Sex differences in placenta-derived markers and later autistic traits in children.

Autism is more prevalent in males and males on average score higher on measures of autistic traits. Placental function is affected significantly by the sex of the fetus. It is unclear if sex differences in placental function are associated with sex differences in the occurrence of autistic traits postnatally. To assess this, concentrations of angiogenesis-related markers, placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) were assessed in maternal plasma of expectant women in the late 1st (mean= 13.5 [SD = 2.0] weeks gestation) and 2nd trimesters (mean=20.6 [SD = 1.2] weeks gestation), as part of the Generation R Study, Rotterdam, the Netherlands. Subsequent assessment of autistic traits in the offspring at age 6 was performed with the 18-item version of the Social Responsiveness Scale (SRS). Associations of placental protein concentrations with autistic traits were tested in sex-stratified and cohort-wide regression models. Cases with pregnancy complications or a later autism diagnosis (n = 64) were also assessed for differences in placenta-derived markers. sFlt-1 levels were significantly lower in males in both trimesters but showed no association with autistic traits. PlGF was significantly lower in male pregnancies in the 1st trimester, and significantly higher in the 2nd trimester, compared to female pregnancies. Higher PlGF levels in the 2nd trimester and the rate of PlGF increase were both associated with the occurrence of higher autistic traits (PlGF-2nd: n = 3469,b = 0.24 [SE = 0.11], p = 0.03) in both unadjusted and adjusted linear regression models that controlled for age, sex, placental weight and maternal characteristics. Mediation analyses showed that higher autistic traits in males compared to females were partly explained by higher PlGF or a faster rate of PlGF increase in the second trimester (PlGF-2nd: n = 3469, ACME: b = 0.005, [SE = 0.002], p = 0.004). In conclusion, higher PlGF levels in the 2nd trimester and a higher rate of PlGF increase are associated with both being male, and with a higher number of autistic traits in the general population.

Cavum Septum Pellucidum in the General Pediatric Population and Its Relation to Surrounding Brain Structure Volumes, Cognitive Function, and Emotional or Behavioral Problems.

BACKGROUND AND PURPOSE: The cavum septum pellucidum, a cavity filled with CSF, is localized between the 2 lateral ventricles of the brain. The cavum is present in all neonates, but it typically closes within 5 months after birth. In some cases, this closure does not occur and a persistent or enlarged cavum septum pellucidum has been linked, in some studies, to psychiatric disorders. However, the clinical relevance in the general population is unknown. In this study, we examined the relationship between the cavum septum pellucidum and volumes of brain structures, cognitive function, and emotional and behavioral problems in children. MATERIALS AND METHODS: This study was embedded in the Generation R Study, a prospective cohort in Rotterdam, the Netherlands. MR imaging studies of 1070 children, 6-10 years of age, were systematically evaluated for the presence and length of a persistent cavum septum pellucidum. An enlarged cavum septum pellucidum was defined as a cavum length of ≥6 mm. Groups without, with persistent, and with enlarged cavum septi pellucidi were compared for brain structure volumes, nonverbal intelligence, and emotional and behavioral problems. RESULTS: The prevalence of cavum septi pellucidi in our sample was 4.6%. Children with an enlarged cavum septum pellucidum had a larger corpus callosum, greater thalamic and total white matter-to-total brain volume ratio, and smaller lateral ventricle volumes. We did not find a relationship between cavum septi pellucidi and cognitive function or emotional and behavioral problems. CONCLUSIONS: The cavum septum pellucidum is a normal structural brain variation without clinical implications in this population-based sample of school-aged children.

Psychotic-like experiences in pre-adolescence: what precedes the antecedent symptoms of severe mental illness?

OBJECTIVE: Adolescent psychotic-like experiences predict the onset of psychosis, but also predict subsequent non-psychotic disorders. Therefore, it is crucial to better understand the aetiology of psychotic-like experiences. This study examined whether (a) child emotional and behavioural problems at 3 and 6 years, or (b) childhood adversities were associated with psychotic-like experiences at age 10 years. METHOD: This prospective study was embedded in the Generation R Study; 3984 children (mean age 10 years) completed a psychotic-like experiences questionnaire. Mothers reported problems of their child at ages 3, 6 and 10 years. Additionally, mothers were interviewed about their child's adversities. RESULTS: Psychotic-like experiences were endorsed by ~20% of children and predicted by both emotional and behavioural problems at 3 years (e.g. emotional-reactive problems: ORadjusted = 1.10, 95% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.03, 95% CI: 1.02-1.05) and 6 years (e.g. anxious/depressed problems: ORadjusted = 1.11, 95% CI: 1.06-1.15, aggressive behaviour: ORadjusted = 1.04, 95% CI: 1.04-1.05). Childhood adversities were associated with psychotic-like experiences (>2 adversities: ORadjusted = 2.24, 95% CI: 1.72-2.92), which remained significant after adjustment for comorbid psychiatric problems. CONCLUSION: This study demonstrated associations between early adversities, childhood emotional and behavioural problems and pre-adolescent psychotic-like experiences, which will improve the understanding of children at increased risk of severe mental illness.

Gestational vitamin D deficiency and autism-related traits: the Generation R Study.

There is intense interest in identifying modifiable risk factors associated with autism-spectrum disorders (ASD). Autism-related traits, which can be assessed in a continuous fashion, share risk factors with ASD, and thus can serve as informative phenotypes in population-based cohort studies. Based on the growing body of research linking gestational vitamin D deficiency with altered brain development, this common exposure is a candidate modifiable risk factor for ASD and autism-related traits. The association between gestational vitamin D deficiency and a continuous measure of autism-related traits at ~6 years (Social Responsiveness Scale; SRS) was determined in a large population-based cohort of mothers and their children (n=4229). 25-hydroxyvitamin D (25OHD) was assessed from maternal mid-gestation sera and from neonatal sera (collected from cord blood). Vitamin D deficiency was defined as 25OHD concentrations less than 25 nmol l-1. Compared with the 25OHD sufficient group (25OHD>50 nmol l-1), those who were 25OHD deficient had significantly higher (more abnormal) SRS scores (mid-gestation n=2866, ß=0.06, P<0.001; cord blood n=1712, ß=0.03, P=0.01). The findings persisted (a) when we restricted the models to offspring with European ancestry, (b) when we adjusted for sample structure using genetic data, (c) when 25OHD was entered as a continuous measure in the models and (d) when we corrected for the effect of season of blood sampling. Gestational vitamin D deficiency was associated with autism-related traits in a large population-based sample. Because gestational vitamin D deficiency is readily preventable with safe, cheap and accessible supplements, this candidate risk factor warrants closer scrutiny.