Risk for cognitive deficit in a population-based sample of U.S. children with autism spectrum disorders: Variation by perinatal health factors

doi:10.1016/j.dhjo.2009.12.001

Disability and Health Journal

Volume 3, Issue 3, July 2010, Pages 202-212

https://doi.org/10.1016/j.dhjo.2009.12.001 Get rights and content

Abstract

Background

From 30% to 60% of children with an autism spectrum disorder (ASD) have an IQ measure that falls in the intellectual disability (ID) range. It is not well studied whether, for children within this ASD subgroup, there is variation in the risk for low IQ based on a child's perinatal risk factors.

Objective/Hypotheses

We assessed whether preterm delivery and term small-for-gestational-age (tSGA) were associated with various measures of cognitive deficit among children with ASDs.

Methods

A sample of 1129 singleton children born in 1994 and identified through school and health record review as having an ASD by age 8 years were selected from a U.S. population-based surveillance network. Mean IQ and dichotomous IQ outcomes indicating various levels of ID were examined according to whether a child was preterm (<37 weeks' gestation) or tSGA (term delivery and birth weight <10th percentile for gestational age of a U.S. referent). Results for the total sample and within race-ethnicity/maternal education strata were adjusted for child sex and ASD subtype classification.

Results

Mean IQ was significantly (p < .05) lower in children delivered preterm (69.5) than term (74.5) and tSGA (69.3) than term appropriate-for gestational age (75.3). In stratified analyses, the preterm-IQ association was significant only among non-Hispanic white (NHW) children with maternal education at birth of high school or less; adjusted mean IQ was 8 points lower among those delivered preterm (65.4) than term (73.8). Term-SGA was associated with a significant 8-point deficit in adjusted mean IQ (75.5 vs. 83.8) in NHW children with maternal education greater than high school and a 6-point deficit that approached significance (68.4 vs. 74.5, p = 0.10) in NHW children with maternal education of high school or less. Non-Hispanic black children in both maternal education groups had significantly lower mean IQs than NHW children with little variation by preterm or tSGA.

Conclusions

In children with ASDs, the risk for concurrent ID or IQ deficit is associated with both preterm delivery and tSGA; these associations may vary by race-ethnicity and SES. Further studies of ASD-ID co-occurrence and the effectiveness of intervention strategies should consider both perinatal and sociodemographic factors.

Section snippets

Study sample

Our study population included children born in 1994 and identified as having an ASD by 2002 (age 8 years) in sites participating in the Autism and Developmental Disabilities Monitoring (ADDM) Network. The ADDM Network is an ongoing, population-based surveillance program maintained by the Centers for Disease Control and Prevention. Thirteen surveillance sites in 14 U.S. states¹

Results

In our study population of 1129 children with an ASD, the proportion of children with an IQ in the ID range (<70) was 43% and an additional 24% had an IQ in the borderline range (70-84) (Figure 1).

Overall, 71% of children in our study population had a prior ASD classification reported in health or education records and 29% were classified by ADDM clinicians as having ASD based on behaviors noted in abstracted evaluations (Table 1). Among children with a previous classification, over 40% were

Discussion

While many studies have assessed risk factors for cognitive deficits among population samples of children, few studies assessed risk factors among children with ASDs. From 30% to 60% of children diagnosed with an ASD have an IQ measure in the ID range [1]. Thus, there is a strong association between the 2 disabilities. However, the extent to which ASD and ID are distinct disabilities versus sharing an underlying etiology is unknown. If the co-occurrence of ID is partially independent of the

Conclusion

We found that in children with ASD, the risk for concurrent ID or IQ deficit is associated with both preterm delivery and tSGA. Our data further suggest that these associations may vary by race-ethnicity and SES. Further studies of the ASD-ID co-occurrence that consider both perinatal and postnatal environmental factors are warranted with the ultimate goal of informing the effectiveness of behavioral intervention programs on reducing the cognitive deficits in children with ASDs.

