Maternal Steroid Hormone Levels in Early Pregnancy and Autism in the Offspring: A Population-Based, Nested Case-Control Study.

BACKGROUND: A role for prenatal steroid hormones in the etiology of autism has been proposed, but evidence is conflicting. METHODS: Here, we examined serum levels of maternal estradiol, testosterone, 17-hydroxyprogesterone (OHP), and cortisol from the first trimester of gestation (mean = 10.1 weeks) in relation to the odds of diagnosed autism with and without co-occurring intellectual disability (ID) in the offspring (n = 118 autism with ID, n = 249 autism without ID, n = 477 control). Levels of maternal hormones were measured using highly sensitive liquid chromatography tandem mass spectrometry, standardized according to gestational timing of sample collection, and analyzed with restricted cubic spline logistic regression models adjusting for child's sex and maternal health, demographic, and socioeconomic factors. RESULTS: We observed significant nonlinear associations between maternal estradiol, 17-OHP, and cortisol with autism, which varied with the presence of co-occurring ID. Compared to mean levels, lower levels of estradiol were associated with higher odds of autism with ID (odds ratio for concentrations 1 SD below the mean = 1.66; 95% CI, 1.24-2.11), while higher cortisol levels were associated with lower odds (odds ratio for 1 SD above the mean = 0.55; 95% CI, 0.36-0.88). In contrast, higher 17-OHP was associated with increased odds of autism without ID (odds ratio for 1 SD above the mean = 1.49; 95% CI, 1.11-1.99). We observed no evidence for interaction with sex of the child. CONCLUSIONS: These findings support the notion that the maternal steroid hormonal environment in early pregnancy may contribute to autism, but also emphasize the complex relationship between early-life steroid exposure and autism.

Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability.

Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. Results: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

Parental Mental Illness and the Likelihood of Child Out-of-Home Care: A Cohort Study.

OBJECTIVES: To detail the relationship between parental mental illness and the likelihood of out-of-home care (OHC) among their children, and to identify factors which modify this relationship. METHODS: Using Swedish national registers, children born in 2000 to 2011 (n = 1 249 463) were linked to their parents. Time-dependent parental mental illness (nonaffective and affective psychosis, substance misuse, depression, anxiety and stress, eating disorders, personality disorders, attention deficit hyperactivity disorder, autism, and intellectual disability), was identified through International Classification of Diseases codes. RESULTS: After adjustment for socioeconomic factors, children living with mentally ill parents were 4 times as likely to be placed in OHC than children without (95% confidence interval [CI] 4.24-4.61). The highest hazard ratio (HR) was in the youngest children aged 0 to 1 year (5.77, 95% CI 5.42-6.14), exposed to maternal illness (HR 4.56, 95% CI 4.37-4.76), and parental intellectual disability (HR 4.73, 95% CI 4.09-5.46). Children with parental mental illness with multiple risk factors were at particularly high risk. Compared with children without parental mental illness, and those with university-educated parents, children whose parents had mental illness and only had education to age 16 had a 15 times higher risk of OHC (95% CI 13.75-16.54). CONCLUSIONS: Children with parental mental illness are considerably more likely to be removed from home into care during childhood, particularly during the first year of life and if they are from socially disadvantaged families. Greater knowledge of these risks should lead to increased support for vulnerable new families.

Refugee status and the incidence of affective psychotic disorders and non-psychotic bipolar disorder: A register-based cohort study of 1.3m people in Sweden.

BACKGROUND: Refugees are at increased risk of non-affective psychotic disorders, but it is unclear whether this extends to affective psychotic disorders [APD] or non-psychotic bipolar disorder [NPB]. METHODS: We conducted a nationwide cohort study in Sweden of all refugees, non-refugee migrants and the Swedish-born population, born 1 Jan 1984-31 Dec 2016. We followed participants from age 14 years until first ICD-10 diagnosis of APD or NPB. We fitted Cox proportional hazards models to estimate hazard ratios [HR] and 95 % confidence intervals [95%CI], adjusted for age, sex and family income. Models were additionally stratified by region-of-origin. RESULTS: We followed 1.3 million people for 15.1 million person-years, including 2428 new APD cases (rate: 16.0 per 100,000 person-years; 95%CI: 15.4-16.7) and 9425 NPB cases (rate: 63.8; 95%CI: 62.6-65.1). Rates of APD were higher in refugee (HRadjusted: 2.07; 95%CI: 1.55-2.78) and non-refugee migrants (HRadjusted: 1.40; 95%CI: 1.16-1.68), but lower for NPBs for refugee (HRadjusted: 0.24; 95%CI: 0.16-0.38) and non-refugee migrants (HRadjusted: 0.34; 95%CI: 0.28-0.41), compared with the Swedish-born. APD rates were elevated for both migrant groups from Asia and sub-Saharan Africa, but not other regions. Migrant groups from all regions-of-origin experienced lower rates of NPB. LIMITATIONS: Income may have been on the causal pathway making adjustment inappropriate. CONCLUSIONS: Refugees experience elevated rates of APD compared with Swedish-born and non-refugee migrants, but lower rates of NPB. This specificity of excess risk warrants clinical and public health investment in appropriate psychosis care for these vulnerable populations.

