Clinical outcomes in pediatric inflammatory bowel disease patients: a systematic review of prospective studies.

BACKGROUND AND AIM: We studied response and remission rates in children and adolescents with inflammatory bowel disease whose real-world data were collected prospectively. METHODS: A systematic literature search was performed in MEDLINE, Embase, and the Improve Care Now registry from inception until March 17, 2022. Inclusion criteria were prospective studies with patients < 18 years at diagnosis (M0) and minimum follow-up of 1 year (M12) mentioning disease phenotype and disease activity. Exclusion criteria were (i) reporting disease activity only at diagnosis, (ii) retrospective studies, and (iii) outcome limited to steroid-free remission. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and the Newcastle-Ottawa scale were applied. Proportions between groups were compared using a chi-square test (α = 0.05). RESULTS: The search yielded 394 records and 7 inclusions with a sample size ranging from 33 to 390 patients (total population: 888) and a median follow-up of 1-5 years. Proportions of disease activity differed between M0 and M12 (P < 0.0001) with more inactive (χ2  = 5.5) and less moderate-to-severe disease (χ2  = 23) at M12. Interestingly, disease activity after 1 year did not differ globally (P = 0.53). Proportions of disease activity in Crohn's disease only and limited to Belgium significantly differed from baseline after 5 years (P < 0.0001 for evolution) but not between 1- and 5-year follow-up (P = 0.94). CONCLUSIONS: The few available prospective cohorts reported a significant decrease in disease activity after 1 year, with no global differences. Proportions of disease activity did not differ between 1- and 5-year follow-up in the Belgian Crohn's disease cohort, suggesting stable disease activity.

Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination for Paediatric Patients With Inflammatory Bowel Diseases.

ABSTRACT: In this communication, the members of the Porto group (the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN], inflammatory bowel diseases [IBD] working group) provide the current available evidence regarding vaccination of children and young adolescents with IBD against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our intent is to help provide meaningful answers to the concerns that parents and adolescents may have.

Long-Term Safety and Efficacy of Prebiotic Enriched Infant Formula-A Randomized Controlled Trial.

The present study aims to evaluate the effects of an infant formula supplemented with a mixture of prebiotic short and long chain inulin-type oligosaccharides on health outcomes, safety and tolerance, as well as on fecal microbiota composition during the first year of life. In a prospective, multicenter, randomized, double-blind study, n = 160 healthy term infants under 4 months of age were randomized to receive either an infant formula enriched with 0.8 g/dL of Orafti®Synergy1 or an unsupplemented control formula until the age of 12 months. Growth, fever (>38 °C) and infections were regularly followed up by a pediatrician. Digestive symptoms, stool consistency as well as crying and sleeping patterns were recorded during one week each study month. Fecal microbiota and immunological biomarkers were determined from a subgroup of infants after 2, 6 and 12 months of life. The intention to treat (ITT) population consisted of n = 149 infants. Both formulae were well tolerated. Mean duration of infections was significantly lower in the prebiotic fed infants (p < 0.05). The prebiotic group showed higher Bifidobacterium counts at month 6 (p = 0.006), and higher proportions of Bifidobacterium in relation to total bacteria at month 2 and 6 (p = 0.042 and p = 0.013, respectively). Stools of infants receiving the prebiotic formula were softer (p < 0.05). Orafti®Synergy1 tended to beneficially impact total daily amount of crying (p = 0.0594). Supplementation with inulin-type prebiotic oligosaccharides during the first year of life beneficially modulates the infant gut microbiota towards higher Bifidobacterium levels at the first 6 months of life, and is associated with reduced duration of infections.

Health Literacy and Quality of Life in Young Adults From The Belgian Crohn's Disease Registry Compared to Type 1 Diabetes Mellitus.

