An Unhealthy Dietary Pattern during Pregnancy is Associated with Neurodevelopmental Disorders in Childhood and Adolescence.

Despite the high prevalence of neurodevelopmental disorders, there are a lack of clinical studies examining the impact of pregnancy diet on child neurodevelopment. This observational clinical study examined the associations between pregnancy dietary patterns and neurodevelopmental diagnoses, as well as their symptoms, in a prospective cohort of 10-year-old children (n=508). Data-driven dietary patterns were derived from self-reported food frequency questionnaires. An Unhealthy dietary pattern in pregnancy (per SD change) was significantly associated with attention deficit hyperactivity disorder (ADHD) OR 1.66 [1.21 - 2.27], p=0.002 and autism diagnosis OR 2.22 [1.33 - 3.74], p=0.002 and associated symptoms p<0.001. Findings for ADHD were validated in two large (n=656, n=348), independent mother-child cohorts via blood metabolome modelling. Objective metabolite scores, assessed at five timepoints in mothers and children in two independent mother-child cohorts, indicated that the strongest association with ADHD was during early-to mid-pregnancy. These results provide evidence for targeted prenatal dietary interventions to prevent neurodevelopmental disorders in children.

High-dose vitamin D3 supplementation in pregnancy and risk of neurodevelopmental disorders in the children at age 10: A randomized clinical trial.

BACKGROUND: Vitamin D deficiency in pregnancy may increase the risk of autism and attention deficit hyperactivity disorder (ADHD). OBJECTIVE: The objective of this study was to estimate the effect of vitamin D3 supplementation in pregnancy on risk of autism and ADHD. DESIGN: This randomized clinical trial was part of the COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPYCH) project nested within the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort comprising a population-based sample of 700 healthy mother-child pairs enrolled at week 24 of pregnancy. Maternal 25-hydroxy-vitamin D (25(OH)D) was measured at inclusion and 623 mothers were randomized 1:1 to either high-dose (2800 IU/d) or standard dose (400 IU/d) vitamin D3 until 1 wk postpartum (315 received high-dose, 308 standard dose). At age 10, diagnoses and symptom load of autism and ADHD, respectively, were established using the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. RESULTS: The psychopathologic evaluation was completed by 591 children aged 10 y, and 16 children (2.7%) were diagnosed with autism and 65 (11.0%) with ADHD. Hereof, 496 children participated in the vitamin D3 trial (246 received high-dose, 250 standard dose). Of these, 12 children (2.4%) were diagnosed with autism and 58 (11.7%) with ADHD. Higher maternal preintervention 25(OH)D levels were associated with a decreased risk of autism [odd ratio (OR) per 10 nmol/L: 0.76 (0.59,0.97); P = 0.034], lower autistic symptom load [ß per 10 nmol/L: -0.03 (-0.05,0.00); P = 0.024), and decreased risk of ADHD diagnosis (OR per 10 nmol/L: 0.88 (0.78,0.99); P = 0.033]. High-dose vitamin D3 supplementation was not associated with risk of autism or ADHD. CONCLUSIONS: Higher maternal preintervention 25(OH)D was associated with a decreased risk of autism, lower autistic symptom load, and decreased risk of ADHD diagnosis, but high-dose vitamin D3 supplementation in pregnancy had no effect on risk of autism and ADHD. This trial was registered at clinicaltrials.gov as NCT00856947.

Dimensional profiling of psychopathology in children and adolescents based on the K-SADS-PL and an analysis of the construct validity of two ADHD symptom dimensions.