Maternal intrahepatic cholestasis of pregnancy and neurodevelopmental conditions in offspring: A population-based cohort study of 2 million Swedish children.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the most common obstetric liver disorder and is associated with an increased risk of iatrogenic preterm birth and adverse infant outcomes. Hence, there are several plausible pathways through which ICP could affect offspring neurodevelopment. However, to the best of our knowledge, no studies have investigated these associations. Thus, we aimed to determine whether ICP is associated with offspring neurodevelopmental conditions. METHODS AND FINDINGS: In this Swedish register-based cohort study, we included singleton non-adopted children born in Sweden between the 1st of January 1987 and the 31st of December 2010, who were resident in Sweden >5 years, with no missing covariate information, which we followed until the 31st of December 2016. Maternal ICP diagnosis and the date of the initial diagnosis during pregnancy were obtained from the National Patient Register. Offspring diagnoses of attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability were obtained from the National Patient Register, and the dispensation of ADHD medications were obtained from the Prescribed Drug Register. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression while controlling for observed confounders and unobserved confounders shared among full siblings and maternal full cousins. A total of 2,375,856 children were included in the study; 81.6% of them were of Nordic origin, and 51.4% were male. Of these, 10,378 (0.44%) were exposed to ICP. During a median of 18 years follow-up (interquartile range 11 to 24), 143,746 (6.05%) of children were diagnosed with a neurodevelopmental condition. After adjusting for child's sex, birth year, birth month, maternal age, highest parental education level, maternal birth country, birth order, maternal psychiatric history, ICP was associated with increased odds of offspring neurodevelopmental conditions (OR 1.22, 95% CI 1.13 to 1.31), particularly among those exposed to early-onset ICP (OR 2.38, 95% CI 1.71 to 3.30) as compared to ICP diagnosed after reaching term (≥37 weeks of gestation) (OR 1.08, 95% CI 0.97 to 1.20). The findings of early-onset ICP were consistent in family-based analyses. Within-family comparisons of full maternal cousins yielded an OR of 2.99 (95% CI 1.48 to 6.04), and comparisons of full siblings showed an OR of 1.92 (95% CI 0.92 to 4.02), though the latter was less precise. The findings were consistent across specific neurodevelopmental conditions and different analytical approaches. The primary limitations of this study included its observational design, the absence of data on ICP therapeutics, and the lack of bile acid measures. CONCLUSIONS: In this study, we observed that exposure to ICP during gestation is associated with an increased likelihood of neurodevelopmental conditions in offspring, particularly in cases of early-onset ICP. Further studies are warranted to better understand the role of early-ICP in offspring neurodevelopment.

Are the estimated needs for mental health care among adolescents from different socioeconomic backgrounds met equally in Sweden? A longitudinal survey-registry linkage study.

Evidence of inequality in the utilisation of mental health care (MHC) by adolescents in Nordic countries is mixed. This study aims to investigate if there are socioeconomic differences in the utilisation of MHC, while accounting for adolescents' mental health status. We analysed a cohort of 3517 adolescents, followed from 7 to 9th grade (ages 13-16), to examine the association between parental socioeconomic position (SEP: education and disposable income), adolescents' estimated needs, and the utilisation of MHC (defined as visits to secondary psychiatric care or receipt of psychotropic medication). Logistic and negative binomial regression models, with mental health status as moderator, were used to predict utilisation during each grade. Lower SEP predicted higher odds of utilising MHC in adolescents with no/mild symptoms (e.g., odds ratio, OR = 1.33, 95% CI 1.04-1.72, lower vs highest education), but not in those with moderate-to-severe symptoms (estimates close to one and non-significant). This pattern was largely explained by treatment of attention deficit hyperactivity disorder/autism spectrum disorders (ADHD/ASD) in boys. For girls with severe symptoms, lower SEP predicted reduced odds of utilising MHC for other mental disorders (OR = 0.48, 95% CI 0.25-0.92, lower education), and fewer outpatient visits when in contact with such care, although non-significant (incidence rate ratio, IRR = 0.51, 95% CI 0.25-1.05, lowest vs highest income). Our findings suggest a more equitable use of MHC for treating ADHD/ASD, but not other mental disorders such as depression and anxiety, particularly among girls.

