Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-30 (of 35 Records) |
Query Trace: Schendel D[original query] |
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Peripheral blood DNA methylation and autism spectrum disorder (preprint)
Andrews SV , Sheppard B , Windham GC , Schieve LA , Schendel DE , Croen LA , Chopra P , Alisch RS , Newschaffer CJ , Warren ST , Feinberg AP , Fallin MD , Ladd-Acosta C . bioRxiv 2018 320622 BackgroundSeveral reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size, and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies.MethodsDNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample.FindingsIn this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12×10−7. Seven CpGs showed differences at p < 1×10−5 and 48 at 1×10−4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpGs hits, which was consistent across EWAS and meQTL discovery p-value thresholds.ConclusionsWe report the largest case-control EWAS study of ASD to date. No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the 7 sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD. |
Infection and fever in pregnancy and autism spectrum disorders: Findings from the Study to Explore Early Development
Croen LA , Qian Y , Ashwood P , Zerbo O , Schendel D , Pinto-Martin J , Daniele Fallin M , Levy S , Schieve LA , Yeargin-Allsopp M , Sabourin KR , Ames JL . Autism Res 2019 12 (10) 1551-1561 Maternal infection and fever during pregnancy have been implicated in the etiology of autism spectrum disorder (ASD); however, studies have not been able to separate the effects of fever itself from the impact of a specific infectious organism on the developing brain. We utilized data from the Study to Explore Early Development (SEED), a case-control study among 2- to 5-year-old children born between 2003 and 2006 in the United States, to explore a possible association between maternal infection and fever during pregnancy and risk of ASD and other developmental disorders (DDs). Three groups of children were included: children with ASD (N = 606) and children with DDs (N = 856), ascertained from clinical and educational sources, and children from the general population (N = 796), randomly sampled from state birth records. Information about infection and fever during pregnancy was obtained from a telephone interview with the mother shortly after study enrollment and maternal prenatal and labor/delivery medical records. ASD and DD status was determined by an in-person standardized developmental assessment of the child at 3-5 years of age. After adjustment for covariates, maternal infection anytime during pregnancy was not associated with ASD or DDs. However, second trimester infection accompanied by fever elevated risk for ASD approximately twofold (aOR = 2.19, 95% confidence interval 1.14-4.23). These findings of an association between maternal infection with fever in the second trimester and increased risk of ASD in the offspring suggest that the inflammatory response to the infectious agent may be etiologically relevant. Autism Res2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multisite study in the United States-the Study to Explore Early Development-we found that women who had an infection during the second trimester of pregnancy accompanied by a fever are more likely to have children with ASD. These findings suggest the possibility that only more severe infections accompanied by a robust inflammatory response increase the risk of ASD. |
Infections in children with autism spectrum disorder: Study to Explore Early Development (SEED)
Sabourin KR , Reynolds A , Schendel D , Rosenberg S , Croen LA , Pinto-Martin JA , Schieve LA , Newschaffer C , Lee LC , DiGuiseppi C . Autism Res 2018 12 (1) 136-146 Immune system abnormalities have been widely reported among children with autism spectrum disorder (ASD), which may increase the risk of childhood infections. The Study to Explore Early Development (SEED) is a multisite case-control study of children aged 30-69 months, born in 2003-2006. Cases are children previously diagnosed and newly identified with ASD enrolled from education and clinical settings. Children with a previously diagnosed non-ASD developmental condition were included in the developmental delay/disorder (DD) control group. The population (POP) control group included children randomly sampled from birth certificates. Clinical illness from infection during the first 28 days ("neonatal," from medical records) and first three years of life (caregiver report) in cases was compared to DD and POP controls; and between cases with and without regression. Children with ASD had greater odds of neonatal (OR = 1.8; 95%CI: 1.1, 2.9) and early childhood infection (OR = 1.7; 95%CI: 1.5, 1.9) compared to POP children, and greater odds of neonatal infection (OR = 1.5; 95%CI: 1.1, 2.0) compared to DD children. Cases with regression had 1.6 times the odds (95%CI: 1.1, 2.3) of caregiver-reported infection during the first year of life compared to cases without regression, but neonatal infection risk and overall early childhood infection risk did not differ. Our results support the hypothesis that children with ASD are more likely to have infection early in life compared to the general population and to children with other developmental conditions. Future studies should examine the contributions of different causes, timing, frequency, and severity of infection to ASD risk. Autism Res 2018. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We looked at infections during early childhood in relation to autism spectrum disorder (ASD). We found that children with ASD were more likely to have an infection in the first 28 days of life and before age three compared to children with typical development. Children with ASD were also more likely than children with other developmental delays or disorders to have an infection in the first 28 days of life. |
Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development.
