-dependency. Methods: In this exploratory prospective multicenter study, plasma acylated (AG) and unacylated (UAG) ghrelin levels were measured in children with short bowel syndrome (SBS) and with functional IF (pseudo-obstruction or any enteropathy) and compared with healthy control subjects. Spearman's rho (rs) was used to assess correlations of AG and UAG with PN-dependency (%PN) and parenteral glucose intake. Results: Sixty-four samples from 36 IF-patients were analyzed. Median baseline AG and UAG levels were respectively 279.2 and 101.0 pg/mL in children with SBS (n = 16), 126.4 and 84.5 pg/mL in children with functional IF (n = 20) and 82.4 and 157.3 pg/mL in healthy children (n = 39). AG levels were higher in children with SBS and functional IF than in healthy children (p = 0.002 and p = 0.023, respectively). In SBS, AG positively correlated with %PN (rs = 0.5, p = 0.005) and parenteral glucose intake (rs = 0.6, p = 0.003). These correlations were not observed in functional IF. Conclusion: Children with IF had raised AG levels which could be related to starvation of the gut. The positive correlation between AG and glucose infusion rate in SBS suggests an altered glucoregulatory function.

Venous Thromboembolic Complications in Pediatric Gastrointestinal Diseases: Inflammatory Bowel Disease and Intestinal Failure.

In children with gastrointestinal disorders such as inflammatory bowel disease (IBD) and intestinal failure (IF), the risk of venous thromboembolism (VTE) is increased. VTE may lead to pulmonary embolism, sepsis and central line infection, stroke and post-thrombotic syndrome. The purpose of this review is to summarize current knowledge and recent advances around VTE management in pediatric gastroenterology with a focus on IBD and IF. The VTE incidence in children with IBD is reported to be around 4-30 per 10,000 patient-years, with higher incidences for hospitalized children. While in general, IF is less common than IBD, the VTE incidence in children with IF is around 750 per 10,000 patient-years. The most common risk factors for development of VTE involve deviations leading to Virchow's triad (endothelial damage, stasis, and hypercoagulability) and include active inflammation, particularly with colonic involvement, presence of a central venous catheter, underlying thrombophilia, reduced mobility, surgery, and hospitalization. Classes of anticoagulants used for treatment of VTE are low molecular weight heparins and vitamin K antagonists. However, the use of direct oral anticoagulants for treatment or prevention of VTE has not been studied in this pediatric population yet. Pediatric gastroenterologists apply different VTE prevention and treatment strategies due to lack of literature and lack of consensus. We discuss the role of primary and secondary prophylactic use of anticoagulants, and provide tools and recommendations for screening, prevention and management for the specific pediatric populations.

Cognitive Outcomes in Children With Conditions Affecting the Small Intestine: A Systematic Review and Meta-analysis.

OBJECTIVES: The aim of the study was to assess cognitive outcomes in children with intestinal failure (IF) and children at high risk of IF with conditions affecting the small intestine requiring parenteral nutrition. METHODS: EMBASE, Cochrane, Web of Science, Google Scholar, MEDLINE, and PsycINFO were searched from inception to October 2020. Studies were included constituting original data on developmental quotient (DQ), intelligence quotient (IQ) and/or severe developmental delay/disability (SDD) rates assessed with standardized tests. We used appropriate standardized tools to extract data and assess study quality. We performed random effects meta-analyses to estimate pooled means of DQ/IQ and pooled SDD rates (general population mean for DQ/IQ: 100, for percentage with SDD: 1.8%) for 4 groups: IF, surgical necrotizing enterocolitis (NEC), abdominal wall defects (AWD), and midgut malformations (MM). Associations of patient characteristics with DQ/IQ were evaluated with meta-regressions. RESULTS: Thirty studies met the inclusion criteria. The pooled mean DQ/IQ for IF, NEC, AWD, and MM were 86.8, 83.3, 96.6, and 99.5, respectively. The pooled SDD rates for IF, NEC, AWD and MM were 28.6%, 32.8%, 8.5%, and 3.7%, respectively. Meta-regressions indicated that lower gestational age, longer hospital stay, and higher number of surgeries but not parenteral nutrition duration, were associated with lower DQ/IQ. CONCLUSIONS: Adverse developmental outcomes are common in children with IF and NEC, and to a much lesser extent in children with AWD and MM. It is important to monitor cognitive development in children with conditions affecting the small intestine and to explore avenues for prevention and remediation.

