To discuss and summarize the scholarly published literature on the difference in obesity rate in treated and untreated attention deficit hyperactivity disorder (ADHD) patients to evaluate the influence of ADHD medication on weight status in these individuals.PubMed, Cochrane Library, and Google Scholar databases were searched for eligible articles from January to December 2020 using the following medical subject headings (MeSH) terms: “attention deficit hyperactivity disorder and other hyperactivity disorders”, “obesity and overweight”, “obesity treatment”.A total of 19,449 study participants included in selected 8 studies were assessed with respect to the prevalence of obesity in medicated and unmedicated subgroups of ADHD patients. The total number of ADHD patients with the prescribed medication was 10,279, while the number of unmedicated ADHD patients was 9,170. The odds ratio was 0.65 with a 95% confidence interval of 0.50 to 0.84 favoring regular medical treatment for management of obesity in case of patients with ADHD.The prevalence of obesity observed in treated ADHD patients was significantly lower compared to that in unmedicated patients. This result suggests that the treatment is not only important for controlling ADHD manifestations but is also associated with lower body mass index. Therefore, further prospective studies with large sample size are required for controlling the confounding factors such as comorbidities and medication status. Physical health problems are frequently observed in mental health patients compared to the general public. Previous studies have confirmed that somatic symptoms significantly contribute to mental health symptoms, and comorbidities play an important role in aggravating primary symptoms, causing physiological impairment, lowering life quality, and enhancing economic burden. While studying comorbidities of psychiatric and medical diseases, Druss et al concluded that approximately 68% of psychiatric patients had one or more somatic disorders. The interlinking of mental and somatic disorders has been understood to a certain extent. For example, mood disorders are seen in hypothyroidism, and schizophrenia and bipolar disorders are associated with metabolic syndrome probably due to that the effect of medication on the development of these complications overrides lifestyle factors. Moreover, it has been well-observed that most psychiatric patients tend to have unhealthy and unhygienic dietary habits and a sedentary lifestyle. It has been reported that impairing symptoms of ADHD in children can persist in adulthood in up to 65% of individuals with a prevalence of ADHD in adulthood of almost 2.5%. The study from Jensen et al found that 87% of ADHD cases had one comorbidity, and 67% of ADHD cases had more than one comorbidity.Similarly, Bidermanet et al stated that 20% of ADHD cases attending clinics had at least 2 comorbidities.All comorbidities seen in ADHD patients could be a manifestation of a single disorder in different ways, or conversely different disorders may have a similar appearance. Therefore, ADHD may be an early manifestation of some other disease or may indicate the development of another disease. Specifically, there has been an increasing amount of evidence on possible association between ADHD and obesity/overweight; this association is important when considering ADHD treatment. The available treatments for ADHD include pharmacological treatments with mainly psychostimulant medications such as methylphenidate, amphetamines, and bupropion. Most common side effects of these treatments are decreased appetite, headache, abdominal pain, sleep disturbances, and irritability, and less frequent side effects include weight loss, social withdrawal, tics, and emotional modifications in some cases.Attention deficit hyperactivity disorder (ADHD) has been found to be the most frequent childhood-onset neurodevelopmental disorder, according to the American Psychiatric Association’s DSM-5, it as the presence of 6 or more symptoms in either the inattentive or hyperactive and impulsive domains, or both, that imposes an enormous burden on the population. Similarly, another recent meta-analysis conducted by Cortese et al reported that patients receiving medications for ADHD were not at a higher risk for obesity, which was not the case in untreated ADHD patients. Therefore, these studies suggest the importance of stimulant treatment in both managing ADHD symptoms and improving nutritional status in obese ADHD patients.A longitudinal clinical intervention was carried out in 2009 to assess the effects of ADHD drugs on weight change by following 78 severely obese adults diagnosed with ADHD (65 received medication for ADHD and 13 were controls) for 466 days. Its findings revealed that ADHD medication is associated with significant long-term weight loss in patients with a previous history of weight loss failure .To elucidate the effect of stimulant pharmacological treatments on nutritional status and weight, it is important to examine the impact of these drugs on ADHD obese patients. The aim of this meta-analysis is to discuss and summarize published scholarly literature on the difference in obesity rate in treated and untreated ADHD patients to evaluate the effect of ADHD medication on weight status in these individuals. The objective is to answer the following question: “Is there a difference in the prevalence between medicated and unmedicated ADHD patients?”This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. All studies evaluating the prevalence of obesity in individuals with ADHD were considered to be eligible for inclusion in the meta-analysis. The studies that mentioned the body mass index (BMI) or obesity status of children aged under 18 years, suffering from obesity in association with ADHD with or without prescribed concomitant stimulant medications were also included in the meta-analysis. The following points were considered as the inclusion criteria: studies that evaluated prevalence of obesity in the ADHD population, studies that included medicated and unmedicated ADHD patients, studies that mentioned the BMI status of study participants or obesity in general, and studies with a parallel study design that enrolled both medicated and unmedicated patients suffering from ADHD who were overweight and at risk of developing obesity or who were diagnosed with obesity. The exclusion criteria consisted of: studies that included patients above 18 years of age, studies that included medicated or unmedicated ADHD patients without the other corresponding arm, studies that considered the health outcomes of patients with ADHD but were lacking any comments with respect to body weight and BMI, and studies mentioning the prevalence and control of obesity in individual suffering from autism spectrum disorders (ASD) and other psychological and psychiatric conditions apart from ADHD. The majority of studies that mentioned the prevalence of obesity were cross-sectional and later performed subgroup analysis to ascertain the prevalence and control of obesity in medicated and unmedicated individuals suffering from ADHD along with a few case reports limited to individual findings. Studies that satisfied the selection criteria but were available in the form of abstracts, incomplete studies , duplicates, and unpublished articles were not considered for inclusion in the meta-analysis. Finally, all eligible articles available in English language were selected for evaluation.Search terminology was defined according to the protocol for identification of the search terms with respect to the prevalence of obesity in medicated and unmedicated individuals with ADHD. The search terms were used with the Boolean operator “AND” to filter the related articles. Free text search utilized the words such as ADHD, treatment, medicated, and unmedicated along with the Boolean operator “OR” in-between them and in association with BMI, obesity, and overweight with the Boolean operator “AND”. In contrast, the controlled language search included the following medical subject headings terms: “attention deficit hyperactivity disorder and other hyperactivity disorders”, “obesity and overweight”, and “obesity treatment”. PubMed, Cochrane Library, and Google Scholar databases were searched for eligible articles from January to December 2020. The reference list of all included studies was further reviewed to include the eligible studies. During the database search for potential studies, titles and abstracts of the articles were screened according to the selection criteria by independent reviewers.Data was extracted individually and recorded in a customized data extraction sheet by 2 independent reviewers. Discrepancies regarding the inclusion of studies were resolved through discussion or arbitration by involving an additional reviewer, as required. Once the selection of preliminary studies was carried out based on the criteria, full texts of the articles were assessed to evaluate the study content for the meta-analysis. Information pertaining to the prevalence of obesity and the effect of medications on the BMI control was extracted and analyzed. The risk of publication bias assessment was independently performed on each study by 2 reviewers. The overall search process resulted in 1,131 articles, which were reduced to 319 after the removal of duplicates. Eligibility screening yielded 29 studies that were then subjected to full text review. Finally, 8 articles were selected for the meta-analysis. To address the heterogeneity of the included studies with respect to the study population, study environment, and trial setting , the findings from individual studies were pooled using the random effects model, which helped to identify potential areas that could significantly alter the results. Forest plot showing the odds ratio (OR) of the point estimates along with 95% confidence interval (CI) for the prevalence of obesity in medicated and unmedicated individuals with ADHD was constructed and represented accordingly. The degree of heterogeneity among the included studies was evaluated using the I test, which acts as a tool to understand the degree to which the studies differ in their clinical trial setting.A descriptive analysis of the extracted data was performed. Similar findings from the studies were identified and quantitatively analyzed, which were then represented accordingly. The meta-analysis was performed using the Revman software version 5.3. The details of identification, screening, eligibility, and inclusion of studies is shown in PRISMA flowchart in After the search and screening process by 2 independent reviewers, a total of 8 studies were selected for meta-analysis. discussed the prevalence of obesity by considering BMI as the criteria for distinction between normal weight and overweight, while remaining 3 studies only described the people who were at risk for developing obesity. The characteristics of the included studies are listed in A total of 19,449 study participants included in those 8 studies were assessed with respect to the prevalence of obesity in medicated and unmedicated subgroups of ADHD patients. The total number of ADHD patients with prescribed medication was 10,279, while the sum of unmedicated ADHD patients was 9,170. A total of 359 obese patients were in the medicated subgroup, while 509 obese patients were in the unmedicated group. Five studies Special emphasis was given to the study aim, study participants, clinical trial design, parameters used for assessment of the primary objective, inclusion and exclusion criteria applied for selection of the study sample, treatment arms, variables used for defining the outcome, exposure, and potential confounders and predictors. Methodological quality of the included studies was evaluated to minimize the probability of bias at different points during study selection. The majority of studies scored well in all above mentioned domains; however, there was no formal sample size calculation mentioned in any of the included studies, which limited the overall scoring of all included studies to below 75%.The quality of included studies was evaluated using the STROBE guidelines for observational studies.The overall summary estimate of the forest plot  favored  The p-value for overall summary estimate was 0.0009 along with a Z score of 3.33. The odds ratio (OR), calculated using the Mantel–Haenszel random effects model for prevalence of obesity was 0.65 with a 95% CI of 0.50 to 0.84. The combined estimate favored regular medical treatment for management of obesity in case of patients with ADHD because the 95% CI for odds ratio of the summary estimate was completely present on one side of the line of zero effect favoring medicated ADHD group.Unmedicated ADHD patients were more prone to develop obesity compared to those on treatment for ADHD. The prevalence of obesity was 4 per 100 patients in the medicated subgroup of ADHD (3.5%), while in the case of patients who did not receive any treatment for ADHD, 6 out of 100 patients suffered from obesity (5.6%). The majority of studies recommended adequate medications to be the key factor for obesity control, while 3 studies indicates that ADHD patients with prescribed medications were at equal risk for developing obesity compared to their unmedicated counterparts. test, Egger’s test was used to assess the heterogeneity of the study. Special precautions were observed to prevent the occurrence of publication bias. The inverted funnel plot , may cause excessive daytime sleepiness that in turn contributes to similar ADHD signs and symptoms. A previous meta-analysis carried out by Cortese et al, which included 12 articles, had similar