Female Infertility and Neurodevelopmental Disorders in Children: associations and evidence for familial confounding in Denmark.

IMPORTANCE: Existing research suggests the impact of infertility on the risk of neurodevelopmental disorders in children, however, studies to date have failed to separate the impact of male and female infertility, often blurring the lines with proxies that encompass all forms of infertility. Moreover, while both health conditions co-occurring with infertility and genetic factors operating upstream have been suggested to influence the association between infertility and child outcomes, their roles and potential impact on observed associations remain unclear. OBJECTIVE: The objectives of this study are to investigate the relationship between female infertility and autism in the child, differentiating it from the effects of male and the couple infertility; consider the role of various maternal and birth factors in the association; and examine the effects of shared familial confounders on the association. DESIGN SETTING AND PARTICIPANTS: Danish population-based cohort study, including all singleton live births in Denmark 1998-2015, their parents and parents' siblings. The cohort was followed up until December 31, 2016. EXPOSURES: The exposure was a history of female infertility in the mother and the mother's sister. We examined four definitions of female infertility based on the ICD-10 codes derived from the Danish National Patient Register - any female infertility; specified female infertility; female exclusive infertility; and female or male infertility. MAIN OUTCOME AND MEASURES: The outcome was diagnosis of autism spectrum disorder (ASD) in the Danish Psychiatric Central Research Register or the national patient register. A multivariable Cox regression model was used to estimate the associations between female infertility and autism, accounting for child's sex, year of birth, maternal age, education level, chronic comorbidities, and pregnancy and birth complications. The effects of shared familial factors on the association were analyzed using exposure information from the child's maternal aunt. RESULTS: The cohort included 1,131,899 mother-child pairs, among which 18,374 children with ASD diagnosis. History of female infertility in the mother (all definitions) was significantly associated with autism in the child, with the association remaining robust after adjustment for covariates (HRadj=1.14 (95% CI, 1.03-1.26) for specified infertility). The diagnosis of infertility in a child's maternal aunt was also significantly linked to the child's autism risk, even after adjustment for maternal infertility (HRadj=1.10 (95% CI, 1.00-1.20). CONCLUSIONS AND RELEVANCE: in This population-based birth cohort study, we found a slightly higher risk of autism in children born to mothers with a history of infertility, with the association remaining consistent across various definitions of female infertility and robust to adjustments for demographic, child, and maternal factors. The study suggests for the first time that shared familial factors, possibly both genetic and non-genetic, could be influencing both female infertility and the risk of autism in children, indicating a need for further investigation into these familial effects.

Psychiatric comorbidities in epilepsy: population co-occurrence, genetic correlations and causal effects.

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.

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.

Primary Intraosseous Granular Cell Tumor of the Sphenoid and Central Skull Base in a Pediatric Patient.

BACKGROUND: Granular cell tumors occur in all ages and many anatomic sites. In the craniofacial region, they typically arise in soft tissue, not bone. We present a primary intra-osseous granular cell tumor of the sphenoid and central skull base arising in a 12- year- old girl. CASE REPORT: A 12-year-old female with sickle cell disease and Jeavons syndrome presented with seizures. Imaging and partial resection revealed an expansile benign granular cell tumor (GCT) involving the sphenoid body, pterygoid process, and central skull base. The disease has remained stable after 36-month follow up. DISCUSSION: GCT primarily involving the osseous sphenoid/skull base has not been previously reported in a child. Although mostly benign, some are aggressive, with malignant transformation in 1-2%. Surgery is the mainstay of treatment, but in the skull base this may be limited by adjacent critical structures. Decision-making is guided by anatomic extent, histology, and clinical behavior.

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.

Associations between maternal metabolic conditions and neurodevelopmental conditions in offspring: the mediating effects of obstetric and neonatal complications.

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.

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.

Preoperative Transfusion in Sickle Cell Disease Children Undergoing Adenotonsillectomy.

