BACKGROUND:Severe maternal morbidity has been linked to maternal mortality and several perinatal complications, but the evidence on associations with children's neurodevelopmental disorders is still unclear. OBJECTIVE:To assess associations between severe maternal morbidity and cerebral palsy in children, overall and by major severe maternal morbidity subtypes. STUDY DESIGN:Longitudinal cohort study of all live births in the province of Ontario, Canada, between 2003 and 2019 followed up through 2020 (n=2,136,816), under a single-payer healthcare system. Severe maternal morbidity (n=41,396) was identified from inpatient or emergency department diagnoses during the index pregnancy or postpartum (20 weeks gestation to 42 days postpartum) based on validated algorithms according to diagnostic and procedure codes. Severe maternal morbidity was categorized into severe hypertensive disorders of pregnancy (severe preeclampsia, Hemolysis, Elevated Liver enzymes, and Low Platelets syndrome, and eclampsia combined), severe hemorrhage (eg, antepartum or postpartum hemorrhage with coagulation defect, red cell transfusion, procedures to the uterus, or hysterectomy), sepsis (puerperal sepsis or septicemia during labor), and other severe maternal morbidities (eg, admission to intensive care, shock). Cerebral palsy in offspring was defined as a single inpatient or 2 or more outpatient diagnoses at least 2 weeks apart between birth and the end of follow-up (age, 1-17 years). Associations were estimated using Poisson regression models. RESULTS:Of 2,136,816 children included in this study (mean [standard deviation] gestational age, 38.9 [1.8] weeks; 1,074,548 males [51.3%]), 41,396 (2.0%) were exposed to severe maternal morbidity. In a median follow-up of 9.5 years (interquartile range, 5.2-13.7), 5352 children were diagnosed with cerebral palsy (0.3%), of which 272 cerebral palsy cases (0.7%) were exposed to severe maternal morbidity. The average annual cerebral palsy incidence rate was 7.5 per 10,000 child-years in those exposed to severe maternal morbidity and 2.5 per 10,000 in those unexposed. Children of mothers with severe maternal morbidity had an increased risk of cerebral palsy (rate ratio, 2.71; 95% confidence interval, 2.39-3.06) after adjusting for maternal sociodemographic and clinical characteristics. All severe maternal morbidity subtypes considered were associated with increased risks of cerebral palsy, with the strongest associations observed for severe hypertension disorders (adjusted rate ratio, 3.29 [2.44-4.33]). Other severe maternal morbidity subtypes also showed similarly increased risks (adjusted rate ratio for sepsis, 2.45 [1.86, 3.15]), severe hemorrhage 2.44 (1.89, 3.09), and other severe maternal morbidity subtypes (2.81 [2.30-3.39]). CONCLUSION:In this population-based study of more than 2 million births, severe maternal morbidity was associated with an increased risk of cerebral palsy. This risk was observed across major severe morbidity subtypes, including hypertensive disorders, hemorrhage, and sepsis. These findings highlight the potential benefits of optimizing maternal health and illustrate potential long-term adverse consequences of severe maternal morbidity in offspring. Children of mothers who experience severe or life-threatening events during the perinatal period may benefit from enhanced surveillance for early cerebral palsy symptoms.