findings yet non-significant results, where patients treated with ADHD medications had rates of obesity that were lower by approximately 40% compared to untreated patients. In addition, the findings of another study, which aimed to evaluate the association of treatment duration with weight loss, showed that after comparing patients treated for less than one year with those treated for more than 3 years, these groups had a significant decrease in BMI, showing that BMI tended to decrease without considering the period of treatment. However, the reason for weight loss in all situations has not yet been established, specifically after knowing that the effects of methylphenidate are generally temporary and become less evident during treatment. Strimas et al and Davis et al suggested that pharmacological treatments are capable of both reducing impulsiveness/inattention and improving inhibitory control, resulting in a decrease in caloric intake with a better and organized diet plan, which in turn may have assisted in weight reduction. However, a naturalistic study by Levy et al reported that appetite suppression was evident within 1-1.5 months after starting the treatment, but then it reduced and vanished in the majority of participants within 2 months; the authors concluded that it was not likely that the temporary anorexigenic impact of psychostimulants contributed to the observed weight loss at follow-up >1 year after the start of treatment.Our meta-analysis revealed that the prevalence of obesity observed in treated ADHD patients was significantly lower compared to that in unmedicated ADHD patients, with OR equal to 0.65 with 95% CI of 0.50–0.84, favoring regular medical treatment for management of obesity in case of patients with ADHD. This result was possibly obtained due to the anorectic effects of methylphenidate causing reduced appetite and resulting in weight loss.Attention deficit hyperactivity disorder must be presented as the main reason of weight loss failure in the obese population. Patients diagnosed and seeking medical or surgical weight loss must be assessed for ADHD and treated accordingly prior to intervention. Similarly, ADHD patients must be evaluated for possible risk of obesity during their assessment and management. This will result in an improved management outcome and reduced occurrence of post-surgical complications due to poor compliance with diet and supplement requirements.Furthermore, a previous systematic review was carried out to assess the effect of physical activity on children with ADHD on the short and long run. Results suggested clinical benefits including alleviated cognitive, behavioural and physical symptoms of ADHD due to exercising. It must be also taken into consideration a re-analysis of the original data  rather than just extracting aggregated data to allow further subgroups analyses. Most study participants in this analysis were obese; hence, future studies are needed to provide more information on patients with less severe grades of weight excess. Another caveat to this review was that we did not focus on duration of illness and medication use due to the limited number of studies that examined these variables. Finally, the long-term effects of psychostimulants on weight was not fully considered in the present study; weight loss may be related to direct anorexic effects of psychostimulants, or long-term normalization of eating patterns, or other indirect mechanisms.Though there are many other databases and indexing services for peer-reviewed literature like PsycINFO, Scopus and Web of Science, but due to our study limitations, we only searched PubMed, Cochrane Library and Google Scholar. This meta-analysis has important clinical and public health implications. Assessing the risk for obesity should be part of the assessment and management of ADHD patients, especially untreated ADHD patients. However, our results showed the following limitations. The publication bias could have occurred from including only studies that were published in English. The analysis excluded unpublished studies that might have been presented at conferences. The analyzed cross-sectional data did not provide deductive conclusions on causality in the association between ADHD medications and obesity status. The definition of obesity in the included studies in children and adolescents was based on different BMI thresholds and definitions, such as Z-scores [85th (at risk for overweight) and 95th percentiles (overweight) of BMI], or BMI adjusted for gender and weight based on WHO’s growth charts and then presented as Z scores.In conclusion, over the last 3 decades, obesity has become an epidemic posing serious public health issues. In the literature, many studies have assessed the association between ADHD and obesity, and preliminary evidence revealed that the prevalence of obesity observed in treated ADHD patients was significantly lower compared to that in unmedicated patients, suggesting that treatment is associated with lower BMI. Therefore, further prospective studies with large sample size controlling for confounding factors, such as population characteristics including comorbidities and medication status must be investigated further in future research. Moreover, behavioral modification and obesity intervention programs must also take these factors into consideration.


Background: Children with Attention Deficit Hyperactivity Disorder (ADHD) having a history of adverse childhood experiences (ACEs) could be very difficult to treat with standard psychotherapeutic approaches. Some children diagnosed with ADHD may have Post-Traumatic Stress Disorder (PTSD) or have had experienced a significant traumatic event. Trauma and PTSD could exacerbate ADHD core symptoms and be a risk factor of poor outcome response. Objective: to report for the first time the history of a patient with ADHD and ACE successfully treated with an EMDR approach. Conclusion: EMDR could be a promising treatment for ADHD children with a history of traumatic experiences in addition to pharmacological treatments.  Adverse childhood experiences (ACEs) are the umbrella term used to explain traumatic experiences during childhood leading to a significant effect on the biological, psychological and social functioning on affected children. These experiences are usually caused by persons with a care role in the child’s life and can be direct  or indirect , . According to the American Psychiatric Association (APA) , trauma In the last few years there has been a growing interest in understanding the possible relationship between hyperactivity-attention deficit disorder (ADHD) and ACEs ,9,10,11.The negative long-term consequences of ACEs on physical and mental health are well-documented , with a The relationship between ADHD and post-traumatic stress disorder (PTSD) has been of interest in the last years. PTSD is defined according to APA criteria as a complex clinical condition characterized by the presence of different clinical signs including disturbing thoughts, feelings or dreams related to the traumatic events, avoidance and trauma-related hyperarousal symptoms after being faced with trauma directly or indirectly, including a real or intimidating manner to death, severe injuries or sexual assault . EpidemiChildren with PTSD have also been shown to have a neuropsychological profile suggestive of impaired prefrontal cortex functioning including deficits in sustained attention, impulsivity and poor performance in cognitive measures evaluating abstract reasoning/executive function . It is uSeveral studies have shown high rates of ADHD ,9,10,11 We report a case study of a patient with ADHD and history of complex childhood trauma treated using eye movement desensitization and reprocessing (EMDR) to target traumatic experiences. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the EC of Fondazione Policlinico Gemelli .A child of Brazilian origin was institutionalized in an orphanage at the age of 3 years and adopted by an Italian family at the age of 9 years together with one of his three sisters. The child’s developmental milestones were reported as normal. His biological mother suffered from substance abuse disorder (narcotic) due to which she was stripped of her parental authority. She died by an overdose in the bedroom of the house when he was 3 years old. It was also reported that the child witnessed the death of 2 sisters by a car accident when he was younger than 9 years. At the age of 12 years, he was treated on an outpatient basis at Service of Child Neuropsychiatry of our hospital where a diagnosis of ADHD, as defined by DSM-5 [For this reason, he started to have symptoms including anger, irritability, loss of control, affective instability and oppositional-defiant attitudes. Therefore, he started aripiprazole therapy (5 mg increased to 10 mg a day) associated to modified release methylphenidate therapy with slight improvement of the affective symptoms and reduction of the irritability. He repeated neuropsychological assessment including the WISC-IV which revealed an intellectual functioning in the normal range  associated with severely specific learning difficulties. Successively, the patient refused to continue CBT therapy. Due to the persistence of oppositional-defiant attitudes and emotional difficulties, in agreement with the adoptive parent and the patient, it was decided to change the psychotherapy treatment plan from CBT to EMDR treatment considering also his previous traumatic experience. EMDR treatment was considered also due to the collaborative efforts between our hospital and the territorial Presidium Prevention of Early Interventions Mental Health (PIPSM). Before starting EMDR treatment he performed a clinical assessment evaluation with the following self-report questionnaires : SymptomFollowing clinical assessment and consolidation of the therapeutic relationship, EMDR treatment was carried out. We used the standard Protocol of EMDR therapy on past memories. EMDR therapy consists of eight phases. These phases occur over multiple sessions, with one session sometimes using parts of several phases. An example of this would be how Phases 1 and 2 typically happen only in early sessions, while Phases 3 through 8 are part of multiple sessions later. For a single disturbing event or memory, it usually takes between three and six sessions. More complex or longer-term traumas may take 8 to 12 sessions (or sometimes more). Sessions usually last between an hour and 90 min , he was treated on this target with EMDR for two 65 min sessions. An avoidant atattachment disorder was considered during EMDR therapy. Even if the attachment disorder may mimic ADHD, in our case both behavioral and neuropsychological findings were compatible with ADHD according to DSM-5 criteria, but the severity was influenced by the attachment disorder and the related PTSD. A follow-up cognitive evaluation was administrated after 9 months of EMDR treatment on n.1 target  showing The symptoms of ADHD and trauma-related symptoms in growing children have certain similarities. In both there is difficulty in sustaining attention, an incapacity to listen, failure to complete duties, difficulty in organization, memory dysfunction, irritability, and restlessness. Trauma and PTSD could also exacerbate dis-attention, impulse regulation, and physiological hyperreactivity symptoms or disruptive behaviors with oppositionality and aggression . HyperacNowadays, ADHD diagnosis includes a wide variety of clinical pictures, reflecting the complexity of his etiology. In clinical practice it often occurs that symptoms that have developed as a result of trauma, single or repeated, can be mistakenly confused with the diagnosis of ADHD. Certainly, further scientific investigations are needed to improve the differential diagnosis between ADHD of a post-traumatic nature and ADHD of a neurobiological nature. Screening for childhood traumatic experiences and PTSD symptoms is warranted in ADHD children with an emphasis on detecting those with subthreshold PTSD symptoms. As the number of children with this diagnosis is increasing, the risk is that the number of children undergoing drug treatment, which is not always necessary, will increase in parallel. In addition, ADHD is the second most frequently diagnosed disorder among a population of sexually abused children with a primary diagnosis of PTSD .The affective relationship as a process of affective attunement is recognized as a fundamental precursor of both the psychic and neurobiological development of the brain . HoweverThe evidence between ACEs and ADHD diagnosis remains, to date, controversial. To our knowledge, the possible explanations are the following: (1) there is a causal effect of ACEs on ADHD symptoms; (2) trauma-related symptoms are mistaken for ADHD symptomatology; (3) there is a bidirectional relationship between ADHD and ACEs. For adults and children who have experienced ACEs, the most recommended treatment is some type of trauma-informed care ,25. EMDRTo date, the literature had described only one case study of an adult patient with ADHD and history of infant trauma successfully treated with EMDR . It is an integrative psychotherapy combining a variety of psychotherapeutic orientations, and its application is guided by an information-processing model . DistresEMDR  could beRecent neuroscience findings have demonstrated the role of the primary affective processes on memories consolidation through thalamic–hypothalamic pathways and additional studies should further investigated on subcortical neural correlates .Future randomized clinical trials will be needed to confirm the efficacy of EMDR treatment on young ADHD patients with ACEs.


