BACKGROUND:High pre-pregnancy body mass index (BMI), accompanied by chronic low-grade inflammation may predispose offspring to adverse health outcomes by interfering with fetal development. However, the association between maternal pre-pregnancy obesity and elevated inflammatory biomarkers in the mother or fetus remains controversial. This study analyzed the association between pre-pregnancy BMI and biomarkers of inflammation in maternal serum and cord blood at birth in two large birth cohorts. METHODS:Pre-pregnancy weight and height were used to calculate pre-pregnancy BMI (underweight [<18.5 kg/m²]; normal [18.5-24.9 kg/m²]; overweight [25.0-29.9 kg/m²]; obese [≥30 kg/m²]). Biomarkers of inflammation (interleukin [IL]-1β, IL-6, IL-10, tumor necrosis factor α [TNF-α]) were measured from maternal serum collected at birth in ELFE (n = 1046) and cord blood collected in both cohorts (EDEN [n = 856 for cytokines]; ELFE [n = 1016]) C-reactive protein (CRP) was additionally measured in the cord blood of both cohorts (EDEN: n = 820; ELFE: n = 1012]). Linear regression models were used to determine the association between BMI categories with biomarker levels, adjusting for confounders. RESULTS:In ELFE, pre-pregnancy obesity was strongly and positively associated with cord blood CRP (adjusted β 0.52 [95% CI 0.32, 0.72]), while in EDEN, maternal overweight was associated with higher levels of cord blood CRP (0.32 [0.12, 0.54]). In ELFE, maternal underweight was also associated with higher levels of cord blood IL-10 in cord blood (0.20 [0.04, 0.35]). Pre-pregnancy BMI was not associated with any of the maternal serum biomarkers in ELFE in the overall analyses. CONCLUSIONS:High pre-pregnancy BMI was associated with elevated CRP levels in cord blood, reflecting higher inflammatory marker levels in the perinatal environment. These findings should be replicated in other large cohort studies. The potential implications of elevated prenatal inflammation on offspring outcomes warrant further investigation.

THIS IS A PRE-PRINT OF AN ARTICLE PUBLISHED IN "BRAIN, BEHAVIOR, AND IMMUNITY". THE FINAL VERSION IS AVAILABLE ONLINE AT: https://doi.org/10.1016/j.bbi.2026.106780 Background: Conditions associated with perinatal inflammation have been identified as risk factors for neurodevelopmental disorders, including Attention-Deficit/Hyperactivity Disorder (ADHD). However, data linking early inflammatory biomarkers with later ADHD symptoms remain scarce. The acute phase C-reactive protein (CRP) is a key marker of systemic inflammation. To date, no studies have examined the association between CRP levels in cord blood (reflecting neonatal inflammation) and subsequent childhood ADHD symptoms. Here, we aimed to investigate whether elevated cord blood CRP concentrations are associated with child’s ADHD symptoms at age 5. Methods: We analyzed data from 1019 and 831 mother–child pairs enrolled in the ELFE and EDEN prospective birth cohorts, respectively. CRP levels in cord blood were measured using an immunoassay. ADHD symptoms were assessed at age 5 using the hyperactivity–inattention subscale of the Strengths and Difficulties Questionnaire (SDQ). Outcomes included both continuous scores and categorical thresholds: borderline (≥6) and abnormal (≥7) hyperactivity–inattention symptoms. Multivariate linear and logistic regression models were conducted within each cohort to assess associations between elevated CRP levels (≥75th percentile) and ADHD symptoms. Results were then pooled using meta-analytic methods. Results: Borderline hyperactivity–inattention scores were observed in 21% of children in the ELFE cohort and 14% in EDEN. After adjusting for maternal sociodemographic, lifestyle, and pregnancy-related factors, as well as child characteristics at birth, elevated cord blood CRP was significantly associated with higher odds of ADHD symptoms: borderline scores (adjusted odds ratio [aOR] = 1.42; 95% CI: 1.08–1.86), abnormal scores (aOR = 1.48; 95% CI: 1.06–2.08), and increased continuous symptom scores (β = 0.29; 95% CI: 0.04–0.54). Conclusions: Higher CRP concentrations in cord blood are associated with greater ADHD symptom severity at age 5. These findings support the hypothesis that early-life inflammation may contribute to the developmental origins of ADHD and suggest that CRP could serve as a potential early biomarker of neurodevelopmental vulnerability.

