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Human milk composition is variable. The identification of influencing factors and interdependencies of components may help to understand the physiology of lactation. In this study, we analyzed linear trends in human milk composition over time, the variation across different European countries and the influence of maternal celiac disease. Within a multicenter European study exploring potential prevention of celiac disease in a high-risk population (PreventCD), 569 human milk samples were donated by women from five European countries between 16 and 163 days postpartum. Some 202 mothers provided two samples at different time points. Protein, carbohydrates, fat and fatty acids, insulin, adiponectin, and insulin-like growth factor II (IGF-II) were analyzed. Milk protein and n-6 long chain polyunsaturated fatty acids decreased during the first three months of lactation. Fatty acid composition was significantly influenced by the country of residence. IGF-II and adiponectin concentrations correlated with protein content ( r = 0.24 and r = 0.35), and IGF-II also correlated with fat content ( r = 0.36), suggesting a possible regulatory role of IGF in milk macronutrient synthesis. Regarding the impact of celiac disease, only the level in palmitic acid was influenced by this disease, suggesting that breastfeeding by celiac disease mothers should not be discouraged., Competing Interests: The authors declare no conflict of interest.

Purpose: To analyze the presence of total IgA and anti-gliadin antibodies (AGA) in BM from CD mothers who follow a gluten-free diet (GFD) and from mothers on a normal gluten-containing diet (ND)., Methods: 218 samples of mature milk were obtained at different months of lactation (1-6) from 83 mothers (2 or more samples per mother) from Italy (Naples), The Netherlands (Leiden) and Spain (Madrid, Valencia and Reus): 42 CD mothers on GFD for more than 2 years and 41 non-CD mothers on a ND. Whey samples were analyzed for AGA-IgA by an indirect homemade ELISA and for total IgA (g/L) by a commercial ELISA kit., Results: AGA-IgA was detected in BM, both in mothers on a GFD and mothers on a ND. AGA-IgA levels in both groups of mothers, CD and non-CD, show the same trend towards decreasing slightly along the months of lactation (p = 0.91). A different trend is observed for total IgA levels, decreasing markedly in CD mothers from the first month of lactation onwards but remaining stable in non-CD mothers (p = 0.048). A statistically significant association was found between the means of total IgA and AGA-IgA (p < 0.001)., Conclusion: AGA-IgA is present in BM from mothers on a ND as well as in BM from mothers who had been on a GFD for years. This reflects the existence of a long-lasting immunological memory independent of the mother's diet. If the presence of these antibodies has any role in promoting the acquisition of gluten tolerance in the infant, our study shows that children of CD mothers would be on equal conditions as children of non-CD mothers.

Background & Aims: Compliance to a gluten free diet (GFD) in celiac disease (CD) is ideally assessed by dietary interviews, albeit time-consuming. Short dietary questionnaires have been developed for adults but not for children. Primary aim was to compare GFD compliance in celiac children, measured by a short dietary questionnaire against a dietary interview. Secondary aims were correlation between both questionnaires and celiac antibodies and identifying variables predicting noncompliance., Methods: Between 2012 and 2014, participants in the E-health CoelKids study, completed a short dietary questionnaire and standardized dietary interview together with measurement of anti-tissue transglutaminase antibodies (TG2A). Results of the questionnaires were assigned under similar categories. Factors possibly influencing dietary compliance were recorded. Where appropriate, Pearson's Chi-square test for trend, unpaired t-test, Cohen's kappa and one-way ANOVA were used., Results: 151 of 165 participating patients were studied, 66% were female. Mean age was 11.3 years (2-26, SD 5.4), mean age at CD diagnosis was 4.9 years (1-23, SD 4.0). The short questionnaire and dietary interview correlated poorly, detecting problems in dietary adherence in 14% and 52% of the patients, respectively (Cohen's kappa 0.034). Only the short questionnaire correlated with TG2A (p = 0.003). Only older age was associated with noncompliance, the mean age of completely nonadherent, adherent but committing errors, and strictly adherent patients were 15.5, 11.5 and 10.1 years, respectively (p < 0.001)., Conclusions: Compared to the dietary interview, short dietary questionnaires and TG2A serology failed to detect dietary transgressions in CD children, wherein adolescents were shown to be at highest risk., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: Breastfeeding is beneficial for mothers and infants. Underlying mechanisms and biochemical mediators thus need to be investigated to develop and support improved infant nutrition practices promoting the child health. We analysed the relation between maternal breast milk composition and infant metabolism., Methods: 196 pairs of mothers and infants from a European research project (PreventCD) were studied. Maternal milk samples collected at month 1 and month 4 after birth were analysed for macronutrient classes, hormone, and fatty acid (FA) content. Phospholipids, acylcarnitines, and amino acids were measured in serum samples of 4-month old infants. Associations between milk components and infant metabolites were analysed with spearman correlation and linear mixed effect models (LME). P-values were corrected for multiple testing (PLME)., Results: Month 1 milk protein content was strongly associated with infant serum lyso-phosphatidylcholine (LPC) 14:0 (PLME = 0.009). Month 1 milk insulin was associated to infant acetylcarnitine (PLME = 0.01). There were no associations between milk protein content and serum amino acids and milk total fat content and serum polar lipids. Middle- and odd-chain FA% in breast milk at both ages were significantly related to serum LPC and sphingomyelins (SM) species in infant serum (all PLME<0.05), while FA% 20:5n-3 and 22:6n-3 percentages were significantly associated to serum LPC 22:6 (PLME = 1.91×10-4/7.93×10-5) in milk only at month 4. Other polyunsaturated fatty acids and hormones in milk showed only weak associations with infant serum metabolites., Conclusions: Infant serum LPC are influenced by breast milk FA composition and, intriguingly, milk protein content in early but not late lactation. LPC 14:0, previously found positively associated with obesity risk, was the serum metabolite which was the most strongly associated to milk protein content. Thus, LPC 14:0 might be a key metabolite not only reflecting milk protein intake in infants, but also relating high protein content in milk or infant formula to childhood obesity risk., Competing Interests: The authors report no conflict of interest with respect to the study reported.