Croen LA , Qian Y , Ashwood P , Daniels JL , Fallin D , Schendel D , Schieve LA , Singer AB , Zerbo O . Autism Res 2018 12 (1) 123-135 Numerous studies have reported immune system disturbances in individuals with autism and their family members; however, there is considerable variability in findings with respect to the specific immune conditions involved, their timing, and the family members affected and little understanding of variation by autism subphenotype. Using data from the Study to Explore Early Development (SEED), a multi-site case-control study of children born 2003-2006 in the United States, we examined the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD). We investigated maternal immune conditions during the pregnancy period, as well as lifetime history of these conditions in several family members (mother, father, siblings, and study child). Logistic regression analyses included 663 children with ASD, 984 children with DD, and 915 controls ascertained from the general population (POP). Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD. Risk estimates varied by specific ASD subphenotypes in association with these exposures. In addition, children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls. No association was observed for paternal history or family history of these immune conditions for either ASD or DD. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes, and further suggest that associations may differ by ASD phenotype of the child. Autism Res 2018., (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multi-site study in the US-the Study to Explore Early Development-we found that women with a history of eczema/psoriasis and asthma are more likely to have children with ASD or DD. In addition, children with ASD are more likely to have a history of psoriasis/eczema or allergies than typically developing children. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes. |
Case-control meta-analysis of blood DNA methylation and autism spectrum disorder.
Andrews SV , Sheppard B , Windham GC , Schieve LA , Schendel DE , Croen LA , Chopra P , Alisch RS , Newschaffer CJ , Warren ST , Feinberg AP , Fallin MD , Ladd-Acosta C . Mol Autism 2018 9 40 Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 x 10(- 7). Seven CpGs showed differences at p < 1 x 10(- 5) and 48 at 1 x 10(- 4). Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD. |
Early elevation in interleukin-6 is associated with reduced growth in extremely low birth weight infants
Denson LA , McDonald SA , Das A , Schendel DE , Skogstrand K , Hougaard DM , Shankaran S , Higgins RD , Carlo WA , Ehrenkranz RA . Am J Perinatol 2016 34 (3) 240-247 Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design GV was determined at 36 weeks' postmenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p < 0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p = 0.12) when controlling for BW and energy intake. Both BW (p = 0.02) and energy intake (p = 0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth. |
Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder
DiGuiseppi CG , Daniels JL , Fallin DM , Rosenberg SA , Schieve LA , Thomas KC , Windham GC , Goss CW , Soke GN , Currie DW , Singer AB , Lee LC , Bernal P , Croen LA , Miller LA , Pinto-Martin JA , Young LM , Schendel DE . Disabil Health J 2016 9 (3) 544-51 BACKGROUND: The Study to Explore Early Development (SEED) is designed to enhance knowledge of autism spectrum disorder characteristics and etiologies. OBJECTIVE: This paper describes the demographic profile of enrolled families and examines sociodemographic differences between children with autism spectrum disorder and children with other developmental problems or who are typically developing. METHODS: This multi-site case-control study used health, education, and birth certificate records to identify and enroll children aged 2-5 years into one of three groups: 1) cases (children with autism spectrum disorder), 2) developmental delay or disorder controls, or 3) general population controls. Study group classification was based on sampling source, prior diagnoses, and study screening tests and developmental evaluations. The child's primary caregiver provided demographic characteristics through a telephone (or occasionally face-to-face) interview. Groups were compared using ANOVA, chi-squared test, or multinomial logistic regression as appropriate. RESULTS: Of 2768 study children, sizeable proportions were born to mothers of non-White race (31.7%), Hispanic ethnicity (11.4%), and foreign birth (17.6%); 33.0% of households had incomes below the US median. The autism spectrum disorder and population control groups differed significantly on nearly all sociodemographic parameters. In contrast, the autism spectrum disorder and developmental delay or disorder groups had generally similar sociodemographic characteristics. CONCLUSIONS: SEED enrolled a sociodemographically diverse sample, which will allow further, in-depth exploration of sociodemographic differences between study groups and provide novel opportunities to explore sociodemographic influences on etiologic risk factor associations with autism spectrum disorder and phenotypic subtypes. |
Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood.