BACKGROUND:Evidence on the association between maternal diabetes and neurodevelopmental disorders in offspring, particularly epilepsy, remains limited and heterogeneous. Moreover, most studies have not distinguished among diabetes subtypes-type 1 (T1DM), type 2 (T2DM), and gestational diabetes mellitus (GDM)-which have distinct etiologies. This study examines the association among these diabetes subtypes and epilepsy in offspring. METHODS:In a retrospective birth cohort of all in-hospital live births between 2002 and 2018 in Ontario, Canada's most populous province, linked with population maternal and child health records up until March 2020, we estimated the crude and adjusted association among T1DM, T2DM, and GDM and epilepsy in children aged younger than 18 years using Cox proportional hazards models. We examined the robustness of results using quantitative bias analyses. RESULTS:Among 2 105 553 children, 160 644 (7.6%) were exposed to maternal diabetes (0.3% T1DM, 1.2% T2DM, and 6.1% GDM). Over a median follow-up of 10.2 years, 17 853 epilepsy cases were diagnosed. After adjusting for maternal socioeconomic and clinical characteristics, children exposed to maternal diabetes had an increased risk of epilepsy in all subcategories of diabetes compared with those unexposed (adjusted HR [aHR] for T2DM, 1.40; 95% CI, 1.24-1.58; aHR for T1DM, 1.32; 95% CI, 1.03-1.69; and aHR for GDM, 1.14; 95% CI, 1.07-1.22). A longer duration of T1DM or T2DM was associated with an increased risk. These results were consistent in our quantitative bias analyses. CONCLUSION:Maternal diabetes, particularly T1DM and T2DM, is associated with an increased epilepsy risk in offspring, with longer disease duration not significantly amplifying this risk. These findings suggest that prenatal metabolic and inflammatory exposures may contribute to the development of epilepsy.

BACKGROUND:Severe maternal morbidity (SMM) is associated with adverse perinatal outcomes. However, its association with longer-term offspring outcomes, including neurodevelopment disorders, is poorly understood. This study aims to examine the association between SMM and the risk of epilepsy in offspring. METHODS:A retrospective birth cohort study of all singleton hospital births between 2002 and 2018 in Ontario, Canada was followed up until March 2020. SMM (20 weeks' gestation to 42 days postpartum) and epilepsy diagnosed before 18 years of age in offspring were identified by using administrative health records. The risk of epilepsy associated with SMM was estimated by using Cox proportional hazard models and the robustness of the results was examined by using quantitative bias analyses (outcome and exposure misclassification and residual or unmeasured confounding). RESULTS:Of 2 060 668 children with a median follow-up time of 10 years, 40 830 (2%) were exposed to severe maternal morbidity and 16 992 (0.8%) were diagnosed with epilepsy (1.2% among those exposed to SMM and 0.8% among those unexposed). After adjustment for maternal, birth, and socioeconomic characteristics, children exposed to SMM had a 45% increased risk of epilepsy diagnosis compared with those unexposed [hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.33-1.59]. This increase was similar across the subtypes of SMM. Estimates accounting for potential misclassification biases and residual or unmeasured confounding (by obesity or maternal education) showed increased risks (HR 1.91, 95% CI 1.50-2.42). CONCLUSION:An increased risk of epilepsy was found in children exposed to SMM, suggesting a perinatal etiology and underlining the importance of ensuring a healthy pregnancy.

IntroductionApproximately 8 per million children and young adults aged < 20 initiate kidney replacement therapy (KRT) per year in France. We hypothesize that social deprivation could be a determinant of childhood-onset kidney failure. The objective of this study was to estimate the incidence of pediatric KRT in France according to the level of social deprivation.MethodsAll patients < 20 years who initiated KRT from 2010 to 2015 in metropolitan France were included. Data were collected from the comprehensive French registry of KRT (REIN). We used a validated ecological index to assess social deprivation, the 2011 French version of the European Deprivation Index (EDI). We estimated the age-standardized incidence rates according to the quintiles of EDI using direct standardization and incidence rate ratio (IRR) using Poisson regression.ResultsWe included 672 children with kidney failure (58.6% males, 30.7% with glomerular or vascular disease, 43.3% starting KRT between 11 and 17 years). 38.8% were from the most deprived areas (quintile 5 of EDI). The age-standardized incidence rate increased with quintile of EDI, from 5.45 (95% CI 4.25-6.64) per million children per year in the least deprived quintile to 8.46 (95% CI 7.41-9.51) in the most deprived quintile of EDI (IRR Q5 vs Q1 1.53 95% CI 1.18-2.01).ConclusionThis study showed that even in a country with a universal healthcare system, there is a strong association between the incidence of pediatric KRT and social deprivation showing that social health inequalities appear from KRT initiation. This study highlights the need to look further into social inequalities in the earliest stage of CKD.