Objective: To perform a systematic review and meta-analysis comparing two pre-operative transfusion regimens (conservative versus aggressive) in children with sickle cell disease(SCD) undergoing adenotonsillectomy in terms of post-operative complications, complications related to SCD and transfusion related complications. Data Sources and Review Methods: A literature review was performed through PubMed, EMBASE, Cochrane, and Ovid databases using the following phrases: (Adenotonsillectomy OR Tonsillectomy) AND (Sickle Cell Disease OR Sickle Cell Trait). Using predetermined inclusion and exclusion criteria, seven articles were selected for systemic review and two control trials were included in meta-analysis. Results: Out of a total of 3,146 results, seven articles were selected for review and two controlled trials were included in the meta-analysis. There was no statistically significant difference in the rate of primary and secondary hemorrhage between the aggressive and conservative transfusion regimens (RR = 3.1, CI = 0.84-11.4, p-value = 0.089). The rate of sickle cell disease related complications including vaso-occlusive crisis and acute chest syndrome was also not statistically significant between the two transfusion groups (RR = 1.4, CI = 0.7-2.8, p-value = 0.339). Even though, the transfusion related complications did not reach statistical significance, there was a higher complication rate in the group receiving aggressive blood transfusion. Conclusion: In SCD children undergoing adenotonsillectomy, an aggressive transfusion regimen that focuses on reducing the Hemoglobin S ratio to below 30% has not been shown to be more effective in reducing post-operative complications when compared to a conservative transfusion regimen. Therefore, it is reasonable to utilize a conservative transfusion regimen, thereby reducing the transfusion-associated risks.

Autonomic function and inflammation in pregnant women participating in a randomized controlled study of Mindfulness Based Childbirth and Parenting.

BACKGROUND: Pregnancy and childbirth are significant events in many women's lives, and the prevalence of depressive symptoms increases during this vulnerable period. Apart from well documented cognitive, affective, and somatic symptoms, stress and depression are associated with physiological changes, such as reduced heart-rate variability (HRV) and activation of the inflammatory response system. Mindfulness Based Interventions may potentially have an effect on both HRV, inflammatory biomarkers, and self-assessed mental health. Therefore, the aim of this study was to assess the effects of a Mindfulness Childbirth and Parenting (MBCP) intervention on HRV, serum inflammatory marker levels, through an RCT study design with an active control group. METHODS: This study is a sub-study of a larger RCT, where significant intervention effects were found on perinatal depression (PND) and perceived stress. Participants were recruited through eight maternity health clinics in Stockholm, Sweden. In this sub-study, we included altogether 80 women with increased risk for PND, and blood samples and HRV measures were available from 60 of the participants (26 in the intervention and 34 in the control group). RESULTS: Participants who received MBCP reported a significantly larger reduction in perceived stress and a significantly larger increase in mindfulness, compared to participants who received the active control treatment. However, in this sub-study, the intervention had no significant effect on PND, inflammatory serum markers or measures of HRV. CONCLUSIONS: No significant differences were found regarding changes in HRV measures and biomarkers of inflammation, larger studies may be needed in the future. TRIAL REGISTRATION: ClinicalTrials.gov ID:  NCT02441595 . Registered 12 May 2015 - Retrospectively registered.

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.

Autoimmune Myelofibrosis in a 12-Year-old Male With Monosomy 7, Systemic Lupus Erythematous and Lupus Nephritis: A Case Report and Review of the Literature.

Complete or partial loss of chromosome 7 is a common and well-known cytogenetic abnormality associated with preleukemic myelodysplasia and myeloid leukemia but not with autoimmune myelofibrosis. Detection of this molecular change represents poor prognosis. When malignant transformation occurs, the condition tends to be chemotherapy-resistant requiring haematopoietic stem cell transplantation (HSCT) to obtain a cure. Disappearance after immunosuppressive therapy has been documented in children with hematological disorders but not in association with cyclophosphamide and systemic lupus erythematous.We present the interesting case of a 12-year-old male with monosomy 7, systemic lupus erythematous, and lupus nephritis with the resolution of the monosomy 7 and autoimmune myelofibrosis after treatment with cyclophosphamide, along with a review of the literature.

