Methylphenidate as a causal test of translational and basic neural coding hypotheses.

Most systems neuroscience studies fall into one of two categories: basic science work aimed at understanding the relationship between neurons and behavior, or translational work aimed at developing treatments for neuropsychiatric disorders. Here we use these two approaches to inform and enhance each other. Our study both tests hypotheses about basic science neural coding principles and elucidates the neuronal mechanisms underlying clinically relevant behavioral effects of systemically administered methylphenidate (Ritalin). We discovered that orally administered methylphenidate, used clinically to treat attention deficit hyperactivity disorder (ADHD) and generally to enhance cognition, increases spatially selective visual attention, enhancing visual performance at only the attended location. Further, we found that this causal manipulation enhances vision in rhesus macaques specifically when it decreases the mean correlated variability of neurons in visual area V4. Our findings demonstrate that the visual system is a platform for understanding the neural underpinnings of both complex cognitive processes (basic science) and neuropsychiatric disorders (translation). Addressing basic science hypotheses, our results are consistent with a scenario in which methylphenidate has cognitively specific effects by working through naturally selective cognitive mechanisms. Clinically, our findings suggest that the often staggeringly specific symptoms of neuropsychiatric disorders may be caused and treated by leveraging general mechanisms.

Hypersensitivity to Distractors in Fragile X Syndrome from Loss of Modulation of Cortical VIP Interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in humans and mice with FXS but not in typically developing controls. In both species, males and females were examined. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the poststimulus period during early distractor trials in WT mice, consistent with their known role as error signals. Strikingly, however, VIP cells from Fmr1 -/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells could be a potential therapeutic target for attentional difficulties in FXS.SIGNIFICANCE STATEMENT Sensory hypersensitivity, impulsivity, and persistent inattention are among the most consistent clinical features of FXS, all of which impede daily functioning and create barriers to learning. However, the neural mechanisms underlying sensory over-reactivity remain elusive. To overcome a significant challenge in translational FXS research we demonstrate a compelling alignment of sensory over-reactivity in both humans with FXS and Fmr1 -/- mice (the principal animal model of FXS) using a novel analogous distractor task. Two-photon microscopy in mice revealed that lack of modulation by VIP cells contributes to susceptibility to distractors. Implementing research efforts we describe here can help identify dysfunctional neural mechanisms associated not only with sensory issues but broader impairments, including those in learning and cognition.

Organic food consumption during pregnancy and symptoms of neurodevelopmental disorders at 8 years of age in the offspring: the Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Partially driven by public concerns about modern food production practices, organic food has gained popularity among consumers. However, the impact of organic food consumption during pregnancy on offspring health is scarcely studied. We aimed to investigate the association between maternal intake of organic food during pregnancy and symptoms of attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in offspring at 8 years of age. METHODS: This study was based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway (MBRN). The total study sample included 40,707 mother-child pairs (children born 2002-2009). Organic food consumption during pregnancy was assessed by six questions from a food frequency questionnaire in mid-pregnancy (sum score 0-18). Symptoms of ADHD and ASD in the offspring aged 8 years were measured by ADHD (0-54) and ASD (0-39) symptom scores based on the Parent/Teacher Rating Scale for Disruptive Behaviour disorders and the Social Communication Questionnaire. Associations between maternal intake of organic food during pregnancy and symptoms of ADHD and ASD in the offspring were analyzed using regression models with adjustment for covariates such as maternal anxiety and depression, including sibling analysis. RESULTS: Mean ADHD and ASD symptom scores in the offspring differed only slightly by maternal intake of organic food. The covariate-adjusted unstandardized regression coefficient (adjusted(Adj)beta) with 95% confidence interval for the ADHD symptom score with one unit increase in organic food sum score was 0.03 (0.01, 0.05). Similarly, Adjbeta for autism symptom score was 0.07 (0.04, 0.10). For ADHD, the adjusted estimates weakened when adjusting for maternal symptoms of ADHD. The sibling analyses showed no significant results with Adjbeta - 0.07 (- 0.15, 0.01) and - 0.001 (- 0.12, 0.12) for ADHD and ASD outcomes, respectively. CONCLUSIONS: We observed weak positive associations between frequent maternal organic food consumption during pregnancy and offspring ADHD and ASD symptom levels at 8 years of age. This trend weakened or disappeared after adjusting for maternal symptoms of ADHD, and in sibling analyses, suggesting that the associations mainly reflect genetic confounding. Our study indicates that consumption of organic food during pregnancy should neither be considered a risk factor nor protective against symptoms of ADHD and ASD in offspring.