OBJECTIVES: The traditional view on psychiatric disorders as categorical and distinct is being challenged by perspectives emphasizing the relevance of dimensional and transdiagnostic assessment. However, most diagnostic instruments are based on a categorical view with a threshold-approach to disease classification. METHODS: We here describe algorithms for dimensionalizing the psychopathological ratings of the widely used diagnostic interview for children and adolescents, the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime Version (K-SADS-PL). We further evaluate the criterion-related construct validity of the dimensionalized attention-deficit/hyperactivity disorder (ADHD) scales using Rasch models in a sample of 590 children (mean age 10.29 (.36), 49% girls). RESULTS: The algorithms generate scores of current symptom load, i.e., the sum of clinician-rated symptoms within each disorder assessed with the interview. We found support for counting symptoms of inattention and hyperactivity/impulsivity, respectively, but not for a single combined ADHD scale. CONCLUSIONS: The algorithms constitute an initial step in creating a framework for clinician-rated dimensional analyses of symptoms derived from the K-SADS-PL, but future studies are needed to further evaluate the construct validity of the remaining scales and the reliability and clinical utility of the method. We believe that our proposed algorithms offer a novel method of dimensional psychopathological assessment, which can be applied in multiple branches of child and adolescent psychiatry.

Maternal inflammation during pregnancy is associated with risk of ADHD in children at age 10.

INTRODUCTION: Maternal inflammation during pregnancy may affect early neurodevelopment in offspring as suggested by preclinical and register data. However, clinical evidence for risk of aberrant neurodevelopment later in childhood is scarce. In the population-based COPSAC2010 mother-child cohort, we investigated associations between maternal inflammation levels during pregnancy and the risk of a diagnosis of ADHD as well as the load of ADHD symptoms in the children at age 10. METHODS: The COPSAC2010 cohort consists of 700 mother-child pairs followed prospectively since pregnancy week 24.Maternal high-sensitivity C-Reactive Protein (hs-CRP) level at week 24 of gestation was investigated in relation to child neurodevelopment by age 10 using logistic and linear regression models with extensive confounder adjustment, including socioeconomic status and maternal polygenic risk of ADHD. The children completed a comprehensive examination of neurodevelopment including categorical (i.e., diagnostic) and dimensional (i.e., symptom load) psychopathology using the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) and parental rated ADHD-Rating Scale (ADHD-RS). RESULTS: A total of 604 (86 %) of the 700 children in the COPSAC2010 cohort participated in the COPSYCH visit at age 10. Sixty-five (10.8 %) fulfilled a research diagnosis of ADHD (16 girls and 49 boys). Higher maternal hs-CRP level in pregnancy at week 24 (median 5.4 mg/L) was significantly associated with increased risk for a diagnosis of ADHD, adjusted OR 1.40, 95 %CI (1.16-1.70), p = 0.001. Additionally, higher maternal hs-CRP was associated with increased ADHD symptom load in the entire cohort, reflected by ADHD-RS raw scores. DISCUSSION: These clinical data demonstrated a robust association of prenatal maternal inflammation assessed by hs-CRP with a diagnosis of ADHD by age 10. Moreover, maternal inflammation was associated with ADHD symptom load in the complete cohort. Identifying inflammation as an important marker will provide a potential target for future increased awareness and prevention during pregnancy thereby ultimately improving neurodevelopmental outcomes in children.

Manifest diabetes after gestational diabetes: a double-cohort, long-term follow-up in a Danish population.

PURPOSE: The aim was to follow-up two cohorts of women with GDM to investigate the incidence and time of diagnosis of manifest diabetes mellitus (DM) postpartum and identify the risk factors for diabetes in our population. METHODS: A follow-up study on two independent cohorts having oral glucose tolerance test (OGTT) in 1991/1992 and 2011-2016: Cohort 1 consisted of 406 women including 54 with GDM and 352 with a non-GDM OGTT-test and cohort 2 had 433 women diagnosed with GDM. The first cohort had nearly 25 years of follow-up and gave information on magnitude, conversion rate and type of diabetes manifestation. The second cohort was started recently to evaluate whether newer diagnostic criteria and baseline information on the old cohort are still valid for prediction of diabetes risk. RESULTS: The risk of manifest diabetes in cohort 1 at the end of follow-up was six times higher in women with previous GDM compared with non-GDM (RR = 6; 95% CI 4-11). We observed a 70% diabetes rate 25 years after pregnancy. Only family history of diabetes in cohort 2 was associated with conversion to manifest diabetes (p = 0.002), also after adjustment for age, BMI, non-Danish origin and smoking during pregnancy (p < 0.001) CONCLUSION: The incidence of diabetes after GDM is higher than that previously reported in Scandinavian populations and the rate of manifest diabetes rises steeply 15 years after pregnancy and after 40 years of age. The women of cohort 2 with recent GDM are at risk of DM at a higher rate. On this background our results are useful in identifying the time where GDM women may benefit from the effective implementation of evidence-based treatment to postpone and advert manifest DM.

