Christina Dalman

Parental depression, maternal antidepressant use during pregnancy, and risk of autism spectrum disorders: population based case-control study

Objective To study the association between parental depression and maternal antidepressant use during pregnancy with autism spectrum disorders in offspring. Design Population based nested case-control study. Setting Stockholm County, Sweden, 2001-07. Participants 4429 cases of autism spectrum disorder (1828 with and 2601 without intellectual disability) and 43 277 age and sex matched controls in the full sample (1679 cases of autism spectrum disorder and 16 845 controls with data on maternal antidepressant use nested within a cohort (n=589 114) of young people aged 0-17 years. Main outcome measure A diagnosis of autism spectrum disorder, with or without intellectual disability. Exposures Parental depression and other characteristics prospectively recorded in administrative registers before the birth of the child. Maternal antidepressant use, recorded at the first antenatal interview, was available for children born from 1995 onwards. Results A history of maternal (adjusted odds ratio 1.49, 95% confidence interval 1.08 to 2.08) but not paternal depression was associated with an increased risk of autism spectrum disorders in offspring. In the subsample with available data on drugs, this association was confined to women reporting antidepressant use during pregnancy (3.34, 1.50 to 7.47, P=0.003), irrespective of whether selective serotonin reuptake inhibitors (SSRIs) or non-selective monoamine reuptake inhibitors were reported. All associations were higher in cases of autism without intellectual disability, there being no evidence of an increased risk of autism with intellectual disability. Assuming an unconfounded, causal association, antidepressant use during pregnancy explained 0.6% of the cases of autism spectrum disorder. Conclusions In utero exposure to both SSRIs and non-selective monoamine reuptake inhibitors (tricyclic antidepressants) was associated with an increased risk of autism spectrum disorders, particularly without intellectual disability. Whether this association is causal or reflects the risk of autism with severe depression during pregnancy requires further research. However, assuming causality, antidepressant use during pregnancy is unlikely to have contributed significantly towards the dramatic increase in observed prevalence of autism spectrum disorders as it explained less than 1% of cases.

Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies?

CONTEXT Studies linking birth weight and mental illness onset are inconclusive. They have primarily focused on the World Health Organization low birth weight threshold (2500 g) and schizophrenia. To our knowledge, low birth weight per se has not been conclusively linked with schizophrenia risk and specificity of the effect to birth weight below the standard threshold or to particular psychiatric diagnoses has not been demonstrated. OBJECTIVES To examine whether (1) low birth weight (<2500 g) is associated with increased risk for adult schizophrenia; (2) risk extends into the normal weight range; and (3) risk is confined to schizophrenia or linked to other adult mental illnesses. DESIGN Population-based cohort study. SETTING Sweden and Denmark. PARTICIPANTS Singleton live births in Sweden (1973-1984) and Denmark (1979-1986) (N = 1.49 million). Births were linked to comprehensive national registers of psychiatric treatment, with follow-up to December 31, 2002 (Sweden), or to June 30, 2005 (Denmark). There were 5445 cases of schizophrenia and 57 455 cases of any adult psychiatric disorder. MAIN OUTCOME MEASURE Crude and adjusted odds ratios for birth weight less than or more than 3500 to 3999 g in consecutive 500-g strata (from 500-1499 g to > or =4500 g) for schizophrenia, any psychiatric diagnoses, and specified psychiatric diagnoses. RESULTS Schizophrenia was associated with birth weight less than 2500 g. The association was not restricted to birth weight less than 2500 g and there was a significant linear trend of increasing odds ratios with decreasing birth weight across the birth weight range. This was mirrored for any psychiatric diagnosis and for each of the categories of psychiatric disorder. CONCLUSIONS Findings suggest there is an association between birth weight and adult mental disorder, but there is no indication this effect is specific to birth weight less than 2500 g or to schizophrenia. Future research should explore common disorder-specific mechanisms that may link birth weight to development of psychiatric disorder in adulthood.

Social adversity contributes to high morbidity in psychoses in immigrants – a national cohort study in two generations of Swedish residents

BACKGROUND Recent reports have indicated that immigrants have an elevated risk of schizophrenia as well as an increasing tendency for social exclusion. The aim of this study was to compare rates of schizophrenia and other psychoses in immigrants and their children of different ethnic groups with the majority population in Sweden in relation to social adversity. METHOD The study population consists of a national cohort of 1.47 million adults (born 1929-1965) and 1.16 million children and youth (born 1968-1979) in family households from the national census of 1985. Multivariate Cox regression analyses was used to study hospital discharge data during 1991-2000 in relation to socio-economic household indicators from 1985 and 1990 (single adult household, adults having received social welfare, parental unemployment, urban residency, housing and socio-economic status). RESULTS First as well as second generation immigrants had higher age and sex adjusted risk ratios for schizophrenia as well as for other psychoses (RRs 1.4-3.1 and 1.0-2.0 respectively) compared with the Swedish majority population. These risk ratios decreased considerably after adjusting for socio-economic indicators, for all groups, but particularly for the non-European immigrants. However, an elevated risk still remained in the Finnish and Eastern and Southern European study groups. CONCLUSIONS A higher risk of schizophrenia and psychoses was found in two generations of immigrants of diverse ethnicity. The results indicate that social adversity contributes to the higher risk.

