Prenatal maternal infection and risk for autism in offspring: A meta-analysis.

While prenatal maternal infection has received attention as a preventable and treatable risk factor for autism, findings have been inconsistent. This paper presents the results of a meta-analysis to determine whether the weight of the evidence supports such an association. Studies with a categorical diagnosis of autism as the outcome and an assessment of its association with prenatal maternal infection or fever (or the data necessary to compute this association) were included. A total of 36 studies met these criteria. Two independent reviewers extracted data on study design, methods of assessment, type of infectious agent, site of infection, trimester of exposure, definition of autism, and effect size. Analyses demonstrated a statistically significant association of maternal infection/fever with autism in offspring (OR = 1.32; 95% CI = 1.20-1.46). Adjustment for evident publication bias slightly weakened this association. There was little variation in effect sizes across agent or site of infection. Small differences across trimester of exposure were not statistically significant. There was some evidence that recall bias associated with status on the outcome variable leads to differential misclassification of exposure status. Nonetheless, the overall association is only modestly reduced when studies potentially contaminated by such bias are removed. Although causality has not been firmly established, these findings suggest maternal infection during pregnancy confers an increase in risk for autism in offspring. Given the prevalence of this risk factor, it is possible that the incidence of autism would be reduced by 12%-17% if maternal infections could be prevented or safely treated in a timely manner. LAY SUMMARY: This study is a meta-analysis of the association of maternal infection during pregnancy and subsequent autism in offspring. In combining the results from 36 studies of this association we find that a significant relationship is present. The association does not vary much across the types of infections or when they occur during pregnancy. We conclude that the incidence of autism could be substantially reduced if maternal infections could be prevented or safely treated in a timely manner.

The Need for a Clinically Useful Schema of Social Communication.

The recent Translations article by Bishop et al.1 draws much-needed attention to social communication (SC) in autism spectrum disorder (ASD) and to the need in autism research for treatment-sensitive measures of this key domain. In this context, the authors define SC ability as "the appropriate use and modulation of verbal and nonverbal behaviors during interactions with others"1(p. 555). "Appropriate" is defined relative to normative behaviors for developmental age and language level based on parent report. This stirred us to share our concern that clinicians, too, need ways to assess SC. Historically, observation of a patient's SC has not been part of the routine psychiatric mental status examination (MSE); clinicians lack even a common basic vocabulary for describing this vital domain. The DSM-52 does not explicitly define SC or distinguish it from social interaction (SI) or language, important terms also used in the criteria for ASD. All three terms are used interchangeably and inconsistently across the literature. Here we offer a definition of SC, distinguish it from SI and language, and propose a schema, or conceptual model, for observing and documenting an impression of a patient's SC.

Executive and non-executive functions in low birthweight/preterm adolescents with differing temporal patterns of inattention.

OBJECTIVE: This study assesses whether low birthweight/preterm (LBW/PT) adolescents with persistent inattention (PIA) have neuropsychological deficits that distinguish them from adolescents with school age limited inattention (SAL) and those largely unaffected (UA). METHOD: Three latent classes (PIA, SAL, UA), derived from an earlier analysis of a LBW/PT birth cohort were compared on non-executive and executive functioning measures assessed at age 16. RESULTS: The PIA class displayed the poorest performance on executive functioning, which was exaggerated in the context of lower IQ. The PIA and the SAL classes had poorer performance on non-executive functioning relative to the UA class. Both types of functioning mediated the relationship of class to school service use and grade retention. CONCLUSION: Neuropsychological impairment characterizes children and adolescents with inattention problems. Problems in executive functioning characterize the subset whose inattention persists through adolescence. Subsequent research can examine the potential for remediating these deficits to address academic and social problems.

Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder.

Gastrointestinal dysfunction in children with autism spectrum disorder (ASD) is common and associated with problem behaviors. This study describes the development of a brief, parent-report screen that relies minimally upon the child's ability to report or localize pain for identifying children with ASD at risk for one of three common gastrointestinal disorders (functional constipation, functional diarrhea, and gastroesophageal reflux disease). In a clinical sample of children with ASD, this 17-item screen identified children having one or more of these disorders with a sensitivity of 84%, specificity of 43%, and a positive predictive value of 67%. If found to be valid in an independent sample of children with ASD, the screen will be useful in both clinical practice and research.

ADHD Symptoms in a Non-Referred Low Birthweight/Preterm Cohort: Longitudinal Profiles, Outcomes, and Associated Features.

