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Key Points: Question: Does acetaminophen use during pregnancy increase children's risk of neurodevelopmental disorders? Findings: In this population-based study, models without sibling controls identified marginally increased risks of autism and attention-deficit/hyperactivity disorder (ADHD) associated with acetaminophen use during pregnancy. However, analyses of matched full sibling pairs found no evidence of increased risk of autism (hazard ratio, 0.98), ADHD (hazard ratio, 0.98), or intellectual disability (hazard ratio, 1.01) associated with acetaminophen use. Meaning: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analyses. This suggests that associations observed in other models may have been attributable to confounding. 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. This nationwide cohort study with sibling control analysis examines the association of acetaminophen use during pregnancy with children's risk of autism, ADHD, and intellectual disability. [ABSTRACT FROM AUTHOR]

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. In this Swedish register-based cohort study, Shuyun Chen, Viktor H. Ahlqvist and colleagues assess the association between maternal intrahepatic cholestasis of pregnancy and neurodevelopmental disorders in children exposed during gestation. Author summary: Why was this study done?: Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder during pregnancy characterized by rising bile acid levels, and it is associated with early delivery and adverse infant outcomes. Less is known about the long-term outcomes of children exposed to ICP. Because ICP may plausibly affect the development of the fetus either directly or via its association with adverse pregnancy outcomes, this study examined the hypothesis that ICP would be associated with an increased likelihood of neurodevelopmental conditions in children exposed during gestation. What did the researchers do and find?: The study analyzed data from the Swedish registers including children born between 1987 and 2010, with follow-up for neurodevelopmental outcomes until the end of 2016. The study recorded cases of mothers diagnosed with ICP and documented the timing of these diagnoses during pregnancy using patient registries. Associations between these diagnoses and neurodevelopmental conditions, including attention deficit/hyperactivity disorder (ADHD), autism, or intellectual disability in children, were estimated using multiple analytical approaches. The results suggested that children exposed to ICP during pregnancy were more likely to receive diagnoses of neurodevelopmental conditions, particularly when ICP was diagnosed early in pregnancy (before 28 weeks of gestation). Because the associations were similar when children were compared to their maternal cousins and to their siblings, these findings do not appear to be explained by factors shared within families, such as genetics and some aspects of the early life environment, that can also influence the likelihood of neurodevelopmental conditions. What do these findings mean?: Diagnosis of ICP during pregnancy, especially early in pregnancy, is associated with an increased likelihood of neurodevelopmental disorders in the children exposed during gestation. Because this study is observational, it is not possible to determine whether ICP is a causative factor in the development of neurodevelopmental conditions in children born to affected mothers. This study did not include information on bile acid concentrations among the pregnant women, and this study was conducted before treatment (using ursodeoxycholic acid) was widely used in Sweden. It will be important for future studies to consider if therapeutic modulation of bile acid levels in pregnant women affected by ICP can mitigate the associations we observe. [ABSTRACT FROM AUTHOR]

Prenatal exposure to tobacco smoke is suggested as a potential risk factor for autism spectrum disorders (ASD). Previous epidemiological studies of this topic have yielded mixed findings. We performed a case-control study of 3,958 ASD cases and 38,983 controls nested in a large register-based cohort in Sweden. ASD case status was measured using a multisource case ascertainment system. In adjusted results, we found that maternal smoking during pregnancy is not associated with increased risk of ASD regardless of presence or absence of comorbid intellectual disability. Apparent associations were attributable to confounding by sociodemographic characteristics of parents such as education, income, and occupation.

