Prenatal, perinatal, and neonatal risk factors of autism spectrum disorder.

BACKGROUND: We explored the association of 29 previously reported neonatal, perinatal, and prenatal conditions, and exposures with later diagnosis of autism spectrum disorder (ASD) in a large sample of children followed over multiple years. METHODS: A retrospective case-cohort study was formed using the Military Health System database. Cases were identified by International Classification of Diseases, Ninth Revision codes for ASD between 2000 and 2013, and were matched 3:1 with controls on sex, date of birth, and enrollment time frame. Exposures included 29 conditions previously associated with ASD; 17 prenatal conditions and their pharmaceutical treatment, 5 perinatal conditions, and 6 neonatal conditions. RESULTS: A total of 8,760 children diagnosed with ASD between the ages of 2 and 18 years were matched with 26,280 controls. ASD is associated with maternal mental illness, epilepsy, obesity, hypertension, diabetes, polycystic ovary syndrome, infection, asthma, assisted fertility, hyperemesis, younger maternal age, labor complications, low birth weight, infant infection, epilepsy, birth asphyxia, and newborn complications. The greatest increased risk was associated with infant epilepsy (odds ratio (OR) 7.57 (5.68-10.07)), maternal mental health (OR 1.80 (1.65-1.96)), and epilepsy (OR 1.60 (1.02-2.50)) medications. CONCLUSION: ASD is associated with a range of prenatal, perinatal, and neonatal factors, with the highest magnitude associations with maternal medication use and neonatal seizure.

Disparities in Access to Healthcare Transition Services for Adolescents with Down Syndrome.

OBJECTIVE: To compare healthcare transition planning in adolescents with Down syndrome with adolescents with other special healthcare needs. STUDY DESIGN: Data were drawn from the 2009-2010 National Survey of Children with Special Health Care Needs, a nationally representative sample with 17 114 adolescents aged 12-17 years. Parents were asked whether providers and the study child had discussed shifting to an adult provider, changing healthcare needs, maintaining health insurance coverage, and taking responsibility for self-care. The transition core outcome was a composite measure based on the results of these 4 questions. Multivariable logistic regression determined the association between Down syndrome and the transition core outcome as well as each of the 4 individual component measures. RESULTS: Although 40% of adolescents with other special healthcare needs met the transition core outcome, 11.0% of adolescents with Down syndrome met this outcome. Adolescents with Down syndrome were less likely to be encouraged to take responsibility for their health (32.2% vs 78.4%). After adjustment for demographic, socioeconomic, and health-related factors, adolescents with Down syndrome had 4 times the odds of not meeting the transition core outcome. For the component measures, Down syndrome adolescents had 4 times the odds of not being encouraged to take responsibility for self-care. Medical home access increased the odds of transition preparation. CONCLUSIONS: Adolescents with Down syndrome experience disparities in access to transition services. Provider goals for adolescents with Down syndrome should encourage as much independence as possible in their personal care and social lives.

Association of Autism Spectrum Disorders and Inflammatory Bowel Disease.

Autism spectrum disorders (ASD) and inflammatory bowel disease (IBD) both have multifactorial pathogenesis with an increasing number of studies demonstrating gut-brain associations. We aim to examine the association between ASD and IBD using strict classification criteria for IBD. We conducted a retrospective case-cohort study using records from the Military Health System database with IBD defined as having one encounter with an ICD-9-CM diagnostic code for IBD and at least one outpatient prescription dispensed for a medication to treat IBD. Children with ASD were more likely to meet criteria for Crohn's disease (CD) and Ulcerative colitis (UC) compared to controls. This higher prevalence of CD and UC in children with ASD compared to controls confirms the association of ASD with IBD.

Autism Spectrum Disorders and Metabolic Complications of Obesity.

OBJECTIVES: To assess for an increased risk of obesity, type 2 diabetes mellitus, hypertension, hyperlipidemia, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis in children with autism spectrum disorders (ASD). Additionally, to determine the rates of prescribed treatment for obesity-related metabolic disorders and to determine whether treatment with psychotropic medications is associated with the development of obesity for children with ASD. STUDY DESIGN: A retrospective 1:5 case-control study was performed by use of the Military Health System database from October 2000 to September 2013. For children with ASD and matched controls, International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes for obesity, type 2 diabetes mellitus, hypertension, hyperlipidemia, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, and prescriptions were obtained. Conditional logistic regression determined ORs and 95% CIs. RESULTS: A total of 48 762 individuals with ASD and 243 810 matched controls were identified. Children with ASD had significantly greater odds of having obesity (OR 1.85; 95% CI 1.78-1.92), having obesity-related disorders, and being prescribed a medication when they had these diseases. In children with ASD, mood stabilizers, antipsychotics, antiepileptic drugs, and selective serotonin reuptake inhibitors were associated with obesity. CONCLUSIONS: Children with ASD have an increased risk of obesity and obesity-related metabolic disorders. They are more likely to be prescribed medications to treat these complications, suggesting they may have more severe disease. There is a significant association between the use of some psychotropic categories and a diagnosis of obesity, suggesting that obesity in children with ASD may be partially iatrogenic.