OBJECTIVE:Epilepsy is one of the most common chronic neurologic diseases in children; however, few recent studies examine the prevalence of epilepsy and its evolution over time according to birth or maternal characteristics. The aim of the study was to examine the prevalence of epilepsy in children born between 2002 and 2020 and the temporal trends by year of birth, in Ontario, Canada, overall, and according to maternal and birth characteristics. METHODS:We included all in-hospital deliveries between 2002 and 2020 (N = 2,343,482) in Ontario, Canada, using linked administrative health dataset. We estimated the overall prevalence of epilepsy diagnosed before the age of 18 years, by birth and maternal characteristics. For temporal trend analyses, we restricted our population to children born up to 2012 (N = 1,405,271) and examined the prevalence of epilepsy diagnosed by age 8 by their year of birth, using Poisson regression. RESULTS:The overall prevalence of epilepsy in our cohort was 8.1 per 1,000 live births (95% CI: 8.0-8.2). Prevalence was higher for boys, for children born preterm, with congenital malformations, from multiple pregnancies, from mothers born in Canada, and for children living in deprived areas. Epilepsy prevalence diagnosed by age 8 increased slightly between 2002 and 2012 cohorts (6.9 [95% CI: 6.2-7.6] to 7.3 [95% CI: 6.6-8.1] per 1,000 live births, respectively). Differences by gestational age as gradient and socioeconomic characteristics were persistent and stable over time, while those by pregnancy plurality and sex decreased. SIGNIFICANCE:In a large population-based birth cohort in Canada, we observed a slight increase in epilepsy prevalence over time among children born in 2002 and those born in 2012 and persistent disparities by gestational age, socioeconomic position, and maternal immigration status. This study highlights the need for continued surveillance of rates to see if this increasing trend is persistent, to understand the potential causes behind it, and to understand the persistence of these disparities.

To describe healthcare professionals' perceptions of social health inequalities in the context of pediatric chronic disease and their insights regarding proportionate universalism as a potential solution to reduce them. Semi-directive interviews were conducted with healthcare professionals from different pediatric chronic disease departments of a single French academic hospital. This qualitative study was based on an inductive thematic analysis; an interview topic guide was used for the interviews and the analysis. In this study, we highlighted three main themes: the healthcare professionals' perceptions of social health inequalities in their practices, their beliefs regarding the causality of those inequalities, and potential solutions proposed by healthcare professionals to reduce them. Healthcare professionals very often associated inequalities with socio-economic precariousness or geographical disparities but were not familiar with the notion of a social gradient. Paradoxically, while they claimed not to differentiate among patients in their practice, they did report adapting care, depending on the social situation. For healthcare professionals, inequalities were the result of misunderstood problems, a lack of family support, a failure of the prevention system, and a lack of financial resources.CONCLUSION:We still need to develop solutions to tackle those inequalities at every level of the healthcare system, and healthcare professionals must be more actively involved in this effort. One approach is to adapt public health principles such as proportionate universalism to individual care.WHAT IS KNOWN:• Social health inequalities exist in pediatric care and a social gradient has been shown in many clinical situations. • Exploring health professionals' perceptions of social health inequalities can lead to solutions to tackle them.WHAT IS NEW:• Pediatricians and pediatric nurses were not fully aware of the social gradient of health. • Although they claimed not to differentiate between patients in their practice, healthcare professionals did adapt care when complicated social situations arose.

Introduction: Socioeconomic status (SES) is recognized as an important determinant of kidney health. We aimed to evaluate the association of social deprivation with different indicators at kidney replacement therapy (KRT) initiation in the French pediatric metropolitan population. Methods: All patients with end-stage kidney disease (ESKD) who started KRT before 20 years old in France between2002and2015were included. We investigateddifferent indicators atKRTinitiation, which are as follows: KRT modality (dialysis vs. pre-emptive transplantation), late referral to a nephrologist, and dialysis modality (hemodialysis [HD] vs. peritoneal dialysis [PD], urgent vs. planned start of dialysis, use of catheter vs. use of fistula for HD vascular access). Anecological index(EuropeanDeprivationIndex[EDI]) was usedas aproxy for socialdeprivation. Results: A total of 1115 patients were included (males 59%, median age at dialysis 14.4 years, glomerular/ vascular diseases 36.8%). The most deprived group represented 38.7% of the patients, suggesting pediatric patients with ESKD come from a more socially deprived background. The most deprived group was more likely to initiate KRT with dialysis versus kidney transplantation. Among patients on HD, the odds of starting treatment in emergency with a catheter was >2-fold higher for the most deprived compared with the least deprived children (adjusted odds ratio [aOR] 2.35, 95% CI 1.16-4.78). Conclusion: Children from the most deprived area have lower access to pre-emptive transplantation, have lower access to PD, tend to be late referred to a nephrologist, and have more urgent initiation of HD with a catheter.