Aim of the current study was to evaluate the inter-observer agreement between pathologists in the diagnosis of celiac disease (CD), in the qualified context of a multicenter study. Biopsies from the "PreventCD" study, a multinational- prospective- randomized study in children with at least one-first-degree relative with CD and positive for HLA-DQ2/HLA-DQ8. Ninety-eight biopsies were evaluated. Considering diagnostic samples with villous atrophy (VA), the agreement was satisfactory (κ = 0.84), but much less when assessing the severity of these lesions. The use of the recently proposed Corazza-Villanacci classification showed a moderately higher level of agreement (κ = 0.39) than using the Marsh-Oberhuber system (κ = 0.31). 57.1% of cases were considered correctly oriented. A number of >4 samples per patient was statistically associated to a better agreement; orientation did not impact on κ values. Agreement results in this study appear more satisfactory than in previous papers and this is justified by the involvement of centers with experience in CD diagnosis and by the well-controlled setting. Despite this, the reproducibility was far from optimal with a poor agreement in grading the severity of VA. Our results stress the need of a minimum of four samples to be assessed by the pathologist., (© 2018 APMIS. Published by John Wiley & Sons Ltd.)

Objective: To investigate whether implementation of a celiac disease (CD)-specific health-related quality of life (HRQOL) questionnaire would add value to CD follow-up visits; we compared patients' self-reported CD-specific HRQOL with the physician's report provided during a regular CD follow-up visit in children and young adults., Methods: A cross-sectional study in the control group of a study on self-management in CD (CoelKids). Eligible patients had CD for ≥1 year and were 25 years or younger. They completed a CD-specific HRQOL questionnaire (CDDUX) after their regular follow-up visit. Their physicians were unaware of the present study's objectives or self-reported HRQOL., Primary Outcome: agreement between physician-reported and self-reported HRQOL., Secondary Outcomes: patient variables predicting a discrepancy between reports, or a lower HRQOL., Results: Physician-reported HRQOL was available in 70 of 78 enrolled patients. The self-reported and physician-reported HRQOL were concordant in 30 of 70 (K = 0.093), 6 of them had a poor self-reported HRQOL. Reports were discrepant in 40 of 70; all 40 self-reported a poor HRQOL. Discrepancies occurred more frequently in patients with a disease duration <9 years (32/40 with discrepant reports were diagnosed <9 years ago vs 17/30 with no discrepancy, P<0.001) and in females (35/40 with discrepant reports were girls versus 16 of 30 with no discrepancy, P = 0.001). Both factors were predictors of a poorer HRQOL., Conclusions: During regular CD follow-up visits, physicians did not report a poor HRQOL in 40 of 46 children and young adults with a poor self-reported HRQOL. This is consistent with previous studies examining other chronic diseases and supports the implementation of self-reported CD-specific HRQOL measurements in CD follow-up visits.

