Hein Heuvelman

Severe bereavement stress during the prenatal and childhood periods and risk of psychosis in later life: population based cohort study

Objective To examine the risk of psychosis associated with severe bereavement stress during the antenatal and postnatal period, between conception to adolescence, and with different causes of death. Design Population based cohort study. Setting Swedish national registers including births between 1973 and 1985 and followed-up to 2006. Participants In a cohort of 1 045 336 Swedish births (1973-85), offspring born to mothers exposed to severe maternal bereavement stress six months before conception or during pregnancy, or exposed to loss of a close family member subsequently from birth to 13 years of age were followed until 2006. Admissions were identified by linkage to national patient registers. Main outcome measures Crude and adjusted odds ratios for all psychosis, non-affective psychosis, and affective psychosis. Results Maternal bereavement stress occurring preconception or during the prenatal period was not associated with a significant excess risk of psychosis in offspring (adjusted odds ratio, preconception 1.24, 95% confidence interval 0.96 to 1.62; first trimester 0.95, 0.58 to1.56; second trimester 0.79, 0.46 to 1.33; third trimester 1.14, 0.78 to 1.66). Risks increased modestly after exposure to the loss of a close family member from birth to adolescence for all psychoses (adjusted odds ratio 1.17, 1.04 to 1.32). The pattern of risk was generally similar for non-affective and affective psychosis. Thus estimates were higher after death in the nuclear compared with extended family but remained non-significant for prenatal exposure; the earlier the exposure to death in the nuclear family occurred in childhood (all psychoses: adjusted odds ratio, birth to 2.9 years 1.84, 1.41 to 2.41; 3-6.9 years 1.47, 1.16 to 1.85; 7-12.9 years 1.32, 1.10 to 1.58) and after suicide. Following suicide, risks were especially higher for affective psychosis (birth to 2.9 years 3.33, 2.00 to 5.56; 6.9 years 1.84, 1.04 to 3.25; 7-12.9 years 2.68, 1.84 to 3.92). Adjustment for key confounders attenuated but did not explain associations with risk. Conclusions Postnatal but not prenatal bereavement stress in mothers is associated with an increased risk of psychosis in offspring. Risks are especially high for affective psychosis after suicide in the nuclear family, an effect that is not explained by family psychiatric history. Future studies are needed to understand possible sources of risk and resilience so that structures can be put in place to support vulnerable children and their families.

Prevalence of Autism Spectrum Disorders with and without Intellectual Disability by Gestational Age at Birth in the Stockholm Youth Cohort: a Register Linkage Study

BACKGROUND Preterm birth has been linked to increased risk of autism spectrum disorders (ASD), but how this risk changes with gestational age at birth has not been well characterised, especially with regard to co-occurring intellectual disability (ID). METHODS Register-based cohort study of singleton births in 1984-2007 in Stockholm County, Sweden (N total: 480 728; n ASD: 10 025). We assessed overall and sex-specific, gestational week-specific prevalence estimates and risk ratios of ASD with and without ID. RESULTS Preterm and postterm births were associated with elevated risk of ASD, and the relationship between gestational age at birth and ASD with and without ID differed in males and females. Risk of ASD without ID was higher in preterm births among both sexes and decreased continuously with increasing length of gestation. Risk of ASD with ID was higher in both preterm and postterm births among both sexes, with postterm birth in females being more highly associated with ASD with ID than that in males. CONCLUSIONS The relationship between gestational age at birth and ASD differs by the presence/absence of co-occurring ID and fetal sex. Both preterm and postterm birth are associated with increased risk of ASD. Risk of ASD is not constant within conventionally defined gestational age at birth periods. Further research on mechanism underlying these associations is needed.

Association of Autistic Traits With Depression From Childhood to Age 18 Years

Importance Population-based studies following trajectories of depression in autism spectrum disorders (ASD) from childhood into early adulthood are rare. The role of genetic confounding and of potential environmental intermediaries, such as bullying, in any associations is unclear. Objectives To compare trajectories of depressive symptoms from ages 10 to 18 years for children with or without ASD and autistic traits, to assess associations between ASD and autistic traits and an International Statistical Classification of Diseases, 10th Revision (ICD-10) depression diagnosis at age 18 years, and to explore the importance of genetic confounding and bullying. Design, Setting, and Participants Longitudinal study of participants in the Avon Longitudinal Study of Parents and Children birth cohort in Bristol, United Kingdom, followed up through age 18 years. Data analysis was conducted from January to November 2017. Main Outcomes and Measures Depressive symptoms were assessed using the Short Mood and Feelings Questionnaire (SMFQ) at 6 time points between ages 10 and 18 years. An ICD-10 depression diagnosis at age 18 years was established using the Clinical Interview Schedule–Revised. Exposures were ASD diagnosis and 4 dichotomized autistic traits (social communication, coherence, repetitive behavior, and sociability). An autism polygenic risk score was derived using the Psychiatric Genomics Consortium autism discovery genome-wide association study summary data. Bullying was assessed at ages 8, 10, and 13 years. Results The maximum sample with complete data was 6091 for the trajectory analysis (48.8% male) and 3168 for analysis of depression diagnosis at age 18 years (44.4% male). Children with ASD and autistic traits had higher average SMFQ depressive symptom scores than the general population at age 10 years (eg, for social communication 5.55 [95% CI, 5.16-5.95] vs 3.73 [95% CI, 3.61-3.85], for ASD 7.31 [95% CI, 6.22-8.40] vs 3.94 [95% CI, 3.83-4.05], remaining elevated in an upward trajectory until age 18 years (eg, for social communication 7.65 [95% CI, 6.92-8.37] vs 6.50 [95% CI, 6.29-6.71], for ASD 7.66 [95% CI, 5.96-9.35] vs 6.62 [95% CI, 6.43-6.81]). Social communication impairments were associated with depression at age 18 years (adjusted relative risk, 1.68; 95% CI, 1.05-2.70), and bullying explained a substantial proportion of this risk. There was no evidence of confounding by the autism polygenic risk score. Analysis in larger samples using multiple imputation led to similar but more precise results. Conclusions and Relevance Children with ASD and ASD traits have higher depressive symptom scores than the general population by age 10 years, which persist to age 18 years, particularly in the context of bullying. Social communication impairments are an important autistic trait in relation to depression. Bullying, as an environmental intermediary, could be a target for interventions.