Changes in anxiety and depression during the COVID-19 pandemic in the European population: A meta-analysis of changes and associations with restriction policies.

BACKGROUND: Early studies of common mental disorders (CMDs) during the COVID-19 pandemic mainly report increases; however, more recent findings have been mixed. Also, studies assessing the effects of restriction measures on CMDs show varied results. The aim of this meta-analysis was to assess changes in levels of CMDs from pre-/early to during the pandemic and the effects of restriction policies in the European population. METHODS: We searched for studies assessing both pre-pandemic and peri-pandemic self-reported emotional distress and symptoms of depression or anxiety among nationally/regionally representative samples in Europe and collected microdata from those studies. Estimates of corona containment index were related to changes in CMDs using random-effects meta-regression. RESULTS: Our search strategy resulted in findings from 15 datasets drawn from 8 European countries being included in the meta-analysis. There was no evidence of change in the prevalence of emotional distress, anxiety, or depression from before to during the pandemic; but from early pandemic periods to later periods, there were significant decreases in emotional distress and anxiety. Increased school restrictions and social distancing were associated with small increases in self-reported emotional distress. CONCLUSIONS: Despite initial concerns of increased emotional distress and mental illness due to the COVID-19 pandemic, the results from this meta-analysis indicate that there was a decrease in emotional distress and no change in anxiety or depression in the general population in Europe. Overall, our findings support the importance of strong governance when implementing periodic and robust restriction measures to combat the spread of COVID-19.

Prevention of Childhood Adversities and Children's Common Mental Disorders and School Grades.

Importance: Adversity during childhood can limit children's chances of achieving their optimal developmental and psychological outcomes. Well-designed observational studies might help identify adversities that are most implicated in this, thereby helping to identify potential targets for developing interventions. Objective: To compare the association between preventing childhood poverty, parental mental illness and parental separation, and the population rate of offspring common mental disorders (ages 16-21 years) or average school grades (age 16 years). Design, Setting, and Participants: A population-based, longitudinal cohort study using Swedish registries was conducted. A total of 163 529 children born in Sweden between January 1, 1996, and December 31, 1997, were followed up until their 21st birthday. They were linked to registries using Sweden's national personal identification number. Children were linked to birth parents, hospital records, and school data. Parents were linked to registries containing health, income, sociodemographic, and obstetric data. Analyses were conducted between January 10, 2021, and August 26, 2022. Exposures: Childhood adversities of relative poverty (household disposable income <50% of the median), parental inpatient admission for a mental illness, or parental separation. Adversities were categorized into developmental periods: ages 0 to 3, 4 to 7, 8 to 11, and 12 to 16 years. Main Outcomes and Measures: The main outcomes were children's hospital records with a diagnosis of anxiety or depression between ages 16 and 21 years and school grades at the end of compulsory education (age 16 years). The parametric g-formula modeled population changes in outcomes associated with the counterfactual, hypothetical preventing adversity exposures, accounting for fixed and time-varying confounders. Adjustments were made for parental demographic characteristics, obstetric variables, and socioeconomic data at birth. Results: A total of 163 529 children were included in the cohort (51.2% boys, 51.4% born in 1996). Preventing all adversities was associated with an estimated change in the prevalence of offspring common mental disorders from 10.2% to 7.6% and an improvement in school grades with an SD of 0.149 (95% CI, 0.147-0.149). Preventing parental separation provided for the greatest improvement, with an estimated 2.34% (95% CI, 2.23%-2.42%) fewer children with a common mental disorder and an improvement in school grades by 0.127 SDs (0.125-0.129). Greater improvements were shown by hypothetically targeting adolescents (age 12-16 years) and those whose parents had a mental illness when the child was born. Conclusions and Relevance: The results of this cohort modeling study suggest that preventing childhood adversity could provide notable improvements in the rates of common mental disorders and school grades. Many children might achieve better life outcomes if resources are properly allocated to the right adversities (parental separation), the right groups (children with parental mental illness), and at the right time (adolescence).

Indications of alcohol or drug use disorders in five different national registers in Sweden: a cross-sectional population-based study.