The gut microbiome is involved in nutrient metabolism and produces metabolites that, via the gut–brain axis, signal to the brain and influence cognition. Human studies have so far had limited success in identifying early metabolic alterations linked to cognitive aging, likely due to limitations in metabolite coverage or follow-ups. Older persons from the Three-City population-based cohort who had not been diagnosed with dementia at the time of blood sampling were included, and repeated measures of cognition over 12 subsequent years were collected. Using a targeted metabolomics platform, we identified 72 circulating gut-derived metabolites in a case–control study on cognitive decline, nested within the cohort (discovery n = 418; validation n = 420). Higher serum levels of propionic acid, a short-chain fatty acid, were associated with increased odds of cognitive decline (OR for 1 SD = 1.40 (95% CI 1.11, 1.75) for discovery and 1.26 (1.02, 1.55) for validation). Additional analyses suggested mediation by hypercholesterolemia and diabetes. Propionic acid strongly correlated with blood glucose (r = 0.79) and with intakes of meat and cheese (r > 0.15), but not fiber (r = 0.04), suggesting a minor role of prebiotic foods per se, but a possible link to processed foods, in which propionic acid is a common preservative. The adverse impact of propionic acid on metabolism and cognition deserves further investigation.

The microbiome is involved in nutrient metabolism and releases metabolites that can influence cognitive aging, likely through the gut-brain axis. Human studies, generally limited in number of metabolites and follow-up, have been inadequate to identify early metabolic alterations leading to cognitive aging. The aim of this study was to investigate the association between circulating levels of a large number of microbial metabolites in plasma and cognitive decline. We studied participants from the Three-City study, a cohort study conducted in 3 French cities (Bordeaux, Dijon ad Montpellier). The subjects were free of dementia at the time of blood sampling and provided repeated measures of cognition over 12 subsequent years. We used a targeted metabolomic approach, combining ultra-high performance liquid chromatography coupled to tandem mass spectrometry. We measured 77 circulating gut-derived metabolites in a case-control sample matched for age, sex and educational level, nested within the cohort. Associations of these metabolites to cognitive decline were investigated in the Bordeaux center (discovery sample, n = 418) using logistic regressions conditioned on matching variables. Associations with a P-value corrected for multiple testing (False Discovery Rate [FDR]) ≤0.15 were tested for validation in the Dijon center (validation sample, n = 424). Models were subsequently adjusted for smoking, alcohol consumption and cardiometabolic health (body mass index, hypertension, hypercholesterolemia and diabetes). Higher serum levels of propionic acid, a short-chain fatty acid, were associated with increased odds of cognitive decline (OR for 1 SD = 1.40 [95% CI 1.11, 1.75] in discovery, and = 1.26 [1.02, 1.55] in the validation stage). Associations were attenuated in the validation sample after multivariable adjustment, and additional analyses suggested mediation by hypercholesterolemia and diabetes. Moreover, propionic acid strongly correlated with blood glucose (r = 0.80) and with meat and cheese intakes (r>0.15) but not with fiber intake (r = 0.04). This exploratory study of the gut-brain axis suggests a deleterious relationship between circulating propionic acid and cognitive decline. Our results suggest a very weak relation to pre-biotic foods, but a possible link with processed foods, where propionic acid is often used as a preservative. Thus, the adverse impact of propionic acid on metabolism and cognition deserves further investigation.