Background and Aims: The management of chronic inflammatory bowel diseases in youth is challenging. We aimed to determine health literacy (HL), quality of life (QoL) and clinical outcomes in young adults from the BELgian CROhn's disease registry (BELCRO) in comparison to type 1 diabetes mellitus (DM) as a control. Methods: In this prospective and observational study, young adults with Crohn's disease (CD) diagnosed < 18 years and with > 5 years disease duration and a comparable group of patients with DM completed validated HL, QoL and work productivity and activity impairment questionnaires (HLS-EU-Q16, EQ-5D-5L and WPAI). HL was scored as sufficient (13-16), problematic (9-12) or inadequate (0-8). QoL was dichotomized into "no problems" (EQ-5D level 1) or "problems" (EQ-5D levels 2 to 5). Non-parametric (Mann-Whitney U) analyses and Spearman correlations were performed. Results: A total of 52 CD (median [IQR] age of 25.0 [23.8-27.0], 64% male) and 50 DM (age 20.0 [19.0-22.0], 50% male) patients were included. HL was 14.0 [11.0-16.0] for CD and 14.0 [11.3-14.8] for DM (p = 0.6) with similar proportions of sufficient (60 vs. 68%, p = 0.4), problematic (34 vs. 26%, p = 0.3) and inadequate HL (both 6%, p = 1). Although QoL was comparable for CD and DM (77.0 [68.8-82.0] vs. 75.0 [65.0-80.0] %, p =0.4), CD had a trend for higher pain/discomfort (50 vs. 32%, p = 0.06). HL and QoL correlated in CD (r = 0.6, p < 0.001) and DM patients (r = 0.6, p < 0.001). Fewer CD patients with recent hospitalization/surgery had sufficient HL (31 vs. 69%, p = 0.01) and had lower QoL (70.0 [60.0-77.0] vs. 80.0 [70.0-85.0], p = 0.04) compared to those without. Conclusions: Selected young Belgian adults suffering from CD for >5 years have similar and sufficient HL compared to DM patients. However, CD patients requiring hospitalization/surgery have lower HL, which indicates the need for targeted educational programs.

Identifying Health Economic Considerations to Include in the Research Protocol of a Randomized Controlled Trial (the REDUCE-RISK Trial): Systematic Literature Review and Assessment.

BACKGROUND: The REDUCE-RISK trial was set up to compare the effectiveness of weekly subcutaneously administered methotrexate with daily oral azathioprine or 6-mercaptopurine in low-risk Crohn disease (CD) or subcutaneously administered adalimumab (ADA) in high-risk CD in a pediatric population (age 6-17 years). OBJECTIVE: The aim of this study is to perform a systematic review to provide input into the research protocol to gather the necessary information to improve the performance of an evidence-based economic evaluation when the trial is finished. METHODS: The Centre for Reviews and Dissemination (CRD) Health Technology Assessment (HTA) database, websites of HTA institutes, CRD's National Health Service Economic Evaluation Database, MEDLINE (OVID), and Embase databases were consulted to retrieve (reviews of) relevant economic evaluations. Studies were eligible if they included a pediatric or adult population with inflammatory bowel diseases (CD and ulcerative colitis [UC]) treated with ADA (Humira). There were no restrictions on the comparator. Only economic evaluations expressing outcomes in life years gained or quality-adjusted life years gained were selected. RESULTS: A total of 12 primary studies were identified. None of these studies included a pediatric population because of a lack of supporting trials. The economic evaluations identified in our systematic review indicate that ADA is an appropriate intervention for inclusion in such a trial. From a health economic point of view, it is important to make an incremental analysis comparing such an intervention with standard care and not immediately versus another (expensive) biological treatment. Information on the impact of children's school attendance and parents' productivity is currently lacking in economic evaluations, and none of the underlying trials measured quality of life (QoL) using a generic utility instrument. CONCLUSIONS: The review of the economic literature on ADA for the treatment of patients with CD supports the performance of a trial with biologicals in pediatric patients, including making a distinction according to disease severity. Conducting an economic literature review enabled us to decide which variables should be added to the research protocol from an economic point of view. Measurements for children's and parents' QoL (EuroQol 5-Dimension questionnaires), children's school attendance, and parents' productivity (WPAI-CD-CG questionnaire) were added to the research protocol. This will provide support for the calculation of the cost-effectiveness of the interventions evaluated in the REDUCE-RISK trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02852694; https://clinicaltrials.gov/ct2/show/NCT02852694.