Importance: Given the critical role that iron plays in neurodevelopment, an association between prenatal iron deficiency and later risk of neurodevelopmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), is plausible.Objective: To test the a priori hypothesis that anemia diagnosed in mothers during pregnancy is associated with an increased risk of ASD, ADHD, and ID in offspring and that the magnitude of the risk varies with regard to the timing of anemia in pregnancy.Design, Setting, and Participants: This cohort study used health and population register data from the Stockholm Youth Cohort to evaluate 532 232 nonadoptive children born from January 1, 1987, to December 31, 2010, in Sweden, with follow-up in health registers until December 31, 2016. Data analysis was performed from January 15, 2018, to June 20, 2018.Exposures: Registered diagnoses of anemia during pregnancy. Gestational timing of the first recorded anemia diagnosis (≤30 weeks or >30 weeks) was considered to assess potential critical windows of development.Main Outcomes and Measures: Registered diagnoses of ASD, ADHD, or ID or co-occurring combinations of these disorders.Results: The cohort included 532 232 individuals (272 884 [51.3%] male) between 6 and 29 years of age at the end of follow-up (mean [SD] age, 17.6 [7.1] years) and their 299 768 mothers. The prevalence of ASD, ADHD, and ID was higher among children born to mothers diagnosed with anemia within the first 30 weeks of pregnancy (4.9% ASD, 9.3% ADHD, and 3.1% ID) compared with mothers with anemia diagnosed later in pregnancy (3.8% ASD, 7.2% ADHD, and 1.1% ID) or mothers not diagnosed with anemia (3.5% ASD, 7.1% ADHD, and 1.3% ID). Anemia diagnosed during the first 30 weeks of pregnancy but not later was associated with increased risk of diagnosis of ASD (odds ratio [OR], 1.44; 95% CI, 1.13-1.84), ADHD (OR, 1.37; 95% CI, 1.14-1.64), and ID (OR, 2.20; 95% CI, 1.61-3.01) in offspring in models that included socioeconomic, maternal, and pregnancy-related factors. Early anemia diagnosis was similarly associated with risk of ASD (OR, 2.25; 95% CI, 1.24-4.11) and ID (OR, 2.59; 95% CI, 1.08-6.22) in a matched sibling comparison. Considering mutually exclusive diagnostic groups, we observed the strongest association between anemia and ID without co-occurring ASD (OR, 2.72; 95% CI, 1.84-4.01). Associations of these disorders with anemia diagnosed later in pregnancy were greatly diminished.Conclusions and Relevance: In contrast to maternal anemia diagnosed toward the end of pregnancy, anemia diagnosed earlier in pregnancy was associated with increased risk of the development of ASD, ADHD, and particularly ID in offspring. Given that iron deficiency and anemia are common among women of childbearing age, our findings emphasize the importance of early screening for iron status and nutritional counseling in antenatal care. [ABSTRACT FROM AUTHOR]

Season of birth has been hypothesized to be a risk factor for autism spectrum disorder (ASD). However, the evidence has been mixed and limited due to methodological challenges. We examine ASD birth trends for 5,464,628 births across 5 countries. ASD birth prevalence data were obtained from the International Collaboration for Autism Registry Epidemiology database, including children born in Denmark, Finland, Norway, Sweden, and Western Australia. Empirical mode decomposition and cosinor modeling were used to assess seasonality. We show seasonal variation in ASD births for the countries of Finland and Sweden. There was a modest increase in risk for children born in the fall and a modest decrease in risk for children born in the spring. Solar radiation levels around conception and the postnatal period were inversely correlated with seasonal trends in ASD risk. In the first multinational study of birth seasonality of ASD, there was evidence supporting the presence of seasonal trends in Finland and Sweden. The observations that risk was highest for fall births (i.e., conceived in the winter) and lowest for spring births (i.e., conceived in the summer), and sunlight levels during critical neurodevelopmental periods explained much of the seasonal trends, are consistent with the hypothesis that a seasonally fluctuating risk factor may influence risk of ASD. [ABSTRACT FROM AUTHOR]