Compared with gestational age less than 37 weeks, the LBW probability of gestational age 37–42 and 42 weeks or older is 85 and 81% lower respectively , compared with normal pregnant women, the probability of neonatal LBW among pregnant women with hypertension is 94% higher [AOR = 1.94 . Compared with neonates with normal birth weight, neonates with LBW are at Apgar 1 min And Apgar 5 min score is lower than 7  higher risk. In conclusion, women’s marital status (single), gestational age (<37 weeks), and combined hypertension are independently associated with LBW, and the higher risk of Apgar 1 min and Apgar 5 min scores <7 is an independent result of LBW.This study aims to evaluate the incidence of low birth weight (LBW) and related maternal risk factors (during pregnancy or childbirth) and neonatal outcomes. A retrospective cross-sectional study design was used to select 7,421 pregnant women who gave birth in our hospital from January 2018 to June 2021. The data were analyzed using STATA 14.1, and the dependent variable (LBW) and risk were analyzed by the chi-square test of independence. The association between factors is used to determine the factors related to LBW through bivariate and multivariate logistic regression. The incidence of LBW in this study was 4.77%. Compared with single pregnant women, the probability of newborn LBW in married pregnant women is 40% lower (AOR = 0.60 95%CI: 0.40–0.90,  Birth weight is critical for neonatal survival, physical health, and development . Low birThe incidence of LBW continues to increase year by year despite efforts and a number of strategies specified . The UNIThis study adopted a retrospective cross-sectional study design, and selected 7,421 pregnant women who delivered in our hospital from September 2018 to June 2021 for retrospective analysis. Inclusion criteria: singleton pregnancy; neonates without congenital diseases. Exclusion criteria: incomplete maternal and infant information, unknown neonatal status , stillbirth, missing birth weight information, non-singleton pregnancy. The study was approved by the hospital ethics approval committee , but no informed consent was obtained because it was a retrospective study.Based on a review of relevant literature , a strucp < 0.05 values were considered statistically significant.Data were analyzed by STATA 14.1, descriptive statistics were used for categorical data, chi-square test was used to test the association between the dependent variable (LBW) and LBW risk factors, and bivariate and multivariate logistic regression was used to identify factors associated with LBW, significant variables in bivariate logistic regression were used for multivariate logistic regression and 346 (4.78%) newborns weighed less than 2,500 g, most (58.2%) pregnant women were between 21–30 years old, 83.6% were married, the majority (63.0%) of pregnant women had secondary or higher education, and male newborns (50.9%) were slightly higher than females 50.9%, .p = 0.043, Bivariate logistic regression analysis showed that compared with single pregnant women, married pregnant women were 31% less likely to have low birth weight neonates [COR = 0.69, 95%CI: 0.47–1.00, p = 0.001, p = 0.016, p < 0.001), the prevalence of LBW was 76% higher among pregnant women with hypertensive disorders , Apgar 5 min score <7 , and neonatal resuscitation  was associated with crying at birth . Bivariate logistic regression analysis also showed that LBW neonates had a higher risk of Apgar 1 min and Apgar 5 min scores less than 7 and a 52% higher neonatal resuscitation rate compared with normal-weight neonates  and a 40% lower rate of postnatal crying , compared with less than 37 weeks gestational age, the odds of LBW were 85 and 81% lower for gestational age 37–42 weeks and over 42 weeks , compared with normal pregnant women, pregnant women with hypertensive disorders had a 94% higher chance of neonatal LBW , compared with neonates with normal birth weight, LBW neonates had Apgar 1min and Apgar 5 min scores of less than 7 . The results of the current study are similar to those reported in the previous literature  and LBW. Multiple studies worldwide have reported that women with HDP have a higher incidence of LBW than women with normotensive blood pressure . Their ffrom LBW . Therefofrom LBW . A studyIn conclusion, this study revealed a low incidence of LBW (4.77%), and that women’s marital status (single pregnant women), gestational age (<37 weeks), and comorbid hypertensive disorders were independent risk factors associated with LBW, while in Apgar Higher risk of 1 min and Apgar 5 min scores less than seven was an independent outcome of low birth weight. The current findings contribute to an understanding of the incidence of LBW and its influencing factors, which can guide healthcare providers, hospital administrators, and planners in the development and implementation of appropriate clinical and public health strategies aimed at reducing LBW. However, this study still has certain limitations. For example, although the sample size investigated is rich, most of them are from a single region, and the reference significance for the whole country is still limited. Secondly, the clinical factors included in this study are relatively few, and further research is needed supplement.


Dermanyssus gallinae poses a significant threat to the health of hens and poultry production. A comprehensive understanding of D. gallinae is necessary to develop sustainable and efficacious control methods. Here we examined 144 D. gallinae collected from 18 poultry farms throughout the Japanese Archipelago for their genetic variations based on mitochondrial cytochrome c oxidase subunit I (COI) sequences, and microbiome variations based on amplicon sequencing of the 16S ribosomal RNA gene. According to COI sequencing, the Japanese samples were categorized into three haplogroups, which did not reflect the geographical distribution. Microbiome analyses found that the major bacteria associated with D. gallinae were Bartonella, Cardinium, Wolbachia, and Tsukamurella, with Bartonella being most predominant. Among 144 individual mites, all possessed one of the two major types of Bartonella (Bartonella sp. A), while 140 mites possessed the other type (Bartonella sp. B). The presence of the two strains of Bartonella was also confirmed by a single copy gene, rpoB. The presence of Bartonella in laid eggs suggested transovarial vertical transmission. Given that obligate blood-feeding arthropods generally require a supply of B vitamins from symbiotic bacteria, Bartonella may play an important role in mite survival. Rickettsiella, a major symbiont in European D. gallinae populations, and suggested to be an important symbiont by genomic data, was rarely found in Japanese populations. Cardinium detected from D. gallinae fell into a major clade found widely in arthropods, whereas Wolbachia detected in Japanese D. gallinae appear to be a new lineage, located at the base of Wolbachia phylogeny. Of the mitochondrial phylogeny, infection patterns of Cardinium and Wolbachia were strongly correlated, possibly suggesting one or both of the symbionts induce reproductive manipulations and increase spread in the host populations.The poultry red mite  Dermanyssus gallinae (Acari: Dermanyssidae), an obligate blood-feeding ectoparasite that feeds on avian blood, is globally distributed  with 50 μl of EB buffer. The DNA samples were stored at −30°C until used. PCR was conducted for mitochondrial cytochrome c oxidase subunit I (COI) using KOD FX Neo , and the primers FCOIDG and RCOIDG designed for COI of D. gallinae (Escherichia coli DH5α competent cells (Takara). Plasmids were extracted using a QIAprep Spin miniprep kit (Qiagen), the purified plasmids were subjected to sequencing reactions using a BigDye Terminator v3.1 Cycle Sequencing Kit  and the sequencing primers M13F or M13RV in the flanking regions of the vector along with the bacterial universal primer 16SA2. The primer sequences are shown in After being crushed using an EOG-sterilized BioMasher II , DNA was extracted from the whole body of each adult gallinae . For 16SThe molecular phylogenetic analyses were conducted utilizing maximum-likelihood estimation methods using MEGA: Molecular Evolutionary Genetics Analysis, ver. 5.2 software  with 1,0D. gallinae microbiome, hypervariable V3/V4 regions of the 16S rRNA gene were sequenced. The libraries created by using 2-step tailed PCR  v.2020.06 pipelines . DenoisiBartonella (Bartonella sp. A and Bartonella sp. B) may represent either the existence of distinct bacteria or the intragenomic operon copies of a single bacterium. To distinguish these possibilities, we performed PCR, cloning, and sequencing for the single copy gene rpoB from an individual (18_4) whose microbiome was occupied mostly with Bartonella sp. A and Bartonella sp. B with similar abundance. A primer set, Univ_rpoB_F_deg and Univ_rpoB_R_deg  benzalkonium chloride followed by two 5 min washes in 70% (v/v) ethanol, and were then subjected to DNA extraction and PCR using 27F-short and 1507R primers (DNA was extracted from a pool of approximately 20 eggs freshly laid by  primers . Cloningin situ hybridization (FISH) targeting bacterial 16S rRNA was performed using the mites collected from Aomori Prefecture following Whole-mount fluorescent Cardinium and Wolbachia, share evolutionary trajectories in maternal lineages, the log marginal likelihood estimated on the COI tree with an assumed independent model was compared with that estimated with an assumed dependent model using BayesTraits V4.0.0.In order to test whether the two bacteria, D. gallinae mites collected from 18 poultry farms , but mitochondrial haplogroups of D. gallinae were not associated with chicken breeds (purposes)  . All 144pearance , is alsoBartonella sp. B, Cardinium, Bartonella sp. A, Wolbachia, Tsukamurella, Micrococcus, Rickettsiella, Staphylococcus, Enterobacter, Rhodopseudomonas, and Psychrobacter in order of relative frequency (Bartonella sp. A (100%), 140 mites had Bartonella sp. B (97.2%), 76 mites had Cardinium (52.8%), 52 mites had Wolbachia (36.1%), 23 mites had Tsukamurella (16.0%), 17 mites had Micrococcus (11.8%), and 2 mites had Rickettsiella (1.4%). Box plots of the 18 poultry farms were drawn according to the Shannon diversity index . An individual 18_4, whose microbiome was mostly occupied by Bartonella sp. A and Bartonella sp. B with a nearly equal ratio, was subjected to PCR, cloning, and sequencing  from Tochigi Prefecture identified two strains of us study . Althougrtonella  because rtonella . To distquencing . All thezobiales . It remaRickettsiella 16S rRNA was obtained from a sample from Hokkaido (2_1) which had a relatively high abundance of Rickettsiella in the amplicon sequencing , matched the sequence of Bartonella obtained from sampled avian blood . Cloning and sequencing of the bacterial 16S rRNA sequences using surface-sterilized D. gallinae eggs from Ibaraki Prefecture (derived from a different farm from those used for amplicon sequencing) identified both Bartonella sp. A and B , which is consistent with the results of the amplicon sequence analysis  from Tochigi Prefecture. Phylogenetically, the Cardinium derived from D. gallinae fell into the group A of Cardinium, the most common group found among various arthropods  to enhance their own transmission (Wolbachia and Cardinium cause cytoplasmic incompatibility (Cardinium causes feminization (Cardinium and Wolbachia in respective mtDNA haplotypes (Cardinum and/or Wolbachia infection rate (infection rate of either bacterium is 25.4% (18/71)), haplogroup AJ1 and haplogroup BJ2 