OBJECTIVE: This study's objective is to differentiate possible ADHD syndromes on the basis of symptom trajectories, prognosis, and associated clinical features in a high-risk cohort. METHOD: Latent class analysis of inattentive (IA) and hyperactive-impulsive (HI) symptoms in 387 non-disabled members of a regional low birthweight/preterm birth cohort who were evaluated for ADHD at 6, 9, and 16 years. Adolescent functional outcomes and other clinical features were examined across the classes. RESULTS: Three latent classes were identified: unaffected (modest IA and HI symptom prevalences at six, remitting by nine), school age limited (relatively high IA and HI symptom prevalences at six and nine, declining by 16), and persistent inattentive (high IA and HI prevalences at six and nine, with high IA levels persisting to 16). The persistent inattentive class was distinctively associated with poor functioning, motor problems, other psychiatric disorders, and social difficulties as indexed by a positive screen for autism spectrum disorder at 16. CONCLUSION: These findings differentiate a potential persistent inattentive syndrome relevant to ADHD evaluation and treatment.

Irritability and Problem Behavior in Autism Spectrum Disorder: A Practice Pathway for Pediatric Primary Care.

OBJECTIVE: Pediatric primary care providers (PCPs) caring for patients with autism spectrum disorder (ASD) often encounter irritability (vocal or motoric outbursts expressive of anger, frustration, or distress) and problem behavior (directed acts of aggression toward other people, self, or property). The Autism Intervention Research Network on Physical Health and Autism Speaks Autism Treatment Network charged a multidisciplinary workgroup with developing a practice pathway to assist PCPs in the evaluation and treatment of irritability and problem behavior (I/PB). METHODS: The workgroup reviewed the literature on the evaluation and treatment of contributory factors for I/PB in ASD. The workgroup then achieved consensus on the content and sequence of each step in the pathway. RESULTS: The practice pathway is designed to help the PCP generate individualized treatment plans based on contributing factors identified in each patient. These factors may include medical conditions, which the PCP is in a key position to address; functional communication challenges that can be addressed at school or at home; psychosocial stressors that may be ameliorated; inadvertent reinforcement of I/PB; and co-occurring psychiatric conditions that can be treated. The pathway provides guidance on psychotropic medication use, when indicated, within an individualized treatment plan. In addition to guidance on assessment, referral, and initial treatment, the pathway includes monitoring of treatment response and periodic reassessment. CONCLUSIONS: The pediatric PCP caring for the patient with ASD is in a unique position to help generate an individualized treatment plan that targets factors contributing to I/PB and to implement this plan in collaboration with parents, schools, and other providers.

Persistence of Cerebral Palsy Diagnosis: Assessment of a Low-Birth-Weight Cohort at Ages 2, 6, and 9 Years.

We examined the stability of nondisabling and disabling cerebral palsy at age 2 in a longitudinally followed tri-county low-birth-weight (<2000 g) birth cohort. A total of 1105 newborns were enrolled, 901 (81.5%) survived to age 2, and 86% (n = 777) were followed up. Of the 113 cerebral palsy diagnoses at age 2, 61 (9% of the cohort, n = 61/777) had disabling cerebral palsy and 52 (7%, n = 52/777) had nondisabling cerebral palsy. Of 48 followed children diagnosed with disabling cerebral palsy at age 2, 98% were again classified as having cerebral palsy at school age, and 1 had an uncertain cerebral palsy status. By contrast, 41% (n = 17) of the 43 children diagnosed with nondisabling cerebral palsy at age 2 were classified as not having cerebral palsy. Of the 517 followed children who were not diagnosed with cerebral palsy at age 2, 7% (n = 35) were classified as having late emerging nondisabling cerebral palsy at school age.

Association between transient hypothyroxinaemia of prematurity and adult autism spectrum disorder in a low-birthweight cohort: an exploratory study.

BACKGROUND: Transient hypothyroxinaemia of prematurity (THOP) is associated with increased risk of cerebral palsy and lower IQ in low-birthweight infants. This study explores whether THOP is also associated with increased risk of autism spectrum disorders (ASD). METHODS: This secondary analysis uses data from a birth cohort of newborns weighing 500 -2000 g (n = 1105) who were followed to age 21 years, when they were assessed for ASD in the second of a two-stage process. Of the 187 assessed at age 21, 14 had ASD. Neonatal thyroxine results were available for 12/14 and 165/173 participants diagnosed with and without ASD, respectively. THOP was defined as thyroxine z-score <-2.6. Unadjusted relative risks (RR) and confidence intervals (CI) were calculated. RESULTS: The mean neonatal thyroxine z-score in young adults diagnosed with ASD was 0.5 SD lower [95% CI -0.16, 1.06] than in those without ASD. Participants with THOP were at 2.5-fold greater risk of ASD (RR 2.5 [95% CI 0.7, 8.4]). While neither of these differences was statistically significant, in a secondary subgroup analysis of those whose mothers did not have hypertension during pregnancy, THOP significantly increased the RR for ASD (5.0 [95% CI 1.2, 20.5]). CONCLUSION: While the primary relation between THOP and ASD found here is not statistically significant, the magnitude of association and significant relationship observed in the subgroup whose mothers did not have hypertension during pregnancy suggest that it is worthy of further investigation.

