Gestational Age and Autism Spectrum Disorder: Trends in Risk Over Time.

Autism Spectrum Disorder (ASD) is a serious neurodevelopmental disorder. Several previous studies have identified preterm birth as a risk factor for ASD but none has studied whether the association between gestational age and ASD has changed over time. This is a Danish population-based follow-up study including live-born singletons born in Denmark between 1980 and 2009, identified in the Danish Medical Birth Registry, a study population of 1,775,397 children. We used a Cox regression model combined with spline to study the risk for ASD by gestational age across three decades of birth cohorts. We included 19,020 children diagnosed with ASD. Across all birth year cohorts, we found that the risk of being diagnosed with ASD increased with lower gestational age (P-value: <0.01). Across all gestational weeks, we found a statistically significant higher risk estimates in birth cohort 1980 to 1989, compared to birth cohorts 1990 to 1999 and 2000 to 2009, respectively. No statistically significant difference in risk estimates was observed between birth cohort 1990 to 1999 and 2000 to 2009. The observed time trend in risk of ASD after preterm birth may reflect: (1) a change in the risk profile of persons with ASD due to the broadening of ASD diagnostic criteria over time; or (2) improved neonatal care for low GA infants, which has reduced risk of adverse outcomes like ASD in preterm children.

ViPAR: a software platform for the Virtual Pooling and Analysis of Research Data.

BACKGROUND: Research studies exploring the determinants of disease require sufficient statistical power to detect meaningful effects. Sample size is often increased through centralized pooling of disparately located datasets, though ethical, privacy and data ownership issues can often hamper this process. Methods that facilitate the sharing of research data that are sympathetic with these issues and which allow flexible and detailed statistical analyses are therefore in critical need. We have created a software platform for the Virtual Pooling and Analysis of Research data (ViPAR), which employs free and open source methods to provide researchers with a web-based platform to analyse datasets housed in disparate locations. METHODS: Database federation permits controlled access to remotely located datasets from a central location. The Secure Shell protocol allows data to be securely exchanged between devices over an insecure network. ViPAR combines these free technologies into a solution that facilitates 'virtual pooling' where data can be temporarily pooled into computer memory and made available for analysis without the need for permanent central storage. RESULTS: Within the ViPAR infrastructure, remote sites manage their own harmonized research dataset in a database hosted at their site, while a central server hosts the data federation component and a secure analysis portal. When an analysis is initiated, requested data are retrieved from each remote site and virtually pooled at the central site. The data are then analysed by statistical software and, on completion, results of the analysis are returned to the user and the virtually pooled data are removed from memory. CONCLUSIONS: ViPAR is a secure, flexible and powerful analysis platform built on open source technology that is currently in use by large international consortia, and is made publicly available at [http://bioinformatics.childhealthresearch.org.au/software/vipar/].

A Descriptive Study on the Neonatal Morbidity Profile of Autism Spectrum Disorders, Including a Comparison with Other Neurodevelopmental Disorders.

The aim of this study was to describe the profile of specific neonatal morbidities in children later diagnosed with autism spectrum disorder (ASD), and to compare this profile with the profile of children with hyperkinetic disorder, cerebral palsy, epilepsy or intellectual disability. This is a Danish population based cohort study, including all children born in Denmark from 1994, through 2010, and surviving the first year of life. Children with ASD as a whole have significantly elevated rates of a range of neurologic, respiratory, inflammatory, and metabolic problems in the neonatal period compared to the general population, but there are few if any indicators of a distinctive neonatal morbidity profile in ASD compared to other neurodevelopmental outcomes.

Interrelationship of cytokines, hypothalamic-pituitary-adrenal axis hormones, and psychosocial variables in the prediction of preterm birth.

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.

Maternal plasma cytokines in early- and mid-gestation of normal human pregnancy and their association with maternal factors.