had very high infection rates of 79.1% (34/43) and 96.7% (29/30), respectively. These conspicuously biased infection rates may indicate that Cardinum and/or Wolbachia manipulate host reproduction. The LBF that inferred dependency between Cardinium and Wolbachia was 26.539, which is very strong evidence for correlation  spread in the host populations.Both smission . In spidtibility , and thanization . Becausenization . This stplotypes . While hrelation . We hypoD. gallinae in Japanese populations. Using Illumina Miseq amplicon sequencing, and full 16S rRNA sequencing using universal primers, we identified the following properties of the D. gallinae microbiome. First, all individual mites had Bartonella sp. A, and most individuals had Bartonella sp. B, which are both closely related to the Bartonella harbored by D. gallinae in Czechia. These Bartonella species, which are probably vertically transmitted through eggs, may play important roles in D. gallinae survival. Second, unlike many European populations, Rickettsiella was rarely found and is unlikely to play an important role in the survival of D. gallinae, at least in Japanese populations. Third, Cardinium and Wolbachia were found at relatively high frequencies, and while the Cardinium identified belonged to a lineage commonly found in insects and other arthropods, the Wolbachia belonged to a novel lineage that is located basally to all other Wolbachia found so far. It is possible that these Cardinium and Wolbachia strongly impact the mitochondrial genome dynamics of D. gallinae. It should also be noted that regarding all the detected bacteria, no direct evidence for their roles within D. gallinae was identified because D. gallinae could not be successfully reared despite multiple attempts following D. gallinae.We investigated the microbiome of the red poultry mite The data presented in the study are deposited in NCBI, accession numbers LC710609-LC710644, LC731006-LC731007, and DRR376882–DRR377025.YN, TS, KW, HE, and DK conceived and designed the experiments. YN organized all the samples and performed experiments. TS analyzed the raw reads of Illumina Miseq. YN wrote the draft manuscript and DK revised the manuscript with the inputs from all authors. All authors contributed to the article and approved the submitted version.The authors declare that this study received funding from SC Environmental Science Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.HE was employed by the company SC Environmental Science Co., Ltd.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Barrett's Esophagus (BE) is a pre-malignant condition defined by the presence of metaplastic columnar epithelial cells above the gastroesophageal junction. Currently, diagnoses is made by endoscopy. Once metaplasia is present, there is 0.5% annual risk of progression to dysplasia and ultimately adenocarcinoma.Cytosponge is a new device and technique to diagnose BE. Furthermore, this test has a strong safety profile. Research has suggested increased patient tolerance for the Cytosponge compared to endoscopy; this has not been demonstrated in a Canadian healthcare setting. Before Cytosponge test can be integrated in Canada, ideally, patient acceptability of this device should be evaluated.To assess patient acceptability, tolerability and integration of Cytosponge in the diagnosis of Barrett's Esophagus in a Canadian healthcare setting. We also assessed the ease of use and familiarity with Cytosponge.A single-centre, prospective cross-sectional study was conducted to evaluate the acceptability and comfort of patients undergoing Cytosponge procedure.Outpatients referred for EGD for Barrett's Esophagus at St. Paul’s Hospital between 03/21-07/22 were included. 36 patients with BE have been enrolled in this project. Acceptability was evaluated through Visual Analogue Scale (VAS), Spielberger State Trait Anxiety Inventory (STAI), and Impact of Events Scale (IOES) on the day of procedure, day 7 post procedure and day 90 post procedure. Data from health care providers administering the Cytosponge were collected using the System Usability Scale (SUS).One-way ANOVA and Tukey’s Honestly Significant Difference tests were completed to assess score differences between follow up.A total of 36 patients met the inclusion criteria and consented to participate. Of these patients 81.6% were successful in swallowing Cytosponge, 18.4% were unsucessful. ANOVA test revealed statistically significant difference in VAS scores, F = 12.59, p < 0.0000005. There were significant differences in VAS between Day 0 and Day 7, p=0.0032. This was also seen in VAS between Day 0 vs Day 90, p=0.0017.There were no statistically significant difference in mean STAI scores between different time points, F = 12.59, p=0.44. ANOVA test also showed statistical difference in IOES scores, F = 8.76, p<0.0005. There was statistical difference between day 0 compared to day 7 and between day 0 and day 90, p=0.0045, and p=0.00045 respectively.Our results demonstrate that Cytosponge is a well tolerated in a Canadian healthcare setting. Follow up scores of VAS and IOES were lower compared to day 0 suggesting that patients found Cytosponge acceptable. A score of 68 and above is considered to be above average on the SUS which measures usability of Cytosponge. The average SUS score in this sample was 65.3, this may suggest that there is a learning curve for health care providers to become familiar with Cytosponge. There were no complications with Cytosponge in this sample.OtherGastroenterology Institute of Research InstituteNone Declared


Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder that results from the interaction of both genetic and environmental risk factors. Genome-wide association studies have started to identify multiple genetic risk loci associated with ADHD, however, the exact causal genes and biological mechanisms remain largely unknown. We performed a multi-step analysis to identify and characterize modules of co-expressed genes associated with ADHD using data from peripheral blood mononuclear cells of 270 ADHD cases and 279 controls. We identified seven ADHD-associated modules of co-expressed genes, some of them enriched in both genetic and epigenetic signatures for ADHD and in biological pathways relevant for psychiatric disorders, such as the regulation of gene expression, epigenetics and immune system. In addition, for some of the modules, we found evidence of potential regulatory mechanisms, including microRNAs and common genetic variants. In conclusion, our results point to promising genes and pathways for ADHD, supporting the use of peripheral blood to assess gene expression signatures in psychiatric disorders. Furthermore, they highlight that the combination of multi-omics signals provides deeper and broader insights into the biological mechanisms underlying ADHD. Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder that affects around 5–6% of children and adolescents worldwide, and in 40–65% of cases persist into adulthood . It is mh2SNP = 14%) [ADHD is a complex disorder that results from the interaction of both genetic and environmental risk factors, with an estimated heritability of 70–80% throughout the lifespan . SeveralP = 14%) . EpigeneP = 14%) . RecentlP = 14%) .Although genetic and epigenetic factors that contribute to the etiology of ADHD have started to be identified through GWAS and EWAS, their biological relevance is difficult to characterize, in part, because genetic risk loci were usually associated with the nearest gene, which may not be necessarily the true causal one. In contrast, the analysis of gene expression profiles provides a closer physiological picture of the disorder that is easier to interpret, and reduces the burden of multiple testing. Transcriptome studies in ADHD, nevertheless, are limited by the inaccessibility of brain samples and have been focused on whole blood or PBMCs. To date, eight transcriptomic studies on ADHD have been performed, highlighting alterations in genes involved in several neuronal functions and the immune system –20. HoweIn the present study, we aimed to perform a multi-step analysis to identify and characterize modules of co-expressed genes associated with ADHD using expression data from PBMCs of ADHD cases and controls. To further understand the biological relevance and provide a more accurate picture of the regulatory mechanisms, we performed a comprehensive characterization of genes in each module and combined genomic and transcriptomic data to identify loci that may regulate the ADHD-associated co-expressed genes.A comprehensive and multi-step approach was applied to identify and characterize modules of co-expressed genes in PBMCs. In the first step we ran a Weighted Gene Correlation Network Analysis (WGCNA) on the processed transcriptomic data from 270 ADHD cases and 279 controls and assessed the association of the resulting co-expression modules with ADHD status. Subsequently, we disentangled the biological relevance of the ADHD-associated co-expression modules by (i) performing enrichment analyses in brain expression, functional pathways, druggable genes and miRNA target genes, (ii) combining results with ADHD genetic, transcriptomic, and epigenetic signatures, and (iii) running a co-expression module eQTL analysis to identify loci regulating the ADHD-associated modules of co-expressed genes Fig. .Fig. 1FlAnalysis of co-expression modules was performed in an in-house sample of 270 ADHD cases  and 279 controls . All subjects were of European ancestry. Clinical assessment was conducted by structured interviews and self-reported questionnaires as previously described . DetaileWGCNA R-package [P < 0.05/27 modules <1E-03).RNA from PBMCs was isolated, hybridized to GeneChip Human Gene 1.1 ST 96-Array plate (Affymetrix) and data were analyzed as previously described  (Supplem-package . A soft-Within each module we examined the correlation between module membership (an indicator of the intramodular connectivity of a gene based on the association between its expression and the module eigengene) and gene significance (effect size of the association between each gene and ADHD) using Pearson correlation Fig. .ABAEnrichment R-package [http://www.webgestalt.org/) [P-value (PFDR) < 0.05 was set as the significance threshold.We assessed whether genes in each ADHD-associated co-expression module were expressed in specific brain regions at different developmental stages using data from the Allen Human Brain Atlas with -package  (additiolt.org/)  were perP < 0.05/27 tests <1.85E−03).In addition, the correlation between the identified miRNA and its corresponding module eigengene was tested using the non-parametric Spearman rank correlation test in a subset of 310 individuals included in the WGCNA  from whom miRNA expression profile data from PBMC were available as described in Sanchez-Mora et al. [Limma R-package [PFDR < 0.05 and fold change (FC) > |1.15| were considered differentially expressed and were used to test for enrichment in the ADHD-associated co-expression modules using a F-Fisher test and Bonferroni correction across all modules (P < 0.05/7 modules <7.1E−03).After quality control and sample processing, differential gene expression profiles between the 270 ADHD cases and 279 controls used in the WGCNA analysis were obtained with -package . Only geP-values obtained from each gene-based analysis. Bonferroni correction was applied to correct for multiple testing The identified ADHD-associated co-expression modules were used as gene sets to test for enrichment in ADHD genetic signatures, considering the European ancestry GWAS summary