Risk and protective factors of asthma and mental health condition multimorbidity in a national sample of Canadian children.

BACKGROUND: The coexistence of childhood asthma and mental health (MH) conditions can impact management and health outcomes but we need to better understand the etiology of multimorbidity. We investigated the association between childhood asthma and MH conditions as well as the determinants of their coexistence. METHODS: We used data from the Canadian Health Survey of Children and Youth 2019 (3-17 years; n = 47,871), a cross-sectional, nationally representative Statistics Canada dataset. Our primary outcome was condition status (no asthma or MH condition; asthma only; MH condition only; both asthma, and a MH condition (AMHM)). Predictors of condition status were assessed using multiple multinomial logistic regression. Sensitivity analyses considered individual MH conditions. RESULTS: MH condition prevalence was almost two-fold higher among those with asthma than those without asthma (21.1% vs. 11.6%, respectively). There were increased risks of each condition category associated with having allergies, other chronic conditions, and family members smoking in the home while there were protective associations with each condition status category for being female and born outside of Canada. Four additional variables were associated with AMHM and MH condition presence with one additional variable associated with both AMHM and asthma. In sensitivity analyses, the associations tended to be similar for most characteristics, although there was some variability. CONCLUSION: There are common risk factors of asthma and MH conditions along with their multimorbidity with a tendency for MH risk factors to be associated with multimorbidity. MH condition presence is common and important to assess among children with asthma.

Association between cumulative maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder: A cohort study.

BACKGROUND: Preclinical studies suggest synergistic effects of maternal inflammatory exposures on offspring neurodevelopment, but human studies have been limited. OBJECTIVES: To examine the cumulative association and potential interactions between seven maternal exposures related to inflammation and child attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a population-based cohort study of children born from July 2001 to December 2011 in New South Wales, Australia, and followed up until December 2014. Seven maternal exposures were identified from birth data and hospital admissions during pregnancy: autoimmune disease, asthma, hospitalization for infection, mood or anxiety disorder, smoking, hypertension, and diabetes. Child ADHD was identified from stimulant prescription records. Multivariable Cox regression assessed the association between individual and cumulative exposures and ADHD and potential interaction between exposures, controlling for potential confounders. RESULTS: The cohort included 908,770 children, one-third (281,724) with one or more maternal exposures. ADHD was identified in 16,297 children (incidence 3.5 per 1000 person-years) with median age of 7 (interquartile range 2) years at first treatment. Each exposure was independently associated with ADHD, and risk increased with additional exposures: one exposure (hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.54, 1.65), two exposures (HR 2.25, 95% CI 2.13, 2.37), and three or more exposures (HR 3.28, 95% CI 2.95, 3.64). Positive interaction was found between smoking and infection. The largest effect size was found for cumulative exposure of asthma, infection, mood or anxiety disorder, and smoking (HR 6.12, 95% CI 3.47, 10.70). CONCLUSIONS: This study identifies cumulative effects of multiple maternal exposures related to inflammation on ADHD, most potentially preventable or modifiable. Future studies should incorporate biomarkers of maternal inflammation and consider gene-environment interactions.

Late effects of medulloblastoma treatment: multidisciplinary approach of survivors.