Ladd-Acosta C , Shu C , Lee BK , Gidaya N , Singer A , Schieve LA , Schendel DE , Jones N , Daniels JL , Windham GC , Newschaffer CJ , Croen LA , Feinberg AP , Daniele Fallin M . Environ Res 2015 144 139-148 Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3-5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure. |
Autism spectrum disorder symptoms among children enrolled in the Study to Explore Early Development (SEED)
Wiggins LD , Levy SE , Daniels J , Schieve L , Croen LA , DiGuiseppi C , Blaskey L , Giarelli E , Lee LC , Pinto-Martin J , Reynolds A , Rice C , Rosenberg CR , Thompson P , Yeargin-Allsopp M , Young L , Schendel D . J Autism Dev Disord 2015 45 (10) 3183-94 This study examined the phenotypic profiles of children aged 30-68 months in the Study to Explore Early Development (SEED). Children classified as autism spectrum disorder (ASD), developmental delay (DD) with ASD symptoms, DD without ASD symptoms, and population comparison (POP) differed significantly from each other on cognitive, adaptive, behavioral, and social functioning and the presence of parent-reported conditions. Children with ASD and DD with ASD symptoms had mild to severe ASD risk on several measures compared to children with other DD and POP who had little ASD risk across measures. We conclude that children in SEED have varying degrees of ASD impairment and associated deficits. SEED thus provides a valuable sample to explore ASD phenotypes and inform risk factor analyses. |
Trends in the prevalence of autism spectrum disorder, cerebral palsy, hearing loss, intellectual disability, and vision impairment, metropolitan Atlanta, 1991-2010
Van Naarden Braun K , Christensen D , Doernberg N , Schieve L , Rice C , Wiggins L , Schendel D , Yeargin-Allsopp M . PLoS One 2015 10 (4) e0124120 This study examined the prevalence and characteristics of autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss (HL), intellectual disability (ID), and vision impairment (VI) over a 15-20 year time period, with specific focus on concurrent changes in ASD and ID prevalence. We used data from a population-based developmental disabilities surveillance program for 8-year-olds in metropolitan Atlanta. From 1991-2010, prevalence estimates of ID and HL were stable with slight increases in VI prevalence. CP prevalence was constant from 1993-2010. The average annual increase in ASD prevalence was 9.3% per year from 1996-2010, with a 269% increase from 4.2 per 1,000 in 1996 to 15.5 per 1,000 in 2010. From 2000-2010, the prevalence of ID without ASD was stable; during the same time, the prevalence of ASD with and without co-occurring ID increased by an average of 6.6% and 9.6% per year, respectively. ASD prevalence increases were found among both males and females, and among nearly all racial/ethnic subgroups and levels of intellectual ability. Average annual prevalence estimates from 1991-2010 underscore the significant community resources needed to provide early intervention and ongoing supports for children with ID (13.0 per 1,000), CP, (3.5 per 1,000), HL (1.4 per 1,000) and VI (1.3 in 1,000), with a growing urgency for children with ASD. |
Urbanicity and autism spectrum disorders
Lauritsen MB , Astrup A , Pedersen CB , Obel C , Schendel DE , Schieve L , Yeargin-Allsopp M , Parner ET . J Autism Dev Disord 2014 44 (2) 394-404 The etiology of autism spectrum disorders (ASD) is for the majority of cases unknown and more studies of risk factors are needed. Geographic variation in ASD occurrence has been observed, and urban residence has been suggested to serve as a proxy for etiologic and identification factors in ASD. We examined the association between urbanicity level and ASD at birth and during childhood. The study used a Danish register-based cohort of more than 800,000 children of which nearly 4,000 children were diagnosed with ASD. We found a dose-response association with greater level of urbanicity and risk of ASD. This association was found for residence at birth as well as residence during childhood. Further, we found an increased risk of ASD in children who moved to a higher level of urbanicity after birth. Also, earlier age of ASD diagnosis in urban areas was observed. While we could not directly examine the specific reasons behind these associations, our results demonstrating particularly strong associations between ASD diagnosis and post-birth migration suggest the influence of identification-related factors such as access to services might have a substantive role on the ASD differentials we observed. |
Maternal infections during pregnancy and cerebral palsy: a population-based cohort study