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

Aim: This study examined maternal and pregnancy risk factors for haemolytic and nonhaemolytic neonatal jaundice in a large population-based cohort study.Methods: We conducted a cohort study of 1 019 220 singleton live births from the Swedish medical birth register from 1987 to 2002, using information on neonatal jaundice and maternal and pregnancy characteristics. Diagnoses of gestational hypertensive disorders were obtained by linkage to the national inpatient register. Multivariate logistic regression analysis provided odds ratios for the risk factors of both forms of jaundice.Results: A total of 6057 (0.6%) births were affected by haemolytic jaundice and 36 869 (3.6%) by nonhaemolytic jaundice. The strongest risk factors for haemolytic jaundice were maternal alloimmunisation, blood group O and neonatal jaundice in older siblings. For nonhaemolytic jaundice, the strongest risk factors were preterm birth, neonatal jaundice in older siblings, maternal origin from East or South-East Asia and maternal obesity. We estimated that 13% of haemolytic jaundice was attributable to alloimmunisation and 39% of nonhaemolytic jaundice was attributable to preterm birth.Conclusion: Haemolytic and nonhaemolytic neonatal jaundice had different risk factor profiles. Interventions to reduce maternal alloimmunisation, preterm birth and maternal obesity may lower the prevalence of neonatal jaundice and the risk of consequent neurological complications. [ABSTRACT FROM AUTHOR]

Importance: Depression is a common cause of morbidity and disability worldwide. Parental depression is associated with early-life child neurodevelopmental, behavioral, emotional, mental, and social problems. More studies are needed to explore the link between parental depression and long-term child outcomes.Objective: To examine the associations of parental depression with child school performance at the end of compulsory education (approximately age 16 years).Design, Setting, and Participants: Parental depression diagnoses (based on the International Classification of Diseases, Eighth Revision [ICD-8], International Classification of Diseases, Ninth Revision [ICD-9], and the International Statistical Classification of Diseases, 10th Revision [ICD-10]) in inpatient records from 1969 onward, outpatient records beginning in 2001, and school grades at the end of compulsory education were collected for all children born from 1984 to 1994 in Sweden. The final analytic sample size was 1,124,162 biological children. We examined the associations of parental depression during different periods (before birth, after birth, and during child ages 1-5, 6-10, and 11-16 years, as well as any time before the child's final year of compulsory schooling) with the final school grades. Linear regression models adjusted for various child and parent characteristics. The dates of the analysis were January to November 2015.Main Outcome and Measure: Decile of school grades at the end of compulsory education (range, 1-10, with 1 being the lowest and 10 being the highest).Results: The study cohort comprised 1,124,162 children, of whom 48.9% were female. Maternal depression and paternal depression at any time before the final compulsory school year were associated with worse school performance. After covariate adjustment, these associations decreased to -0.45 (95% CI, -0.48 to -0.42) and -0.40 (-0.43 to -0.37) lower deciles, respectively. These effect sizes are similarly as large as the observed difference in school performance between the lowest and highest quintiles of family income but approximately one-third of the observed difference between maternal education of 9 or less vs more than 12 years. Both maternal depression and paternal depression at different periods (before birth, after birth, and during child ages 1-5, 6-10, and 11-16 years) generally were associated with worse school performance. Child sex modified the associations of maternal depression with school performance such that maternal depression had a larger negative influence on child school performance for girls compared with boys.Conclusions and Relevance: Diagnoses of parental depression throughout a child's life were associated with worse school performance at age 16 years. Our results suggest that diagnoses of parental depression may have a far-reaching effect on an important aspect of child development, with implications for future life course outcomes. [ABSTRACT FROM AUTHOR]