statistics on ADHD described by Demontis et al. . Gene-baP-value < 0.01 to select differentially methylated proves (n = 3967 CpG sites). We considered enrichment in epigenetic signatures in a co-expression module when the three approaches used .To test for enrichment in ADHD epigenetic marks in modules of co-expressed genes we used the summary statistics of an EWAS on PBMCs from 103 ADHD patients and 100 controls  (90% sam gsameth ) were siP-value < 1E−06 and functionally annotated using the FUMA protocol  [Genetic information was available from a subset of 231 ADHD subjects and 264 controls included in the WGCNA. A GWAS with each module eigengene as the dependent variable were performed to identify genetic variants associated with each co-expression module. After ascertain normality of module eigengene Table , seven glab.nl/)   were not assigned to any module and remained in the module M0. Seven co-expression modules were associated with ADHD after multiple testing correction , suggesting that the higher the connectivity of a gene within the module, the stronger the association with ADHD , covalent chromatin remodeling (M4) or immune system and inflammatory response (M5), among others , which also remained significant when considering only highly connected genes  and epigenetics  signatures for ADHD, using data from GWAS meta-analysis [Then, we further explored the ADHD-associated co-expression modules by integrating transcriptomics with genetic and epigenetic data on ADHD. We explored whether genes differentially expressed between ADHD cases and controls were grouped in any of the identified ADHD-associated modules of co-expressed genes, and found a significant enrichment in module M5 P < 2.2E−6, which analysis  on ADHD P < 1E−06) with different module eigengenes , which suggest that ZSCAN30 may be upstream regulator of the M1 module of co-expressed genes.We performed a co-expression module eQTL analysis to identify loci regulating ADHD-associated modules in a subset of 495 individuals included in the WGCNA 91.3%) from whom genomic and gene expression profiles were available. After strict quality control criteria, we ran a GWAS on module eigengenes of each of the seven ADHD-associated co-expression modules independently , were enriched in genes involved in  of ADHD . In the  of ADHD , and com of ADHD  or miR-1 of ADHD –45. Inteing ADHD , and RICor cells .processing of messenger RNA (mRNA), which includes any process related to the conversion of a primary mRNA transcript into one or more mature mRNAs. mRNA processing and alternative splicing are key processes for both the diversification of protein isoforms and the spatio-temporal control of transcripts, essential for the neuronal development, maturation, and synaptic function [Module M1, as well as M2 and M6, were also enriched in genes that encode proteins involved in the function , and genfunction , as wellfunction .immune system and inflammatory response, pathways known to play an important role in the development of neuropsychiatric disorders [Antiinfective for systemic use and Antineoplastic and immunomodulating agents), pointing to genes in these co-expression networks as potential therapeutic targets. Importantly, a recent study that explored the druggable genome in ADHD also pointed to drugs to treat autoimmune disorders and malignancies as a potential novel path for the treatment of ADHD [Module M5 was enriched in genes involved in isorders , 51, 52,isorders . Moreove of ADHD . Besidesregulation of gene expression and epigenetic mechanisms, were enriched in both genetic and epigenetic signatures previously described for ADHD [PNPLA2 and IQSEC1 were the central genes in the module more significantly associated with ADHD using both methods. PNPLA2 encodes an enzyme involved in the hydrolysis of triglycerides in adipose tissue, and has been related to obesity [PNPLA2 as one of the most high-confidence causal genes for ADHD, after combining GWAS, eQTL and gene expression data [IQSEC1 encodes a guanine nucleotide exchange factor, essential for the maintenance of glutamatergic synapses [The integrative analysis of transcriptomics, genomics, and epigenomics data on ADHD revealed that genes in module M4, also involved in the for ADHD , 7. We u obesity , a highl obesity . In addiion data . IQSEC1 synapses , one of synapses , 60.P < 1e−06) with the different module eigengenes. We identified a genetic variant associated with the co-expression module M1, rs62096513, which is located in a blood and brain regulatory region of a transcription factor, ZSCAN30, and regulates its expression in PBMCs. Interestingly, module M1 was enriched in target genes for ZSCAN30 that is also included in the same module, suggesting that this transcription factor is an upstream regulator of the co-expressed genes in the module. Besides, we identified another genetic variant associated with the M1 module eigengene, rs73170578, located in CNTNAP2, which encodes a neuronal transmembrane protein member of the neurexin superfamily that function as cell adhesion molecules and receptors. Both rare and common genetic variants in CNTNAP2 have been associated with neurodevelopmental disorders [SP3 gene in PBMCs, a transcription factor involved in synaptic plasticity [CUX1 gene, a transcription factor involved in the control of neuronal differentiation and the regulation of dendritic branching, spine development, and synapse formation in cortical neurons [The eQTL analysis did not reveal any genetic variant that overcame the genome-wide significance threshold, but we found 12 independent genomic loci that showed suggestive evidence of association , limiting their statistical power. In contrast, we improved the resolution and robustness of gene networks by considering more than 500 subjects, which allowed the identification of seven ADHD-associated modules enriched in relevant and highly significant biological pathways. However, although our transcriptomic analyses were performed mainly in medication-naive ADHD patients without comorbid disorders , we cannot discard that these conditions may have influenced the results of the present study. So, further studies in the same cell type are required to confirm our results. Additionally, the identified modules were based on expression data from PBMCs, a non-invasive peripheral tissue whose expression profile has been proposed as a surrogate for expression profiling in the central nervous system [Gene networks analyses reduce the dimensionality of genome-wide gene expression data without losing important biological information and alleviate the multiple testing burden associated with the traditional gene-based methods. Similar network-based studies have been performed using gene expression data in both brain and blood in several psychiatric disorders like autism, schizophrenia and bipolar disorder –28. Thess system , and furIn summary, we conducted a multi-step analysis to identify and characterize modules of co-expressed genes associated with ADHD using expression data from PBMCs in ADHD cases and controls. We identified seven ADHD-associated modules of co-expressed genes, some of them being enriched in both genetic and epigenetic signatures for ADHD and on biological pathways relevant for psychiatric disorders, such as the regulation of gene expression, epigenetic mechanisms and immune signaling. We also found preliminary evidence for some potential regulatory mechanisms, including microRNAs and genetic variants, for some of the ADHD-associated modules of co-expressed genes identified. These results pinpoint promising genes and pathways for ADHD, support the use of peripheral blood to assess gene expression signatures for the disorder and highlight that the combination of multi-omics signals provides deeper and broader insights into the biological mechanisms underlying the disorder.Supplementary informationSupplementary tables


Psychosocial interventions for adolescents with attention-deficit/hyperactivity disorder (ADHD), targeting emotional dysregulation and impulsive behaviors, have been requested, but the heterogeneity within this group makes it unlikely that there is one treatment that fits all. The aim of this study was to identify which adolescents with ADHD might have an effect from a structured skills training group (SSTG) based on dialectical behavioral therapy, by exploring pre-treatment characteristics as potential moderators of long-term treatment outcome.n = 71) to a psychoeducational control intervention (n = 57) for adolescents with ADHD (15–18 years old). Clinical characteristics  were explored as potential moderators of pre-treatment to follow-up change in ADHD symptoms and functional impairment. Moderation analyses were performed using the PROCESS macro for SPSS.This study was based on follow-up data from a randomized controlled trial comparing the SSTG  were identified in regard to the outcome self-rated change in ADHD symptoms. Participants with elevated pre-scores on these variables had a better effect of the SSTG than of the psychoeducational control intervention. No moderators were found in regard to the parental-rated outcomes.The SSTG seems to be beneficial for adolescents with ADHD who perceive pronounced symptoms of hyperactivity/impulsivity, conduct problems and emotional dysregulation. Our findings need to be confirmed in future trials evaluating dialectical behavioral therapy-based skills training for adolescents with ADHD, where these moderators could be used as criteria for inclusion or stratification.https://doi.org/10.1186/ISRCTN17366720, retrospectively registered.The online version contains supplementary material available at 10.1186/s12888-022-04435-8. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by symptoms of inattention, hyperactivity and impulsivity . AdolescThe heterogeneity among adolescents with ADHD makes it unlikely that there is one treatment that fits all . While pRandomized controlled trials (RCTs) are regarded as the gold standard method for evaluating the effectiveness of interventions . While tModerators and predictors of treatment outcome of psychosocial interventions for adolescents with ADHD have been investigated only scarcely , 26–28. Regarding type and severity of ADHD symptoms and psychiatric comorbidity, previous studies have revealed mixed findings. In one study evaluating the effect of a sleep intervention for children with ADHD, individuals with high severity of ADHD symptoms had a larger reduction in ADHD symptoms after treatment . In the Overall, these findings indicate that degree of ADHD symptoms, symptoms of psychiatric comorbidity and sex can have an impact on treatment outcome for patients with ADHD. However, the response patterns across subgroups may vary in different study populations and need to be considered in relation to the specific interventions and outcomes used in each study. In our RCT, both interventions contained psychoeducation and strategies for planning and organization . In addiDue to the heterogeneity among adolescents with ADHD, exploration of potential treatment moderators is warranted , 19, 21.n = 184) were thereafter randomly assigned to one of the two treatment conditions, at a 1:1 ratio, using a computer-generated allocation sequence (https://www.randomizer.org), with separate sequence lists for each treatment center. The principal investigator (JI), who was blinded to the participants, performed the treatment allocation.This was an explorative study where the study sample stemmed from a multi-center RCT conducted at seven child and adolescent psychiatric (CAP) outpatient units in Sweden . The pron = 164), two weeks