Miller JE , Pedersen LH , Streja E , Bech BH , Yeargin-Allsopp M , Van Naarden Braun K , Schendel DE , Christensen D , Uldall P , Olsen J . Paediatr Perinat Epidemiol 2013 27 (6) 542-52 BACKGROUND: Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child. METHODS: Liveborn singletons in Denmark between 1997 and 2003 were identified from the Danish National Birth Registry and followed from 1 year of life until 2008. Redemption of antibiotics from the National Register of Medicinal Product Statistics and maternal infections reported by the National Hospital Register were used as markers of maternal infection during pregnancy. CP diagnoses were obtained from the Danish Cerebral Palsy Registry. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated by Cox proportional hazard models. RESULTS: Of the 440 564 singletons with follow-up data, 840 were diagnosed with congenital CP. Maternal genito-urinary tract infections (HR 2.1, 95% CI 1.4, 3.2) were associated with CP in all births, in term births (HR 1.9, 95% CI 1.1, 3.2), in children with spastic CP (HR 2.1, 95% CI 1.4, 3.3), and among first-born children (HR 1.9, 95% CI 1.4, 3.3). Overall, we found associations between redeemed nitrofurantoin (HR 1.7, 95% CI 1.1, 2.8) and CP. Among trimester-specific exposures, CP risk was associated with prescriptions redeemed in the first trimester for any antibacterials, beta-lactam antibacterials, and nitrofurantoin, an antibiotic commonly used to treat lower urinary tract infection, and genito-urinary tract infections in the third trimester. CONCLUSION: Genito-urinary tract infections and antibiotic use during pregnancy were associated with increased risks of CP, indicating that some maternal infections or causes of maternal infections present in prenatal life may be part of a causal pathway leading to CP. |
Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism
Christensen J , Gronborg TK , Sorensen MJ , Schendel D , Parner ET , Pedersen LH , Vestergaard M . JAMA 2013 309 (16) 1696-703 IMPORTANCE: Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism. OBJECTIVE: To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS: Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES: Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy. RESULTS: Of 655,615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate. CONCLUSIONS AND RELEVANCE: Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control. |
Hospitalizations among people with Down syndrome: a nationwide population-based study in Denmark
Zhu JL , Hasle H , Correa A , Schendel D , Friedman JM , Olsen J , Rasmussen SA . Am J Med Genet A 2013 161 (4) 650-7 Most persons with Down syndrome (DS) now survive to adulthood, but their health care needs beyond childhood are not well described. We followed a national cohort of 3,212 persons with DS and a reference cohort of persons without DS through the Danish National Hospital Register from January 1, 1977, to May 31, 2008. Poisson regression was used to calculate rate ratios for numbers of overnight hospital admissions and hospital days. During the study period, persons with DS had more than twice the rate of hospital admissions and nearly three times as many bed-days as the population as a whole. Malformations, diseases of the respiratory system, and diseases of the nervous system or sensory organs were the principal indications for hospital admissions. The higher rate ratios for hospital admissions were seen especially among persons less than 20 years of age. Hospitalizations for neoplasms or for diseases of the musculoskeletal system or connective tissue were much less frequent among adults with DS. As survival among persons with DS continues to improve, these findings are likely to be useful for health care planning, although the potential utility may be different for different health care systems. |
Association between blood spot transforming growth factor-beta and patent ductus arteriosus in extremely low-birth weight infants
Natarajan G , Shankaran S , McDonald SA , Das A , Ehrenkranz RA , Goldberg RN , Stoll BJ , Tyson JE , Higgins RD , Schendel D , Hougaard DM , Skogstrand K , Thorsen P , Carlo WA . Pediatr Cardiol 2013 34 (1) 149-54 Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-beta appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-beta on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-beta measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-beta on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642-1,896]; median 1,386 pg/ml [range 868-1,913]) compared with others without PDA (median 1,334 pg/ml [range 760-2,064]; median 1,712 pg/ml [range 1,014-2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-beta levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-beta was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83-1.17; day 7 OR 0.88, 95 % CI 0.74-1.04) on adjusted analyses. Our results suggest that blood spot TGF-beta alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment. |
Survival among people with Down syndrome: a nationwide population-based study in Denmark.
Zhu JL , Hasle H , Correa A , Schendel D , Friedman JM , Olsen J , Rasmussen SA . Genet Med 2013 15 (1) 64-9 PURPOSE: Several studies have shown substantially longer survival among persons with Down syndrome in recent decades. We examined survival patterns among Danish persons with Down syndrome by karyotype. METHODS: A national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population were followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. RESULTS: Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% confidence interval 3.51-7.08), 8.94 (8.32-9.60), and 10.23 (7.50-13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects. CONCLUSION: Recent birth cohorts of persons with Down syndrome experienced declining mortality, likely due to treatment for congenital heart defects, and persons with mosaic trisomy 21 had better survival than persons with other Down syndrome karyotypes. (Genet Med 2013:15(1):64-69.) |
Neonatal encephalopathy or hypoxic-ischemic encephalopathy?