OBJECTIVE: The purpose of this study is to examine the prevalence of indications of alcohol or drug use disorders in five different national Swedish registers and to investigate the correlation between these registers. Furthermore, the intent is to investigate whether combining data from different registers increases the prevalence of these indications in the population due to the identification of different demographic groups in different registers. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Individuals living in Sweden aged 20-64 years in 2006, n=5 453 616. PRIMARY OUTCOME: National registers included the Registers of Inpatient Care, Outpatient Care, Medications, Social Insurance and Convictions. Demographic variables were sex, age, migrant status, education and civil status. Indications of alcohol or drug use disorders were presented as prevalence in percentage (%), correlation was examined using phi correlation coefficients and differences across demographic factors were studied using logistic regression. RESULTS: The prevalence of an indication of alcohol or drug use disorder varied between registers, meaning that prevalence increased when all registers were considered together. The prevalence of alcohol use disorder increased by 60% and 66% among men and women, respectively, while the prevalence of drug use disorder increased by 45% and 80% among men and women, respectively, when all registers were combined, compared with only using the register with the highest prevalence. Registers contributed different indications of drug and alcohol use disorders. CONCLUSIONS: Accurate estimates of alcohol or drug use disorders are critical for healthcare and rehabilitation. This study shows that using a single register alone underestimates the burden of disease unevenly, while combining a range of registers can provide a more accurate picture.

Social Deprivation and Population Density Trajectories Before and After Psychotic Disorder Diagnosis.

Importance: People with psychosis are more likely to be born and live in densely populated and socioeconomically deprived environments, but it is unclear whether these associations are a cause or consequence of disorder. Objective: To investigate whether trajectories of exposure to deprivation and population density before and after diagnosis are associated with psychotic disorders or nonpsychotic bipolar disorder. Design, Setting, and Participants: This nested case-control study included all individuals born in Sweden between January 1, 1982, and December 31, 2001, diagnosed for the first time with an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychotic disorder or nonpsychotic bipolar disorder between their 15th birthday and cohort exit (December 31, 2016). One sex- and birth year-matched control participant per case was selected. Data analysis was performed from July 2021 to June 2023. Exposures: The main exposures were quintiles of neighborhood-level deprivation and population density each year from birth to age 14 years and from first diagnosis until cohort exit. Main Outcomes and Measures: The main outcomes were the odds of a serious mental illness outcome associated with trajectories of deprivation and population density, before and after diagnosis in cases. Group-based trajectory modeling was used to derive trajectories of each exposure in each period. Logistic regression was used to examine associations with outcomes. Results: A total of 53 458 individuals (median [IQR] age at diagnosis in case patients, 23.2 [15.0-34.8] years; 30 746 [57.5%] female), including 26 729 case patients and 26 729 control participants, were studied. From birth to early adolescence, gradients were observed in exposure to deprivation and population density trajectories during upbringing and psychotic disorder, with those in the most vs least deprived (adjusted odds ratio [AOR], 1.17; 95% CI, 1.08-1.28) and most vs least densely populated (AOR, 1.49; 95% CI, 1.34-1.66) trajectories at greatest risk. A strong upward mobility trajectory to less deprived neighborhoods was associated with similar risk to living in the least deprived trajectory (AOR, 1.01; 95% CI, 0.91-1.12). Only 543 case patients (2.0%) drifted into more deprived areas after diagnosis; people with psychotic disorder were more likely to belong to this trajectory (AOR, 1.38; 95% CI, 1.16-1.65) or remain in the most deprived trajectory (AOR, 1.36; 95% CI, 1.24-1.48) relative to controls. Patterns were similar for nonpsychotic bipolar disorder and deprivation but weaker for population density. Conclusions and Relevance: In this case-control study, greater exposure to deprivation during upbringing was associated with increased risk of serious mental illness, but upward mobility mitigated this association. People with serious mental illness disproportionately remained living in more deprived areas after diagnosis, highlighting issues of social immobility. Prevention and treatment should be proportionately located in deprived areas according to need.

Genetic Contribution to the Heterogeneity of Major Depressive Disorder: Evidence From a Sibling-Based Design Using Swedish National Registers.