Necrotizing Enterocolitis in a Dutch Cohort of Very Preterm Infants: Prevalence, Mortality, and Long-Term Outcomes.

INTRODUCTION: To improve counseling of parents and to guide care strategies, we studied the disease course and outcomes of necrotizing enterocolitis (NEC) up to 2 years of corrected age (CA) from a multidisciplinary perspective. MATERIALS AND METHODS: This was a retrospective cohort study in preterm infants (birth weight < 1,500 g, gestational age < 32 weeks), diagnosed with NEC (Bell's stage ≥ II) from 2008 through 2020. Data on prevalence, mortality, surgery, intestinal failure (IF), growth, and neurodevelopment at 2-year follow-up were separately analyzed for medically and surgically treated children. RESULTS: Of 3,456 preterm infants, 200 (6%) were diagnosed with NEC, of whom 135 developed an indication for surgery within 7 days after the diagnosis; 28/135 died before surgery, and 37/107 died after an open-and-close procedure. An enterostomy was constructed in 62 patients and an end-to-end anastomosis in 15. The postoperative course was described for 77 patients, of whom 23 developed surgical complications (12/23 incisional hernias, 9/23 anastomotic strictures), 13/77 a short bowel, and 25/77 IF. Sixty-day survival after birth for medical NEC patients was 88% (hazard ratio [HR]: 0.698; p = 0.318), and for surgically treated NEC patients was 40% (HR: 3.729; p < 0.001). At 2-year follow-up, one patient received parenteral nutrition. Severe delay in weight for age, motor, and cognitive development was seen in 3, 6, and 2%, respectively. CONCLUSION: In this cohort, the mortality rate was high, especially in surgically treated NEC patients. The surgical complication rate is comparable to previous studies, but in surviving patients, persisting IF and severe delay in growth and neurodevelopment at 2 years CA were relatively rare.

Gut microbiota and its diet-related activity in children with intestinal failure receiving long-term parenteral nutrition.

BACKGROUND: This study characterized gut microbiota and its diet-related activity in children with intestinal failure (IF) receiving parenteral nutrition (PN) compared with those of healthy controls (HC) and in relation to disease characteristics. METHODS: The fecal microbiota and short-chain fatty acids (SCFAs) were measured in 15 IF patients (n = 68) and 25 HC (n = 25). RESULTS: Patients with IF had a lower bacterial load (P = .003), diversity (P < .001), evenness (P < .001) and richness (P = 0.006) than HC. Patients with surgical IF had lower diversity (P < .039) than those with functional IF. Propionic acid and butyric acid (p < .001) were lower and d-lactate and l-lactate were higher (p < 0.001) in IF patients than in HC. The energy supplied by PN (%PN) was negatively associated with microbiota diversity and SCFA profile. IF patients had more Escherichia-Shigella (P = .006), Cronobacter (P = .001), and Staphylococcus (Operational Taxonomic Unit 14, P < .001) and less Faecalibacterium (P < 0.001) and Ruminococcus 1 and 2 (P < .001). Duration of PN (P = .005), %PN (P = .005), and fiber intake (P = .011) were predictive of microbiota structure. Higher intake of enteral nutrition was associated with microbiota structure and function closer to those of HC. CONCLUSIONS: Microbiota composition and its diet-related function are altered in IF, with depletion of beneficial SCFAs and species and supraphysiological increase of potentially harmful pathobionts. The influence of this compositional and functional microbial dysbiosis on patients' outcomes and management warrants further exploration.

Anthropometrics and fat mass, but not fat-free mass, are compromised in infants requiring parenteral nutrition after neonatal intestinal surgery.