Schendel D , Nelson KB , Blair E . Ann Neurol 2012 72 (6) 984-5 We agree with Dr Volpe1 that a diagnosis of hypoxic–ischemic encephalopathy (HIE) is appropriate for neonates who have experienced asphyxial birth events such as uterine rupture or cord prolapse, followed by marked acidosis and neonatal neurologic depression, if other known causes of neonatal encephalopathy (NE) have been excluded. However, population-based studies of human infants with NE/HIE, and the few studies in clinical samples that have examined a range of antecedents, have observed that many infants with NE/HIE have not had recognized asphyxial birth events. Unless clinical details are carefully examined in NE, and criteria for HIE have been carefully applied, the probability of overidentifying etiology as hypoxic–ischemic may be high. | Volpe acknowledges that in NE, “…in the typical clinical situation, …the underlying mechanisms are not entirely known,” and cautions that “the clinician must exert great vigilance not to miss the great mimickers of neonatal HIE.” He considers a combination of signs such as abnormal fetal heart rate patterns, meconium in the amniotic fluid, low Apgar scores, and acidosis together with neuroimaging abnormalities, such as basal ganglia–thalamic injuries, to warrant a diagnosis of HIE. However, none of these signs is etiologically specific, even the neuroimaging abnormalities having been identified in infants with placental inflammation and no asphyxial birth events.2, 3 |
Cytokines and posthemorrhagic ventricular dilation in premature infants
Ambalavanan N , Carlo WA , McDonald SA , Das A , Schendel DE , Thorsen P , Hougaard DM , Skogstrand K , Higgins RD . Am J Perinatol 2012 29 (9) 731-740 OBJECTIVE: To determine in extremely low-birth-weight infants if elevated blood interferon-gamma (IFN-gamma), interleukin (IL)-1beta, IL-18, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta are associated with need for shunt following severe intraventricular hemorrhage (IVH) or with ventricular dilation following milder grades/no IVH. STUDY DESIGN: Whole blood cytokines were measured on postnatal days 1, 3, 7, 14, and 21. Maximum IVH grade in the first 28 days, and shunt surgery or ventricular dilation on subsequent ultrasound (28 days' to 36 weeks' postmenstrual age) were determined. RESULTS: Of 902 infants in the National Institute of Child Health and Human Development Neonatal Research Network Cytokine study who survived to 36 weeks or discharge, 3.1% had shunts. Of the 12% of infants with severe (grade III to IV) IVH, 26% had a shunt associated with elevated TNF-alpha. None of the infants without IVH (69%) or with grade I (12%) or II (7%) IVH received shunts, but 8.4% developed ventricular dilation, associated with lower IFN-gamma and higher IL-18. CONCLUSION: Statistically significant but clinically nondiscriminatory alterations in blood cytokines were noted in infants with severe IVH who received shunts and in those without severe IVH who developed ventricular dilation. Blood cytokines are likely associated with brain injury but may not be clinically useful as biomarkers for white matter damage. |
Patterns of contact with hospital for children with an autism spectrum disorder: a Danish register-based study
Atladottir HO , Schendel DE , Lauritsen MB , Henriksen TB , Parner ET . J Autism Dev Disord 2012 42 (8) 1717-28 The aim of this study was to study patterns of contact with hospital for children with autism spectrum disorder (ASD) using Danish population based register data. We included all children born in Denmark from 1994 through 2002. We found that children diagnosed with ASD had an increased rate of contact with hospital, almost regardless of the cause for the hospital contact. Given the overall association between hospital contact for various causes and ASD observed in these data, hospital data should be used cautiously in future studies searching for associations between a specific disease and ASD. If the increased rate of hospital contact overall for children with ASD is not considered, then misleading over interpretations might be made of observed associations between specific diseases and ASD. |
Using maternally reported data to investigate the association between early childhood infection and autism spectrum disorder: the importance of data source