Autism Spectrum Disorders in the Stockholm Youth Cohort: Design, Prevalence and Validity

Objective Reports of rising prevalence of autism spectrum disorders (ASD), along with their profound personal and societal burden, emphasize the need of methodologically sound studies to explore their causes and consequences. We here present the design of a large intergenerational resource for ASD research, along with population-based prevalence estimates of ASD and their diagnostic validity. Method The Stockholm Youth Cohort is a record-linkage study comprising all individuals aged 0–17 years, ever resident in Stockholm County in 2001–2007 (N = 589,114). ASD cases (N = 5,100) were identified using a multisource approach, involving registers covering all pathways to ASD diagnosis and care, and categorized according to co-morbid intellectual disability. Prospectively recorded information on potential determinants and consequences of ASD were retrieved from national and regional health and administrative registers. Case ascertainment was validated through case-note review, and cross validation with co-existing cases in a national twin study. Results The 2007 year prevalence of ASD in all children and young people was 11.5 per 1,000 (95% confidence interval 11.2–11.8), with a co-morbid intellectual disability recorded in 42.6% (41.0–44.2) of cases. We found 96.0% (92.0–98.4) of reviewed case-notes being consistent with a diagnosis of ASD, and confirmed ASD in 85.2% (66.2–95.8) of affected twins. Conclusions Findings from this contemporary study accords with recently reported prevalence estimates from Western countries at around 1%, based on valid case ascertainment. The Stockholm Youth Cohort, in light of the availability of extensive information from Swedens registers, constitutes an important resource for ASD research. On-going work, including collection of biological samples, will enrich the study further.

Individuals, schools, and neighborhood: a multilevel longitudinal study of variation in incidence of psychotic disorders

CONTEXT Incidence of schizophrenia and other nonaffective psychoses is greater in urban than rural areas, but the reason is unclear. Few studies have examined whether both individual and neighborhood characteristics can explain this association. Furthermore, as has been shown for ethnicity, the effect of individual characteristics may depend on neighborhood context. OBJECTIVES To examine (1) whether individual, school, or area characteristics are associated with psychosis and can explain the association with urbanicity and (2) whether effects of individual characteristics on risk of psychosis vary according to school context (reflecting both peer group and neighborhood effects). DESIGN Multilevel longitudinal study of all individuals born in Sweden in 1972 and 1977. Diagnoses were identified through linkage with the Swedish National Patient Register until December 31, 2003. SETTING Population-based. PARTICIPANTS A total of 203 829 individuals with data at individual, school, municipality, and county levels. MAIN OUTCOME MEASURES Any nonaffective psychosis, including schizophrenia (881 subjects; 0.43% cumulative incidence). For the study of interactions, the outcome was any psychosis (1944 subjects; 0.95% cumulative incidence). RESULTS Almost all the variance in risk of nonaffective psychosis was explained by individual-level rather than higher-level variation. An association between urbanicity and nonaffective psychosis was explained by higher-level characteristics, primarily school-level social fragmentation. We observed cross-level interactions between individual- and school-level markers of ethnicity, social fragmentation, and deprivation on risk of developing any psychotic disorder, all with qualitative patterns of interaction. CONCLUSIONS The association between urbanicity and psychosis appears to be a reflection of increased social fragmentation present within cities. The qualitative interactions observed are consistent with a hypothesis that certain characteristics that define individuals as being different from most other people in their local environment may increase risk of psychosis. These findings have potentially important implications for understanding the etiology of psychotic disorders and for informing social policy.

Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders.

Animal models indicate that maternal infection during pregnancy can result in behavioral abnormalities and neuropathologies in offspring. We examined the association between maternal inpatient diagnosis with infection during pregnancy and risk of ASD in a Swedish nationwide register-based birth cohort born 1984-2007 with follow-up through 2011. In total, the sample consisted of 2,371,403 persons with 24,414 ASD cases. Infection during pregnancy was defined from ICD codes. In the sample, 903 mothers of ASD cases (3.7%) had an inpatient diagnosis of infection during pregnancy. Logistic regression models adjusted for a number of covariates yielded odds ratios indicating approximately a 30% increase in ASD risk associated with any inpatient diagnosis of infection. Timing of infection did not appear to influence risk in the total Swedish population, since elevated risk of ASD was associated with infection in all trimesters. In a subsample analysis, infections were associated with greater risk of ASD with intellectual disability than for ASD without intellectual disability. The present study adds to the growing body of evidence, encompassing both animal and human studies, that supports possible immune-mediated mechanisms underlying the etiology of ASD.

Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study.