Background: We previously found that the introduction of small quantities of gluten at 4-6 mo of age did not reduce the risk of celiac disease (CD) in a group of high-risk children. However, the consumption of high amounts of gluten early in life has been suggested to increase CD risk. Objective: The aim of this study was to evaluate this hypothesis by using data from the previous study of the PreventCD trial (www.preventcd.com). Design: Gluten intake was prospectively quantified by using specific food records between 11 and 36 mo of age in 715 children positive for the human leukocyte antigen ( HLA )- DQ2 and/or HLA -DQ8 from 5 European countries. According to the PreventCD protocol, infants received 100 mg immunologically active gluten/d or placebo from 4 to 6 mo of age, with a stepwise and fixed gluten increase until age 10 mo and unrestricted intake thereafter. The primary outcome of the present study was the impact of the amount of gluten consumed from age 10 mo onward on CD development. Results: Mean daily gluten intakes from 10 mo onward were significantly different between countries for children at all ages ( P < 0.001) but not between children who developed CD and those who did not within the same country ( P > 0.05). The variables country, sex, intervention group, and gluten consumption pattern did not show significant associations with CD development risk (HRs not significant). In addition, the interaction between HLA risk group and gluten consumption pattern showed no significant risk on CD development, except for the DQ2.2/DQ7 haplotype (HR: 5.81; 95% CI: 1.18, 28.74; P = 0.031). Conclusions: Gluten consumption patterns as well as the amount of gluten consumed at 11-36 mo of age do not influence CD development for most related HLA genotypes in children with a genetic risk. This study reports the gluten consumption pattern in children at risk of CD from different European countries. This trial was registered at www.controlled-trials.com as ISRCTN74582487., (© 2017 American Society for Nutrition.)

Objectives and Study: In the development of Celiac Disease (CD) both genetic and environmental factors play a crucial role. The Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 loci are strongly related to the disease and are necessary but not sufficient for the development of CD. Therefore, increasing interest lies in examining the mechanisms of CD onset from the early beginning. Differences in serum and urine metabolic profiles between healthy individuals and CD patients have been reported previously. We aimed to investigate if the metabolic pathways were already altered in young, 4 month old infants, preceding the CD diagnosis., Methods: Serum samples were available for 230 four month old infants of the PreventCD project, a multicenter, randomized, double-blind, dietary intervention study. All children were positive for HLA-DQ2 and/or HLA-DQ8 and had at least one first-degree relative diagnosed with CD. Amino acids were quantified after derivatization with liquid chromatography - tandem mass spectrometry (MS/MS) and polar lipid concentrations (acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins) were determined with direct infusion MS/MS. We investigated the association of the metabolic profile with (1) the development of CD up to the age of 8 years (yes/no), (2) with HLA-risk groups, (3) with the age at CD diagnosis, using linear mixed models and cox proportional hazards models. Gender, intervention group, and age at blood withdrawal were included as potential confounder., Results: By the end of 2014, thirty-three out of the 230 children (14%) were diagnosed with CD according to the ESPGHAN criteria. Median age at diagnosis was 3.4 years (IQR, 2.4-5.2). Testing each metabolite for a difference in the mean between healthy and CD children, we (1) could not identify a discriminant analyte or a pattern pointing towards an altered metabolism (Bonferroni corrected P > 0.05 for all). Metabolite concentrations (2) did not differ across the HLA-risk groups. When investigating the age at diagnosis using (3) survival models, we found no evidence for an association between the metabolic profile and the risk of a later CD diagnosis., Conclusion: The metabolic profile at 4 months of age was not predictive for the development of CD up to the age of 8 years. Our results suggest that metabolic pathways reflected in serum are affected only later in life and that the HLA-genotype does not influence the serum metabolic profile in young infants before introduction of solid food., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: To determine the frequency of nutritional deficiencies and thyroid dysfunction in children with celiac disease (CD) and during follow-up after initiation of a gluten-free diet. Laboratory investigations of hemoglobin, ferritin, calcium, folate, vitamin B12, vitamin D, and thyroid function are regularly ordered in children with CD despite sufficient evidence for these., Study Design: Between 2009 and 2014, test results of hemoglobin, ferritin, folate, vitamin B12, calcium, vitamin D (25[OH]D), free thyroxin, and thyroid stimulating hormone of children with CD regularly seen at the Leiden University Medical Center were investigated. Laboratory reference ranges were used to define abnormal results. Pearson χ(2) test for trend, unpaired t test, and 1-way ANOVA were used for statistical analysis., Results: Of the 182 children evaluated, 119 were newly diagnosed. On average, 17% of results per year were missing because of incomplete blood investigations. Iron deficiency (28%) and iron deficiency anemia (9%) were found at the time of diagnosis of CD. Folate (14%), vitamin B12 (1%), and vitamin D deficiencies (27%) were also seen. No hypocalcemia or thyroid dysfunction was found. At follow-up, iron deficiency, iron deficiency anemia, and folate and vitamin D deficiency were observed in 8%, 2%, 3%, and 25% of patients, respectively. Vitamin B12 deficiency, hypocalcemia, and thyroid disease were not found., Conclusions: Complementary blood investigations are relevant at the time of diagnosis of CD but have little diagnostic yield during follow-up visits once the patient is placed on a gluten-free diet. Thus, we recommend that these variables only be assessed on indication, such as fatigue or abnormal growth., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Gluten-related disorders such as coeliac disease, wheat allergy and noncoeliac gluten sensitivity are increasingly being diagnosed in children. Coeliac disease occurs frequently, affecting 1-3% of the Western population. The condition manifests at a very young age, more so in girls, and is related to the HLA genotype. Coeliac disease might be considered a public health problem and, as primary prevention is not possible, the debate on mass screening should be reopened. Wheat proteins, including gluten, are responsible for one of the most common food allergies in children: wheat allergy. Unlike coeliac disease and wheat allergy, noncoeliac gluten sensitivity is an unclear and controversial entity. These three gluten-related disorders are treated with a gluten-free diet. In coeliac disease, the diet should be strictly followed, whereas wheat allergy only requires wheat elimination and in noncoeliac gluten sensitivity occasional trials of gluten reintroduction can be done. A good diagnostic work-up is important for gluten-related disorders in childhood to avoid unnecessary restrictive diets in children. In this Review, we provide an overview of the pathogenesis, diagnosis and management of the most common gluten-related disorders in children.