Atladottir HO , Henriksen TB , Schendel DE , Parner ET . Paediatr Perinat Epidemiol 2012 26 (4) 373-85 BACKGROUND: Childhood infections have been found to be associated with autism spectrum disorder (ASD) in previous studies using hospital data or medical records to identify infections. We aimed to replicate these findings using maternal reports of childhood infection. METHODS: We used the Danish National Birth Cohort consisting of 92,583 live singletons born from 1997 to 2003 in Denmark. ASD diagnoses were retrieved from the Danish Psychiatric Central Register, and a total of 945 children from the cohort were diagnosed with ASD. Data were analysed using Cox proportional hazards regression. We studied the association between ASD and maternal reports of infectious disease in the child from birth to 19 months. Furthermore, we performed secondary analyses using hospital registers to investigate the association between ASD and hospital contact in general as well as hospital contact for various infections. RESULTS: We did not find a general association between maternal reports of infectious illness and ASD. However, hospital contact for all causes was associated with an increased risk for an ASD diagnosis. Danish children with ASD do not appear to have a general pattern of illness from infection in early life, but do have more contact with medical specialists for infections and other indications compared with the general population. CONCULSION: Hospital data should be used cautiously when studying the co-morbidity of ASD; if the increased rate of hospital contact overall for children with ASD is not considered, then misleading interpretations might be made of observed associations between specific diseases and ASD. |
The Study to Explore Early Development (SEED): a multisite epidemiologic study of autism by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) network
Schendel DE , Diguiseppi C , Croen LA , Fallin MD , Reed PL , Schieve LA , Wiggins LD , Daniels J , Grether J , Levy SE , Miller L , Newschaffer C , Pinto-Martin J , Robinson C , Windham GC , Alexander A , Aylsworth AS , Bernal P , Bonner JD , Blaskey L , Bradley C , Collins J , Ferretti CJ , Farzadegan H , Giarelli E , Harvey M , Hepburn S , Herr M , Kaparich K , Landa R , Lee LC , Levenseller B , Meyerer S , Rahbar MH , Ratchford A , Reynolds A , Rosenberg S , Rusyniak J , Shapira SK , Smith K , Souders M , Thompson PA , Young L , Yeargin-Allsopp M . J Autism Dev Disord 2012 42 (10) 2121-40 The Study to Explore Early Development (SEED), a multisite investigation addressing knowledge gaps in autism phenotype and etiology, aims to: (1) characterize the autism behavioral phenotype and associated developmental, medical, and behavioral conditions and (2) investigate genetic and environmental risks with emphasis on immunologic, hormonal, gastrointestinal, and sociodemographic characteristics. SEED uses a case-control design with population-based ascertainment of children aged 2-5 years with an autism spectrum disorder (ASD) and children in two control groups-one from the general population and one with non-ASD developmental problems. Data from parent-completed questionnaires, interviews, clinical evaluations, biospecimen sampling, and medical record abstraction focus on the prenatal and early postnatal periods. SEED is a valuable resource for testing hypotheses regarding ASD characteristics and causes. |
Cytokines and neurodevelopmental outcomes in extremely low birth weight infants
Carlo WA , McDonald SA , Tyson JE , Stoll BJ , Ehrenkranz RA , Shankaran S , Goldberg RN , Das A , Schendel D , Thorsen P , Skogstrand K , Hougaard DM , Oh W , Laptook AR , Duara S , Fanaroff AA , Donovan EF , Korones SB , Stevenson DK , Papile LA , Finer NN , O'Shea TM , Poindexter BB , Wright LL , Ambalavanan N , Higgins RD . J Pediatr 2011 159 (6) 919-925 e3 OBJECTIVE: To determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants. STUDY DESIGN: Infants with birth weights ≤1000 g (n = 1067) had blood samples collected at birth and on days 3 +/- 1, 7 +/- 1, 14 +/- 3, and 21 +/- 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1beta; IL-8; tumor necrosis factor-alpha; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants. RESULTS: IL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-beta, soluble IL R alpha, macrophage inflammatory protein 1beta) were found to be altered on days 0-4 in infants who developed CP. CONCLUSIONS: CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin. |
Have secular changes in perinatal risk factors contributed to the recent autism prevalence increase? Development and application of a mathematical assessment model
Schieve LA , Rice C , Devine O , Maenner MJ , Lee LC , Fitzgerald R , Wingate MS , Schendel D , Pettygrove S , Naarden Braun KV , Durkin M . Ann Epidemiol 2011 21 (12) 930-45 BACKGROUND: A 57% increase in the U.S. prevalence of autism spectrum disorders (ASD) for 8-year-old children born in 1994 versus 1998 was recently reported. METHODS: To quantify the possible contributions of given risk/predictive factors on the recent ASD prevalence increase, we formulated a mathematical model based on the baseline risk factor prevalence (RFP), the proportionate change in RFP (cRFP), and the magnitude of the association between the risk factor and ASD [estimated relative risk (RR)]. We applied this model to several pregnancy-related factors (preterm, very preterm, low and very low birth weight, multiple birth, cesarean delivery, breech presentation, and assisted reproductive technology use). RFP and cRFP estimates for each factor were obtained from U.S. population-based surveillance datasets. Estimated RRs were obtained from a series of systematic literature reviews. RESULTS: We estimate that each risk factor examined, alone or in various combinations, accounted for a very small proportion (<1%) of the ASD increase. Additionally, hypothetical scenarios indicate RFP, cRFP, and RR all need to be sizable for a risk factor to appreciably influence ASD prevalence. CONCLUSIONS: Thus, although various pregnancy factors have been found to be associated with ASDs, the contribution of many of these factors to the recently observed ASD increase is likely minimal. |