A growing body of literature suggests that exposure to infections, particularly maternal infections, during pregnancy confers risk for later development of psychotic disorder. Though brain development proceeds throughout childhood and adolescence, the influence of infections during these ages on subsequent psychosis risk is insufficiently examined. The aim of this study was to investigate the potential association between infections during childhood and nonaffective psychoses in a large population-based birth cohort with follow up long enough to include peak incidence of nonaffective psychosis. We included all individuals born in Sweden between 1973 and 1985, (N = 1172879), with follow up on first time inpatient care with nonaffective psychosis from age 14 years until 2006, (N = 4638). Following adjustment for differences in sex, socioeconomic status, family history of psychosis, and hospital admissions involving noninfectious, nonpsychiatric care, we observed a small but statistically significant association between hospital admissions for infections, in general, throughout childhood (0–13 years) and a later diagnosis of nonaffective psychosis, hazard ratio (HR) = 1.10 (95% CI 1.03–1.18), and this association seemed to be driven by bacterial infection, HR = 1.23 (95% CI 1.08–1.40). Bacterial infections and central nervous system infections during preadolescence (10–13 years) conferred the strongest risk, HR 1.57 (95% CI 1.21–2.05) and HR 1.96 (95% CI 1.05–3.62), respectively. Although preadolescence appeared to be a vulnerable age period, and bacterial infection the most severe in relation to psychosis development, the present findings can also indicate an increased susceptibility to hospital admission for infections among children who will later develop nonaffective psychosis due to social or familial/genetic factors. [ABSTRACT FROM PUBLISHER]

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 Sweden's registers, constitutes an important resource for ASD research. On-going work, including collection of biological samples, will enrich the study further. [ABSTRACT FROM AUTHOR]

Background: Although screening for maternal red blood cell antibodies during pregnancy is a standard procedure, the prevalence and clinical consequences of non-anti-D immunization are poorly understood. The objective was to create a national database of maternal antibody screening results that can be linked with population health registers to create a research resource for investigating these issues. Study Design and Methods: Each birth in the Swedish Medical Birth Register was uniquely identified and linked to the text stored in routine maternal antibody screening records in the time window from 9 months prior to 2 weeks after the delivery date. These text records were subjected to a computerized search for specific antibodies using regular expressions. To illustrate the research potential of the resulting database, selected antibody prevalence rates are presented as tables and figures, and the complete data (from more than 60 specific antibodies) presented as online moving graphical displays. Results: More than one million (1,191,761) births with valid screening information from 1982-2002 constitute the study population. Computerized coverage of screening increased steadily over time and varied by region as electronic records were adopted. To ensure data quality, we restricted analysis to birth records in areas and years with a sustained coverage of at least 80%, representing 920,903 births from 572,626 mothers in 17 of the 24 counties in Sweden. During the study period, non-anti-D and anti-D antibodies occurred in 76.8/10,000 and 14.1/10,000 pregnancies respectively, with marked differences between specific antibodies over time. Conclusion: This work demonstrates the feasibility of creating a nationally representative research database from the routine maternal antibody screening records from an extended calendar period. By linkage with population registers of maternal and child health, such data are a valuable resource for addressing important clinical questions, such as the etiological significance of non-anti-D antibodies. [ABSTRACT FROM AUTHOR]

Background: Possible negative effects, including increased mortality, among persons who receive stored red blood cells (RBCs) have recently garnered considerable attention. Despite many studies, including 4 randomized trials, no consensus exists.Objective: To study the association between the length of RBC storage and mortality in a large population-based cohort of patients who received transfusions, allowing detection of small yet clinically significant effects.Design: Binational cohort study.Setting: All transfusion recipients in Sweden and Denmark.Patients: 854 862 adult patients who received transfusions from 2003 to 2012.Measurements: Patients were followed from first blood transfusion. Relative and absolute risks for death in 30 days or 1 year in relation to length of RBC storage were assessed by using 3 independent analytic approaches. All analyses were conducted by using Cox proportional hazards regression.Results: Regardless of the analytic approach, no association was found between the length of RBC storage and mortality. The difference in 30-day cumulative mortality between patients receiving blood stored for 30 to 42 days and those receiving blood stored for 10 to 19 days was -0.2% (95% CI, -0.5% to 0.1%). Even among patients who received more than 6 units of RBCs stored for 30 days or longer, the hazard ratio of death was 1.00 (CI, 0.96 to 1.05) compared with those who received no such units.Limitation: Observational study; risk of confounding by indication.Conclusion: Consistent with previous randomized trials, this study found no association between the length of storage of transfused RBCs and patient mortality. Results were homogeneous, with differences in absolute mortality consistently less than 1% among the most extreme exposure categories. These findings suggest that the current practice of storing RBCs for up to 42 days does not need to be changed.Primary Funding Source: The Swedish Research Council, Swedish Heart-Lung Foundation, Swedish Society for Medical Research, Strategic Research Program in Epidemiology at Karolinska Institutet, and Danish Council for Independent Research. [ABSTRACT FROM AUTHOR]