Feeding Disorders in Children With Autism Spectrum Disorders Are Associated With Eosinophilic Esophagitis.

OBJECTIVES: Eosinophilic esophagitis (EoE) can present as food selectivity or feeding disorders in children. Children with autism spectrum disorders (ASDs) commonly demonstrate behavioral food selectivity in type and texture, which often leads to the diagnosis of feeding disorder. We sought to evaluate the association of ASD with EoE. METHODS: A retrospective matched case-cohort study was performed using the Military Health System database from October 2008 to September 2013. We performed a 1:5 case-control match by age, sex, and enrollment timeframe. Feeding disorders, EoE, and atopic disorders were defined using diagnostic and procedure codes. RESULTS: There were 45,286 children with ASD and 226,430 matched controls. EoE was more common in children with ASD (0.4%) compared with controls (0.1%). Feeding disorders were associated with EoE in both children with ASD and controls. Feeding disorders also had a higher odds ratio for EoE compared with other atopic conditions, among both children with ASD (7.17, 95% confidence interval [CI] 4.87-10.5) and controls (11.5, 95% CI 7.57-17.5). Compared with controls with a feeding disorder, children with ASD and a feeding disorder had no difference in the rate of diagnosed EoE (0.85, 0.95% CI 0.39-1.88). CONCLUSIONS: Children with ASD are more likely to be diagnosed with EoE compared with controls; however, among children with feeding disorders, there is no difference in the odds of EoE. A diagnosis of feeding disorder was strongly associated with EoE. Feeding disorders in children with ASD should not be assumed to be solely behavioral and an esophagogastroduodenoscopy should be performed to evaluate for EoE.

Prevalence of Diagnosed Sleep Disorders and Related Diagnostic and Surgical Procedures in Children with Autism Spectrum Disorders.

OBJECTIVE: Sleep disorders are common and important comorbid conditions in children with autism spectrum disorder (ASD) and can contribute to cognitive and behavioral problems. Sleep-disordered breathing (SDB) is a diagnosable and treatable cause of behavioral problems in children. We aimed to quantify the relative risk for children with ASD versus controls of being diagnosed with sleep disorders including SDB and undergoing related diagnostic and surgical procedures. METHOD: This retrospective case-cohort study included 48,762 children with ASD aged 2 to 18 years enrolled in the military health system (MHS) from 2000 to 2013. Children with ASD were matched 1:5 by birthdate, sex, and enrollment time to children without an ASD diagnosis. The MHS database was queried for International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for sleep disorders or ICD-9-CM and Current Procedural Terminology codes for diagnostic and surgical procedures. Relative risks (RR) and 95% confidence intervals (CI) were determined with binary Poisson regression conditional on the match and adjusting for confounders. RESULTS: Children with ASD were at higher risk of receiving any sleep disorder diagnosis (RR: 1.97 [95% CI, 1.91-2.02]) including SDB (RR: 1.96 [95% CI, 1.88-2.05]). Children with ASD also were at increased risk of undergoing polysomnography (RR: 3.74 [95% CI, 3.56-3.93]) and sleep disorder-related surgery (RR: 1.50 [95% CI, 1.46-1.54]). CONCLUSION: Children with ASD are more likely to be given a sleep disorder diagnosis including SDB and are more likely to undergo related diagnostic and surgical procedures compared with controls without ASD.

Otitis Media and Related Complications Among Children with Autism Spectrum Disorders.

Acute otitis media (AOM) symptoms can be masked by communication deficits, common to children with autism spectrum disorders (ASD). We sought to evaluate the association between ASD and otitis media. Using ICD-9-CM diagnostic codes, we performed a retrospective case-cohort study comparing AOM, and otitis-related diagnoses among children with and without ASD. Children with ASD had a significantly increased rate of AOM, otitis media with effusion, otorrhea, and PE tube placement. Children with ASD were more than twice as likely to develop mastoiditis, and to undergo mastoidectomy and tympanoplasty. Children with ASD are more likely to have middle ear infections and otitis-related complications, highlighting the importance of routine middle ear examinations and close attention to hearing impairment in this population.