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.

Parental inflammatory bowel disease and autism in children.

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.

Maternal Levels of Cytokines in Early Pregnancy and Risk of Autism Spectrum Disorders in Offspring.

Previous studies indicate a role of immune disturbances during early development in the etiology of autism spectrum disorders (ASD). Any potential disturbances during fetal development are best addressed by prospective evaluation of maternal markers of inflammation. Previous studies have investigated maternal cytokines, a group of powerful effectors of the immune system, with inconsistent results. In this study, we aimed to clarify the relationship between maternal cytokines and ASD by evaluating levels of 17 cytokines in first trimester maternal serum samples, from 318 mothers to ASD-cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. Overall, we observed no consistent associations between levels of maternal cytokines and ASD. While we observed a number of individual associations, the patterns varied across the diagnostic sub-groups. Levels above the 90th percentile of IL-1ß (OR = 2.31, 95% CI 1.16-4.60), IL-7 (OR = 2.28, 95% CI 1.20-4.33), IL-13 (OR = 2.42, 95% CI 1.29-4.55), and MCP-1 (OR = 2.09, 95% CI 1.03-4.24) were associated with increased odds of ASD with co-occurring intellectual disability (ID), whereas GMCSF (OR = 2.06, 95% CI 1.03-4.11) and TNF-α (OR = 2.31, 95% CI 1.18-4.50) were associated with increased odds of ASD with ADHD but none survived correction for multiple comparisons. Also, none of the measured maternal cytokines were associated with ASD without co-occurring ID or ADHD. Implementing a data-driven approach using machine learning (Random Forest's Variable Importance measurement), we found no evidence to suggest that adding these cytokines and other markers of maternal immunity, to register-based maternal factors (e.g., psychiatric history) improves prediction of ASD. In summary, we found no robust evidence of an association between maternal immune markers during early pregnancy and ASD.

Maternal levels of acute phase proteins in early pregnancy and risk of autism spectrum disorders in offspring.

Previous research supports a contribution of early-life immune disturbances in the etiology of autism spectrum disorders (ASD). Biomarker studies of the maternal innate (non-adaptive) immune status related to ASD risk have focused on one of the acute phase proteins (APP), C-reactive protein (CRP), with conflicting results. We evaluated levels of eight different APP in first-trimester maternal serum samples, from 318 mothers to ASD cases and 429 mothers to ASD-unaffected controls, nested within the register-based Stockholm Youth Cohort. While no overall associations between high levels of APP and ASD were observed, associations varied across diagnostic sub-groups based on co-occurring conditions. Maternal levels of CRP in the lowest compared to the middle tertile were associated with increased risk of ASD without ID or ADHD in offspring (OR = 1.92, 95% CI 1.08-3.42). Further, levels of maternal ferritin in the lowest (OR = 1.78, 95% CI 1.18-2.69) and highest (OR = 1.64, 95% CI 1.11-2.43) tertiles were associated with increased risk of any ASD diagnosis in offspring, with stronger associations still between the lowest (OR = 3.81, 95% CI 1.91-7.58) and highest (OR = 3.36, 95% CI 1.73-6.53) tertiles of ferritin and risk of ASD with ID. The biological interpretation of lower CRP levels among mothers to ASD cases is not clear but might be related to the function of the maternal innate immune system. The finding of aberrant levels of ferritin conferring risk of ASD-phenotypes indicates a plausibly important role of iron during neurodevelopment.

Childhood infections and autism spectrum disorders and/or intellectual disability: a register-based cohort study.