T cell cytokines and the risk of blood stream infection in extremely low birth weight infants
Schelonka RL , Maheshwari A , Carlo WA , Taylor S , Hansen NI , Schendel DE , Thorsen P , Skogstrand K , Hougaard DM , Higgins RD . Cytokine 2011 53 (2) 249-255 Cytokines mediate the host immune response to infectious micro-organisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6, and IL-10) and inflammatory cytokines (Interferon-gamma [INF-gamma], tumor necrosis factor-beta [TNF-beta], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the five sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (p=0.01), and higher levels of the regulatory cytokines, IL-6 (p=0.01) and IL-10 (p<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population. |
Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders
Atladottir HO , Thorsen P , Ostergaard L , Schendel DE , Lemcke S , Abdallah M , Parner ET . J Autism Dev Disord 2010 40 (12) 1423-30 Exposure to prenatal infection has been suggested to cause deficiencies in fetal neurodevelopment. In this study we included all children born in Denmark from 1980, through 2005. Diagnoses of autism spectrum disorders (ASDs) and maternal infection were obtained through nationwide registers. Data was analyzed using Cox proportional hazards regression. No association was found between any maternal infection and diagnosis of ASDs in the child when looking at the total period of pregnancy: adjusted hazard ratio = 1.14 (CI: 0.96-1.34). However, admission to hospital due to maternal viral infection in the first trimester and maternal bacterial infection in the second trimester were found to be associated with diagnosis of ASDs in the offspring, adjusted hazard ratio = 2.98 (CI: 1.29-7.15) and adjusted hazard ratio = 1.42 (CI: 1.08-1.87), respectively. Our results support prior hypotheses concerning early prenatal viral infection increasing the risk of ASDs. |
Use of special education services among children with and without congenital gastrointestinal anomalies
Hamrick SE , Strickland MJ , Shapira SK , Autry A , Schendel D . Am J Intellect Dev Disabil 2010 115 (5) 421-32 Our objective was to evaluate the relationship between congenital gastrointestinal anomalies requiring neonatal surgery and neurodevelopmental outcome. Among the children born in metropolitan Atlanta during 1982-2001 who survived to age 1 year (N = 762,824), we identified children with congenital gastrointestinal anomalies via linkage with the Metropolitan Atlanta Congenital Defects Program and children who received special education services via linkage with the Special Education Database of Metropolitan Atlanta. Several modest increases in special education service use were observed among children with isolated congenital gastrointestinal anomalies; no association was statistically significant. Among children with Hirschsprung disease, gastroschisis, esophageal atresia, intestinal malrotation, bowel atresia, or imperforate anus who had multiple anomalies, we observed statistically significant increases in special education service use. |
The contribution of rare diseases to understanding the epidemiology of neurodevelopmental disabilities
Schendel D , Rice C , Cunniff C . Adv Exp Med Biol 2010 686 433-53 Our objective is to describe the contribution of rare diseases to our understanding of the epidemiology of neurodevelopmental disabilities (NDDs) by comparing and contrasting the epidemiologic features of NDDs classified according to key characteristics of developmental delay or deviance in such areas as behavior or cognition (the phenotypic approach; autism spectrum disorders and intellectual disability as examples) versus classification based on the identification of an etiologic diagnosis (the etiologic approach; 22q11.2 deletion syndrome and fragile X syndrome as examples). We suggest specific applications in which consideration of rare etiology-based NDDs might further our understanding of NDD epidemiology overall; what is needed to integrate the two classification approaches; and identify practical challenges in achieving that integration. Understanding commonalities and differences in the epidemiologic features of the phenotypically and etiologically defined NDD classifications provides a useful framework for furthering our understanding of the prevalence, distribution, and causes of NDDs, as well as delivering appropriate diagnostic resources, appropriate treatments, accurate prognostic information, and estimates of recurrence risk for these disorders. |