Due to the association of coeliac disease and HLA-specificities DQ2 and DQ8, HLA-typing can be used for risk determination of the disease. This study was designed to evaluate the knowledge of parents from coeliac families regarding HLA-typing and the impact of HLA-typing on the perception of the health of their children. A structured questionnaire was sent to the Dutch, Spanish and German parents participating with their child in the European PreventCD study on disease prevention in high-risk families, addressing parents' understanding of and attitude towards HLA-typing, distress related to HLA-typing and perceived health and health-related quality of life of their children. Sixty-eight percent of parents of 515 children returned the questionnaires, with 85% of children being DQ2/DQ8 positive. The majority of all parents answered the questions on knowledge correctly. Forty-eight percent of parents of DQ2/DQ8-negative children thought their child could develop coeliac disease. More distress was reported by parents of DQ2/DQ8-positive children (P<0.001). All parents showed few regrets and would repeat HLA-typing in future children. Perceived health and health-related quality of life were similar. In conclusion, we can say that misinterpretation of DQ2/DQ8-negative results by parents is frequent. DQ2/DQ8-positive results do not affect perceived health and health-related quality of life of children but may cause temporary negative feelings among parents. Parents of coeliac families seem to support HLA-typing.

Celiac disease is a common condition with a variable presentation, and is frequently not recognized by the physician. Although a gluten-free diet has a positive effect on the health of the celiac patient, prevention would be even more beneficial. In this article we outline the different possibilities for primary and secondary prevention of celiac disease. Results of recent prospective studies show that at this moment primary prevention is not possible, but secondary preventive strategies can be applied to decrease the morbidity associated with this disease; mass screening is one option. Results of recent studies concerning this topic will be discussed.

Background: A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age., Methods: We performed a multicenter, randomized, double-blind, placebo-controlled dietary-intervention study involving 944 children who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age., Results: Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention., Conclusions: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.).

In a recently published article in Pediatrics on the Swedish coeliac disease 'epidemic', it is suggested that the gradual introduction of gluten-containing foods from 4 months of age, preferably while breastfeeding is still ongoing, is favourable for the prevention of coeliac disease. This stirred up the discussion about the timing of introduction of gluten to the diet of infants in the Netherlands, where gluten-containing foods are mostly introduced from 6 months of age onwards. The retrospective character of data collection, however, has to be taken into account when interpreting the Swedish study. Future results of prospective studies on gluten introduction and coeliac disease, such as the PreventCD family study (www.preventcd.com), should provide the information necessary for deciding on a change in the Dutch guidelines for the introduction of gluten to the diet of young children.