OBJECTIVE: To explore the associations between childhood infections and subsequent diagnoses of autism spectrum disorder (ASD), intellectual disability (ID), and their co-occurrence. METHODS: The association between specialized care for any infection, defined by ICD-codes, and later ASD or ID was investigated in a register-based cohort of 556,732 individuals born 1987-2010, resident in Stockholm County, followed from birth to their 18th birthday or December 31, 2016. We considered as potential confounders children's characteristics, family socioeconomic factors, obstetric complications, and parental histories of treatment for infection and psychiatric disorders in survival analyses with extended Cox regression models. Residual confounding by shared familial factors was addressed in sibling analyses using within-strata estimation in Cox regression models. Sensitivity analyses with the exclusion of congenital causes of ASD/ID and documented risk for infections were also performed. RESULTS: Crude estimates indicated that infections during childhood were associated with later ASD and ID with the largest risks observed for diagnoses involving ID. Inclusion of covariates, exclusion of congenital causes of ASD/ID from the population, and sibling comparisons highlighted the potential for confounding by both heritable and non-heritable factors, though risks remained in all adjusted models. In adjusted sibling comparisons, excluding congenital causes, infections were associated with later "ASD without ID" (HR 1.24, 95%CI 1.15-1.33), "ASD with ID" (1.57, 1.35-1.82), and "ID without ASD" (2.01, 1.76-2.28). Risks associated with infections varied by age at exposure and by age at diagnosis of ASD/ID. CONCLUSIONS: Infections during childhood may contribute to a later diagnosis of ID and ASD.

Multisystem Inflammatory Syndrome in a Pediatric Patient With Sickle Cell Disease and COVID-19: A Case Report.

To this day, there are limited data about the effects and management of coronavirus disease infection in pediatric patients with sickle cell disease. We present the management and successful clinical course of an 8-year-old female with homozygous sickle cell disease (SS) and severe acute chest syndrome secondary to coronavirus disease 2019 infection, complicated by cortical vein thrombosis.

Maternal antibodies to gliadin and autism spectrum disorders in offspring-A population-based case-control study in Sweden.

While individuals diagnosed with autism spectrum disorders (ASD) have higher levels of antibodies directed towards gliadin, a component of wheat gluten, no study has examined anti-gliadin antibodies (AGA) in etiologically relevant periods before diagnosis. The objective of this study was to investigate if maternal levels of AGA, during pregnancy and at the time of birth, are associated with ASD in offspring. We analyzed AGA in archived neonatal dried blood spots (NDBS) for 921 ASD cases and 1090 controls, and in paired maternal sera collected earlier in pregnancy for a subset of 547 cases and 428 controls. We examined associations with ASD diagnoses as a group and considering common comorbidities (intellectual disability [ID] and attention-deficit/hyperactivity disorder). We compared 206 cases to their unaffected siblings to examine the potential for confounding by shared familial factors. Odds of ASD tended to be lower among those with the highest levels (≥90th percentile) of AGA compared to those with low levels (<80th percentile; OR 0.78, 95% CI 0.56-1.09, measured in NDBS). This pattern was more apparent for ASD with comorbid ID when measured in NDBS (0.51, 0.30-0.87), with a similar trend in maternal sera (0.55, 0.24-1.29). High levels of AGA were similarly associated with lower odds of ASD in the sibling comparison. In summary, we found little association between maternal antibodies raised against components of gluten and risk of ASD in general. Exposure to high levels of AGA in the pre- and perinatal periods may be protective in terms of risk for ASD with ID. LAY SUMMARY: There is a debate among both scientists and community members as to whether an immune reaction to gluten exposure could be considered a cause of autism. We examined antibodies that are directed against gliadin, a part of gluten, in samples collected from pregnant mothers and their newborn babies. We did not see any major differences in the antibody level among those children diagnosed with ASD or their mothers compared to children who were not diagnosed with ASD. High levels of the antibodies were in fact associated with a somewhat lower risk of ASD with co-occurring intellectual disabilities, though we cannot tell from this study why that might be the case.