OBJECTIVE: Major depressive disorder (MDD) is highly heterogeneous. Standard typology partly captures the disorder's symptomatic heterogeneity, although whether it adequately captures etiological heterogeneity remains elusive. The aim of this study was to investigate the genetic characterization of MDD heterogeneity. METHODS: Using Swedish patient register data on 1.5 million individuals, the authors identified 46,255 individuals with specialist-diagnosed MDD. Eighteen subgroups were identified based on nine comparison groups defined by clinical and psychosocial features, including severity, recurrence, comorbidities, suicidality, impairment, disability, care unit, and age at diagnosis. A sibling-based design and classic quantitative genetic models were applied to estimate heritability of MDD subgroups and genetic correlations between subgroups. RESULTS: Estimates of heritability ranged from 30.5% to 58.3% across subgroups. The disabled and youth-onset subgroups showed significantly higher heritability (55.1%-58.3%) than the overall MDD sample (45.3%, 95% CI=43.0-47.5), and the subgroups with single-episode MDD and without psychiatric comorbidity showed significantly lower estimates (30.5%-34.4%). Estimates of genetic correlations between the subgroups within comparison groups ranged from 0.33 to 0.90. Seven of nine genetic correlations were significantly smaller than 1, suggesting differences in underlying genetic architecture. These results were largely consistent with previous work using genomic data. CONCLUSIONS: The findings of differential heritability and partially distinct genetic components in subgroups provide important insights into the genetic heterogeneity of MDD and a deeper etiological understanding of MDD clinical subgroups.

Random capillary glucose levels throughout pregnancy, obstetric and neonatal outcomes, and long-term neurodevelopmental conditions in children: a group-based trajectory analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with both short- and long-term risks, although it is unknown if risks vary by severity, timing, and duration of gestational hyperglycemia. We aimed to identify trajectories of random capillary glucose (RCG) levels throughout pregnancy and assess their associations with both obstetric/neonatal outcomes and children's risk of neurodevelopmental conditions (NDCs) (i.e., autism, intellectual disability, and attention-deficit/hyperactivity disorders [ADHD]). METHODS: A population-based cohort study was conducted involving 76,228 children born to 68,768 mothers without pregestational diabetes. Group-based trajectory modeling was utilized to identify distinct glucose trajectories across RCG values throughout the course of pregnancy. The associations between these trajectory groups and obstetric/neonatal outcomes as well as children's NDCs were then assessed using generalized estimating equation models with a logit link. The Benjamini-Hochberg (BH) procedure was employed to adjust P-values for multiple comparisons, controlling the false discovery rate (FDR). RESULTS: Five distinct glucose trajectory groups were identified, each with varying percentages diagnosed with GDM. Their associations with obstetric/neonatal outcomes as well as children's NDCs varied. For example, when compared to the "Persistently Low" group, other groups exhibited varying degrees of increased risk for large-for-gestational-age babies, with the exception of the "High in Early Pregnancy" group. Compared to the "Persistently Low" group, all other trajectory groups were associated with NDC outcomes, except the "High in Mid-Pregnancy" group. However, none of the associations with offspring NDCs remained significant after accounting for the FDR correction. CONCLUSIONS: Persistent high glucose levels or moderately elevated glucose levels throughout pregnancy, as well as transient states of hyperglycemia in early or mid-pregnancy, were found to be associated with increased risks of specific obstetric and neonatal complications, and potentially offspring NDCs. These risks varied depending on the severity, timing, duration, and management of hyperglycemia. The findings underscore the need for continuous surveillance and individualized management strategies for women displaying different glucose trajectories during pregnancy. Limitations such as potential residual confounding, the role of mediators, and small sample size should be addressed in future studies.

Rates of maternal weight gain over the course of pregnancy and offspring risk of neurodevelopmental disorders.