PURPOSE: Medulloblastoma is one of the brain tumors with increased life expectancy due to improvements in treatment approaches. Besides the promising results, various undesirable effects can be encountered. This study's aim is to review long-term follow-up outcomes of our cases with medulloblastoma. METHODS: Age at diagnosis, histological type of medulloblastoma, resection extension, chemotherapy and radiotherapy schemes, follow-up duration, and endocrinological, neuropsychiatric, cardiological, auditory, and visual examination results were evaluated in 20 patients diagnosed between 2007 and 2018 and followed 5 years and more. RESULTS: Twenty of 53 patients were included to the study. Eleven (55%) were male. Mean age at diagnosis was 6.95 years; mean age at the time of the study was 14 years. Mean follow-up time was 8.95 years. In terms of surgery, 14 (70%) were gross total, 1 (5%) was near total, and 2 (10%) were subtotal resection. In histopathological examination, 14 (70%) were classical medulloblastoma, 4 (20%) were desmoplastic medulloblastoma, and 1 (5%) was anaplastic medulloblastoma. With regard to endocrinological evaluation, 15 (75%) patients had hypothyroidism, 5 (25%) had growth hormone deficiency, 7 (35%) had clinical growth hormone deficiency, and 5 (25%) had sex hormone disorders. In neuropsychiatric examination, 11 (55%) patients had neurological sequelae, 18 (90%) patients had psychiatric issues, and 14 (70%) patients had two or more neuropsychiatric problems simultaneously. One (5%) patient had mitral valve insufficiency. Twelve patients (60%) had hearing loss. According to visual examination, 6 (30%) patients had refraction problem, 4 (20%) had cataract, and 1 (5%) had dry eye. CONCLUSION: Careful monitoring of long-term side effects is important for improving the quality of life of medulloblastoma patients. Besides endocrinological and other somatic sequelae of the disease and treatment, increased neuropsychiatric problems showed us that only cure is not the issue while treating childhood medulloblastoma.

Placebo-related improvement with methylphenidate treatment in children with ADHD.

Non-specific effects of methylphenidate treatment, including expectancy and regression to the mean effects, contribute to the overall effect of methylphenidate on attention-deficit/hyperactivity disorder (ADHD) symptoms. Knowledge on the extent to which non-specific effects contribute to the overall effect and whether regression to the mean explains part of the non-specific effects, is currently lacking. A double-blind, randomized, placebo-controlled, cross-over trial was used to compare parent and teacher ratings of child ADHD symptoms at baseline and during treatment with placebo and 5, 10, 15 and 20 mg of methylphenidate, twice daily. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). The extent to which non-specific effects contributed to the effects of methylphenidate was determined by ADHD symptom reductions observed with placebo versus reductions observed with active doses of methylphenidate. The influence of regression to the mean was examined by estimating the contribution of baseline ADHD symptom severity to the effects observed with placebo treatment. Data were analyzed using multilevel analyses. We observed significant non-specific effects of methylphenidate for parent-rated ADHD symptoms, but not for teacher-rated symptoms. For parent reported hyperactive/impulsive symptoms, higher baseline symptoms predicted larger effects with placebo, indicating regression to the mean effects. For parent-reports, a significant part of the overall effect of methylphenidate treatment is explained by non-specific effects. Our findings stress the importance of taking non-specific effects into account when evaluating methylphenidate treatment, by including teacher-reports and using a double baseline assessment during titration. Comparing active medication with a placebo in the titration trial has the potential to identify non-specific effects.

Attention-deficit hyperactivity disorder and psychostimulant use in patients seeking dental care-Associations with common orofacial pain complaints.

BACKGROUND: Dental medicine should expand its scope to properly assess medical and psychosocial factors that might have an impact on patients' oral health. Based on previous literature and clinical experience, attention-deficit/hyperactivity disorder and psychostimulant medications might represent factors associated with orofacial pain symptoms. OBJECTIVE: The aim of the study was to assess whether common orofacial pain complaints such as jaw pain, jaw clicking, teeth clenching and headaches are more prevalent in dental patients who have an ADHD diagnosis and/or use psychostimulant medications. METHODS: Orofacial pain symptoms prevalence was compared among four groups from a sample of new patients seeking dental care at Tufts University School of Dental Medicine (n = 11 699) based on ADHD diagnosis and psychostimulants intake: G1: no ADHD, no stimulants; G2: yes ADHD, yes stimulants; G3: yes ADHD, no stimulants; G4: no ADHD, yes stimulants. RESULTS: In multivariable logistic regression models adjusting for age, gender, tobacco use, and alcohol consumption, significant differences were found for clenching (p < .0001), jaw pain (p < .0001), and headache (p < .0001). Compared to G1, two groups (G2 and G4) exhibited significantly higher odds of clenching and headaches, whereas only G2 exhibited significantly higher odds of jaw pain. CONCLUSIONS: In comparison with patients without ADHD and not taking psychostimulants medications, dental patients using psychostimulants with and without ADHD diagnosis report headaches and teeth clenching more frequently, while jaw pain is reported more frequently only by those taking psychostimulants with an ADHD diagnosis. Further research is necessary to assess the nature of these associations and their clinical relevance.