We evaluated the association between the inflammatory potential of the maternal diet during pregnancy and levels of inflammatory biomarkers measured in cord blood and maternal serum at birth. Dietary inflammatory potential was calculated using the energy-adjusted dietary inflammatory index (E-DII) in the French EDEN and ELFE birth cohorts. Biomarkers of inflammation (interleukin [IL]-1β, IL-6, IL-10, tumor necrosis factor α [TNF-α]) were measured from cord blood (EDEN [n = 758]; ELFE [n = 899]) and maternal serum (in ELFE only; [n = 911]) collected at birth. Additionally, leptin was also measured from cord blood in EDEN (n = 1202) and C-reactive protein was measured from cord blood in ELFE (n = 895). Linear regression models, adjusted for confounders, were used to investigate the association between tertiles of the E-DII score and each log-transformed biomarker. There were no significant associations between the E-DII score and maternal or cord blood biomarkers in either cohort. The energy-adjusted dietary inflammatory index score during pregnancy was not associated with concentrations of inflammatory biomarkers in either maternal serum or cord blood at birth.

Major Depressive Episode (MDE) is one of the most common psychiatric disorders. Often difficult to treat, this disease is one of the leading causes of suicide. A recent study showed an association between GPR56/ADGRG1 mRNA, MDE and response to antidepressant treatment in blood and in brain. Among GPR56 splicing variant, the S4 isoform has recently been associated with microglial synaptic pruning, while microglia are already known as a central player in MDE. Therefore, we hypothesized that S4 is the specific isoform associated to MDE and antidepressant response. To test our hypothesis, an in silico analysis was first performed to identify the different proteins and transcript isoforms of GPR56. This analysis allowed to design PCR and qPCR primers. GPR56 total, S4 and S3 were assessed by RT-qPCR in leukocytes from a cohort of 46 MDE patients including non-responders (NR, n = 31) and responders-remitters (R, n = 17) to antidepressant treatment. We replicated the result of one of our previous studies, which described an increase in total GPR56 mRNA in Rs. Additionally, we observed that this variation differs among mRNA splicing variants, with S4 exhibiting a similar pattern of variation while S3 shows no significant change. The differences observed withstood statistical correction for covariates of interest such as smoking, gender and suicidal ideation, demonstrating the robustness of the model. These findings confirm our hypothesis that certain mRNA splicing variants of GPR56 may play a more significant role in depression. This study highlighted a link between the GPR56-S4 and response to antidepressant treatment.

ABSTRACT Aim To describe cardiometabolic health profiles at age 5–6 years, their correlation with age at adiposity rebound (AR) and associations with maternal hyperglycaemia at 24–28 weeks' gestation (gestational diabetes, fasting (FPG), 1‐hour postload plasma glucose), in mothers without pre‐existing diabetes. Methods BMI, %fat mass, blood pressure (BP), FPG, HOMA‐IR and lipids were assessed in children from the EDEN study, a French bicentric birth cohort. Sex‐specific cardiometabolic health profiles were derived using principal component analysis and examined against age at AR with Pearson's correlation. Associations with maternal hyperglycaemia were studied using multiple linear regressions adjusted for parental factors. Results Among 674 children, four profiles were identified per sex: ‘higher adiposity, BP, insulin resistance (IR)’; ‘higher BP and lower adiposity’; ‘higher IR and lower adiposity’; ‘higher triglycerides and LDL‐c and lower HDL‐c’. The profile of ‘higher adiposity, BP, IR’ was correlated with earlier age at AR in both sexes. Higher maternal FPG was positively associated with the profile of ‘higher adiposity, BP, IR’ in boys and ‘higher triglycerides and LDL‐c and lower HDL‐c’ in girls. Conclusion ‘Higher adiposity, BP, IR’ profile at age 5–6 years was associated with earlier age of adiposity rebound. Marginal associations were observed with maternal hyperglycaemia in pregnancy.