Protocol for a multinational risk-stratified randomised controlled trial in paediatric Crohn's disease: methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or high risk for aggressive disease course.

INTRODUCTION: Immunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn's disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups. AIMS: To compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation. METHODS AND ANALYSIS: REDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6-17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk). ETHICS AND DISSEMINATION: ClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access. TRIAL REGISTRATION NUMBER: NCT02852694; Pre-results.

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study.

INTRODUCTION: Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient's development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors. METHODS AND ANALYSIS: In this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease <18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent's smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up. ETHICS AND DISSEMINATION: Medical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications. TRIAL REGISTRATION NUMBER: NCT03571373.

A Review on the Use of Anti-TNF in Children and Adolescents with Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) presents with disabling symptoms and may lead to insufficient growth and late pubertal development in cases of disease onset during childhood or adolescence. During the last decade, the role of anti-tumor necrosis factor (TNF) in the treatment of paediatric-onset IBD has gained more ground. The number of biologicals presently available for children and adolescents with IBD has increased, biosimilars have become available, and practices in adult gastroenterology with regards to anti-TNF have changed. The aim of this study is to review the current evidence on the indications, judicious use, effectiveness and safety of anti-TNF agents in paediatric IBD. A PubMed literature search was performed and included articles published after 2000 using the following terms: child or paediatric, Crohn, ulcerative colitis, inflammatory bowel disease, anti-TNF, TNF alpha inhibitor, infliximab, adalimumab, golimumab and biological. Anti-TNF agents, specifically infliximab and adalimumab, have proven to be effective in moderate and severe paediatric IBD. Therapeutic drug monitoring increases therapy effectiveness and safety. Clinical predictors for anti-TNF response are currently of limited value because of the variation in outcome definitions and follow-ups. Future research should comprise large cohorts and clinical trials comparing groups according to their risk profile in order to provide personalized therapeutic strategies.

Nutrition in Pediatric Inflammatory Bowel Disease: A Position Paper on Behalf of the Porto Inflammatory Bowel Disease Group of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition.

BACKGROUND AND AIMS: A growing body of evidence supports the need for detailed attention to nutrition and diet in children with inflammatory bowel disease (IBD). We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of pediatric IBD patients. METHODS: A group of 20 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to Nutrition Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Porto, IBD Interest, and Nutrition Committee. A list of 41 predefined questions was addressed by working subgroups based on a systematic review of the literature. RESULTS: A total of 53 formal recommendations and 47 practice points were endorsed with a consensus rate of at least 80% on the following topics: nutritional assessment; macronutrients needs; trace elements, minerals, and vitamins; nutrition as a primary therapy of pediatric IBD; probiotics and prebiotics; specific dietary restrictions; and dietary compounds and the risk of IBD. CONCLUSIONS: This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD.

Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Immunosuppressive therapy for inflammatory bowel disease (IBD) in pediatric patients is thought to increase the risk of malignancy and lymphoproliferative disorders, including hemophagocytic lymphohistiocytosis (HLH). We compared unadjusted incidence rates of malignancy and HLH in pediatric patients with IBD exposed to infliximab (IFX) with patients not exposed to biologics and calculated standardized incidence ratios (SIRs). METHODS: We collected and analyzed data from 5766 participants in a prospective study of long-term outcomes of pediatric patients with IBD (NCT00606346), from May 31, 2007 through June 30, 2016. Patients were 17 years old or younger and had Crohn's disease, ulcerative colitis, or IBD-unclassified with 24,543.0 patient-years of follow-up. We estimated incidence rates for malignancy and HLH as events/1000 patient-years of follow-up. We calculated age-, sex-, and race-adjusted SIRs, with 95% confidence intervals (CIs), using the Surveillance, Epidemiology, and End Results Program (SEER) database. RESULTS: Thirteen of the 15 patients who developed a malignancy and all 5 of the patients who developed HLH had been exposed to thiopurines; 10 patients with malignancy had also been exposed to a biologic agent. Unadjusted incidence rates showed no increased risk of malignancy (0.46/1000 patient-years) or HLH (0.0/1000 patient-years) in patients exposed to IFX as the only biologic vs those unexposed to biologics (malignancy: 1.12/1000 patient-years; HLH: 0.56/1000 patient-years). SIRs did not demonstrate an increased risk of malignancy among patients exposed to IFX (SIR, 1.69; 95% CI, 0.46-4.32) vs patients not exposed to a biologic agent (SIR, 2.17; 95% CI, 0.59-5.56), even when patients were stratified by thiopurine exposure. CONCLUSIONS: In determination of age-, sex-, and race-adjusted SIRs using data from a large clinical study and the SEER database, we found that IFX exposure did not associate with increased risk of malignancy or HLH in pediatric patients with IBD. Thiopurine exposure is an important precedent event for the development of malignancy or HLH in pediatric patients with IBD.

Treatment Options and Outcomes of Pediatric IBDU Compared with Other IBD Subtypes: A Retrospective Multicenter Study from the IBD Porto Group of ESPGHAN.

BACKGROUND: Inflammatory bowel disease unclassified (IBDU) is the rarest IBD subtype with treatment based on extrapolation from ulcerative colitis (UC) and Crohn's disease (CD) studies. We compared IBDU treatment choices with other colonic IBDs and explored long-term outcomes. METHODS: This was a multicenter retrospective longitudinal study of 23 centers of pediatric IBD with isolated colitis, including a mild ileitis consistent with backwash. RESULTS: Of note, 797 children (median age: 11.6 years, range: 2-18.4) were included: 250 with CD, 287 with UC, and 260 with IBDU (median follow-up: 2.8 [interquartile range: 1.6-4.2] years). IBDU differed from UC with lower corticosteroid (154 [59%] versus 204 [71%]; P = 0.004) and higher exclusive enteral nutrition use (26 [10%] versus 2 [0.6%]; P < 0.0001). Compared to patients with CD, patients with IBDU received less exclusive enteral nutrition and immunomodulators (26 [10%] versus 93 [37%]; P < 0.0001 and 67 [26%] versus 129 [52%]; P < 0.0001, respectively) but more aminosalicylates (228 [88%] versus 159 [64%]; P < 0.0001). Biological treatment was significantly higher in CD (82 [34%]) than in IBDU and UC (24 [12%] and 47 [17%], respectively; P < 0.0001). At last follow-up, 135 (69%) patients with IBDU had remission/mild disease activity compared with 100 (46%; P < 0.0001) patients with CD and 174 (64%; P = 0.3) patients with UC. Four (2%) of 194 patients with IBDU underwent surgery compared with 22 (8%) of 270 patients with UC (P = 0.009) and 20 (8%) of 238 patients with CD (P = 0.008). CONCLUSIONS: Children with IBDU have a lower medication burden and lower surgery rates than other IBD subtypes. The disease course at follow-up is generally mild, supporting an initial trial with 5-ASA before using more aggressive therapies.

Paediatric Crohn Disease: Disease Activity and Growth in the BELCRO Cohort After 3 Years Follow-up.