post-treatment (n = 132) and at a follow-up six months post-treatment (n = 128). To minimize the number of analyses and to focus on the long-term outcomes, follow-up was selected as the primary endpoint in this study. Accordingly, the moderator analyses were based on data from the 128 participants who completed the follow-up measurements . Participants who completed the pre-treatment measures but none of the follow-up measures were regarded as internal drop-outs and were included only in the attrition analysis (n = 36). Randomized participants who did not complete the pre-treatment measures (n = 20) were defined as external drop-outs and were not included in the attrition analysis due to the lack of data. Reasons for external drop-out has been reported elsewhere [Ratings were completed by the adolescents and their parents before treatment . Both challenges and strengths of ADHD were discussed. PowerPoint presentations were used to visualize the contents, and group discussions and homework assignments were included in both interventions.The treatment is an age-adapted version of a manualized DBT-based group program originally developed for adults with ADHD , 33. SpeThe control intervention is a manual-based psychoeducational group program named SKILLS, which was developed by members of the research team. The intervention consists of three two-hour sessions, where the main focus is psychoeducation about ADHD and closely related difficulties. The participants also receive a book describing tools to facilitate schoolwork. The control intervention does not contain any DBT-related components. Each group was led by two therapists, who were clinicians working at the CAP units. The psychoeducational control intervention has been described in greater detail in previous papers , 36.The following pre-treatment characteristics were explored as potential moderators of treatment outcome.Sex and age were derived from the participants’ personal identity numbers. Both sex and age were treated as dichotomous variables, where sex was categorized as male or female, and age was dichotomized into a younger (15–16 years) and an older (17–18 years) group, with each participant’s age rounded to the nearest full year.The use of ADHD medication was reported by the parents and this variable was dichotomized as either no medication or use of medication.n = 3) were categorized into the hyperactive/impulsive presentation, this group was merged with the combined presentation, as both groups included patients with hyperactivity and impulsivity. ADHD presentation was treated as a categorical variable in the analyses.Current ADHD presentation was assessed pre-randomization by clinical psychologists who interviewed the participants and their parents, using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) . CurrentSeverity of ADHD symptoms was measured with self-ratings and parental ratings on the subscales of inattention and hyperactivity/impulsivity from the Adult ADHD self-report scale for adolescents (ASRS-A) , 39. TheSymptoms of depression and anxiety were assessed using self-ratings on the respective subscales of the Hospital Anxiety and Depression Scale , 41. EacConduct problems were assessed using self-ratings and parental ratings on the subscale of conduct problems within the Strength and difficulties questionnaire (SDQ) –44. ThisImpairment of emotional dysregulation was assessed using the following question from the questionnaire Impact of ADHD Symptoms, constructed by the research team : “In theFunctional impairment in daily activities was assessed using self-ratings and parental ratings on the Swedish version of the Child Sheehan Disability Scale (CSDS) . The selThe treatment outcomes were defined as the change in ADHD symptoms and functional impairment between the pre-treatment assessment and the follow-up assessment. Change in ADHD symptoms was assessed using self-ratings and parental ratings on the full scale of ASRS-A , 39. ChaUse of ADHD medication during the study was categorized as: stable medication , major change of medication  or no medication .Attendance at the group sessions was registered by the group leaders for each treatment condition (max 14 sessions in the SSTG and max 3 sessions in the control condition).* power, version 3.1. Specifically, to obtain a moderate effect size (f2 = 0.15), with a power of 80%, a = 0.05, a sample size of at least 77 participants was needed. All analyses were conducted with IBM SPSS Statistics, version 27.0. Baseline differences between the two treatment groups were examined for all potential moderators, for changes in medication and attendance at sessions, using t-tests for continuous variables and chi-squared tests for the dichotomous and categorical variables. The same statistics were used for the attrition analysis, where the study sample was compared to the internal drop-outs. Potential moderators were explored using the PROCESS macro for SPSS [The original power calculation determining the sample size for the RCT was based on the main analyses and has been described in previous papers , 36. A sfor SPSS . The chafor SPSS . Figurest = 4.10, p < 0.001). Specifically, the SSTG had an average of 70.0% attendance  and the control group had an average of 87.7% attendance . Most of the participants in both groups had pharmacological treatment for ADHD when entering the study (71.8% in the SSTG and 82.5% in the control group), and a majority of these participants continued with ADHD medication throughout the study (86.3% in the SSTG and 82.6% in the control group). One fifth of the participants underwent a major change in ADHD medication  during the study (21.1% in the SSTG and 17.9% in the control group), while some participants had no ADHD medication (16.9% in the SSTG and 12.5% in the control group). No significant group differences were found in regard to patterns/changes in medication. The attrition analysis identified one significant group difference for parental-rated inattention , where the internal drop-outs had a higher score (mean = 27.70) than those who completed the follow-up assessment (mean = 25.45). No other significant differences were found in the attrition analysis.Sample characteristics before treatment exposure are described in Table As illustrated in Figs. b = -0.46, p = 0.031, 95% CI = -0.88; -0.04) showed that the SSTG was more effective than the control intervention for participants with higher severity of hyperactivity/impulsivity. A significant group difference was present from ≥ 19 points on the ASRS-A hyperactivity/impulsivity subscale. The sensitivity analysis confirmed the interaction . A one-point increase on the prescore of hyperactivity/impulsivity was associated with a 0.71  point decrease in ADHD symptoms for the SSTG, while the corresponding estimate for the control group was b = -0.25 .For pre-treatment symptoms of hyperactivity/impulsivity, the interaction effect with treatment condition on changes in ADHD symptoms . A significant group difference was identified from the value of 3.2 of the SDQ subscale; this continued to be significant as the value of the moderator increased. Accordingly, for participants who had elevated symptoms of conduct problems, the SSTG was more effective than the control intervention. The interaction remained significant in the sensitivity analysis . A one-point increase in the subscale of conduct problems was associated with a 2.79  point decrease on ADHD symptoms for the SSTG. Conduct problems was not a significant predictor of change in ADHD symptoms for the control group .Moreover, an interaction with treatment condition and conduct problems on changes in ADHD symptoms was found in favor of the SSTG  demonstrated that participants who reported much impairment of emotional dysregulation  had a greater effect from the SSTG than from the control intervention. This finding was confirmed in the sensitivity analysis . The participants in the SSTG who reported much impairment of emotional dysregulation had a 6.63 larger decrease in ADHD symptoms than those who reported little impairment . In the control group, a nonsignificant increase of ADHD symptoms was observed for the participants who reported much impairment of emotional dysregulation  when compared with those with little impairment.The interaction between treatment condition and impairment of emotional dysregulation on changes in ADHD symptoms  where the SSTG outperformed the control group regarding the effect on functional impairment. In addition, no moderators were found in regard to the parental-rated outcomes.DBT was originally developed for patients with suicidal behaviors and borderline personality disorder (BPD) . The oveHowever, far from all patients with ADHD have pronounced symptoms of hyperactivity, impulsivity, disruptive behavior and emotional dysregulation , 9, 10. No moderation effect was observed for the parental-rated outcomes, in contrast to the self-ratings. Hence, the parental ratings did not confirm the superiority of the SSTG for any subgroup, why the results based on the self-ratings need to be interpreted with some caution. In the main analysis of the RCT , the parThe absence of moderators regarding the effect of functional impairment showed that even when pre-treatment characteristics were considered, the SSTG was not superior to the control group in reducing functional impairment. Hypothetically, to achieve improvement in daily adaptive functions at home or in school, more extensive practicing of skills that are needed in those specific contexts might be necessary , 62. In This study has some limitations that need to be considered. The pre-treatment measures were assessed after randomization, we included only participants who had completed the follow-up measurements and the study suffered from relatively large drop-out. Hence, there is a risk of selective drop-out, restricted power for moderator analyses and systematic differences between the groups. However, the comparative analyses of the two treatment conditions indicated no systematic group differences before treatment exposure. The attrition analysis did reveal one difference, indicating that patients with severe attentional deficits had more problems with completing follow-up measures. Apart from that, the study sample corresponded well to the original sample used in the RCT . Since tAlthough clinically relevant characteristics were explored as potential moderators, several factors were not measured in this study and were therefore not included. Demographic factors such as socioeconomic status, degree of parent-teen conflict, parental stress and parental depression have previously been shown to have an impact on treatment outcome for youths with ADHD , 64 and This study also has some strengths. The relatively large sample size of the RCT enabled the exploration of potential treatment moderators. Due to the research gap on long-term effects in this area , the focBecause of the clinical heterogeneity among adolescents with ADHD, the exploration of treatment moderators is crucial to identify which patients benefit from a certain treatment , 19, 21.Additional file 1: Table 1. Interactions between treatment condition and potential moderators of self-rated change in ADHD symptoms (n=118). Table 2. Interactions between treatment condition and potential moderators of self-rated change in functional impairment (n=118). Table 3. Interactions between treatment condition and potential moderators of parent-rated change in ADHD symptoms (n=125). Table 4. Interactions between treatment condition and potential moderators of parent-rated change in functional impairment (n=125).