Orthodontic aligner therapy outcomes in children with autism spectrum disorder.

BACKGROUND: Children with autism spectrum disorder (ASD) face unique challenges in oral care. Aligner therapy offers a promising alternative to conventional approaches for this patient group. AIM: To evaluate orthodontic aligner therapy outcomes in children with ASD using the Peer Assessment Rating (PAR) Index and the Index of Complexity, Outcome, and Need (ICON), and to investigate whether concomitant disorders affect ICON, PAR scores, and treatment duration. DESIGN: Two calibrated observers assessed digital dental casts and intraoral pictures of 37 children with ASD before (T0) and after (T1) their treatment. At T0, the participants' average age was 12.9 years (SD = 1.68); at T1, post-therapy, the average age was 14.9 years (SD = 1.51). All participants underwent orthodontic aligner therapy. Statistical methods employed in this study included descriptive analysis, Wilcoxon tests, and univariate linear regression. RESULTS: Posttreatment, median ICON scores decreased significantly from 74 to 14, and median PAR scores from 36 to 8 (p < .0001), demonstrating "excellent to substantial" improvement in 89.2% (n = 33) of the children. Comorbidities, present in 62% of patients, did not significantly affect treatment duration (22.6 ± 11.02 months). CONCLUSION: Children with ASD significantly benefit from orthodontic aligner therapy, emphasizing the need for tailored orthodontic care.

ADDing up?

OBJECTIVE: To hypothesise that a possible increased prevalence of adult-onset attention-deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD) may reflect mobile technology and digital media use being an aetiological factor. CONCLUSIONS: Data and clinical observations support but do not prove the hypothesis.

Expected changes in parenting after an online parent training for ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents. Treatments for this population should be multidisciplinary and must be initiated as early as possible. Non-pharmacological interventions for ADHD include psychoeducation, parent behavioural training programs and school interventions and accommodations. In response to the COVID-19 pandemic, we developed an online version of a combined psychoeducation and behavioural training program to facilitate access to mental health treatment and ensure continuity of care. OBJECTIVE: The study assessed the acceptability of this online parent training program, among parents and caretakers of children and adolescents with ADHD. METHODS: The program consisted of ten online sessions over the course of two consecutive days (five sessions a day). Satisfaction, usefulness and general comments about the program were assessed with open-ended questions and visual-analogous scales. Parents/caretakers' use of strategies to manage behavioural problems was assessed using the Parenting and Family Adjustment Scales. RESULTS: A total of 206 parents participated in the online program 175 of whom completed the evaluation. Participants were satisfied with the content of the program. More than half of participants had already started using strategies included in the program. The engagement was high and no major obstacles were identified other than some internet connection issues. DISCUSSION: In our survey, online delivery was described as more convenient, and participants were satisfied with the content of the program finding it beneficial for their child. Despite this, some difficulties in implementing new strategies were observed. Online BTP increased access to the BTP programs while being effective on ADHD symptoms and behavioural disturbances. CONCLUSIONS: With these measures, we hope to improve engagement in online psychoeducation and behavioural therapy programs. Future research evaluating online behavioural training programs should focus on ways to make them more accessible and adaptable to families' obstacles.

Validation and bifactor structure of the French Adult ADHD Symptoms Rating Scale v1.1 (ASRS).

BACKGROUND: Three scoring methods for the widely available Adult ADHD Symptoms Rating Scale v1.1 (ASRS) have been proposed to screen for ADHD, but these three methods have rarely been compared against formal clinical diagnoses. We aimed to validate the French version of the ASRS against a clinical interview using DSM-IV and DSM-5 diagnostic algorithms. METHODS: One hundred five adults from a convenience sample were evaluated with the ASRS and the DIVA 2.0, using both DSM-IV and DSM-5 criteria. We used Confirmatory Factor Analysis to investigate the underlying structure of the ASRS. Sensitivity, specificity, and classification accuracy were compared between the rating algorithms of the ASRS. RESULTS: The full score method had worse predictive performance than the Screener and the 2-stage scoring method. All characteristics of the three scoring methods for the ASRS were worse when applying DSM-5 criteria. The best-fitting structure was a bi-factor model with a general ADHD factor and three specific factors. CONCLUSIONS: ADHD was best conceived as a one-dimensional construct. The 2-stage scoring method superseded the Screener with comparable sensitivity and specificity.