OBJECTIVE: The Belgian registry for paediatric Crohn disease (BELCRO) cohort is a prospective, multicentre registry for newly diagnosed paediatric patients with Crohn disease (CD) (<18 years) recruited from 2008 to 2010 to identify predictive factors for disease activity and growth. METHODS: Data from the BELCRO database were evaluated at diagnosis, 24 and 36 months follow-up. RESULTS: At month 36 (M36), data were available on 84 of the 98 patients included at diagnosis. Disease activity evolved as follows: inactive 5% to 70%, mild 19% to 24%, and moderate to severe 76% to 6%. None of the variables such as age, sex, diagnostic delay, type of treatment, disease location, disease activity at diagnosis, and growth were associated with disease activity at M36. Paediatricians studied significantly less patients with active disease at M36 compared with adult physicians. Sixty percent of the patients had biologicals as part of their treatment at M36. Adult gastroenterologists initiated biologicals significantly earlier. They were the only factor determining biologicals' initiation, not disease location or disease severity at diagnosis. Median body mass index (BMI) z score evolved from -0.97 (range -5.5-2.1) to 0.11 (range -3.4-2) and median height z score from -0.15 (range -3.4-1.6) to 0.12 (range -2.3-2.3) at M36. None of the variables mentioned above influenced growth over time. CONCLUSIONS: Present treatment strategies lead to good disease control in the BELCRO cohort after 3 years. Logistic regression analysis did not show any influence of disease location or present treatment strategy on disease activity and growth, but patients under paediatric care had significantly less severe disease at M36.

Gastric Emptying of Liquids in Children.

OBJECTIVES: The present study was performed to determine normal values for gastric half-emptying time (t1/2GE) of liquids in healthy children. METHODS: Gastric emptying (GE) of a standardized test milk-drink measured with technetium scintigraphy and the C-acetate breath test (C-ABT) was compared in 19 children ages between 4 and 15 years with upper gastrointestinal symptoms. The C-ABT was subsequently used to determine normal values for GE of the same liquid test meal in 133 healthy children ages between 1 and 17 years. RESULTS: In the group of children with upper gastrointestinal symptoms, the results showed a significant correlation (r = 0.604, P = 0.0006) between t1/2GE measured with both techniques. In the group of healthy children, the results of t1/2GE showed that there was no influence of age, sex, weight, height, and body mass index on GE. CONCLUSIONS: Normal values for GE of a standardized test milk-drink in healthy children were determined with the C-ABT. This technique is considered reliable and is well accepted by the patients.

Use of Placebo in Pediatric Inflammatory Bowel Diseases: A Position Paper From ESPGHAN, ECCO, PIBDnet, and the Canadian Children IBD Network.

Performing well-designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, 4 organizations (the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Crohn's and Colitis Organization; the Canadian Children IBD Network; and the Global Pediatric IBD Network) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94 of 100 (94%) voting committees' members that placebo should only be used if there is genuine equipoise between the active treatment and placebo; for example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an "add-on" to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. It has been, however, agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD regarding pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.

The course of anaemia in children and adolescents with Crohn's disease included in a prospective registry.

AIM: The aim of this study is to determine the prevalence and evolution of anaemia in prospectively followed children and adolescents diagnosed with Crohn's disease (CD). METHODS: The BELCRO registry (inclusion May 2008-April 2010), describing current clinical treatment practice of children diagnosed with CD, provided data on age, height, body mass index (BMI), paediatric Crohn's disease activity index (PCDAI), therapy and haemoglobin (Hb) at diagnosis 12 and 24 months follow-up. Anaemia was defined as Hb < -2 sd, while severe anaemia was defined as Hb < -4 sd. Patients were classified as child ≤13 and adolescent >13 years of age. RESULT: Ninety-six were included, 13 dropped out due to insufficient Hb data (37 females/46 males; median age 13.3 years, range 2.2-17.8 years). At diagnosis, the median Hb sd was -2.66 (-8.4; 1.07) and was correlated with the PCDAI (p = 0.013). At diagnosis, 51/83 (61%) were anaemic and all had active disease. Hb z-score significantly improved (p < 0.0001) but 26/68 (38%) remained anaemic at 12 months and 29/76 (38%) at 24 months of follow-up. The correlation to the PCDAI disappeared. At 24 months, children were more likely to be anaemic. There was no difference in iron dose nor duration of iron supplements between children and adolescents. Iron treatment was more readily given to patients presenting with anaemia. Hb did not differ between patients with (n = 28) or without iron supplements. Half of the patients with persisting anaemia were given iron supplements, of which, only three were given intravenously. CONCLUSION: Anaemia remains an important extra-intestinal manifestation of CD in children. Physicians, lacking optimal treatment strategies, undertreat their patients.