Autism spectrum disorder is associated with ventricular enlargement in a low birth weight population.

OBJECTIVE: To determine the relation of neonatal cranial ultrasound abnormalities to autism spectrum disorders (ASD) in low birth weight (LBW) adult survivors, a population at increased ASD risk. STUDY DESIGN: This is a secondary analysis of a prospectively-followed regional birth cohort of 1105 LBW infants systematically screened for perinatal brain injury with cranial ultrasound in the first week of life and later assessed for ASD using a two-stage process [screening at age 16 years (n = 623) followed by diagnostic assessment at age 21 years of a systematically selected subgroup of those screened (n = 189)]; 14 cases of ASD were identified. For this analysis, cranial ultrasound abnormalities were defined as ventricular enlargement (indicative of diffuse white matter injury), parenchymal lesions (indicative of focal white matter injury), and isolated germinal matrix/intraventricular hemorrhage. RESULTS: Compared with no cranial ultrasound abnormalities, any type of white matter injury (ventricular enlargement and/or parenchymal lesion) tripled the risk for screening positively for ASD [3.0 (2.2, 4.1)]. However, the risk of being diagnosed with ASD depended on type of white matter injury. With ventricular enlargement, the risk of ASD diagnosis was almost seven-fold that of no cranial ultrasound abnormality [6.7 (2.3, 19.7)], and no elevated risk was found for parenchymal lesion without ventricular enlargement [1.8 (0.2, 13.6)]. Isolated germinal matrix/intraventricular hemorrhage did not increase risk for a positive ASD screen or diagnosis. CONCLUSION: In LBW neonates, cranial ultrasound evidence of ventricular enlargement is a strong and significant risk factor for subsequent development of rigorously-diagnosed ASD.

Prevalence of autism spectrum disorder in adolescents born weighing <2000 grams.

OBJECTIVE: To estimate the diagnostic prevalence of autism spectrum disorders (ASDs) in a low birth weight (LBW) cohort. METHODS: Participants belonged to a regional birth cohort of infants (N = 1105) born weighing <2000 g between October 1, 1984, and July 3, 1989, and followed up by periodic assessments to 21 years of age. At 16 years (n = 623), adolescents were screened for ASD using a wide net (previous professional diagnosis of an ASD or a score above a liberal cutoff on the Social Communication Questionnaire or the Autism Spectrum Symptoms Questionnaire). At 21 years (n = 189), 60% of screen positives and 24% of screen negatives were assessed for diagnoses of ASD by the Autism Diagnostic Observation Schedule or the Autism Diagnostic Interview-Revised. RESULTS: Samples retained at ages 16 and 21 years were representative of samples assessed at earlier ages except for lower levels of social risk. Of positive screens, 11 of 70 had ASD; of negative screens, 3 of 119 had ASD. The fractions of the 2 screening groups with ASD (14.3% in screen-positives and 2.5% in screen negatives) were weighted by fractions of screen-positives and screen-negatives among the adolescents (18.8% and 81.2%, respectively). This calculation produced an estimated prevalence rate of ASD in the entire cohort of 5% (31 of 623). CONCLUSIONS: The diagnostic prevalence of ASD in this LBW preterm cohort was higher than that reported by the Centers for Disease Control and Prevention for 8-year-olds in the general US population in 2006.

Neonatal head ultrasound abnormalities in preterm infants and adolescent psychiatric disorders.