BACKGROUND: Previous studies have suggested that gestational weight gain (GWG) outside an optimal range increases the risks of neurodevelopmental disorders (NDDs) in offspring including autism spectrum disorder (ASD), intellectual disability (ID), and attention deficit/hyperactivity disorder (ADHD). The sequential development of the fetal brain suggests that its vulnerability may vary depending on the timing of exposure. Therefore, we aimed to investigate the associations of not only gestational age-standardized total GWG (GWG z-scores) but also the rate of GWG (RGWG) in the second and third trimesters with risks of NDDs in offspring. METHODS: In this population-based cohort study, we used maternal weight data from antenatal care records collected for 57,822 children born to 53,516 mothers between 2007 and 2010 in the Stockholm Youth Cohort. Children were followed from 2 years of age to December 31, 2016. GWG z-scores and RGWG (kg/week) in the second and third trimesters were considered as continuous variables in cox regression models, clustered on maternal identification numbers. Nonlinear relationships were accommodated using restricted cubic splines with 3 knots. RGWG were also categorized according to the 2009 US Institute of Medicine (IOM) guidelines for optimal GWG. According to the IOM guidelines, the optimal rate of GWG for the second and third trimesters for underweight, normal weight, overweight, and obese categories were 0.44-0.58, 0.35-0.50, 0.23-0.33, and 0.17-0.27 kg/week, respectively. RESULTS: During a mean follow-up of 5.4 years (until children were on average 7.4 years old), 2205 (3.8%) children were diagnosed with NDDs, of which 1119 (1.9%) received a diagnosis of ASD, 1353 (2.3%) ADHD, and 270 (0.5%) ID. We observed a J-shaped association between total GWG z-score and offspring risk of NDDs, with higher total GWG (GWG z-score = 2) associated with 19% increased risk of any NDD (95% CI = 3-37%) and lower total GWG (GWG z-score = - 2) associated with 12% increased risk of any NDDs (95% CI = 2-23%), compared to the reference (GWG z-score = 0). In the second trimester, lower RGWG (0.25 kg/week) was associated with a 9% increased risk of any NDD diagnosis (95% CI = 4-15%) compared to the median of 0.57 kg/week, with no apparent relationship between higher RGWG and risk of NDDs. In the third trimester, there was no apparent association between lower RGWG and risk of NDDs, though higher RGWG (1 kg/week) was associated with a 28% increased risk of NDD diagnosis (95% CI = 16-40%), compared to the median (0.51 kg/week). When considering categorized RGWG, we found that slow weight gain in the second trimester followed by rapid weight gain in the third trimester most significantly increased the risk of ADHD (HRadjusted = 1.55, 1.13-2.13) and ID (HRadjusted = 2.53, 1.15-5.55) in offspring. The main limitations of our study are the relatively few years for which detailed GWG data were available and the relatively short follow-up for the outcomes, limiting power to detect associations and misclassifying children who receive an NDD diagnosis later in childhood. CONCLUSIONS: The relationship between maternal weight gain and children's risk of NDDs varied according to timing in pregnancy, with the greatest risks associated with slow weight gain in the second trimester and rapid weight gain in the third trimester.

Objective and subjective neighbourhood characteristics and suicidality: a multilevel analysis.

BACKGROUND: Characteristics of the neighbourhood environment, including population density, social fragmentation, and trust, have been linked to mental health outcomes. Using a longitudinal population-based cohort, we explored the relationship between objective and subjective neighbourhood characteristics and the odds of suicidal thoughts and attempts. METHODS: We conducted a longitudinal study of 20764 participants living in Stockholm County who participated in the Stockholm Public Health Survey. We used multilevel modelling to examine if suicidal thoughts and attempts were associated with neighbourhood characteristics, independent of individual associations. We included objective and subjective measures to explore if there was a different relationship between these measures of the neighbourhood environment and suicidality. RESULTS: Associations between neighbourhood factors and suicidality were predominantly explained by individual characteristics, with the exception of neighbourhood-level deprivation and average residential trust. Each unit increase of deprivation was linked to increased odds of suicidal thoughts [Odds ratio (OR) 1.04, 95% confidence interval (CI) 1.00-1.07] and attempts (OR 1.11, 95% CI 1.06-1.17). Decreasing residential trust was associated with increased odds of suicide attempts (OR 1.09, 95% CI 1.02-1.17). There was no evidence that neighbourhood-level fragmentation or average trust in public and political institutions had an independent effect on suicidality once individual and sociodemographic factors were accounted for. CONCLUSIONS: This study showed that much of the neighbourhood-level variation in suicidal thoughts and attempts could be explained by compositional factors, including sociodemographic clustering within neighbourhoods. The independent effect of neighbourhood-level deprivation and average residential trust provide evidence that the neighbourhood context may exert an independent effect on suicidality beyond the impact of individual characteristics.

Association of trauma, post-traumatic stress disorder and non-affective psychosis across the life course: a nationwide prospective cohort study.