The article presents a population based case-control study of the offspring at a risk of autism spectrum disorder, particularly autism without intellectual disability whose mothers used antidepressants during pregnancy. Conditional logistic regression analysis displaying the relation between maternal depression, antidepressant use during pregnancy, and autism spectrum disorder in offspring (with and without intellectual disability) is also presented.

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Animal studies indicate that early life vitamin D is crucial for proper neurodevelopment. Few studies have examined whether maternal and neonatal vitamin D concentrations influence risk of autism spectrum disorders (ASD). Participants were sampled from the Stockholm Youth Cohort, a register-based cohort in Sweden. Concentrations of total 25-hydroxyvitamin D (25OHD) were assessed from maternal and neonatal biosamples using a highly sensitive liquid chromatography tandem mass spectrometry method. The maternal sample consisted of 449 ASD cases and 574 controls, the neonatal sample: 1399 ASD cases and 1607 controls; and the paired maternal-neonatal sample: 340 ASD cases and 426 controls. Maternal 25OHD was not associated with child ASD in the overall sample. However, in Nordic-born mothers, maternal 25OHD insufficiency (25 - <50 nmol/L) at ~11 weeks gestation was associated with 1.58 times higher odds of ASD (95% CI: 1.00, 2.49) as compared with 25OHD sufficiency (≥50 nmol/L). Neonatal 25OHD < 25 nmol/L was associated with 1.33 times higher odds of ASD (95% CI: 1.02, 1.75) as compared with 25OHD ≥ 50 nmol/L. Sibling-matched control analyses indicated these associations were not likely due to familial confounding. Children with both maternal 25OHD and neonatal 25OHD below the median had 1.75 (95% CI: 1.08, 2.86) times the odds of ASD compared with children with maternal and neonatal 25OHD both below the median. Our results are consistent with an increasing body of evidence suggesting that vitamin D concentrations in early life may be associated with increased risk of neurodevelopmental disorders including ASD.

Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well understood. In this population-based cohort study, we examined the familial risk and heritability of ASD with and without co-occurring intellectual disability (ID). We estimated odds ratios and heritability of ASD with ID (ASD+ID) and ASD without ID (ASD-ID) using register-based diagnosis data of 567,436 index persons born in 1984-2009 in Stockholm County, Sweden, and their parents, siblings, cousins, aunts, and uncles. The familial risk profile exhibited differences between ASD-ID and ASD+ID, most notably for index persons with affected parents. For example, for an index person who had at least one parent with ASD, the child's odds of ASD-ID and ASD+ID (95% confidence interval (CI)) increased by 16.2 (14.2-18.6) and 7.4 (5.5-10.0) folds, respectively. The more closely related a family member with ASD was, the greater the observed risk was of ASD in the index person, especially for ASD-ID. The broad-sense heritability (95% CI) for ASD - ID and ASD+ID were 64.6% (46.0-100.0%) and 33.4% (14.4-58.4%), respectively. Familial risk and heritability of ASD may vary by intellectual ability, which implies that risk factors between these ASD phenotypes may differ. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies. LAY SUMMARY: Autism spectrum disorder (ASD) is highly heritable, yet how its familial risk and heritability may vary by cognitive ability is not well-understood. In a population-based cohort study on families of 567,436 index persons using Swedish registers data, we found that the familial risk profile differed between ASD with and without intellectual disability. Our findings from the heritability analysis and familial risk analysis suggest that ASD-ID may have a greater genetic basis than ASD+ID, although this should be verified in future studies., (© 2020 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

