Background: Sibling-matched designs control for shared familial confounding but remain vulnerable to non-shared confounders. Bi-directional sensitivity analyses, which stratify families by whether the older or younger sibling was exposed, are commonly used to assess carryover effects. We aimed to demonstrate how this methodological approach can introduce severe confounding by parity. Methods: We conducted simulations motivated by a recent epidemiological study. The true causal effect of a hypothetical exposure (prenatal acetaminophen) on neurodevelopmental outcomes was set to strictly null. To introduce parity-related confounding, baseline exposure and outcome probabilities were varied slightly by birth order. We compared conditional logistic regression effect estimates from total sibling models against bi-directional stratified models. Results: In the total simulated sibling cohort, models yielded the true null effect (odds ratio = 1.00) when adjusting for parity. However, the bi-directional analyses exhibited divergent artifactual signals. Because parity is perfectly collinear with exposure in these stratified subsets, it cannot be adjusted for. For example, when the older sibling was exposed, the odds ratio for autism spectrum disorder was 1.68; when the younger was exposed, the odds ratio was 0.60. Conclusions: Divergent estimates in bi-directional sibling analyses can be a predictable artifact of parity confounding rather than evidence of carryover effects or invalidating unmeasured bias. Overall sibling models adjusting for parity may remain robust despite divergent stratified sensitivity results. ### Competing Interest Statement Disclosures BKL reports speaking fees from Gerson Lehrman Group; consulting fees from AlphaSights; ser-vice as an academic council member for Cura AI; and work as an expert reviewer for SciPinion, all outside the submitted work. VHA reports speaking fees from Angelini Pharma, outside the submitted work. ### Funding Statement Funding VHA is funded by Swedish Society for Medical Research (PG-24-0427) BKL is funded by NIH 1OT2OD040415. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the Supplement.

BACKGROUND:Suicide is more common among males and in older age, but the understanding of sex-specific and age-specific risk indicators is limited. OBJECTIVE:To describe the sex-specific and age-specific prevalence of 25 suicide risk indicators in the year preceding suicide and estimate their associations with suicide. METHODS:Register-based population-nested case-control study in Sweden, 2009-2021, comprising 19 741 suicide cases and 197 296 general population controls matched by sex, age and county of residence. Death by suicide was collected from the cause of death register. 25 suicide risk indicators covering psychiatric history, somatic disorders, bereavement and sociodemographic factors in the previous year were collected from nationwide registers. Sex-specific and age-specific ORs of suicide for the presence/absence of each risk indicator in the prior year were estimated and complemented by risk differences. FINDINGS:Suicide cases were 70% male, 9% were aged 15-24 years, 29% 25-44 years, 36% 45-64 years and 26% 65+ years. In the year preceding suicide, the prevalence of most risk indicators was the lowest among males and people aged 65+ years. Most risk indicators also showed weaker 1-year associations with suicide in these groups. The median OR (IQR) of suicide across the 25 risk indicators was 14.6 (5.2, 29.1) in females versus 10.3 (4.3, 21.3) in males, and 17.4 (6.5, 28.9) in 24-44 year-olds versus 8.0 (3.6, 23.7) in people aged 65+years. Risk differences of suicide were larger in males across nearly all risk indicators. CONCLUSIONS:There was considerable heterogeneity across sex and age groups, both in the prevalence of risk indicators preceding suicide and in their associations with suicide. Risk indicators were generally less common and displayed weaker associations with suicide on the relative risk scale among males and older people. CLINICAL IMPLICATIONS:Suicides in males and older people may be harder to predict, as indicators are rarer. When males present with risk indicators, they generally have a higher absolute risk of suicide, making them important targets for prevention even when risk indicators do not cause suicide. Our findings underscore the importance of considering sex-specific and age-specific risk indicators for individualised suicide prediction and prevention.

( JAMA . 2024;331(14):1205–1214. doi:10.1001/jama.2024.3172) The potential link between acetaminophen (paracetamol) use during pregnancy and increased risks of neurodevelopmental disorders in children, such as autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability, has been a major subject of concern. Confounding bias may play a role in existing findings. If such a link were found, it could significantly impact how fever and pain are managed during pregnancy.