BACKGROUND: Children with intestinal failure (IF) receiving long-term parenteral nutrition (PN) have altered body composition (BC), but data on BC changes from start of PN onwards are lacking. OBJECTIVES: We aimed to assess growth and BC in infants after neonatal intestinal surgery necessitating PN and at risk of IF, and to explore associations with clinical parameters. METHODS: A prospective cohort study in infants after intestinal surgery. IF was defined as PN dependency for >60 d. SD scores (SDS) for anthropometry were calculated until 6-mo corrected age. In a subgroup, fat mass (FM) and fat-free mass (FFM) were measured with air-displacement plethysmography at 2- and 6-mo corrected age. SDS for length-adjusted FM index and FFM index were calculated. Associations between cumulative amount of PN and BC parameters were analyzed with linear mixed-effect models. RESULTS: Ninety-five neonates were included (54% male, 35% born <32 wk) and 39 infants (41%) had IF. Studied infants had compromised anthropometric parameters during follow-up. At 6-mo corrected age, they remained smaller (median weight-for-age SDS -0.9 [IQR -1.5, 0.1], P < 0.001) than the normal population. In 57 infants, 93 BC measurements were performed. FM index SDS was lower than in healthy infants at 2- and 6-mo corrected age (-0.9 [-1.6, -0.3], P < 0.001 and -0.7 [-1.3, 0.1], P = 0.001, respectively), but FFM index SDS did not differ. A higher cumulative amount of PN predicted a higher FM index in female infants but lower FM index in male infants. CONCLUSIONS: In this cohort of infants receiving PN after intestinal surgery, compromised anthropometrics, decreased FM, and adequate FFM were observed during the first 6 mo. Male and female infants seemed to respond differently to PN when it comes to FM index. Continuing growth monitoring after the age of 6 mo is strongly recommended, and further research should explore the benefit of incorporating ongoing BC monitoring during follow-up.

Longitudinal Development of Health-related Quality of Life and Fatigue in Children on Home Parenteral Nutrition.

OBJECTIVES: The aim of the study was to describe the longitudinal development of health-related quality of life (HRQOL) and fatigue in children with chronic intestinal failure (CIF) on home parenteral nutrition (PN) and compare these children to the general population. METHODS: Prospective, observational study conducted over 7 years in patients suffering from CIF receiving home PN from 2 tertiary hospitals in the Netherlands. Every 6 months, parents (if child <8 years old) or patients (if child ≥8 years old) completed 2 questionnaires: Pediatric Quality of Life Inventory 4.0 (PedsQL) Generic and Fatigue on the KLIK (kwaliteit van leven in kaart [Dutch Acronym for Quality of Life in Clinical Practice]) Patient Reported Outcome Measures portal, which were compared with the general population. Linear mixed models (LMMs) were constructed to investigate the course of HRQOL over time. RESULTS: Thirty-five patients were included (40% girls). At time of last KLIK contact, patients received HPN for a median of 5.3 years (interquartile range [IQR]: 2.9-9.7). In total, 272 questionnaires were completed. PedsQL generic total score for ages 5 to 7 and 8 to 12 years was significantly lower than the general population (P < 0.01 for both age groups) with effect sizes of 0.73 and 0.71, respectively. PedsQL fatigue total score for ages 5 to 7 years was also significantly lower (P = 0.01; effect size 0.70). LMMs for PedsQL Generic and Fatigue total score 2 to 7 and 8 to 18 years showed no significant coefficient for duration of home PN. CONCLUSIONS: Children suffering from CIF receiving home PN ages 5 to 12 years report lower HRQOL scores than the general population. HRQOL and fatigue do not change during long-term treatment with home PN in these children.

Role of Dietary Factors, Food Habits, and Lifestyle in Childhood Obesity Development: A Position Paper From the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition.

ABSTRACT: Childhood obesity has high societal and economic impact but current treatment approaches are sub-optimal. In the last decade, important studies have been conducted aiming to identify strategies to prevent obesity during critical periods of life. Updated recommendations for childhood obesity prevention are needed. We present data from systematic reviews and meta- analysis, randomised controlled trials (RCTs) and large observational studies, published from 2011 onwards that consider the possible role of the following factors in obesity development: breast-feeding; macronutrient composition and method of complementary feeding; parenting style; dietary patterns; sugar-sweetened beverage consumption; eating behaviour (eg, skipping breakfast, family dinners. etc); meal frequency and composition (fast foods, snacking), portion size; dietary modulators of gut microbiota (including pre-, pro-, and synbiotics); physical activity and sedentary behaviour. We used the Medline database and the Cochrane Library to search for relevant publications. Important research gaps were also identified. This position paper provides recommendations on dietary factors, food habits, and lifestyle to prevent childhood obesity development, based on the available literature and expert opinion. Clinical research and high-quality trials are urgently needed to resolve numerous areas of uncertainty.

Nutritional Management of the Critically Ill Neonate: A Position Paper of the ESPGHAN Committee on Nutrition.