Gestational age at birth and academic performance: population-based cohort study

Background Numerous studies suggest pre-term birth is associated with cognitive deficit. However, less is known about cognitive outcomes following post-term birth, or the influence of weight variations within term or post-term populations. We examined associations between gestational age (GA) and school performance, by weight-for-GA, focusing on extremely pre- and post-term births. Method Record linkage study of Swedish children born 1973-94 ( n =  2 008 102) with a nested sibling comparison ( n =  439 629). We used restricted cubic regression splines to examine associations between GA and the grade achieved on leaving secondary education, comparing siblings to allow stronger causal inference with regard to associations between GA and school performance. Results Grade averages of both pre- and post-term children were below those of full-term counterparts and lower for those born small-for-GA. The adjusted grades of extremely pre-term children (at 24 completed weeks), while improving in later study periods, were lower by 0.43 standard deviations (95% confidence interval 0.38-0.49), corresponding with a 21-point reduction (19 to 24) on a 240-point scale. Reductions for extremely post-term children (at 45 completed weeks) were lesser [-0.15 standard deviation (-0.17 to -0.13) or -8 points (-9 to -7)]. Among matched siblings, we observed weaker residual effects of pre-term and post-term GA on school performance. Conclusions There may be independent effects of fetal maturation and fetal growth on school performance. Associations among matched siblings, although attenuated, remained consistent with causal effects of pre- and post-term birth on school performance.

Association Between Autism Spectrum Disorders With or Without Intellectual Disability and Depression in Young Adulthood

Key Points Questions Are individuals with autism spectrum disorders more likely to have depression in adulthood than the general population, and do these risks have a familial basis and differ by coexisting intellectual disability? Findings In this Swedish population-based cohort study of 223 842 participants with a nested sibling comparison, individuals with autism spectrum disorders, especially those without intellectual disability, had a greater risk of a depression diagnosis in young adulthood than the general population and their nonautistic siblings. Meaning According to this study’s results, depression is overrepresented in autism spectrum disorders, and this higher risk may not be explained by shared familial liability; research identifying modifiable pathways may help develop preventive interventions.

Gestational Age At Birth And Risk Of Intellectual Disability Without A Common Genetic Cause: Findings From The Stockholm Youth Cohort

Background Preterm birth is linked to intellectual disability and there is evidence to suggest post-term birth may also incur risk. However, these associations have not yet been investigated in the absence of common genetic causes of intellectual disability (where risk associated with late delivery may be preventable) or with methods allowing stronger causal inference from non-experimental data. We aimed to examine risk of intellectual disability without a common genetic cause across the entire range of gestation, using a matched-sibling design to account for unmeasured confounding by shared familial factors. Methods and Findings We conducted a population-based retrospective study using data from the Stockholm Youth Cohort (n=499,621) and examined associations in a nested cohort of matched siblings (n=8,034). Children born at non-optimal gestational duration (before/after 40 weeks 3 days) were at greater risk of intellectual disability. Risk was greatest among those born extremely early (adjusted OR24 weeks=14.54 [95% CI 11.46–18.44]), lessening with advancing gestational age toward term (aOR32 weeks=3.59 [3.22–4.01]; aOR37 weeks=1.50 [1.38–1.63]); aOR38 weeks=1.26 [1.16-1.37]; aOR39 weeks=1.10 [1.04-1.17]) and increasing with advancing gestational age post-term (aOR42 weeks=1.16 [1.08–1.25]; aOR42 weeks=1.41 [1.21–1.64]; aOR44 weeks=1.71 [1.34–2.18]; aOR45 weeks=2.07 [1.47–2.92]). Associations persisted in a nested cohort of matched outcome-discordant siblings suggesting they were robust against confounding from shared genetic or environmental traits, although there may have been residual confounding by unobserved non-shared characteristics. Risk of intellectual disability was greatest among children showing evidence of fetal growth restriction, especially when birth occurred before or after term. Conclusions Birth at non-optimal gestational duration may be linked causally with greater risk of intellectual disability. The mechanisms underlying these associations need to be elucidated as they will be relevant to clinical practice concerning elective delivery within the term period and the mitigation of risk in children who are born post-term.