[A creative approach to psychoeducation for ADHD in adults]. / Une offre de soins créative de psychoéducation du TDAH chez l'adulte.

A group-based online psycho-education program for adults with attention deficit hyperactivity disorder (ADHD) and their families has been set up by a multi-professional psychiatric team. Feedback from users has mainly shown benefits in terms of improving self-esteem, destigmatization and accessibility to care. This suggests a real interest in developing this care offer in the pathway of ADHD adults.

Safety outcomes of selective serotonin reuptake inhibitors in adolescent attention-deficit/hyperactivity disorder with comorbid depression: the ASSURE study.

BACKGROUND: Attention deficit-hyperactivity disorder (ADHD) is related to depressive disorder, and adolescents with both present poor outcomes. However, evidence for the safety of concomitantly using a methylphenidate (MPH) and a selective serotonin reuptake inhibitor (SSRI) among adolescent ADHD patients is limited, a literature gap aimed to address through this investigation. METHODS: We conducted a new-user cohort study using a nationwide claims database in South Korea. We identified a study population as adolescents who were diagnosed both ADHD and depressive disorder. MPH-only users were compared with patients who prescribed both a SSRI and a MPH. Fluoxetine and escitalopram users were also compared to find a preferable treatment option. Thirteen outcomes including neuropsychiatric, gastrointestinal, and other events were assessed, taking respiratory tract infection as a negative control outcome. We matched the study groups using a propensity score and used the Cox proportional hazard model to calculate the hazard ratio. Subgroup and sensitivity analyses were conducted in various epidemiologic settings. RESULTS: The risks of all the outcomes between the MPH-only and SSRI groups were not significantly different. Regarding SSRI ingredients, the risk of tic disorder was significantly lower in the fluoxetine group than the escitalopram group [HR 0.43 (0.25-0.71)]. However, there was no significant difference in other outcomes between the fluoxetine and escitalopram groups. CONCLUSION: The concomitant use of MPHs and SSRIs showed generally safe profiles in adolescent ADHD patients with depression. Most of the differences between fluoxetine and escitalopram, except those concerning tic disorder, were not significant.

Long-term childhood outcomes for babies born at term who were exposed to antenatal corticosteroids.

BACKGROUND: Antenatal corticosteroids improve neonatal outcomes when administered to infants who are at risk of preterm delivery. Many women who receive antenatal corticosteroids for threatened preterm labor proceed to deliver at term. Thus, long-term outcomes should be evaluated for term-born infants who were exposed to antenatal corticosteroids in utero. OBJECTIVE: This study aimed to compare long-term outcomes between term-born children aged ≥5 years who were born to women who received antenatal corticosteroids for threatened preterm labor and children whose mothers were also evaluated for threatened preterm labor but did not receive antenatal corticosteroids. STUDY DESIGN: We performed a retrospective cohort study of children born at ≥37 weeks' gestation, aged ≥5 years, and born to mothers diagnosed with threatened preterm labor during pregnancy. The primary exposure of interest was receiving antenatal corticosteroids. Among the collected childhood medical conditions, the primary outcome of interest was a diagnosis of asthma. RESULTS: Of the 3556 term-born children aged ≥5 years, 629 (17.6%) were exposed to antenatal corticosteroids (all betamethasone), and 2927 (82.3%) were controls whose mothers were evaluated for threatened preterm birth but did not get antenatal corticosteroid injections. Women receiving antenatal corticosteroids had higher rates of maternal comorbidities (diabetes mellitus, hypertension; P≤.01). Antenatal corticosteroid-exposed children had no difference in diagnosis of asthma (12.6% vs 11.6%), attention deficit disorder, or developmental delay (P=.47, .54, and .10, respectively). Controlling for maternal and neonatal characteristics, asthma was not different between those exposed to antenatal corticosteroids and controls (odds ratio, 1.05; 95% confidence interval, 0.79-1.39). The odds of the child's weight percentile being <10% were increased for antenatal corticosteroid-exposed children born at term (odds ratio, 2.00; 95% confidence interval, 1.22-3.25). CONCLUSION: Children born at term who were exposed to antenatal corticosteroids may have increased odds of being in a lower growth percentile than those not exposed. However, rates of diagnoses such as asthma, developmental delay, and attention deficit disorders were not different.