BACKGROUND: We aimed to examine the temporal relationships between traumatic events (TE), post-traumatic stress disorder (PTSD) and non-affective psychotic disorders (NAPD). METHODS: A prospective cohort study of 1 965 214 individuals born in Sweden between 1971 and 1990 examining the independent effects of interpersonal and non-interpersonal TE on incidence of PTSD and NAPD using data from linked register data (Psychiatry-Sweden). Mediation analyses tested the hypothesis that PTSD lies on a causal pathway between interpersonal trauma and NAPD. RESULTS: Increasing doses of interpersonal and non-interpersonal TE were independently associated with increased risk of NAPD [linear-trend incidence rate ratios (IRR)adjusted = 2.17 [95% confidence interval (CI) 2.02-2.33] and IRRadjusted = 1.27 (95% CI 1.23-1.31), respectively]. These attenuated to a relatively small degree in 5-year time-lagged models. A similar pattern of results was observed for PTSD [linear-trend IRRadjusted = 3.43 (95% CI 3.21-3.66) and IRRadjusted = 1.45 (95% CI 1.39-1.50)]. PTSD was associated with increased risk of NAPD [IRRadjusted = 8.06 (95% CI 7.23-8.99)], which was substantially attenuated in 5-year time-lagged analyses [IRRadjusted = 4.62 (95% CI 3.65-5.87)]. There was little evidence that PTSD diagnosis mediated the relationship between interpersonal TE and NAPD [IRRadjusted = 0.92 (percentile CI 0.80-1.07)]. CONCLUSION: Despite the limitations to causal inference inherent in observational designs, the large effect-sizes observed between trauma, PTSD and NAPD in this study, consistent across sensitivity analyses, suggest that trauma may be a component cause of psychotic disorders. However, PTSD diagnosis might not be a good proxy for the likely complex psychological mechanisms mediating this association.

Hospital inpatient admissions of children of mothers with severe mental illness: A Western Australian cohort study.

BACKGROUND: Children of parents with mental illness face a number of adversities, potentially contributing to poor health. AIM: The aim of this study was to quantify the association between maternal severe mental illness and children's hospital admissions. METHOD: Record linkage cohort study of 467,945 children born in Western Australia between 1 January 1980 and 31 December 2001. Follow-up was from age 28 days until fifth birthday. Linked registers captured information on potential confounders. Rate ratios and adjusted rate ratios measured relative change in the numbers of admissions and total days of stay, while rate differences measured absolute change in outcomes. Cause-specific increases were calculated for ICD-9 chapters and for 'potentially preventable' conditions. RESULTS: After adjusting for potential confounders, children of mothers with severe mental illness had a 46% relative increased rate in hospital admissions (95% confidence interval = [38%, 54%]) and an absolute increase in 0.69 extra days in hospital per child, per year (95% confidence interval = [0.67, 0.70]). The relative increase in admissions was greatest in the child's first year of life (adjusted rate ratio = 1.76, 95% confidence interval = [1.64, 1.88]; rate difference = 0.32, 95% confidence interval = [0.30, 0.34]). Rates of admissions were increased for a range of causes, particularly injuries, infections and respiratory disease, and for conditions classified as 'potentially preventable'. CONCLUSION: Children of mothers with severe mental illness have a substantial excess in hospital use compared to children of well mothers. This vulnerable group should be targeted with interventions to avert preventable morbidity and premature mortality in later life.

Effects of the COVID-19 pandemic and previous pandemics, epidemics and economic crises on mental health: systematic review.

BACKGROUND: A rise in mental illness is expected to follow the COVID-19 pandemic, which has also been projected to lead to a deep global economic recession, further adding to risk factors. AIMS: The aim of this review was to assess the impact of the COVID-19 pandemic and previous pandemics, epidemics and economic crises on mental health. METHOD: Searches were conducted in PubMed, Web of Science, PsycINFO and Sociological Abstracts. We included studies of all populations exposed to the COVID-19 pandemic, and other similar pandemics/epidemics and economic crises, compared with non-exposed time periods or regions. The outcome was mental health. RESULTS: The 174 included studies assessed mental health impacts of the COVID-19 pandemic (87 studies), 2008 economic crisis (84 studies) and severe acute respiratory syndrome (SARS) epidemic (three studies). Outcomes were divided into affective disorders, suicides, mental healthcare utilisation and other mental health. COVID-19 pandemic studies were of lesser quality than those for the economic crisis or SARS epidemic. Most studies for all exposures showed increases in affective disorders and other mental health problems. For economic crisis exposure, increases in mental healthcare utilisation and suicides were also found, but these findings were mixed for COVID-19 pandemic exposure. This is probably because of quarantine measures affecting help-seeking and shorter follow-ups of studies of COVID-19 pandemic exposure. CONCLUSIONS: Our findings highlight the importance of available, accessible and sustainable mental health services. Also, socioeconomically disadvantaged populations should be particular targets of policy interventions during the COVID-19 pandemic.

Epidemiology of posttraumatic stress disorder: A prospective cohort study based on multiple nationwide Swedish registers of 4.6 million people.