OBJECTIVES: The nutritional management of critically ill term neonates and preterm infants varies widely, and controversies exist in regard to when to initiate nutrition, mode of feeding, energy requirements, and composition of enteral and parenteral feeds. Recommendations for nutritional support in critical illness are needed. METHODS: The ESPGHAN Committee on Nutrition (ESPGHAN-CoN) conducted a systematic literature search on nutritional support in critically ill neonates, including studies on basic metabolism. The Medline database and the Cochrane Library were used in the search for relevant publications. The quality of evidence was reviewed and discussed before voting on recommendations, and a consensus of 90% or more was required for the final approval. Important research gaps were also identified. RESULTS: This position paper provides clinical recommendations on nutritional support during different phases of critical illness in preterm and term neonates based on available literature and expert opinion. CONCLUSION: Basic research along with adequately powered trials are urgently needed to resolve key uncertainties on metabolism and nutrient requirements in this heterogeneous patient population.

Exome sequencing in patient-parent trios suggests new candidate genes for early-onset primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole-exome sequencing (WES) has contributed to understanding the molecular basis of very early-onset IBD, but rare protein-altering genetic variants have not been identified for early-onset PSC. We performed WES in patients diagnosed with PSC ≤ 12 years to investigate the contribution of rare genetic variants to early-onset PSC. METHODS: In this multicentre study, WES was performed on 87 DNA samples from 29 patient-parent trios with early-onset PSC. We selected rare (minor allele frequency < 2%) coding and splice-site variants that matched recessive (homozygous and compound heterozygous variants) and dominant (de novo) inheritance in the index patients. Variant pathogenicity was predicted by an in-house developed algorithm (GAVIN), and PSC-relevant variants were selected using gene expression data and gene function. RESULTS: In 22 of 29 trios we identified at least 1 possibly pathogenic variant. We prioritized 36 genes, harbouring a total of 54 variants with predicted pathogenic effects. In 18 genes, we identified 36 compound heterozygous variants, whereas in the other 18 genes we identified 18 de novo variants. Twelve of 36 candidate risk genes are known to play a role in transmembrane transport, adaptive and innate immunity, and epithelial barrier function. CONCLUSIONS: The 36 candidate genes for early-onset PSC need further verification in other patient cohorts and evaluation of gene function before a causal role can be attributed to its variants.

Association between faecal pH and fat absorption in children with cystic fibrosis on a controlled diet and enzyme supplements dose.

BACKGROUND: Despite treatment with pancreatic enzyme replacement therapy (PERT), patients with cystic fibrosis (CF) can still suffer from fat malabsorption. A cause could be low intestinal pH disabling PERT. The aim of this study was to assess the association between faecal pH (as intestinal pH surrogate) and coefficient of fat absorption (CFA). Additionally, faecal free fatty acids (FFAs) were quantified to determine the amount of digested, but unabsorbed fat. METHODS: In a 24-h pilot study, CF patients followed a standardised diet with fixed PERT doses, corresponding to theoretical optimal doses determined by an in vitro digestion model. Study variables were faecal pH, fat and FFA excretion, CFA and transit time. Linear mixed regression models were applied to explore associations. RESULTS: In 43 patients, median (1st, 3rd quartile) faecal pH and CFA were 6.1% (5.8, 6.4) and 90% (84, 94), and they were positively associated (p < 0.001). An inverse relationship was found between faecal pH and total fat excretion (p < 0.01), as well as total FFA (p = 0.048). Higher faecal pH was associated with longer intestinal transit time (p = 0.049) and the use of proton pump inhibitors (p = 0.009). CONCLUSIONS: Although the clinical significance of faecal pH is not fully defined, its usefulness as a surrogate biomarker for intestinal pH should be further explored. IMPACT: Faecal pH is a physiological parameter that may be related to intestinal pH and may provide important physiopathological information on CF-related pancreatic insufficiency. Faecal pH is correlated with fat absorption, and this may explain why pancreatic enzyme replacement therapy is not effective in all patients with malabsorption related to CF. Use of proton pump inhibitors is associated to higher values of faecal pH. Faecal pH could be used as a surrogate biomarker to routinely monitor the efficacy of pancreatic enzyme replacement therapy in clinical practice. Strategies to increase intestinal pH in children with cystic fibrosis should be targeted.