Levels of neonatal Acute Phase Proteins (APPs) have been associated with autism and schizophrenia. The relative contributions of genetic and environmental factors to variation in APP levels in the neonatal period are not known. Therefore, we used one of the largest twin samples to date to map the proportions of heritable and non-heritable factors to variations in APPs measured shortly after birth. Moreover, we investigated if any association existed between neonatal APP levels and autism, among monozygotic and dizygotic twins discordant for autism. Twins were identified and enrolled from registers and a clinical twin study of autism in Sweden. The distributions of APPs measured in dried blood spots taken a few days after birth as part of a national screening program were standardized to reduce any analytical artifacts. The additive genetic (A), common (C) and unique (E) environment components were estimated, using the ACE model, on a sample of 92 twin pairs. We included 61 autism discordant twin pairs for estimating the association between the APPs and autism, using both non-fixed (between) and fixed (within) effects regression models. For the ACE models, variations in α-2 macroglobulin, C-reactive protein, ferritin, fibrinogen, haptoglobin, serum amyloid A and serum amyloid P were all largely explained by additive genetic factors (70-90 %). Variation in tissue plasminogen activator and procalcitonin were predominantly explained by common environmental factors (60-70 %) with a negligible contribution by genetic factors. Variations in levels of tissue plasminogen activator and procalcitonin in the neonatal period appear to be mainly explained by pregnancy and birth related factors. Variations in levels of other investigated acute phase proteins were largely explained by additive genetic factors. None of the APPs exhibited any significant association with autism in discordant mono- or dizygotic twin pairs. Our findings highlight the importance of considering potential familial confounding in future studies of association between any APP and autism.

Background Psychiatric comorbidities are common in patients with epilepsy. Reasons for the co-occurrence of psychiatric conditions and epilepsy remain poorly understood.Aim We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these conditions.Methods Using nationwide Swedish health registries, we quantified the lifetime prevalence of psychiatric disorders in patients with epilepsy. We then used summary data from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score regression. Finally, we assessed the potential bidirectional relationships using two-sample Mendelian randomisation.Results In a cohort of 7 628 495 individuals, we found that almost half of the 94 435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime (adjusted lifetime prevalence, 44.09%; 95% confidence interval (CI) 43.78% to 44.39%). We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric conditions. For example, we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder (rg=0.18, 95% CI 0.09 to 0.27, p<0.001)—a correlation that was more pronounced in focal epilepsy (rg=0.23, 95% CI 0.09 to 0.36, p<0.001). Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric conditions.Conclusions Psychiatric comorbidities are common in patients with epilepsy. Genetic correlations may partially explain some comorbidities; however, there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric conditions. These findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psychiatric comorbidities in epilepsy.

BackgroundIntrahepatic 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 findingsIn 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.ConclusionsIn 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.

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.

The maternal immune activation hypothesis has gained attention over the past two decades as a potential contributor to the etiology of autism. This hypothesis posits that maternal conditions associated with inflammation during pregnancy may increase the risk of autism in offspring. Autism is highly heritable, and causal environmental contributors to autism largely remain elusive. We review studies on maternal conditions during pregnancy, all associated with some degree of systemic inflammation; namely, maternal infections, autoimmunity, and high BMI. We additionally review studies of inflammatory markers in biological samples collected from the mother during pregnancy or from the neonate and their relationship with autism assessed in children later in life. Recent reports indicate familial clustering of autism, autoimmunity and infections, as well as genetic correlations between autism and aspects of immune function. In light of this literature, there is an apparent risk of confounding of the reported associations between inflammatory exposures and autism by familial genetic factors in both clinical and epidemiological cohort studies. We highlight recent studies that have attempted to address potential confounding to assess evidence of causal effects of inflammation during early life in autism.

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.

BackgroundGestational 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]).MethodsA 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).ResultsFive 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.ConclusionsPersistent 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.

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 (HR adjusted = 1.55, 1.13–2.13) and ID (HR adjusted = 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.