Head circumference at birth and intellectual disability: a nationwide cohort study.

BACKGROUND: Intellectual disability (ID) is a prevalent chronic disability affecting up to 1-3% of the general population. Small head circumference at birth, a surrogate measure of foetal cerebral growth, may be a risk factor for ID. We aimed to investigate the association between the full distribution of head circumference at birth and ID. METHODS: This cohort study was based on Danish nationwide registries and included all Danish singletons born alive from 1997 to 2013. Follow-up ended at October 2015. The data was analysed using a Cox proportional hazards regression model adjusted for a large number of potential confounders. RESULTS: The cohort comprised 986,909 infants. Neither microcephaly nor macrocephaly at birth was consistently associated with the risk of ID. Within the normal range of head circumference, larger head circumference was associated with a decreased risk of ID (HR per standard deviation increase in head circumference z score 0.85, 95% CI 0.81-0.88). The association detected within the normal range was consistent in all sensitivity analyses. CONCLUSIONS: Intrauterine brain growth restriction may be a risk factor for ID.

Head circumference at birth and school performance: a nationwide cohort study of 536,921 children.

BACKGROUND: Early measures of cognitive function are of great public health interest. We aimed to estimate the association between head circumference at birth, a measure of cerebral size, and school performance. METHODS: We conducted a nationwide cohort study of all liveborn singletons in Denmark, 1997-2005. The association between birth head circumference z score and test scores in reading and mathematics from a nationwide mandatory computer-based school test program (7-16 years) was estimated by multivariable linear regression adjusted for potential confounders. RESULTS: The cohort included 536,921 children. Compared to normocephalic children, children with microcephaly [<-2 standard deviations (SD)] had lower mean reading scores: second grade: -0.08 SD (95% CI -0.10 to -0.06), eighth grade: -0.07 SD (95% CI -0.10 to -0.04). Macrocephaly (>+2 SD) was associated with higher scores. In normocephalic children, each SD increase in head circumference was associated with a 0.03 SD (95% CI 0.03 to 0.04) increase in mean reading scores. The results were similar across grades within both reading and mathematics. CONCLUSION: Prenatal brain growth may be causally related to childhood school performance. The demonstrated differences are unlikely to be clinically relevant at the individual level but may be important at a public health level.

Head circumference at birth and childhood developmental disorders in a nationwide cohort in Denmark.

BACKGROUND: Early markers of Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) may improve the understanding and early recognition of these disorders. We aimed to estimate the association between head circumference at birth, a measure of cerebral size at birth, and the risk of ADHD and ASD. METHODS: We present a register-based cohort study of all Danish singletons born alive between 1997 and 2013. Cox proportional hazards regression was used for the statistical analyses. Sibling-matched analyses were performed to account for unmeasured confounding shared by siblings. RESULTS: The analyses included 986 909 new-borns. Compared to normocephalic children, microcephaly was associated with an increased risk of ADHD (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.12, 1.32). Macrocephaly was associated with a decreased risk of ADHD (HR 0.90, 95% CI 0.82, 0.99). Neither microcephaly nor macrocephaly were associated with ASD (HR 1.06, 95% CI 0.94, 1.19 and 1.03, 95% CI 0.90, 1.19). The largest difference was found within the normocephalic children. A head circumference at the lower limit of normocephaly compared to a head circumference at the upper limit was associated with an increased risk of ADHD (HR 1.52, 95% CI 1.43, 1.63). The sibling analyses confirmed the increased risk of ADHD with decreasing head circumference in the normocephalic children. No other clear associations were present in the sibling analyses. CONCLUSIONS: Within normocephalic children, smaller head circumference at birth was associated with a higher risk of ADHD. Restricted foetal brain growth may be a risk factor for the development of ADHD but not ASD.