The increased risk of developing attention-deficit hyperactivity disorder (ADHD) in extremely preterm infants is well-documented. Better understanding of perinatal risk factors, particularly those that are modifiable, can inform prevention efforts.N = 734) and assessed at age 15 with a structured diagnostic interview (MINI-KID) to evaluate for the diagnosis of ADHD (N = 575). We studied associations of pre-pregnancy maternal body mass index (BMI), pregestational and/or gestational diabetes, maternal smoking during pregnancy (MSDP), and hypertensive disorders of pregnancy (HDP) with 10-year and 15-year ADHD outcomes. Relative risks were calculated using Poisson regression models with robust error variance, adjusted for maternal age, maternal educational status, use of food stamps, public insurance status, marital status at birth, and family history of ADHD. We defined ADHD as a positive screen on the CSI-4 at age 10 and/or meeting DSM-5 criteria at age 15 on the MINI-KID. We evaluated the robustness of the associations to broadening or restricting the definition of ADHD. We limited the analysis to individuals with IQ ≥ 70 to decrease confounding by cognitive functioning. We evaluated interactions between maternal BMI and diabetes status. We assessed for mediation of risk increase by alterations in inflammatory or neurotrophic protein levels in the first week of life.We examined data from the Extremely Low Gestational Age Newborns (ELGAN) Study. Participants were screened for ADHD at age 10 with the Child Symptom Inventory-4 (Elevated maternal BMI and maternal diabetes were each associated with a 55–65% increase in risk of ADHD, with evidence of both additive and multiplicative interactions between the two exposures. MSDP and HDP were not associated with the risk of ADHD outcomes. There was some evidence for association of ADHD outcomes with high levels of inflammatory proteins or moderate levels of neurotrophic proteins, but there was no evidence that these mediated the risk associated with maternal BMI or diabetes.Contrary to previous population-based studies, MSDP and HDP did not predict ADHD outcomes in this extremely preterm cohort, but elevated maternal pre-pregnancy BMI, maternal diabetes, and perinatal inflammatory markers were associated with increased risk of ADHD at age 10 and/or 15, with positive interaction between pre-pregnancy BMI and maternal diabetes. Attention-deficit hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in children, affecting approximately 5% of the general population, with at least another 5% having substantial difficulties with inattention, overactivity, and impulsivity but not meeting the threshold for diagnosis . It is cChildren born very preterm are much more likely to be diagnosed with ADHD, with a recent follow-up at age 15 of the Extremely Low Gestational Age Newborn (ELGAN) cohort  reportinOur group has previously reported on the effects of these modifiable maternal risk factors on age 10 outcomes of the same cohort. Active smoking during pregnancy and maternal BMI ≥ 30 were identified as two of the risk factors associated with ADHD at age 10 . HoweverWe aimed to extend these previous studies to evaluate these risk factors in a longitudinal preterm cohort, considering ADHD outcomes at age 10 and 15 years. The current study builds on the previous work by: (1) extending the time period of assessment to incorporate age 10 and 15 data; (2) including the family history of ADHD as a potential confounder to control for potential genetic confounding; (3) including a broader IQ range than previous studies; and (4) incorporating ADHD medication status as an indicator of severity of ADHD to evaluate the robustness of the effects. Also, given the association between obesity and diabetes, we explored whether their effects on ADHD outcomes are independent or whether there may be additive or multiplicative effects of these interrelated risk factors. Therefore, we also assessed the interaction between elevated body mass index (BMI) and diabetes. Further, we examined the evidence for mediation of these effects by perinatal inflammation as indicated by elevations of inflammatory or neurotrophic proteins in the neonate. We hypothesized that: (1) MSDP, HDP, elevated maternal BMI, and/or maternal diabetes increase the risk of ADHD symptoms at age 10 and 15; (2) elevated maternal BMI and maternal diabetes demonstrate positive interaction in the increased risk of ADHD; and (3) perinatal inflammation is a common mediating pathway for these risk factors to contribute to increased ADHD risk.The ELGAN Study is a US multicenter prospective, observational study of the risk of structural and functional neurologic disorders in extremely preterm infants . The stuAfter delivery, a trained research nurse interviewed each mother in her native language using a structured data collection form and obtained information about characteristics of the mother and pregnancy, as well as exposures during pregnancy.z-score represents the number of standard deviations the infant’s birth weight was above or below the median weight of infants at the same gestational age in referent samples not delivered for preeclampsia or fetal indications . We collapsed these BMI groups into <25 (reference), 25–29.9 (overweight), and ≥30 kg/m2 (obese).Each mother was asked to provide her height and pre-pregnancy weight shortly before, or shortly after, delivery when they were interviewed, usually by a research nurse. These data were used to calculate her BMI. The United States government classifies BMIs as follows: <18.5 kg/mPrenatal maternal passive and active tobacco smoke exposure was ascertained by maternal interview at the time of participant enrollment . In thisMaternal hypertensive disorders diagnosed before pregnancy was ascertained by maternal interview around the time of participant enrollment. Maternal hypertensive disorders during pregnancy, including pregnancy-induced hypertension, preeclampsia, eclampsia, and HELLP  syndrome, were ascertained by study coordinators’ reviews of maternal obstetric records.Pre-pregnancy maternal diabetes and gestational diabetes were ascertained by maternal interview around the time of participant enrollment. The interview did not distinguish between type 1 and type 2 pre-pregnancy diabetes. We defined maternal diabetes as having either pre-pregnancy maternal diabetes and/or gestational diabetes. We did not obtain data on diabetes management during pregnancy.At the 10-year assessment, the parent or caregiver completed questionnaires regarding the child’s medical and neurological status and behavior, including the Child Symptom Inventory-4, Parent Checklist (CSI-4) . The parN = 575), the majority (N = 564) of adolescents were interviewed alone, with a small subset either supplemented with parent report (N = 9) or diagnosed by parent interview alone (N = 2). The MINI-KID follows the structure and format of the adult version of the interview, which has been validated against the Structured Clinical Interview for DSM-III-R and against the World Health Organization–designed Composite International Diagnostic Interview. The MINI-KID has diagnostic sections/modules and is administered using branching tree logic . The instrument screens for 24 DSM-5 and ICD-10 psychiatric disorders and for suicidality. The MINI-KID has substantial to excellent concordance with the gold standard Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version. The MINI-KID has been updated to version 7.0.2 to map onto DSM-5 diagnostic criteria. For this report, we used a current MINI-KID diagnosis of ADHD (any subtype) consistent with DSM-5 duration of past 6 months. Those who met criteria for current DSM-5 diagnosis of ADHD were included in the outcome group.The MINI-KID is a structured clinical diagnostic interview designed to assess the presence of current DSM-5 and ICD-10 psychiatric disorders in youths aged 6–17 years . The intIn order to test for sensitivity of our results to more stringent or inclusive criteria, we also used data from parent interviews at age 10 and age 15 about current or past medications being taken for ADHD treatment. We identified participants as being on medication for ADHD if the parent identified any current or past use of any ADHD medication, and the primary author confirmed that the medication was either a stimulant, alpha-2-agonist, or atomoxetine. For a more inclusive definition of the ADHD outcome, we included children who were not identified as positive for ADHD by CSI-4 at age 10 or by MINI-KID at age 15, but who had taken medication for ADHD. Presumably the children on medications, but without meeting outcome criteria, had symptoms of ADHD in the past that were either resolved or were well-managed by medication. For more stringent criteria for ADHD outcome, we included only those children who were identified as positive for ADHD by CSI-4 at age 10 or by MINI-KID at age 15, and also reported current or past use of medication for ADHD at age 10 or 15. Presumably these children had symptoms of ADHD that were severe enough to continue to meet criteria even with medication treatment.We evaluated the relationship between the various definitions of ADHD and maternal exposures, previously defined. To estimate the relative risk of ADHD with 95% confidence intervals (CI), Poisson regression models were fit. A robust error variance procedure was used to relax variance assumptions . All modTo investigate modification of the effect of maternal BMI on ADHD by maternal diabetes, interaction models were used. Similar to the previous analyses, Poisson regression models with a robust error variance were fit to estimate the relative risk of ADHD. To assess this interaction, overweight or obese, as previously defined, were combined into one overweight or obese maternal BMI category. An interaction term between maternal diabetes and the overweight/obese variable was included in the model adjusting for maternal age, maternal education status, maternal food and nutritional services