Background Maternal pre-gestational diabetes (PGDM), gestational diabetes mellitus (GDM), and overweight/obesity have been associated with increased risks of offspring neurodevelopmental conditions (NDCs) including autism, intellectual disability (ID), and attention deficit/hyperactivity disorder (ADHD). Less is known about whether and how obstetric and neonatal complications (e.g., preterm birth, neonatal asphyxia) could mediate these associations. Methods In this Swedish register-based cohort study, we examined complications during pregnancy, delivery, and the neonatal period as potential mediators of the relationships between maternal metabolic conditions and offspring NDCs. We quantified the extent to which these obstetric and neonatal factors could mediate the associations of maternal metabolic conditions with offspring NDCs by applying parametric regression models for single mediation analyses and weighting-based methods for multiple mediation analyses under counterfactual frameworks. Results The study sample included 2,352,969 singleton children born to 1,299,692 mothers from 1987–2010 who were followed up until December 31, 2016, of whom 135,832 children (5.8%) were diagnosed with at least one NDC. A substantial portion of the association between maternal PGDM and children’s odds of NDCs could be explained by the combined group of obstetric and neonatal complications in the multiple mediation analysis. For instance, these complications explained 44.4% of the relationship between maternal PGDM and offspring ID risk. The proportion of the relationship between maternal overweight/obesity and children’s risk of NDCs that could be explained by obstetric and neonatal complications was considerably smaller, ranging from 1.5 to 8.1%. Some complications considered on their own, including pregnancy hypertensive diseases, preterm birth, neonatal asphyxia, and hematological comorbidities, could explain at least 10% of the associations between maternal PGDM and offspring NDCs. Complications during the neonatal period showed a stronger joint mediating effect for the relationship between PGDM and offspring NDCs than those during pregnancy or delivery. Conclusions Obstetric and neonatal complications could explain nearly half of the association between maternal PGDM and offspring risk of NDCs. The mediating effects were more pronounced for complications during the neonatal period and for specific complications such as pregnancy hypertensive diseases, preterm birth, neonatal asphyxia, and hematological comorbidities. Effective preventive strategies for offspring NDCs should holistically address both the primary metabolic issues related to PGDM and the wide array of potential complications, especially those in the neonatal period. Graphical Abstract

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 center dot 7%] were female and 281 972 [51 center dot 3%] were male; mean age at censoring 13 center dot 5 years [SD 5 center dot 0; range <1 to 18]; 142 597 [25 center dot 9%] had a mother who was not born in Sweden). 445 (1 center dot 3%) of 34 013 children exposed to maternal infection during pregnancy were diagnosed with intellectual disability and 1123 (3 center dot 3%) with autism. 5087 (1 center dot 0%) of 515 954 unexposed children were diagnosed with intellectual disability and 13 035 (2 center dot 5%) with autism. Maternal infection during pregnancy was associated with autism (hazard ratio [HR] 1 center dot 16, 95% CI 1 center dot 09-1 center dot 23) and intellectual disability (1 center dot 37, 1 center dot 23-1 center dot 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 center dot 25, 95% CI 1 center dot 14-1 center dot 36), but was not associated with intellectual disability (1 center dot 09, 0 center dot 94-1 center dot 27). In sibling comparisons, the associations with maternal infection during pregnancy were attenuated for autism (HR 0 center dot 94, 95% CI 0 center dot 82-1 center dot 08; n=21 864), but not to the same extent for intellectual disability (1 center dot 15, 0 center dot 95-1 center dot 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.

Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.

ABSTRACT Emerging evidence implicates the role of inflammation and immunity in autism. However, little is known about the involvement of specific immunological pathways and their causal role. In 18,381 autism cases and 27,969 controls from the PGC and the iPSYCH consortia, we investigated whether 15 cytokines implicated in the differentiation and function of CD4 + T cell subsets (T H 1, T H 2, T H 9, T FH , T H 17, T Reg ) could be causally linked to autism. Within a Mendelian randomization framework, we used protein quantitative trait loci (pQTLs; N=1,000-3,394) to assess the effects of genetically proxied levels of plasma cytokines on autism. We additionally used brain cortex expression quantitative trait loci (eQTLs; N= 6,601) to investigate whether genetically predicted expression of the genes encoding the cytokines of interest influence autism. We performed colocalisation to assess the possibility that the identified effects were confounded due to Linkage Disequilibrium (LD). We also assessed the possibility of reverse causation. We report consistent evidence for causal effects of genetically predicted levels of IFN-γR1, IL-12Rβ1 (T H 1), and IL-4RA, IL-5RA, IL-13RA1 (T H 2) on autism. We identified brain-specific effects of genetically predicted expression of IFNGR1, IL12RB1, IL23A , which in the case of IFNGR1 and IL23A were additionally supported by evidence suggestive of colocalisation. Findings appeared unlikely to be influenced by reverse causation. Our findings are consistent with a potentially causal effect of T H 1 and T H 2 pathway cytokines in autism, and further research is required to elucidate the pathways via which T H 1 and T H 2 influence its phenotypic presentation.