BACKGROUND: Experiencing exceptionally threatening or horrifying traumas can lead to posttraumatic stress disorder (PTSD). Increasing political unrest/war/natural disasters worldwide could cause more traumatic events and change the population burden of PTSD. Most PTSD research is based on surveys, prone to selection/recall biases with inconsistent results. The aim was therefore, to use register-based data to identify the occurrence of PTSD and contributing factors in the Swedish general population. METHODS: This register-based cohort study used survival analysis. Individuals born between 1960-1995, aged ≥15 years, registered and living in Sweden, not emigrating, anytime between 1990-2015, not receiving specialized care for PTSD before 2006 were included (N = 4,673,764), and followed from their 15th/16th birth date until first PTSD diagnosis between 2006-2016 or study endpoint (31-December-2016). PTSD cases (ICD-10: F43.1) were identified from the national patient register. Mean follow-up time was 18.8 years. RESULTS: Between 2006-2016, the incidence of specialized healthcare utilization for PTSD nearly doubled, and 0.7% of the study population received such care. The highest risk was observed for refugees [aHR 8.18; 95% CI:7.85-8.51] and for those with depressive disorder [aHR 4.51; 95% CI:3.95-5.14]. Higher PTSD risk was associated with female sex, older age, low education, single parenthood, low household income, urbanicity, and being born to a foreign-born parent. CONCLUSIONS: PTSD is more common among refugee migrants, individuals with psychiatric disorders, and the socioeconomically disadvantaged. It is important that provision of services for PTSD are made available, particularly to these higher risk, and often hard-to-reach groups.

Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study.

BACKGROUND: Maternal infections during pregnancy are associated with intellectual disability and autism in exposed children. Whether these associations are causal, and therefore should be targets of preventive strategies, remains unknown. We aimed to investigate these associations, to determine whether there is a causal role of maternal infection during pregnancy for children's risk of autism and intellectual disability, by accounting for unmeasured familial factors. METHODS: We used a register-based cohort study design, and included children living in Stockholm County, Sweden, who were born in 1987-2010. We excluded children not born in Sweden, adopted children, and children with unknown biological mothers or fathers. Maternal infections during pregnancy, defined by ICD-8, ICD-9, and ICD-10 codes, were identified in the National Patient Register and Medical Birth Register. Children were followed up from birth to an outcome or a censoring event (death, migration from Stockholm, age 18 years, or Dec 31, 2016, whichever occurred first). The primary outcomes were diagnosis of autism or diagnosis of intellectual disability. We did a survival analysis to examine the association between inpatient and outpatient specialised care for any infection during pregnancy and likelihood of autism or intellectual disability in the child. To address potential residual confounding, we also estimated the relationship between maternal infection in the year preceding pregnancy as a negative control exposure and conducted a matched sibling analysis of sibling pairs who were discordant for autism or intellectual disability. FINDINGS: 647 947 children living in Stockholm County were identified and, after excluding 97 980 children, we included 549 967 in the study (267 995 [48·7%] were female and 281 972 [51·3%] were male; mean age at censoring 13·5 years [SD 5·0; range <1 to 18]; 142 597 [25·9%] had a mother who was not born in Sweden). 445 (1·3%) of 34 013 children exposed to maternal infection during pregnancy were diagnosed with intellectual disability and 1123 (3·3%) with autism. 5087 (1·0%) of 515 954 unexposed children were diagnosed with intellectual disability and 13 035 (2·5%) with autism. Maternal infection during pregnancy was associated with autism (hazard ratio [HR] 1·16, 95% CI 1·09-1·23) and intellectual disability (1·37, 1·23-1·51) in exposed children compared with unexposed children. Maternal infection in the year before pregnancy (negative control exposure) was also associated with autism (HR 1·25, 95% CI 1·14-1·36), but was not associated with intellectual disability (1·09, 0·94-1·27). In sibling comparisons, the associations with maternal infection during pregnancy were attenuated for autism (HR 0·94, 95% CI 0·82-1·08; n=21 864), but not to the same extent for intellectual disability (1·15, 0·95-1·40; n=9275). INTERPRETATION: Although infections in pregnant women are associated with both autism and intellectual disability in their children, the association with autism does not appear to reflect a causal relationship, but is more likely to be explained by factors shared between family members such as genetic variation or aspects of the shared environment. Thus, infection prevention is not expected to reduce autism incidence. For intellectual disability, unmeasured familial factors might not fully explain the observed associations, and a causal role of maternal infections cannot be excluded. Causal effects of specific but rare infections or infections not requiring health care contact cannot be excluded in either autism or intellectual disability. FUNDING: Swedish Research Council, Stanley Medical Research Institute, and Autism Speaks. TRANSLATION: For the Swedish translation of the abstract see Supplementary Materials section.