To describe cardiometabolic health profiles at age 5–6 years, their correlation with age at adiposity rebound (AR) and associations with maternal hyperglycaemia at 24–28 weeks' gestation (gestational diabetes, fasting (FPG), 1-hour postload plasma glucose), in mothers without pre-existing diabetes. BMI, %fat mass, blood pressure (BP), FPG, HOMA-IR and lipids were assessed in children from the EDEN study, a French bicentric birth cohort. Sex-specific cardiometabolic health profiles were derived using principal component analysis and examined against age at AR with Pearson's correlation. Associations with maternal hyperglycaemia were studied using multiple linear regressions adjusted for parental factors. Among 674 children, four profiles were identified per sex: ‘higher adiposity, BP, insulin resistance (IR)’; ‘higher BP and lower adiposity’; ‘higher IR and lower adiposity’; ‘higher triglycerides and LDL-c and lower HDL-c’. The profile of ‘higher adiposity, BP, IR’ was correlated with earlier age at AR in both sexes. Higher maternal FPG was positively associated with the profile of ‘higher adiposity, BP, IR’ in boys and ‘higher triglycerides and LDL-c and lower HDL-c’ in girls. ‘Higher adiposity, BP, IR’ profile at age 5–6 years was associated with earlier age of adiposity rebound. Marginal associations were observed with maternal hyperglycaemia in pregnancy.

Background Schizophrenia (SZ) commonly manifests through multiple relapses, each impeding the path to recovery and incurring personal and societal costs. Despite the identification of various risk factors associated to the risk of relapse, the development of accurate algorithms predictive of relapse has been limited, partly due to inadequate statistical methods. Additionally, despite the wealth of data showing strong associations between inflammation and schizophrenia, the two existing studies failed to demonstrate whether inflammatory parameters could predict relapse. Our goal is then to identify clinical and inflammatory parameters associated with relapse in schizophrenia and to develop model to predict relapse in each patient. Methods We have used classical Cox regression, survival penalized regression, as well as survival random forests to analyze clinical and inflammatory biological data collected in the network of the Schizophrenia Expert Centers in France in which individuals with SZ are clinically assessed and followed up annually for 3 years. Results Among 247 individuals with SZ, 71 (29 %) experienced a psychotic relapse during the 3-year follow-up period. The variables most consistently associated with relapses were smoking status, severity of positive symptoms and low global functioning. From a panel of inflammatory parameters, only IL-8 serum levels were associated with time to relapse. The predictive performance, assessed using C-index, was 0.54 using both penalized regression and random forests. Conclusions We found several clinical and biological variables consistently associated with relapses across three distinct statistical methods. However, despite these associations, the predictive capacity of these models remained low, highlighting that association does not necessarily mean prediction.

There is growing evidence that in utero imbalance immune activity plays a role in the development of neurodevelopmental and psychiatric disorders in children. Mood dysregulation (MD) is a debilitating transnosographic syndrome whose underlying pathophysiological mechanisms could be revealed by studying its biomarkers using the Research Domain Criteria (RDoC) model. Our aim was to study the association between the network of cord serum cytokines, and mood dysregulation trajectories in offsprings between 3 and 8 years of age. We used the data of a study nested in the French birth cohort EDEN that took place from 2003 to 2014 and followed motherchild dyads from the second trimester of pregnancy until the children were 8 years of age. The 2002 mother -child dyads were recruited from the general population through their pregnancy follow-up in two French university hospitals. 871 of them were included in the nested cohort and cord serum cytokine levels were measured at birth. Children 's mood dysregulation symptoms were assessed with the Strengths and Difficulties Questionnaire Dysregulation Profile at the ages 3, 5 and 8 years in order to model their mood dysregulation trajectories. Out of the 871 participating dyads, 53% of the children were male. 2.1% of the children presented a high mood dysregulation trajectory whereas the others were considered as physiological variations. We found a significant negative association between TNF- alpha cord serum levels and a high mood dysregulation trajectory when considering confounding factors such as maternal depression during pregnancy (adjusted Odds Ratio (aOR) = 0.35, 95% Confidence Interval (CI) [0.18 -0.67]). Immune imbalance at birth could play a role in the onset of mood dysregulation symptoms. Our findings throw new light on putative immune mechanisms implicated in the development of mood dysregulation and should lead to future animal and epidemiological studies.