On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of Social Inequalities in Health, the following key messages were retained. Social inequalities in health exist throughout the journey of a patient with chronic kidney disease and manifest as territorial inequalities in access to home-based or independent dialysis treatment and to transplant, whether preemptive or otherwise. SIH are observed in adults as well as in the paediatric population. The female gender appears to be associated with a disparity in access to kidney transplant. (C) 2022 Societe francophone de nephrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.

À l’occasion des 20 ans du REIN (Réseau Epidémiologie et Information en Néphrologie), un travail de synthèse sur les apports du registre a été mené. Sur la question des inégalités sociales de santé, les messages clés suivants ont été retenus.Les inégalités sociales de santé existent tout au long du parcours du patient atteint d’une maladie rénale chronique et se traduisent par des inégalités territoriales d’accès au traitement par dialyse au domicile ou autonome, à la greffe qu’elle soit préemptive ou non.Les ISS sont retrouvées chez l’adulte mais aussi dans la population pédiatrique.Le genre féminin semble associé à une disparité d’accès à la greffe rénale.© 2022 Société francophone de néphrologie, dialyse et transplantation. Publié par Elsevier Masson SAS. Tous droits réservés.

Le microbiote intestinal (MI) participe à la digestion et au métabolisme de nombreux nutriments en libérant des métabolites dans le tube digestif, dont certains gagnent la circulation sanguine et traversent la barrière hémato-encéphalique, interagissant ainsi directement avec le cerveau. Cependant, les connaissances sur le lien entre MI et santé cérébrale sont en grande partie précliniques, et peu d’études ont porté sur les métabolites microbiotiques circulants et le vieillissement cognitif chez l’homme. L’objectif de cette étude était d’analyser et de valider, dans un cas-témoin niché dans une grande cohorte de sujets âgés, l’association entre des dizaines de métabolites sanguins dérivés du MI et le déclin cognitif au long cours. Cette étude met à profit les données de la cohorte des trois-cités (3C, Bordeaux, Dijon et Montpellier) chez des personnes âgées de 65 ans ou plus à l’inclusion. Les participants non déments au moment du prélèvement sanguin et dont la cognition a été mesurée de façon répétée au cours des 12 années suivantes étaient éligibles pour le cas-témoin niché. Un échantillon de découverte a été défini dans 3C Bordeaux, incluant les 209 participants avec la pente de déclin cognitif la plus importante, appariés à 209 témoins avec une cognition plus stable (pente > pente médiane) et de même âge, sexe et niveau d’études. Un échantillon de validation a été défini de façon similaire dans 3C Dijon (210 paires cas-témoin). Une analyse en métabolomique ciblée a permis de quantifier 76 métabolites liés à l’alimentation et potentiellement dérivés du MI. L’association entre chaque métabolite et le déclin cognitif a été étudiée dans l’échantillon de découverte en utilisant des régressions logistiques conditionnelles. Les métabolites dont la P-valeur corrigée pour les tests multiples (FDR) était ≤ 0,15 ont été testés pour réplication. 7 métabolites étaient associés au déclin cognitif avec une P-FDR ≤ 0,15 dans l’échantillon de découverte : la phénylacétylglutamine, l’acide indole-lactique, l’acide kynurénique, la bétaïne, la vitamine B5, le propionate et le 3,4-DHPV-S. Seul le propionate était répliqué (OR = 1,26, 95 % IC [1,02 ;1,55]). Cette association était atténuée de façon importante après ajustement sur les facteurs de risque cardiométaboliques dans l’échantillon de validation (une population à risque vasculaire plus important que la population de découverte). Cette étude suggère une relation délétère entre l’acide propionique circulant et le déclin cognitif. Le rôle de la santé cardiométabolique dans cette relation mérite d’être approfondi.