Objective: Original case descriptions of autism noted that parents of the affected children tended to be highly educated and intelligent, a characterization that has endured publicly. Recent genetic studies indicate that risk for autism spectrum disorders (ASD) is associated with high intelligence. We examined the association between paternal intelligence and ASD, considering co-occurring intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD)., Method: We used a register-based cohort study design including 360,151 individuals with fathers conscripted to the Swedish military, resident in Stockholm, Sweden, born from 1984 to 2008, and followed until December 31, 2011, for diagnosis of ASD, ADHD, and/or ID. Risk of neurodevelopmental disorders relative to paternal IQ (rated on a 9-point scale) was assessed using a score of 5 (average intelligence) as the referent in models accounting for potentially nonlinear relationships and clustering of siblings., Results: We observed an association between high paternal IQ and offspring risk of ASD without ID/ADHD in models adjusted for individual and family characteristics (OR IQ=9 1.32, 95% CI 1.15-1.52), an association that appeared to be driven largely by the fathers' score on the technical comprehension portion of the test (OR Technical IQ = 9 1.53, 95% CI 1.31-1.78). Conversely, low paternal IQ was associated with ASD+ID (OR IQ = 1 1.78, 95% CI 1.27-2.49) and ASD+ADHD (OR IQ = 1 1.40, 95% CI 1.16-1.70); low paternal IQ was strongly associated with ID (OR IQ = 1 4.46, 95% CI 3.62-5.49) and present also for ADHD (OR IQ = 1 1.56, 95% CI 1.42-1.72)] without co-occurring ASD or ID., Conclusion: The relationship between paternal IQ and offspring risk of ASD was nonmonotonic and varied by the presence of co-occurring disorders, probably reflecting phenotypic diversity among affected individuals., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Familial aggregation of mental and neurological disorders is often observed in autism spectrum disorders (ASD), but reports have generally focused on single disorders and are limited to first-degree relatives., Objectives: To examine family history of mental and neurological disorders among first- to fourth-degree relatives and risk of ASD with and without intellectual disability (ID) in index persons., Design, Setting, and Participants: In this population-based cohort study, 567 436 index persons were identified from the Stockholm Youth Cohort, an ongoing longitudinal register-linkage cohort study of the total population aged 0 to 17 years residing in Stockholm County, Sweden. Index persons were nonadopted singleton births born between 1984 and 2009 who were at least 2 years of age at the end of follow-up on December 31, 2011, had resided in Stockholm County for at least 2 years since birth, and could be linked to both biological parents. Data analysis was conducted from May 2017 to December 2018., Exposure: Mental and neurological diagnoses of relatives of the index persons., Main Outcomes and Measures: Diagnosis of ASD, with or without co-occurring ID, in the index persons., Results: The cohort included 567 436 index persons (291 191 [51.3%] male; mean [SD] age at the end of follow-up, 14.3 [7.5] years). The prevalence of ASD with and without ID was 0.4% and 1.5%, respectively. Positive family history of mental and neurological disorders was associated with higher odds of ASD in index persons; 6895 (63.1%) of index persons with ASD had a parent with history of mental and/or neurological disorders, compared with 252 454 (45.4%) of index persons without ASD. Family history of multiple disorders was associated with higher odds of ASD in index persons, including history of ASD (odds ratio among first-degree relatives for ASD with and without ID: 14.2, 9.0), intellectual disability (7.6, 2.3), attention-deficit/hyperactivity disorder (3.3, 4.7), obsessive compulsive disorder (1.9, 2.1), schizophrenia and other nonaffective psychotic disorders (2.1, 1.8), depression (1.4, 2.0), bipolar disorder (1.4, 2.2), personality disorder (2.1, 2.6), cerebral palsy (2.2, 1.5), and epilepsy (2.0, 1.3). The more closely related the affected family member was, the higher the odds was of ASD for the index person. ASD without intellectual disability was associated with more disorders compared to ASD with intellectual disability. ASD with intellectual disability exhibited a weaker familial association with other mental disorder diagnoses but a stronger familial association with some neurological diagnoses as compared to ASD without intellectual disability., Conclusions and Relevance: This study suggests that family history of mental and neurological disorders is associated with increased risk of ASD. The familial component of ASD etiology may differ by presence or absence of co-occurring ID.