Risk of accidents and unintentional injuries in men and women with attention deficit hyperactivity disorder across the adult lifespan.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is associated with risk-taking behavior, leading to accidents and unintentional injuries (summarized here as incidents). Main aim of this study is to determine if men and women with and without ADHD differ in the risk of mild (treated outpatient) and severe (treated inpatient) incidents across the adult lifespan (age groups: 18-29; 30-59, and ≥60 years). Secondary aim: investigate the role of comorbid mental disorders and drugs for the treatment of these comorbidities, and ADHD-medication. METHODS: Using anonymized German claims data (N = 4,575,027), adults with ADHD diagnosis during 2016-2019 (N = 17,041) were compared with a 1:4 age and sex-matched group without ADHD diagnosis. Regression analyses statistically tested group differences. RESULTS: Incidents occur in a U-shaped form across the adult lifespan. Individuals with ADHD show the same pattern but at a substantially increased risk of both mild and severe incidents throughout the lifespan. Women without ADHD are at lower risk in young adulthood than men but at higher risk in older adulthood. Women with ADHD show the same pattern for severe incidents, but for mild incidents they have the highest risk throughout the lifespan. Co-occurring anxiety disorder and the use of psycholeptics and ADHD-medication decreased the incident risk. CONCLUSION: We extend available knowledge which has hitherto focused on young adult males and traffic accidents. ADHD is associated with increased incidents across the adult lifespan, with distinct patterns regarding age, sex, and incident severity. An accurate diagnosis of ADHD in adulthood provides the first step towards prevention of accidents and unintentional injuries.

In utero acetaminophen exposure and child neurodevelopmental outcomes: Systematic review and meta-analysis.

BACKGROUND: Acetaminophen is a frequently used analgesic for pain and fever. There have been reports of adverse neurodevelopmental outcomes associated with in utero acetaminophen exposure. However, it is unclear whether this association is related directly to acetaminophen use, or the reasons for use. OBJECTIVES: To summarise the literature on the association between in utero acetaminophen exposure and child neurodevelopmental outcomes, and assess the extent to which the association is due to confounding by indication. DATA SOURCES: OVID for Medline, Embase, and PsycINFO, and EBSCO for CINAHL, from inception to August 18, 2022. STUDY SELECTION AND DATA EXTRACTION: We searched for peer-reviewed, English-language studies on in utero acetaminophen exposure and child neurodevelopmental outcomes. Data were extracted using a standardised form created a priori, and quality was assessed using the Systematic Assessment of Quality in Observational Research. SYNTHESIS: We generated pooled risk ratios (RR) for outcomes examined by ≥3 studies using random-effects models; outcomes that could not be meta-analysed were narratively summarised following Synthesis Without Meta-Analysis guidelines. RESULTS: Twenty-two studies including 23 cohorts were eligible (n = 367,775 total participants; median: 51.7% with acetaminophen exposure). Studies were primarily prospective cohort studies from Europe and the US, with attention deficit/hyperactivity disorder (ADHD) being the most common outcome. Quality assessments resulted in 13.6% of studies being classified as high, 59.1% as medium, 22.7% as low, and 4.5% as very low quality. In utero acetaminophen exposure was associated with an elevated risk of ADHD (unadjusted pooled RR 1.32, 95% confidence interval [CI] 1.20, 1.44; I2  = 47%, n = 7 studies), with little difference after adjusting for confounders, including indications for acetaminophen use (adjusted pooled RR 1.34, 95% CI 1.15, 1.55; I2  = 50%, n = 4 studies). CONCLUSIONS: Confounding by indication did not explain the association between in utero acetaminophen exposure and child ADHD. Further, high-quality research is needed on this and other neurodevelopmental outcomes.