Prebiotics in infant formula.

The gastrointestinal microbiota of breast-fed babies differ from classic standard formula fed infants. While mother's milk is rich in prebiotic oligosaccharides and contains small amounts of probiotics, standard infant formula doesn't. Different prebiotic oligosaccharides are added to infant formula: galacto-oligosaccharides, fructo-oligosaccharide, polydextrose, and mixtures of these. There is evidence that addition of prebiotics in infant formula alters the gastrointestinal (GI) microbiota resembling that of breastfed infants. They are added to infant formula because of their presence in breast milk. Infants on these supplemented formula have a lower stool pH, a better stool consistency and frequency and a higher concentration of bifidobacteria in their intestine compared to infants on a non-supplemented standard formula. Since most studies suggest a trend for beneficial clinical effects, and since these ingredients are very safe, prebiotics bring infant formula one step closer to breastmilk, the golden standard. However, despite the fact that adverse events are rare, the evidence on prebiotics of a significant health benefit throughout the alteration of the gut microbiota is limited.

Public-private collaboration in clinical research during pregnancy, lactation, and childhood: joint position statement of the Early Nutrition Academy and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

This position statement summarises a view of academia regarding standards for clinical research in collaboration with commercial enterprises, focussing on trials in pregnant women, breast-feeding women, and children. It is based on a review of the available literature and an expert workshop cosponsored by the Early Nutrition Academy and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. Clinical research collaborations between academic investigators and commercial enterprises are encouraged by universities, public funding agencies, and governmental organisations. One reason is a pressing need to obtain evidence on the effects, safety, and benefits of drugs and other commercial products and services. The credibility and value of results obtained through public-private research collaborations have, however, been questioned because many examples of inappropriate research practice have become known. Clinical research in pregnant and breast-feeding women, and in infants and children, raises sensitive scientific, ethical, and societal questions and requires the application of particularly high standards. Here we provide recommendations for the conduct of public-private research collaborations in these populations. In the interest of all stakeholders, these recommendations should contribute to more reliable, credible, and acceptable results of commercially sponsored trials and to reducing the existing credibility gap.

Pediatric applications of inulin and oligofructose.

Inulin-type fructans have been used in infants and children because of their prebiotic potential to modulate the intestinal flora and influence the innate and adaptive immune response favorably. A mixture of long chain inulin (5-60 monomers) in combination with galactooligosaccharides (GOS) (2-7 monomers) has been added to infant formula in Europe in a 10-90% ratio for over 5 y. Clinical studies have demonstrated that these prebiotic formulas have significant effects on flora composition, improve stool consistency, decrease intestinal permeability, and reduce the incidence of gastrointestinal (GI) and respiratory infections and atopic dermatitis. Oligofructose in weaning foods consumed by toddlers increases fecal Bifidobacteria counts and decreases fecal Clostridia counts during consumption, leading to softer stools and fewer fever episodes and other GI symptoms. Synergy, a mixture of oligofructose and long chain inulin, is protective of the Bifidus flora during amoxicillin treatment. Few studies are available in adolescents. Calcium absorption is improved especially by Synergy. The same product, combined with Lactobacillus Rhamnosus and Acidophilus, induces significantly favorable effects on colonic ammonia (NH3) metabolism. The demonstrated bifidogenic effect of inulin and oligofructose on intestinal microbiota is probably not the only mechanism involved but may be the key to important immune mediated effects.