Importance: Depression is a common cause of morbidity and disability worldwide. Parental depression is associated with early-life child neurodevelopmental, behavioral, emotional, mental, and social problems. More studies are needed to explore the link between parental depression and long-term child outcomes., Objective: To examine the associations of parental depression with child school performance at the end of compulsory education (approximately age 16 years)., Design, Setting, and Participants: Parental depression diagnoses (based on the International Classification of Diseases, Eighth Revision [ICD-8], International Classification of Diseases, Ninth Revision [ICD-9], and the International Statistical Classification of Diseases, 10th Revision [ICD-10]) in inpatient records from 1969 onward, outpatient records beginning in 2001, and school grades at the end of compulsory education were collected for all children born from 1984 to 1994 in Sweden. The final analytic sample size was 1,124,162 biological children. We examined the associations of parental depression during different periods (before birth, after birth, and during child ages 1-5, 6-10, and 11-16 years, as well as any time before the child's final year of compulsory schooling) with the final school grades. Linear regression models adjusted for various child and parent characteristics. The dates of the analysis were January to November 2015., Main Outcome and Measure: Decile of school grades at the end of compulsory education (range, 1-10, with 1 being the lowest and 10 being the highest)., Results: The study cohort comprised 1,124,162 children, of whom 48.9% were female. Maternal depression and paternal depression at any time before the final compulsory school year were associated with worse school performance. After covariate adjustment, these associations decreased to -0.45 (95% CI, -0.48 to -0.42) and -0.40 (-0.43 to -0.37) lower deciles, respectively. These effect sizes are similarly as large as the observed difference in school performance between the lowest and highest quintiles of family income but approximately one-third of the observed difference between maternal education of 9 or less vs more than 12 years. Both maternal depression and paternal depression at different periods (before birth, after birth, and during child ages 1-5, 6-10, and 11-16 years) generally were associated with worse school performance. Child sex modified the associations of maternal depression with school performance such that maternal depression had a larger negative influence on child school performance for girls compared with boys., Conclusions and Relevance: Diagnoses of parental depression throughout a child's life were associated with worse school performance at age 16 years. Our results suggest that diagnoses of parental depression may have a far-reaching effect on an important aspect of child development, with implications for future life course outcomes.