CONTEXT: Infants born prematurely are at risk for a perinatal encephalopathy characterized by white and gray matter injuries that affect subsequent cortical development and neural connectivity and potentially increase risk for later psychiatric disorder. OBJECTIVE: To determine the relation of perinatal brain injury, as detected by neonatal head ultrasound, to psychiatric disorders in adolescents who were born prematurely. DESIGN: Prospective cohort. SETTING: Community. PARTICIPANTS: Adolescent survivors of a population-based low-birth-weight (<2000 g; 96% preterm; born 1984-1987) cohort (n = 1105) screened as neonates with serial head ultrasounds. Neonatal head ultrasound abnormalities were categorized as either (1) germinal matrix and/or intraventricular hemorrhage or (2) parenchymal lesions and/or ventricular enlargement. Of 862 eligible survivors, 628 (72.9%) were assessed at age 16 years. The sample consisted of 458 nondisabled survivors assessed in person. Main Outcome Measure  Adolescent current and lifetime psychiatric disorders assessed with parent report on the Diagnostic Interview Schedule for Children-IV. RESULTS: Compared with no abnormality, germinal matrix/intraventricular hemorrhage increased risk for current major depressive disorder (odds ratio, 2.7; 95% confidence interval, 1.0-6.8) and obsessive-compulsive disorder (9.5; 3.0-30.1). Parenchymal lesions/ventricular enlargement increased risk for current attention-deficit/hyperactivity disorder-inattentive type (odds ratio, 7.6; 95% confidence interval, 2.0-26.5), tic disorders (8.4; 2.4-29.6), and obsessive-compulsive disorder (7.6; 1.39-42.0). Parenchymal lesions/ventricular enlargement were not related to lifetime attention-deficit/hyperactivity disorder-inattentive type, but all other relations were similar for lifetime disorders. Control for other early risk factors did not alter these relations. Most of these relations persisted with control for concurrent cognitive or motor problems. CONCLUSION: In preterm infants, 2 distinct types of perinatal brain injury detectable with neonatal head ultrasound selectively increase risk in adolescence for psychiatric disorders in which dysfunction of subcortical-cortical circuits has been implicated.

Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report.

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

Indices of body and brain size at birth and at the age of 2 years: relations to cognitive outcome at the age of 16 years in low birth weight infants.

OBJECTIVE: To determine in low birth weight infants the relations of being small for gestational age at birth, microcephalic at birth, low weight for age at 2 years, and microcephalic at 2 years to full scale intelligence quotient (FSIQ) at the age of 16 years. METHODS: A prospective observational study of 422 of 837 eligible nondisabled low birth weight (<2000 g) adolescents from the newborn brain hemorrhage cohort with weight and head circumference at birth and at the age of 2 years in whom FSIQ was assessed with the Wechsler Abbreviated Scales of Intelligence at the age of 16 years. RESULTS: In a multiple regression analysis, being small for gestational age (beta = -0.14, p = .02) and microcephalic at 2 years (beta = -0.18, p < .001), but not low weight for age at 2 years or microcephaly at birth, had significant independent effects on 16-year FSIQ. After adjusting for pre-, peri-, and postnatal risk factors for poor cognitive performance, the independent effects of being small for gestational age (beta = -0.13, p = .004) and microcephalic at 2 years (beta = -0.13, p = .01) persisted. In this analysis, birth social risk had the largest significant independent effect on 16-year FSIQ (beta = -0.28, p < .001). CONCLUSIONS: Being small for gestational age at birth, but not low weight for age at 2 years, and microcephaly at 2 years, but not at birth, were independently related to FSIQ of nondisabled low birth weight adolescents, both with and without control for pre-, peri-, and postnatal risk factors.

Eating attitudes and weight concerns in female low birth weight adolescents.

OBJECTIVE: Studies of clinically referred patients have implicated low birth weight (LBW) as a possible risk factor for eating disorders. This study examines eating attitudes and weight concerns in nonreferred LBW female adolescents. METHOD: 274 LBW girls (mean age 15.9) belonging to a prospective regional LBW birth cohort completed the Eating Attitudes Test (EAT-26) and items from the Eating Symptoms Inventory on weight perception and weight dissatisfaction. RESULTS: Only 2.3% scored above threshold for eating disorder risk on the EAT-26. A total of 25% perceived themselves as overweight and 18.7% perceived themselves as underweight, while 63.4% desired to lose and 17.7% desired to gain weight. Girls who perceived themselves as overweight or desired to lose weight had higher mean EAT scores than those who did not. CONCLUSION: Nonreferred adolescent girls born at LBW are not, as a whole, at risk for abnormal eating attitudes and negative perceptions of their weight.

Weight concerns in male low birth weight adolescents: relation to body mass index, self-esteem, and depression.