Few studies have assessed longitudinal changes in circulating cytokine levels during normal pregnancy. We have examined the natural history of maternal plasma cytokines from early- to mid-pregnancy in a large, longitudinal cohort. Multiplex flow cytometry was used to measure interleukin (IL)-2, IL-6, IL-12, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) in early- (median [IQR]: 8.5 weeks [7.1, 10.0]) and mid-pregnancy (25.0 [24.1, 26.1]) from 1274 Danish women delivering singleton term infants. GM-CSF decreased from early- to mid-pregnancy (median percent change [95% CI]: -51.3% [-59.1%, -41.8%]), while increases were observed in IL-6 (24.3% [4.6%, 43.9%]), IL-12 (21.3% [8.9%, 35.7%]) and IFN-gamma (131.7% [100.2%, 171.6%]); IL-2 (-2.8% [-11.5%, 0.0%]) and TNF-alpha (0% [-5.9%, 25.6%]) remained stable. Positive correlations were found between all cytokines, both in early- and mid-pregnancy (all p<0.001). Early- and mid-pregnancy levels were rank-correlated for IL-2, IL-12, TNF-alpha and GM-CSF, but not IL-6 and IFN-gamma; these correlations were generally weaker than correlations between different cytokines at a single time point in pregnancy. Women with a pre-pregnancy BMI <18.5 had reduced levels of IFN-gamma and GM-CSF compared to women in other BMI categories, while women aged >or=35 years had elevated IL-2, IL-6, TNF-alpha and IFN-gamma. Early-pregnancy levels of TNF-alpha were higher in women with a prior preterm delivery. Cytokine levels were not associated with gravidity. In conclusion, cytokines were detected in plasma during early- and mid-pregnancy, with IL-6, IL-12, IFN-gamma and GM-CSF concentrations varying over pregnancy. Concentrations may depend on BMI, maternal age and prior preterm delivery.

Identification of biological/biochemical marker(s) for preterm delivery.

Fetal and neonatal mortality and morbidity rates are strongly associated with gestational age for delivery: the risk for poor outcome increases as gestational age decreases. Attempts to predict preterm delivery (PTD, spontaneous delivery before 37 weeks' gestation) have been largely unsuccessful, and rates of PTD have not improved in recent decades. More recently, the reported associations between infections in pregnancy and PTD suggest preventive initiatives that could be taken. The overall objective of the current study is to assess whether specific markers of infection (primarily interleukin (IL) 1beta, tumour necrosis factor (TNF) alpha, IL-6, and IL-10) obtained from maternal blood during pregnancy, alone or in combination with other risk factors for PTD, permit identification of women at risk for spontaneous PTD. To achieve this objective, data are obtained from two Danish prospective cohort studies involving serial collection of maternal blood samples, newborn cord blood samples, and relevant confounders and other risk factors for PTD. The first study consists of a completed Danish regional cohort of 3000 pregnant women enrolled in a study of microbiological causes of PTD, upon which a nested case-control study of PTD in 84 cases and 400 controls has been performed. The second study is a nested case-control study of 675 PTD cases (equally divided into three gestational age categories of 24-29 weeks' gestation, 30-33 weeks' gestation, and 34-36 weeks' gestation) and 675 controls drawn from the ongoing Danish National Birth Cohort study of 100 000 pregnant women enrolled during 1997-2001. The second study will provide the opportunity to refine and retest hypotheses from the first study, as well as to explore new hypotheses. Our preliminary work suggests that a single predictive marker effectively accounting for a large proportion of PTD is unlikely to be found. Rather, a search for multiple markers indicative of the multifactorial aetiology of PTD is likely to be more successful. Knowledge gained from the proposed studies will be implemented in a third, clinical intervention study against PTD. The first phase of the clinical intervention study will be to establish a risk-assessment model based on the "best" combination of biological/biochemical measures and other factors associated with PTD in order to identify pregnant women at very high risk of PTD. The second phase will be to apply an intervention model of tailored obstetric care to the very high-risk pregnant women for PTD identified in phase one. The intervention will be carried out against each specific risk factor associated with PTD identified for the individual. The aim is to reduce the risk for PTD attributed to the combination of risk factors included in the clinical intervention study.