Background: Prenatal environmental factors such as maternal adiposity may influence the risk of offspring autism spectrum disorders (ASD), though current evidence is inconsistent. The objective of this study was to assess the relationship of parental BMI and gestational weight gain (GWG) with risk of offspring ASD in a population-based cohort study using family-based study designs., Methods: The cohort was based in Stockholm County, Sweden, including 333,057 individuals born 1984-2007, of whom 6420 were diagnosed with an ASD. We evaluated maternal body mass index (BMI) at first antenatal visit, GWG and paternal BMI at the time of conscription into the Swedish military as exposures using general estimating equation (GEE) models with logit link., Results: At the population level, maternal overweight/obesity was associated with increased risk of offspring ASD [odds ratio (OR)25 ≤ BMI < 30 1.31, 95% confidence interval = 1.21-1.41; ORBMI ≥ 30 1.94, 1.72-2.17], as was paternal underweight (ORBMI < 18.5, 1.19, 1.06-1.33) and obesity (ORBMI ≥ 30 1.47, 1.12-1.92) in mutually adjusted models. However, in matched sibling analyses, the relationship between elevated maternal BMI and ASD risk was not apparent. GWG had a U-shaped association with offspring ASD at the population level (ORinsufficient 1.22, 1.07-1.40; ORexcessive 1.23, 1.08-1.40). Matched sibling analyses were suggestive of elevated risk with excessive GWG (ORinsufficient 1.12, 0.68-1.84; ORexcessive 1.48, 0.93-2.38)., Conclusions: Whereas population-level results suggested that maternal BMI was associated with ASD, sibling analyses and paternal BMI analyses indicate that maternal BMI may also be a proxy marker for other familial risk factors. Evidence is stronger for a direct link between GWG and ASD risk., (© The Author 2015. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Although the risks of adverse pregnancy outcomes associated with anti-D antibodies are well-recognized, much less is known concerning alloimmunization with other red blood cell antibodies detected during routine maternal screening. To date, most reports of adverse pregnancy outcomes associated with non-anti-D antibodies have been from small case studies. The aim of this study was to examine the associations of maternal alloimmunization with specific red blood cell antibodies and the risks of preterm birth and stillbirth in the Swedish population., Methods: All antibody screening, outcome and covariate data were obtained through linkages of Swedish national health and data registers. Follow-up in these population-based registers was available up to 31 December 2002. The final study sample consisted of 1,022,569 singleton births from 668,952 mothers during 1987-2002., Results: In total, 1.3% of the 1,022,569 study pregnancies were alloimmunized. In adjusted logistic regression models, compared with having no antibodies, alloimmunization with anti-D, anti-E, anti-C and anti-c was associated with increased risk of both stillbirth and preterm birth. In addition, anti-Kell was associated with increased risk of preterm birth and anti-Lea with increased risk of stillbirth. Compared with firstborn children, risk of preterm birth associated with alloimmunization was greater in subsequent births, Conclusions: In the largest study to date, alloimmunization with Rhesus, K- and -Lea red blood cell antibodies increased the risk of preterm birth and/or stillbirth. The association of anti-Lea with stillbirth was an unexpected finding. Further study of the consequences of non-anti-D alloimmunization is warranted., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: The objectives of this study were to examine the independent and dependent associations of maternal and paternal age and risk of offspring autism spectrum disorders (ASD), with and without intellectual disability (ID)., Methods: The sample consisted of 417 303 Swedish children born 1984-2003. ASD case status (N = 4746) was ascertained using national and regional registers. Smoothing splines in generalized additive models were used to estimate associations of parental age with ASD., Results: Whereas advancing parental age increased the risk of child ASD, maternal age effects were non-linear and paternal age effects were linear. Compared with mothers at the median age 29 years, those <29 had similar risk, whereas risk increased after age 30, with an odds ratio (OR) of 1.75 [95% (CI): 1.63-1.89] at ages 40-45. For fathers, compared with the median age of 32 years, the OR for ages 55-59 was 1.39 (1.29-1.50). The risk of ASD was greater for older mothers as compared with older fathers. For example, mothers aged 40-45 (≥97.2th percentile) had an estimated 18.63 (95% CI: 17.25-20.01) ASD cases per 1000 births, whereas fathers aged 55-59 (≥99.7th percentile) had 16.35 (95% CI: 15.11-17.58) ASD cases per 1000 births. In analyses stratified by co-parental age, increased risk due to advancing paternal age was evident only with mothers ≤35 years. In contrast, advancing maternal age increased risk regardless of paternal age. Advancing parental age was more strongly associated with ASD with ID, compared with ASD without ID., Conclusions: We confirm prior findings that advancing parental age increases risk of ASD, particularly for ASD with ID, in a manner dependent on co-parental age. Although recent attention has emphasized the effects of older fathers on ASD risk, an increase of n years in maternal age has greater implications for ASD risk than a similar increase in paternal age.

Prenatal exposure to tobacco smoke is suggested as a potential risk factor for autism spectrum disorders (ASD). Previous epidemiological studies of this topic have yielded mixed findings. We performed a case-control study of 3,958 ASD cases and 38,983 controls nested in a large register-based cohort in Sweden. ASD case status was measured using a multisource case ascertainment system. In adjusted results, we found that maternal smoking during pregnancy is not associated with increased risk of ASD regardless of presence or absence of comorbid intellectual disability. Apparent associations were attributable to confounding by sociodemographic characteristics of parents such as education, income, and occupation.