assistance, maternal public insurance status, maternal marital status, and any familial history of ADHD. Assessment of additive and multiplicative interaction was performed using standard calculations for relative excess risk due to interaction, proportion of risk attributable to interaction, synergy index, and ratio of relative risks .To test for mediation effects of inflammatory or neurotrophic proteins, we followed a traditional 3-step regression framework . First, p-values.All analyses were conducted in R version 4.1.2 . The R pThe sample flowchart for sample selection is shown in N = 101), 62% were not diagnosed with ADHD by interview at age 15. Likewise, of those assessed at both time points and diagnosed with ADHD at age 15 (N = 87), 56% had not screened positive for symptoms at age 10. Nine percent (N = 52) of the participants who did not meet criteria for ADHD at either age 10 or 15 (N = 567) were either currently or previously treated with medications for ADHD, and 43% of those who met criteria for ADHD at either age 10 or 15 had never been treated with medications for ADHD.N = 734) and using only ADHD outcomes at age 15 (N = 575), as shown in the last two columns of N = 902).The model predicting ADHD outcomes with perinatal inflammatory protein level as the exposure demonstrated some evidence that high levels of inflammatory proteins, but not moderate levels, were associated with ADHD outcomes . While oIn this longitudinal follow-up study of an extremely preterm cohort, we demonstrated a relationship between prenatal maternal modifiable risk factors and ADHD at age 10 and 15. After adjusting for socioeconomic variables and family history of ADHD, MSDP and maternal HDP were not related to ADHD outcomes, but elevated maternal BMI and pregestational or gestational diabetes were associated with an approximately 55–65% increase in risk individually. Furthermore, there was evidence of an additive and multiplicative interaction between elevated BMI and diabetes, such that those mothers with both conditions had a 2.8-fold increase in risk of their children developing ADHD compared to those mothers with neither condition. We hypothesized that a common characteristic of these risk factors may be the creation of an inflammatory state prenatally and that maternal inflammation may lead to a neonatal inflammatory state that could mediate neurodevelopmental changes. Contrary to this hypothesis, we did not find evidence that alterations in either inflammatory or neurotrophic proteins in the first week of life mediated long-term ADHD outcomes.This study is novel in that it specifically evaluates modifiable risk factors for ADHD in an extremely preterm cohort. Prematurity itself has been identified as an independent risk factor for the development of ADHD , with a We capitalized on the longitudinal nature of the ELGAN study to develop a broad ADHD outcome measure to examine ADHD-related clinical symptoms across a spectrum of severities. This outcome captures individuals with symptoms related to hyperactivity/impulsivity or inattention either at age 10 or 15 years. By including both age groups, we are including those individuals who may struggle with symptoms at younger ages but function better during adolescence, as well as those who may be able to manage symptoms more adaptively at younger ages until academic demands outstrip their ability to adapt. We included this broader range of indicators of ADHD outcomes to increase the power of the study to detect associations. We limited our analyses to any ADHD diagnosis, and not individual subtypes  because the small numbers of children in each subgroup substantially limited power and did not allow for robust analyses. The ADHD literature is supportive of this unitary concept of ADHD , with faThe potential limitations of our chosen outcome measures are that individuals may be misclassified due to (i) inclusion of individuals with symptoms but not meeting the criteria of clinical impairment, or (ii) by under-inclusiveness by missing individuals whose symptoms are well-managed with appropriate treatment and thus do not meet the cutoffs for the CSI-4 or MINI-KID, both of which require current reporting of symptom counts. To address each of these concerns respectively, we conducted a sensitivity analysis by which we evaluated the relative risks (i) including only those who met the symptom cutoffs for the CSI-4 or MINI-KID and had also been clinically treated for ADHD with medication, and (ii) including anyone who had been treated with ADHD medications even if they did not meet the symptom cutoffs for the outcome measures. The pattern of relative risks was not changed by use of these different outcome groups, and the magnitude of the risk increase was greatest for those most severely affected by ADHD symptoms, that is, those who were treated with ADHD medication and continued to exhibit symptoms consistent with a diagnosis of ADHD.We found a strong association between elevated maternal pre-pregnancy BMI and risk of ADHD, with similar increase in risk for overweight and obese mothers. Previous studies have also identified this associated risk increase in large population-based cohorts, although typically with evidence of greater risk increase for obese mothers than overweight mothers. For example, a systematic review and meta-analysis including data from 36 cohorts found that risk of ADHD was 30% greater for offspring of overweight mothers and 62% greater for obese mothers . Our stuWe also found a significant increase in risk for ADHD in children born to mothers with pregestational or gestational diabetes. This has also been reported previously in population-based cohorts, but ours is the first study to demonstrate this association in a preterm cohort. A previous retrospective cohort study, including 333,132 singletons in the United States, identified a 57% increase in risk of ADHD associated with type 1 diabetes and a 43% increase in risk associated with type 2 diabetes . In thatOurs is the first study in preterm infants to investigate the interaction between elevated maternal pre-pregnancy BMI and maternal diabetes on the increase in ADHD risk in offspring, and we found evidence for both a multiplicative as well as an additive effect of interaction, with the combination of the two increasing the risk 2.8-fold compared to the absence of either. While multiplicative interaction is often reported from a statistical model, it is generally accepted in epidemiologic studies that the additive interaction is most suggestive of a significant biologic interaction between two exposures . Two preSeveral mechanisms have been postulated for how maternal elevated BMI and maternal diabetes may affect fetal neurodevelopment, and the overlap between suggested mechanisms may explain possible synergistic effects between these exposures. Both obesity  and diabin utero nicotine exposure and increased motor activity in offspring  had gestational diabetes, and epidemiologic reports on pregnancy in the United States during the time period of this cohort  identifiFinally, there is no data available on the levels of inflammatory and neurotrophic proteins in the general population, so the cutoff for a clinically relevant elevation in these proteins is unknown. We have previously reported extensively on relationships with perinatal inflammation in this extremely low gestational age cohort using the dichotomization at the 75th percentile, indicating that this is a clinically significant cutoff in this population e.g., . HoweverBecause this is a study of preterm births, the effect of maternal factors on ADHD may be underestimated given that the inherent study design is controlling for gestational age by restriction of the population studied. It is quite possible that preterm birth itself, or other factors associated with preterm birth, may mediate a relationship between the risk factors and ADHD outcome. Any indirect effects of the risk factors on ADHD, mediated by preterm birth, would not be evident in these analyses. This may partially explain the lack of an effect of MSDP or HDP on ADHD in this population.While MSDP and maternal HDP were not associated with significant risk increase for ADHD in a large preterm cohort at age 10 or age 15, maternal pre-pregnancy BMI and maternal diabetes were both associated with elevated risk, independent of other socioeconomic variables. Also, we found moderate evidence of an association between high levels of perinatal inflammation or moderate levels of neurotrophic proteins and ADHD, but these did not mediate the elevated risk associated with maternal BMI or diabetes. Importantly, maternal overweight/obesity status and diabetes interacted to elevate risk for ADHD in offspring above what would be expected based on individual exposures. Future efforts will be needed to determine if obesity prevention, diabetes management strategies or interventions that modify perinatal inflammation, either during conception planning or early in pregnancy, can mitigate the risk of long-term neurodevelopmental outcomes such as ADHD. Also, further work is needed on investigating potential mediators by which these exposures may increase risk, including epigenetic effects, oxidative stress, metabolic effects, and fetal hypoxia.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the institutional review boards of all participating institutions. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.DC, EJ, JF, IJ, SK, KR, RJ, SH, HS, KK, RF, and TO’S contributed to the conceptualization, investigation, and writing – review and editing. JF, HS, RF, and TO’S contributed to the data curation. DC, KR, EJ, and TO’S contributed to the formal analysis. JF, RJ, SH, HS, KK, RF, and TO’S contributed to the funding acquisition. DC, EJ, KR, and TO’S contributed to the methodology. DC, JF, RJ, SH, HS, KK, RF, and TO’S contributed to the project administration. DC, KR, and TO’S contributed to the writing – original draft. All authors contributed to the article and approved the submitted version.