Infection in pregnancy and cerebral palsy.

Infections in pregnancy, including the most common congenital infections (TORCH: toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus), are known causes of long-term neurodevelopmental disabilities, although the proportion of children with specific disabilities attributable to TORCH infections appears to be 5% to 10% or less. Intrauterine infection, especially subclinical infection of the kind associated with preterm birth, is under investigation as a cause of neurodevelopmental disability. These studies have focused almost exclusively on cerebral palsy. Summary estimates from a published meta-analysis suggest that chorioamnionitis is associated with a twofold increased risk of cerebral palsy in preterm and a fivefold increased risk in term children. In some studies, cytokine levels in amniotic fluid or newborn blood have also been found to be significantly elevated in preterm and term children with cerebral palsy compared to controls. These data suggest that factors related to the fetal inflammatory response, including cytokines, may be causal agents in brain damage and neurodevelopmental disability associated with intrauterine infection. We need to greatly improve both our understanding of and our ability to measure the relevant exposures related to infection and inflammation, to further understand differences in the association between intrauterine infection and cerebral palsy relative to gestational age, and to investigate a broad range of neurodevelopmental outcomes as potential adverse effects of intrauterine infection.

Tocolytic magnesium sulfate exposure and risk of cerebral palsy among children with birth weights less than 1,750 grams.

The authors examined the relation between intrapartum magnesium sulfate exposure and risk of cerebral palsy in a case-control study of low birth weight children designed to control for confounding by the clinical indications for magnesium in pregnancy. Case children (n = 97) included all singleton children with cerebral palsy who were born in 1985-1989 in Atlanta, Georgia with a birth weight less than 1,750 g and whose mothers had not had a hypertension-related disease during pregnancy. Control children (n = 110) were randomly selected from the infant survivors using identical selection criteria. Data on magnesium sulfate exposure, labor and delivery, and infant characteristics were abstracted from hospital records. The authors found no association between exposure to magnesium sulfate and cerebral palsy risk (odds ratio = 0.9; 95% confidence interval: 0.3, 2.6) either in all children or in subgroups with varying likelihoods for exposure to magnesium. However, the association did vary by birth weight, with a protective effect being seen in children born weighing less than 1,500 g and an elevated risk in children with birth weights of 1,500 g or more; all confidence intervals included 1.0 except for the combined <1,500 g group. Several ongoing randomized clinical trials of magnesium and cerebral palsy may shed more definitive light on this relation.

Relation between very low birth weight and developmental delay among preschool children without disabilities.

The authors examined the relation between very low birth weight (VLBW: < 1,500 g) and possible developmental delay (DELAY) in the absence of frank developmental disability among young children. The prevalence of DELAY in a population-based cohort (Missouri resident births born from December 1989 through March 1991) of singleton VLBW children (n = 367) was compared with the prevalence of DELAY among both moderately low birth weight (MLBW: 1,500-2,499 g; n = 553) and normal birth weight (NBW: > or = 2,500 g; n = 555) singleton control children. DELAY was defined by nine measures of performance on the Denver Developmental Screening Test II at a median adjusted age of 15 months (range: 9-34 months). Subjects were asymptomatic for disabling conditions at developmental follow-up. Apparently well VLBW children were consistently at greater risk for both moderate and severe measures of DELAY and for DELAY across four functional areas than were either the MLBW (adjusted odds ratios: 1.4-2.7) or NBW children (adjusted odds ratios: 2.1-6.3). The greatest prevalence of DELAY tended to be among appropriate-for-gestational age VLBW children who were also the most premature. This study supports developmental follow-up of nondisabled VLBW children because of the significantly elevated risk for DELAY among apparently normal infants.