ABSTRACTImportanceEvidence linking parental diagnoses of inflammatory bowel disease (IBD) with offspring autism is inconclusive.ObjectiveTo investigate associations between parental diagnoses of IBD and offspring autism and elucidate their underlying aetiology by conducting four complementary studies.Design, Setting and Participants(1) Nationwide population-based cohort study using Swedish registers to examine associations between parental IBD diagnoses and autism diagnoses in offspring, (2) Linkage disequilibrium (LD)-score regression to estimate the genetic correlation between the phenotypes. (3) Polygenic risk score (PRS) analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate associations between maternal genetic liability to IBD and autism factor mean score in offspring. (4) Two-sample Mendelian randomization (MR) to assess bidirectional causal links between genetic liability to IBD and autism.ResultsObservational analyses provided evidence of an association between parental IBD diagnoses and offspring autism diagnosis in mutually adjusted models (maternal: OR= 1.32; 95% CI: 1.25 to 1.40; p<0.001; paternal: OR= 1.09; 95% CI: 1.02 to 1.17; p=0.012; n=2 324 227, 52.3% male). PRS analyses in ALSPAC indicated associations between maternal PRS for IBD subtypes and a measure of broad autism phenotype, autism factor mean score, in the offspring (UC: βPRS= 0.02; 95%CI: 0.003 to 0.05; p= 0.02; R2=0.06; Crohn’s: βPRS= 0.03; 95%CI: 0.01 to 0.05; p= 0.004; R2= 0.06; n= 7357, 50.3% male). MR analyses provided evidence of a potential causal effect of genetic liability for IBD, especially ulcerative colitis, on autism (ORMR= 1.03; 95%CI: 1.01 to 1.06). There was little evidence to suggest a causal effect of genetic liability to autism on risk of IBD, or a genetic correlation between the two conditions.Conclusions and relevanceTriangulating evidence from a nationwide register-based cohort study, genetic correlation, polygenic risk score analyses and MR, we found evidence of a potentially causal link between parental, particularly maternal, diagnoses and genetic liability to IBD and offspring autism. Perinatal immune system dysregulation, micronutrient malabsorption and anaemia may be implicated.

Objective Individuals diagnosed with autism spectrum disorders (ASD) are reported to have higher levels of antibodies directed towards gliadin, a component of wheat gluten. However, no study has examined such antibodies in etiologically-relevant periods before diagnosis. The objective of this study is to investigate if maternal levels of immunoglobulin G antibodies directed at gliadin, during pregnancy and at the time of birth, are associated with ASD in offspring. Methods In this population-based study set in Sweden with 921 ASD cases and 1090 controls, we analyzed levels of anti-gliadin antibodies (AGA) in archived neonatal dried blood spots (NDBS, as maternal IgG is transferred to the fetus) and in paired maternal sera collected earlier in pregnancy for a subset of 547 cases and 428 controls. We examined associations to any ASD diagnosis and considering common comorbidities (i.e. intellectual disability [ID] and attention-deficit/hyperactivity disorder [ADHD]). We compared 206 ASD cases to their unaffected siblings to examine the potential for confounding by shared familial factors. Results High levels (≥90th percentile) of maternal AGA were associated with decreased odds of ASD, particularly ASD with comorbid ID, when measured in NDBS (OR 0.51, 95% CI 0.30–0.87) with a similar trend in maternal sera (0.55, 0.24-1.29). High levels of maternal AGA were similarly associated with lower odds of ASD with ID in the sibling comparison. Conclusions This first study of exposure to AGA in the pre- and perinatal periods suggests that high levels of maternal AGA are associated with lower odds of ASD with ID.