OBJECTIVE Epidemiological studies in the United States consistently find autism spectrum disorders (ASD) to be overrepresented in high socioeconomic status (SES) families. These findings starkly contrast with SES gradients of many health conditions, and may result from SES inequalities in access to services. We hypothesized that prenatal measures of low, not high, parental SES would be associated with an increased risk of offspring ASD, once biases in case ascertainment are minimized. METHOD We tested this hypothesis in a population-based study in Sweden, a country that has free universal healthcare, routine screening for developmental problems, and thorough protocols for diagnoses of ASD. In a case-control study nested in a total population cohort of children aged 0 to 17 years living in Stockholm County between 2001 and 2007 (N = 589,114), we matched ASD cases (n = 4,709) by age and sex to 10 randomly selected controls. We retrieved parental SES measures collected at time of birth by record linkage. RESULTS Children of families with lower income, and of parents with manual occupations (OR = 1.4, 95% CI = 1.3-1.6) were at higher risk of ASD. No important relationships with parental education were observed. These associations were present after accounting for parental ages, migration status, parity, psychiatric service use, maternal smoking during pregnancy, and birth characteristics; and regardless of comorbid intellectual disability. CONCLUSIONS Lower, not higher, socioeconomic status was associated with an increased risk of ASD. Studies finding the opposite may be underestimating the burden of ASD in lower SES groups.

Cannabis, schizophrenia and other non-affective psychoses: 35 years of follow-up of a population-based cohort.

BACKGROUND There is now strong evidence that cannabis use increases the risk of psychoses including schizophrenia, but the relationship between cannabis and different psychotic disorders, as well as the mechanisms, are poorly known. We aimed to assess types of psychotic outcomes after use of cannabis in adolescence and variation in risk over time. METHOD A cohort of 50 087 military conscripts with data on cannabis use in late adolescence was followed up during 35 years with regard to in-patient care for psychotic diagnoses. RESULTS Odds ratios for psychotic outcomes among frequent cannabis users compared with non-users were 3.7 [95% confidence interval (CI) 2.3-5.8] for schizophrenia, 2.2 (95% CI 1.0-4.7) for brief psychosis and 2.0 (95% CI 0.8-4.7) for other non-affective psychoses. Risk of schizophrenia declined over the decades in moderate users but much less so in frequent users. The presence of a brief psychosis did not increase risk of later schizophrenia more in cannabis users compared with non-users. CONCLUSIONS Our results confirm an increased risk of schizophrenia in a long-term perspective, although the risk declined over time in moderate users.

Childhood infection and adult schizophrenia: A meta-analysis of population-based studies

Objective To determine whether exposures to infectious illness during childhood involving the CNS or elsewhere is associated with adult schizophrenia or other psychoses. Method Systematic review and meta-analysis of published literature identified by electronic and manual search meeting three inclusion criteria: population-base, objective assessment of childhood infection at the individual level, standard definition of adult psychotic outcomes. We calculated risk ratio for all CNS infection, and separately for viral and bacterial infection in relation to non-affective psychosis and schizophrenia, which was combined in meta-analysis. Results Seven studies were included. Meta-analysis involving 2424 cases and over 1.2 million controls showed CNS viral infection was associated with nearly two-fold increased risk of adult non-affective psychosis (risk ratio 1.70; 95% CI 1.13–2.55; p = 0.01). There was no significant heterogeneity between studies (p = 0.26; I2 = 20%). Separate meta-analysis involving 1035 cases and over 1.2 million controls suggested all childhood CNS infections, particularly viral infections, may be associated with nearly two-fold risk of adult schizophrenia. However, there was evidence of some heterogeneity between these studies (p = 0.07; I2 = 70%). CNS bacterial infections were not associated with risk of psychosis. Data on childhood infections with no obvious involvement of the CNS is insufficient. Conclusions These findings indicate childhood CNS viral infections increase the risk of adult psychotic illness. Possible mechanisms may include both direct effects of pathogens, and the effects of inflammatory response on the developing brain.

Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress

BACKGROUND Preconception, prenatal and postnatal maternal stress is associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between maternal bereavement stress and offspring autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt and completed suicide. METHOD Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992-2000 for childhood outcomes and 2,155,221 offspring born 1973-1997 for adult outcomes with follow-up to 2009. Maternal stress was defined as death of a first-degree relative during (a) the 6 months before conception, (b) pregnancy or (c) the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HRs) in unadjusted and adjusted analyses. RESULTS Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third-trimester prenatal stress increased the risk of ASD [adjusted HR (aHR) 1.58, 95% confidence interval (CI) 1.15-2.17] and ADHD (aHR 1.31, 95% CI 1.04-1.66). First postnatal year stress increased the risk of offspring suicide attempt (aHR 1.13, 95% CI 1.02-1.25) and completed suicide (aHR 1.51, 95% CI 1.08-2.11). Bereavement stress during the second postnatal year increased the risk of ASD (aHR 1.30, 95% CI 1.09-1.55). CONCLUSIONS Further research is needed regarding associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases the risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases the risk of offspring suicide attempt, completed suicide and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.