Prenatal magnesium sulfate exposure and the risk for cerebral palsy or mental retardation among very low-birth-weight children aged 3 to 5 years.

OBJECTIVE: To examine the relationship between prenatal magnesium sulfate exposure and the risk for cerebral palsy (CP) or mental retardation (MR) among very low-birth-weight (VLBW; <1500 g) children. Secondarily, to investigate the effect of prenatal magnesium sulfate exposure on VLBW infant mortality. DESIGN: Cohort study with follow-up to 1 year of age; a subset followed up to 3 to 5 years. SETTING: Twenty-nine Georgia counties, including the 5-county Atlanta metropolitan area. PARTICIPANTS: All VLBW births (N=1097) occurring during 2 years (1986-1988); all metropolitan Atlanta VLBW neonates who survived infancy (N=519). MAIN OUTCOME MEASURES: Infant mortality as determined from vital statistics records. Development of CP or MR by 3 to 5 years of age among metropolitan Atlanta VLBW survivors as determined from the Metropolitan Atlanta Developmental Disabilities Surveillance Program. RESULTS: For the entire cohort, there was no association between prenatal magnesium sulfate exposure and infant mortality (adjusted rate ratio, 1.02; 95% confidence interval [CI], 0.83-1.25). Among Atlanta-born survivors, those exposed to magnesium sulfate had a lower prevalence of CP or MR than those not exposed (CP: magnesium sulfate, 0.9%, no magnesium sulfate, 7.7%, crude odds ratio [OR], 0.11, 95% CI, 0.02-0.81; MR: magnesium sulfate, 1.8%, no magnesium sulfate, 5.8%, crude OR, 0.30, 95% CI, 0.07-1.29). Multivariable adjustment had no appreciable effect on the ORs for CP or MR, but the CIs included 1.0. CONCLUSIONS: A reduced risk for CP, and possibly MR, among VLBW children is associated with prenatal magnesium sulfate exposure. The reduced risk for childhood CP or MR does not appear to be due to selective mortality of magnesium sulfate-exposed infants.

Prevalence of selected developmental disabilities in children 3-10 years of age: the Metropolitan Atlanta Developmental Disabilities Surveillance Program, 1991.

PROBLEM/CONDITION: Serious developmental disabilities affect approximately 2% of school-age children and are lifelong conditions that incur substantial financial and societal costs. REPORTING PERIOD: January 1991-December 1991. DESCRIPTION OF SYSTEM: The Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) monitors the prevalence of four serious developmental disabilities--mental retardation, cerebral palsy, vision impairment, and hearing impairment--among children 3-10 years of age in the five-county metropolitan-Atlanta area. Children who have at least one of the four developmental disabilities are ascertained through annual review of records at schools, hospitals, and other sources. RESULTS AND INTERPRETATION: During 1991, rates for mental retardation varied by age, race, and sex; rates ranged from 5.2 per 1,000 children to 16.6 per 1,000 children. Regardless of the absolute rate of mental retardation in each of the age-, race-, and sex-specific categories, severe mental retardation (i.e., an intelligence quotient of <50) accounted for one third of all cases. The overall crude rate of cerebral palsy was 2.4 per 1,000 children; however, the rate was higher among black children (3.1 per 1,000 children) than among white children (2.0 per 1,000 children). The rate of moderate to severe hearing impairment was 1.1 per 1,000 children, and the rate of vision impairment was 0.8 per 1,000 children. Rates of hearing impairment were higher among black males than among children in the other race and sex groups, whereas rates for vision impairment varied only slightly between these groups. The rates of the developmental disabilities were not adjusted for possible confounding factors (e.g., maternal education, family income, and various medical conditions). Consequently, the variation in rates may reflect social or other characteristics unique to the study population. ACTIONS TAKEN: MADDSP data will be used to direct early childhood intervention efforts to reduce the prevalence of these four developmental disabilities. MADDSP data also are being used to measure progress toward the year 2000 national objectives for the prevention of serious mental retardation.