OBJECTIVE: To compare weight concerns and self-reported body mass index (BMI) of low birth weight (LBW) adolescent boys to those of a normative sample and examine relationships among BMI, weight concerns, self-esteem, and depression in the LBW cohort. METHODS: LBW boys (n = 260; mean age, 16.0) belong to the Neonatal Brain Hemorrhage Study birth cohort. Normative boys (n = 305; mean age, 16.5) belong to the National Health and Nutrition Examination Survey. Both samples were assessed in 2001-2004 with self-report questionnaires. BMI was calculated from self-reported height and weight. Weight perception and weight dissatisfaction were assessed with the Eating Symptoms Inventory. In LBW boys, self-esteem was measured with the Rosenberg Self-Esteem Scale and depression with the Beck Depression Inventory. RESULTS: Based on self-reported height and weight, LBW boys were more likely to be healthy weight or underweight and less likely to be overweight than normative boys. Despite having healthier self-reported BMIs, LBW boys reported more weight concerns than the normative sample. A total of 46.9% of LBW boys perceived their weight as abnormal, and 76.5% desired weight change. Weight concerns in LBW boys mostly reflected a perception of being underweight (31.2% of the cohort) and a desire to gain weight (47.5% of the cohort), although only 6.5% were clinically underweight. Weight concerns, but not BMI, were related to clinical depression and lower self-esteem. CONCLUSIONS: LBW adolescent boys are at high risk of experiencing weight concerns. Weight concerns rather than BMI are associated with emotional problems in LBW boys.

Motor and cognitive outcomes in nondisabled low-birth-weight adolescents: early determinants.

OBJECTIVES: To describe motor and cognitive outcomes in nondisabled low-birth-weight (LBW) adolescents and to determine the relation of specific prenatal, perinatal, and neonatal risk factors to these outcomes. DESIGN: A prospective epidemiological study. SETTING: An adolescent follow-up of a regional LBW (<2000 g) cohort born in or admitted to 3 hospitals between September 1, 1984, and June 30, 1987 (n = 1105). Of 862 eligible survivors, 628 (72.9%) underwent assessment at a mean age of 16 years; of these, 33 had severe disability that precluded psychometric evaluation. The 474 nondisabled adolescents undergoing assessment at home had slightly less social risk at birth than did all other nondisabled eligible adolescents. PARTICIPANTS: The 474 nondisabled LBW adolescents assessed at home. Main Exposures Basic birth characteristics (social risk, sex, fetal growth ratio, and gestational age), neonatal cranial ultrasound abnormalities, and other early medical complications. MAIN OUTCOME MEASURES: Riley Motor Problems Inventory and Wechsler Abbreviated Scales of Intelligence. RESULTS: Nondisabled LBW adolescents had an excess of motor problems compared with the normative sample. The IQ scores, although within the normal range, were significantly lower than population norms. Independent predictors of total motor problems included male sex, white matter injury on neonatal ultrasound, and days of ventilation. Independent predictors of lower Full Scale IQ scores included social disadvantage, fetal growth ratio, and white matter injury on neonatal ultrasound. CONCLUSIONS: Specific prenatal, perinatal, and neonatal risk factors influence motor and cognitive performance in nondisabled LBW survivors well into adolescence, even when controlling for social risk. Advances in maternal-fetal and neonatal care can substantially improve these long-term outcomes.

Menstrual functioning and psychopathology in a county-wide population of high school girls.

OBJECTIVE: To examine the association between menstrual functioning and depressive disorder symptoms (DDS), obsessive-compulsive disorder symptoms (OCDS), and eating disorder symptoms (EDS) in high school girls. METHOD: Survey data from a county-wide high school population (completion rate 91%) were used. Associations between menstrual indices and scores above clinical cutoff on the Beck Depression Inventory, Leyton Obsessive-Compulsive Inventory-Child Version, and Eating Attitudes Test were examined by using logistic regression ( = 2,547 girls). RESULTS: Controlling for chronological age and other risk factors, late menarche was associated with DDS (odds ratio [OR] = 2.26, 95% confidence interval [CI] = 1.16-4.18). Gynecological year 1 (GY1) was associated with DDS (OR = 3.13, CI = 1.23-7.33), EDS (OR = 3.11, CI = 1.00-8.09), and OCDS, both number (OR = 5.75, CI = 1.79-15.74) and interference (OR = 12.55, CI = 3.20-41.4). Secondary amenorrhea was associated with DDS (OR = 1.94, CI = 11.30-2.84) and EDS (OR = 2.32, CI = 1.51-3.49); polymenorrhea with EDS (OR = 1.92, CI = 1.27-2.86); and irregular cycles with EDS (OR = 1.70, CI = 1.11-2.54) and DDS (OR = 1.76, CI = 11.21-2.53). CONCLUSIONS: In high school girls, late menarche, GY1, and menstrual cycle abnormalities are associated differentially with DDS, OCDS, and EDS.