Association of Autism Spectrum Disorders With Neonatal Hyperbilirubinemia.

Autism spectrum disorders (ASD) are a common neurodevelopmental disorder of unknown etiology. Studies suggest a link between autism and neonatal jaundice. A 1:3 matched case-control study was conducted with children enrolled in the Military Health System born between October 2002 and September 2009. Diagnostic and procedure codes were used for identifying ASD and hyperbilirubinemia. Two definitions for hyperbilirubinemia were evaluated: an inpatient admission with a diagnosis of jaundice and treatment with phototherapy. A total of 2917 children with ASD and 8751 matched controls were included in the study. After adjustment, there remained an association between ASD in children and an admission with a diagnosis of jaundice (odds ratio = 1.18; 95% confidence interval = 1.06-1.31; P = .001) and phototherapy treatment (odds ratio = 1.33; 95% confidence interval = 1.04-1.69; P = .008). Children who develop ASD are more likely to have an admission with a diagnosis of jaundice in the neonatal period and more likely to require treatment for this jaundice.

Complementary and alternative medicine used by children in military pediatric clinics.

OBJECTIVES: The objective of this study was to evaluate the prevalence, types, perceived effects, and factors that influence the use of complementary and alternative medicine (CAM) by military children. DESIGN: A parent survey was administered in two military general pediatric clinics from June to September 2009. Parents completed surveys about their children including the following items: demographic information, a list of specific CAM therapies, family CAM use, and child health status. RESULTS: Caregivers completed 278 surveys. The overall use of CAM was 23%. The most common type of CAM used was herbal therapy (34%). The CAM therapies most commonly reported to be very helpful were special diets (67%), melatonin (57%), vitamins and minerals used at doses higher than the recommended daily allowance (50%), and massage therapy (50%). The majority of users reported no side-effects (96%). Among CAM users, 53% had discussed their CAM use with a physician and 47% had seen a CAM practitioner. Factors associated with CAM use in multiple regression analysis included chronic conditions (p = 0.001), parent/sibling use of CAM (p < 0.001), and parent age over 30 years (p = 0.02). Primary sources of CAM information were friends and family (68%) and doctors (44%). Common reasons for using CAM were to promote general health (70%), to relieve symptoms (56%), and to improve quality of life (48%). Eighty percent (80%) of all respondents indicated they would use CAM if recommended by a physician. CONCLUSIONS: In this military population with access to universal health care, CAM use is higher than the U.S. national average and nearly double that of the 2007 National Health Interview Survey study. Patients with chronic conditions, family members using CAM, and parental age over 30 years are more likely to use CAM. CAM is perceived as helpful with minimal to no side-effects. Pediatricians should inquire about CAM use and be prepared to provide guidance on this topic.

Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations.

PURPOSE: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type. METHODS: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. RESULTS: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. CONCLUSIONS: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations.

Ghrelin levels in young children with Prader-Willi syndrome.

OBJECTIVE: To explore the hypothesis that high ghrelin levels contribute to obesity in Prader-Willi syndrome (PWS), we assessed whether the increased levels observed in older persons with PWS exist in very young children, before the onset of hyperphagia. STUDY DESIGN: We measured ghrelin levels in nine children with PWS (17-60 months of age) and eight healthy control subjects of equivalent body mass index (BMI), age, and sex. RESULTS: PWS and control groups had equivalent BMI (16.8 +/- 1.4 vs 16.1 +/- 0.9 kg/m(2), respectively; P = .24), age (37.8 +/- 15.4 vs 50.3 +/- 17.7 months; P = .14), and sex. PWS and control groups also had equivalent fasting levels of total ghrelin (787 +/- 242 vs 716 +/- 135 pg/mL, respectively; P = .24), bioactive ghrelin (102 +/- 35 vs 91 +/- 23 pg/mL; P = .45), insulin, and glucose. Ghrelin correlated negatively with BMI among controls (r = -0.760, P = .029) but not PWS (r = 0.015, P = .97). CONCLUSIONS: Children <5 years of age with PWS, who had not yet developed hyperphagia or excessive obesity, had normal ghrelin levels, in contrast with the hyperghrelinemia of older, hyperphagic people with PWS. It is possible that ghrelin levels increase suddenly before hyperphagia develops.