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Childhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (EDs) is associated with internalizing behaviours in infants, the associations with prenatal exposure to EDs in mixture remain poorly addressed. In addition, the biological mediators of EDs in mixture effects on internalizing behaviours remain unexplored. EDs do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which prenatal exposure to EDs in mixture could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether exposure to a mixture of EDs increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α measured at birth were mediators of this effect. To determine both the joint and individual associations of prenatal exposure to EDs with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex mixture of EDs has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1β, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours in boys at age 3. Further studies on larger cohorts are warranted to refine the deleterious effects of EDs in mixtures on internalizing behaviours and identify possible mediating pathways.

BACKGROUND:Cord blood leptin is an indicator of neonatal fat mass and could shape postnatal adiposity trajectories. Investigating genetic polymorphisms of the leptin receptor gene (LEPR) could help understand the mechanisms involved.OBJECTIVES:We aimed to investigate the association of cord blood leptin level and the LEPR rs9436303 polymorphism, with body mass index (BMI) at adiposity peak (AP) and age at adiposity rebound (AR).METHODS:In the EDEN cohort, BMI at AP and age at AR were estimated with polynomial mixed models, for 1713 and 1415 children, respectively. Multivariable linear regression models allowed for examining the associations of cord blood leptin level and LEPR rs9436303 genotype with BMI at AP and age at AR adjusted for potential confounders including birth size groups. We also tested interactions between cord blood leptin level and rs9436303 genotype.RESULTS:Increased leptin level was associated with reduced BMI at AP and early age at AR (comparing the highest quintile of leptin level to the others). Rs9436303 G-allele carriage was associated with increased BMI at AP and later age at AR but did not modulate the association with leptin level.CONCLUSION:These results illustrate the role of early life body composition and the intrauterine environment in the programming of adiposity in childhood.

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The “Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)” is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration: http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044

Most researchers working in the field of immunopsychiatry would agree with the statement that "severe psychiatric disorders are associated with inflammation and more broadly with changes in immune variables". However, as many other fields in biology and medicine, immunopsychiatry suffers from a replication crisis characterized by lack of reproducibility. In this paper, we will comment on four types of immune variables which have been studied in psychiatric disorders: Acute Phase Proteins (AAPs), cytokines, lipid mediators of inflammation and immune cell parameters, and discuss the rationale for looking at them in blood. We will briefly describe the analytical methods that are currently used to measure the levels of these biomarkers and comment on overlooked analytical and statistical methodological issues that may explain some of the conflicting data reported in the literature. Lastly, we will briefly summarize what cross-sectional, longitudinal and mendelian randomization studies have brought to our understanding of schizophrenia (SZ).