Multiplicity and early gestational age contribute to an increased risk of cerebral palsy from assisted conception: a population-based cohort study
Hvidtjorn D , Grove J , Schendel D , Svaerke C , Schieve LA , Uldall P , Ernst E , Jacobsson B , Thorsen P . Hum Reprod 2010 25 (8) 2115-23 BACKGROUND: This paper assesses the risk of cerebral palsy (CP) in children born after assisted conception compared with children born after natural conception (NC). METHODS: This population based follow-up study included all 588,967 children born in Denmark from 1995 to 2003. Assisted conception was defined as IVF, with or without ICSI, and ovulation induction (OI), with or without subsequent insemination. RESULTS: There were 33 139 (5.6%) children born in Denmark from 1995 to 2003 as a result of assisted conception and through to June 2009, 1146 (0.19%) children received a CP diagnosis. Children born after assisted conception had an increased risk of a CP diagnosis, crude hazard rate ratio (HRR) 1.90 (95% CI: 1.57-2.31) compared with NC children. Divided into IVF and OI children compared with NC children, the risk was HRR 2.34 (95% CI: 1.81-3.01) and HRR 1.55 (95% CI: 1.17-2.06), respectively. When we included the intermediate factors multiplicity and gestational age in multivariate models, the risk of CP in assisted conception disappeared. In general, children with CP born after assisted conception had similar CP subtypes and co-morbidities as children with CP born after NC. CONCLUSION: The risk of CP is increased after both IVF and OI. The increased risk of CP in children born after assisted conception, and in particular IVF, is strongly associated with the high proportion of multiplicity and preterm delivery in these pregnancies. A more widespread use of single embryo transfer warrants consideration to enhance the long-term health of children born after IVF. |
Interrelationship of cytokines, hypothalamic-pituitary-adrenal axis hormones, and psychosocial variables in the prediction of preterm birth
Pearce BD , Grove J , Bonney EA , Bliwise N , Dudley DJ , Schendel DE , Thorsen P . Gynecol Obstet Invest 2010 70 (1) 40-6 BACKGROUND/AIMS: To examine the relationship of biological mediators (cytokines, stress hormones), psychosocial, obstetric history, and demographic factors in the early prediction of preterm birth (PTB) using a comprehensive logistic regression model incorporating diverse risk factors. METHODS: In this prospective case-control study, maternal serum biomarkers were quantified at 9-23 weeks' gestation in 60 women delivering at <37 weeks compared to 123 women delivering at term. Biomarker data were combined with maternal sociodemographic factors and stress data into regression models encompassing 22 preterm risk factors and 1st-order interactions. RESULTS: Among individual biomarkers, we found that macrophage migration inhibitory factor (MIF), interleukin-10, C-reactive protein (CRP), and tumor necrosis factor-alpha were statistically significant predictors of PTB at all cutoff levels tested (75th, 85th, and 90th percentiles). We fit multifactor models for PTB prediction at each biomarker cutoff. Our best models revealed that MIF, CRP, risk-taking behavior, and low educational attainment were consistent predictors of PTB at all biomarker cutoffs. The 75th percentile cutoff yielded the best predicting model with an area under the ROC curve of 0.808 (95% CI 0.743-0.874). CONCLUSION: Our comprehensive models highlight the prominence of behavioral risk factors for PTB and point to MIF as a possible psychobiological mediator. |
Evaluation of a records-review surveillance system used to determine the prevalence of autism spectrum disorders
Avchen RN , Wiggins LD , Devine O , Van Naarden Braun K , Rice C , Hobson NC , Schendel D , Yeargin-Allsopp M . J Autism Dev Disord 2010 41 (2) 227-36 We conducted the first study that estimates the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a population-based autism spectrum disorders (ASD) surveillance system developed at the Centers for Disease Control and Prevention. The system employs a records-review methodology that yields ASD classification (case versus non-ASD case) and was compared with classification based on clinical examination. The study enrolled 177 children. Estimated specificity (0.96, [CI(.95) = 0.94, 0.99]), PPV (0.79 [CI(.95) = 0.66, 0.93]), and NPV (0.91 [CI(.95) = 0.87, 0.96]) were high. Sensitivity was lower (0.60 [CI(.95) = 0.45, 0.75]). Given diagnostic heterogeneity, and the broad array of ASD in the population, identifying children with ASD is challenging. Records-based surveillance yields a population-based estimate of ASD that is likely conservative. |
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