IntroductionSocioeconomic status is recognized as an important determinant of kidney health. We aimed to assess the association of social deprivation with different indicators at kidney replacement therapy (KRT) initiation in the French pediatric population.DescriptionData from the REIN registry.MethodsAll end-stage kidney disease (ESKD) patients who started KRT before 20 years old in France between 2002 and 2015 were included. We investigated different indicators at KRT initiation: KRT modality (dialysis vs. pre-emptive transplantation), dialysis modality (hemodialysis [HD] vs. peritoneal dialysis [PD]), urgent vs. planned start of dialysis, use of catheter vs. fistula for HD vascular access, and late referral to a nephrologist. An ecological index, the European Deprivation Index (EDI), was used as a proxy for social deprivation.ResultsIn total, 1115 patients were included (males 59%, median age at dialysis 14.4 years, glomerular/vascular diseases 36.8%). The most deprived group represented 38.7% of the patients, suggesting that pediatric ESKD patients come from a more socially deprived background. Social deprivation was significantly associated with the initial modality of KRT. Patients from the most deprived areas were more likely to initiate KRT with dialysis (adjusted OR: 1.88; 95% CI: 1.15–3.07) than those from the least deprived areas, and more often with HD than with PD. Among HD patients, the odds of starting treatment in emergency with a catheter was two-fold higher for the most deprived compared to the least deprived children (adjusted OR: 2.08; 95% CI: 1.07–4.04). There was a trend towards later referral in patients from the most deprived areas.ConclusionChildren from the most deprived areas have lower access to pre-emptive kidney transplantation, lower access to PD, have more urgent initiation of HD with a catheter, and tend to be later referred to a nephrologist.

BACKGROUNDThere is growing evidence that the Mediterranean (Medi) diet may lower the risk of type 2 diabetes mellitus (T2DM). Whether this association is due to the Medi diet by itself or is mediated by a diet -associated lower rate of overweight is uncertain. Our aim was to disentangle these relationships among UK adults.METHODSBased on 21 585 participants from the UK Biobank cohort, the adherence to the Medi diet (high fruits, vegetables, legumes, cereals, fish, olive oil; low meat, dairy products; and intermediate alcohol intakes) was assessed (range 0-18). Data on diabetes were self-reported, and overweight was defined as a body mass index (BMI) ≥ 25 kg/m². A mediation analysis was implemented to disentangle the role of overweight in the Medi diet-T2DM relationship.RESULTSThe average baseline Medi diet score was 8.8 [standard deviation (SD) 2.6]. During a mean follow-up of 6.1 years, 473 individuals developed T2DM. A higher adherence to a Medi diet (+1 point) was associated with 14% decreased risk of T2DM [hazard ratio (HR): 0.86, 95% confidence interval (CI): 0.82-0.90]. This association split into an indirect effect of 10%, mediated by lower odds of overweight (HR: 0.90, 95% CI: 0.87-0.92), and a direct effect of the Medi diet of 4% (HR: 0.96, 95% CI: 0.93-0.99), regardless of the effect mediated by overweight.CONCLUSIONSConsidered as a single mediator, reduced overweight mainly contributes to the association between greater Medi diet adherence and lower risk of T2DM on this British subsample. However, the direct effect of the diet on the risk of T2DM, even weaker, should not be overlooked.

Socioeconomic status is an important determinant of health. Its impact on kidney transplantation outcome has been studied among adults but data in children are scarce, especially in Europe. Here, we investigate the association between the level of social deprivation (determined by the continuous score European Deprivation Index) and graft failure risk in pediatric kidney transplant recipients. All patients listed under 18 years of age who received a first kidney transplant between 2002 and 2014 in France were included. Of 1050 kidney transplant recipients (males 59%, median age at transplantation 13.2 years, preemptive transplantation 23%), 211 graft failures occurred within a median followup of 5.9 years. Thirty-seven percent of these patients belong to the most deprived quintile, suggesting that deprivation is more frequent in pediatric patients with end-stage kidney disease (ESKD) than in the general population. Five- and ten-year graft survival were 85% and 69%, respectively, in the most deprived quintile vs. 90% and 83%, respectively, in the least deprived quintile. At any time after transplantation, patients in the most deprived quintile had almost a two-fold higher hazard of graft failure compared with the least deprived quintile, after adjustment for age at renal replacement therapy, duration of dialysis, primary kidney disease, and rural/urban living environment (hazard ratio 1.99; 95% confidence interval 1.20-3.28). The hazard of graft failure did not differ significantly between girls and boys. Thus, our findings suggest a lower socioeconomic status is independently associated with poor graft outcome in pediatric kidney transplantation.