Association between 5-min Apgar score and attention deficit hyperactivity disorder: a Scotland-wide record linkage study of 758,423 school children.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) affects around 1 in 20 children and is associated with life-long sequelae. Previous studies of the association between Apgar score and ADHD have reported inconsistent findings. METHODS: Record linkage of maternity, prescribing and school pupil census databases was used to conduct a population e-cohort study of singleton children born in Scotland and attending school in Scotland at any point between 2009 and 2013. Binary logistic regression analysis was used to investigate the association between 5-min Apgar score and treated ADHD adjusting for sociodemographic and maternity confounders. RESULTS: Of the 758,423 children, 7,292 (0.96%) received ADHD medication. The results suggested a potential dose-response relationship between Apgar score and treated ADHD independent of confounders. Referent to an Apgar score of 10, risk of treated ADHD was higher for scores of 0-3 (adjusted OR 1.76, 95% CI 1.32-2.34), 4-6 (adjusted OR 1.50, 95% CI 1.21-1.86) and even 7-9 (adjusted OR 1.26, 95% CI 1.18-1.36) which are traditionally considered within the normal range. CONCLUSIONS: In addition to reinforcing the need to maximise Apgar score through good obstetric practice, the findings suggest that Apgar score may be useful in predicting future risk of ADHD and therefore facilitating early diagnosis and treatment.

Predicting childhood ADHD-linked symptoms from prenatal and perinatal data in the ABCD cohort.

This study investigates the capacity of pre/perinatal factors to predict attention-deficit/hyperactivity disorder (ADHD) symptoms in childhood. It also explores whether predictive accuracy of a pre/perinatal model varies for different groups in the population. We used the ABCD (Adolescent Brain Cognitive Development) cohort from the United States (N = 9975). Pre/perinatal information and the Child Behavior Checklist were reported by the parent when the child was aged 9-10. Forty variables which are generally known by birth were input as potential predictors including maternal substance-use, obstetric complications and child demographics. Elastic net regression with 5-fold validation was performed, and subsequently stratified by sex, race/ethnicity, household income and parental psychopathology. Seventeen pre/perinatal variables were identified as robust predictors of ADHD symptoms in this cohort. The model explained just 8.13% of the variance in ADHD symptoms on average (95% CI = 5.6%-11.5%). Predictive accuracy of the model varied significantly by subgroup, particularly across income groups, and several pre/perinatal factors appeared to be sex-specific. Results suggest we may be able to predict childhood ADHD symptoms with modest accuracy from birth. This study needs to be replicated using prospectively measured pre/perinatal data.

Maternal pre-pregnancy BMI and offspring hyperactivity-inattention trajectories from 3 to 8 years in the EDEN birth cohort study.

Evidence suggests obesity during pregnancy is associated with offspring attention-deficit hyperactivity disorder. However, studies have been limited to evaluating the association at a single age with inadequate data on important maternal lifestyle confounders and unmeasured familial confounding. The objective of this study was to examine the association between maternal pre-pregnancy body mass index (BMI) and child hyperactivity-inattention symptoms (HIS) at 3, 5 and 8 years. Data came from the EDEN mother-child cohort. Maternal pre-pregnancy BMI status (kg/m2) was calculated using pre-pregnancy weight and height (self-reported by mothers or measured by midwives). HIS were assessed by parental-report on the Strengths and Difficulties Questionnaire at 3, 5 and 8 years of age and used to derive developmental trajectories of HIS (n = 1428). Multivariate models were adjusted for confounders including socioeconomic status, maternal lifestyle behaviours (exercise, diet, smoking, alcohol), childcare and a stimulating home environment. Paternal BMI was used as a negative control. Compared to a normal pre-pregnancy BMI, pre-pregnancy maternal obesity was positively associated with increased odds of a high HIS trajectory between 3 and 8 years old in both unadjusted and adjusted logistic regression (adjusted odds ratio [aOR] 1.87 [95% CI 1.12, 3.12]). Pre-pregnancy overweight was not significantly associated after adjustment for confounders (aOR 1.32 [0.87, 2.01]). Maternal pre-pregnancy obesity, but not overweight, was associated with increased likelihood of a high HIS trajectory in children from 3 to 8 years old. This association persisted despite controlling for many important maternal lifestyle factors and paternal BMI. Further research is warranted to identify possible mediators involved.