Sleep is essential for optimal child development and health during the life course. However, sleep disturbances are common in early childhood and increase the risk of cognitive, metabolic and inflammatory disorders throughout life. Sleep and immunity are mutually linked, and cytokines secreted by immune cells could mediate this interaction. The sleep modulation of cytokines has been studied mostly in adults and adolescents; few studies have focused on school-aged children and none on preschoolers. We hypothesized that night sleep duration affects cytokine levels in preschoolers. In a sample of 687 children from the EDEN French birth cohort, we studied the associations between night sleep duration trajectories from age to 2-5 years old and serum concentrations of four cytokines (Tumor necrosis factor alpha [TNF-alpha], Interleukin 6 [IL-6], IL-10, Interferon gamma [IFN)-gamma] at age 5, adjusting for relevant covariates. As compared with the reference trajectory (R-.111h30/night sleep, 37.4% of children), a shorter sleep duration trajectory (<10 h/night, 4.5% of children), and changing sleep duration trajectory (>= 11h30/night then 10h30/night, 5.6% of children) were associated with higher serum levels of IL-6 and TNF-alpha, respectively at age 5. We found no associations between sleep duration trajectories and IL-10 or IFN-gamma levels. This first longitudinal study among children aged 2-5 years old suggests an impact of sleep duration on immune activity in early childhood. Our study warrants replication studies in larger cohorts to further explore whether and how immune activity interacts with sleep trajectories to enhance susceptibility to adverse health conditions.

Abstract Introduction There is a reciprocal interaction between sleep and the immune system. Activation of the immune system changes the quality of sleep, and sleep regulates innate and adaptive immune responses. While these interactions have been studied in adults and adolescents, only a few studies have focused on school age children and none on preschoolers. Here, we have studied the association between night sleep trajectories between the age of 2 and 5 and serum levels of four cytokines in 5-year-old children. Methods A total of 687 children (44% girls) from the EDEN French birth cohort were included. Information on night sleep trajectories between 2 and 5 was available in all included individuals, as well as the levels of Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, interferon gamma (IFN-gamma), and IL-10 in 5-year-old children. The associations between sleep trajectories and cytokines were assessed by multivariate linear regressions adjusted for socioeconomic, familial, maternal, perinatal and child factors. Results A shorter sleep duration trajectory (<10h/night, 4.5% of children) was associated with higher levels of IL-6 when compared to the reference trajectory (≈11h30/night, 37.4% of children). A longer sleep duration trajectory (≥11h3/night, 40.9% of children) was associated with higher levels of IL-10. A changing sleep duration trajectory (≥11h30/night followed by 10h30/night, 5.6% of children) was associated with increased levels of TNF-alpha. No statically significant association was observed between sleep duration trajectories and IFN-gamma. Conclusion This first longitudinal study in preschoolers demonstrates an association between sleep duration trajectories and blood levels of IL-6, IL-10 and TNF-alpha. While association does not imply causation, our results are compatible with an impact of sleep duration on low-grade inflammation in preschool children. Should our results be replicated in an independent study sample, it would pave the way for a better understanding of the interactions between sleep and the immune system. Support (if any):

Déterminer si la concentration de leptine dans le sang de cordon prédit l’indice de masse corporelle au pic d’adiposité (IMCPA) et l’âge au rebond d’adiposité (ARA), indépendamment de la trophicité à la naissance. Nous avons estimé, à l’aide de modèles mixtes, l’IMCPA et l’ARA respectivement pour 1713 et 1415 enfants de la cohorte EDEN. Nous avons analysé l’association entre les concentrations de leptine dans le sang du cordon et l’IMCPA et l’ARA, à l’aide de modèles de régression linéaire ajustés sur le niveau d’études et l’IMC des parents, l’âge de la mère à l’accouchement, le gain de poids gestationnel, le tabagisme maternel pendant la grossesse et les caractéristiques des nouveau-nés, incluant la trophicité. Dans le modèle multi-ajusté, la leptine mesurée dans le sang de cordon était négativement et linéairement associée à l’IMCPA. Une leptine élevée (5e quintile) était associée à un ARA plus précoce. Les enfants nés petit pour l’âge gestationnel avaient en moyenne un IMCPA plus faible et à un ARA plus précoce, alors que les enfants nés gros pour l’âge gestationnel avaient un IMCPA plus élevé. La leptine dans le sang de cordon semble jouer un rôle prédictif indépendant de la trophicité à la naissance sur la trajectoire d’IMC au moment du pic et du rebond. Marqueur de l’accumulation fœtale de masse grasse, le taux de leptine pourrait également refléter un environnement intra-utérin défavorable, impliqué dans la programmation du développement de l’adiposité dans l’enfance.