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It is speculated that some developmental disorders, including ASD, may be mediated in part or worsened by seizures [4,6-9]. The correlation between ELS and long-term neurological deficits begs the question: Do ELS cause or worsen outcomes associated with neurodevelopmental disorders [10], such as ASD? Due to the lack of effective clinical treatments of ELS to isolate the effects of seizures themselves from the causes, the impact of ELS on long-term detrimental outcomes, such as social communication deficits is unresolved.
Early-life seizures (ELS) are associated with autism spectrum disorder (ASD); however, due to a lack of effective treatments for ELS, it is not clear whether ELS plays a causal role, potentiates the ASD phenotype, or is the result of a common pathophysiology. Deficits in communications are a core feature of ASD. To isolate the impact of ELS on communication, we probed the behavioral consequences of a single episode of kainic acid-induced early-life seizures (KA-ELS) in male and female Sprague–Dawley (CD) rats. Deficits in auditory communication were observed in adult male rats as assessed by behavioral response to ultrasonic vocalization (USV) playback. Ultrasonic vocalizations are classified into two major categories – 50-kHz (positive) calls and 22-kHz (aversive) calls. Behavioral response was assessed via rat preference for different USV playback in a radial arm maze. Response to 22-kHz calls was not impacted by ELS while response to 50-kHz calls was impacted. All rats demonstrated positional preference for the arms adjacent to where 50-kHz calls were playing compared to background noise; however, male ELS rats demonstrated a greater positional preference for the arms adjacent to where 50-kHz calls were playing compared to male control rats. These studies demonstrate that responses to socially relevant auditory cues are chronically altered in adult male rats following a single episode of ELS. We speculate that these changes contribute to previously reported social deficits associated with ELS.
Sex differences in the diagnosis of autism spectrum disorder and effects of comorbid mental retardation and attention-deficit hyperactivity disorder
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Considering the small sample size, we were not able to further analyze the consequences of acquiring concurrent diagnoses, nor were we able to identify the causal relationship; nevertheless, we speculated that there might exist a correlation between diagnostic behavior and comorbid disease. A high prevalence of comorbid MR has been noted in ASD subjects, as mentioned above, with a prevalence of 30%–60%.31 Co-occurring ASD and ADHD is also very common, with a prevalence of ADHD symptoms ranging from 40% to 70% in ASD subjects.32
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Based on the Taiwan Longitudinal Health Insurance Database (LHID)-2000 and data from 1996 through 2008, the cumulative incidence of ASD over time was compared between the sexes (both cohorts n = 38,117) using the log-rank test. The effects of comorbid MR and ADHD on the incidence of ASD were evaluated using Cox proportional hazard regression analysis. The age at first diagnosis of ASD in the two sexes was compared using the independent-sample t-test.
The incidence was higher in males than in females (0.0007 vs. 0.0002) across ages. Comorbid MR or ADHD increased the incidence of ASD in both sexes; comorbid MR or ADHD also decreased the male to female hazard ratio of ASD, with no significant differences in the incidence density of ASD between sexes. ADHD delayed diagnosis in both sexes (males: 6.61 vs 5.10, p < 0.0001; females: 6.83 vs 4.69, p = 0.0037).
The general concept of a higher incidence of ASD among males was noted in this study of a Taiwanese population, but disappeared in those with comorbid MR or ADHD, indicating unique vulnerabilities to MR/ADHD or under-identification of high-functioning females with ASD in childhood. Increasing the diagnostic sensitivity of ASD in those with comorbid ADHD is important due to a delayed diagnostic age in this group.
Intrauterine inflammation reduces postnatal neurogenesis in the hippocampal subgranular zone and leads to accumulation of hilar ectopic granule cells
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Similar to findings with microglia, exposure to intrauterine inflammation did not alter the number of astrocytes in the various regions of the hippocampus in any of the regions analyzed at P14 (Fig. 6B) or P28 (not shown). Exposure to prenatal inflammation has been strongly associated with a spectrum of adverse neurobehavioral outcomes in exposed offspring, including motor-sensory deficits, delayed learning and neurological disease, such as schizophrenia, autism spectrum disorder and epilepsy Anderson and Doyle, 2003; Cordeiro et al., 2015; Fazzi et al., 2009; Hack et al., 2005; Indredavik, 2010; Johnson et al., 2010a, b; Lee et al., 2011; Schieve et al., 2010. However, there is still a paucity of data on how an inflammatory environment in utero leads to fetal brain injury, causing neurobehavioral abnormalities in childhood and adulthood.
Prenatal inflammation is associated with poor neurobehavioral outcomes in exposed offspring. A common route of exposure for the fetus is intrauterine infection, which is often associated with preterm birth. Hippocampal development may be particularly vulnerable to an inflammatory insult during pregnancy as this region remains highly neurogenic both prenatally and postnatally. These studies sought to determine if intrauterine inflammation specifically altered hippocampal neurogenesis and migration of newly produced granule neurons during the early postnatal period. Microglial and astroglial cell populations known to play a role in the regulation of postnatal neurogenesis were also examined. We show that intrauterine inflammation significantly reduced hippocampal neurogenesis between postnatal days 7 (P7) and P14 as well as decreased granule cell density at P28. Ectopic migration of granule cells was observed in LPS-exposed mice at P14, but not at P28. Intrauterine inflammation had no effect on hippocampal astrocyte or microglia density or on apoptosis rate at the postnatal time points examined. Thus, exposure to intrauterine inflammation disrupts early postnatal neurogenesis and leads to aberrant migration of newly born granule cells.
Sound Environments Surrounding Preterm Infants Within an Occupied Closed Incubator
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Preterm infants often exhibit functional disorders due to the stressful environment in the neonatal intensive care unit (NICU). The sound pressure level (SPL) in the NICU is often much higher than the levels recommended by the American Academy of Pediatrics. Our study aims to describe the SPL and sound frequency levels surrounding preterm infants within closed incubators that utilize high frequency oscillation (HFO) or nasal directional positive airway pressure (nasal-DPAP) respiratory settings.
This is a descriptive research study of eight preterm infants (corrected age < 33 weeks) exposed to the equipment when placed in an incubator. The actual noise levels were observed and the results were compared to the recommendations made by neonatal experts.
Increased noise levels, which have reported to affect neonates' ability to self-regulate, could increase the risk of developing attention deficit disorder, and may result in tachycardia, bradycardia, increased intracranial pressure, and hypoxia.
The care provider should closely assess for adverse effects of higher sound levels generated by different modes of respiratory support and take measures to ensure that preterm infants are protected from exposure to noise exceeding the optimal safe levels.
Using mouse models of autism spectrum disorders to study the neurotoxicology of gene-environment interactions
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Of the select chemicals that have been identified only 10 have been confirmed to be neurotoxic for human development, with an additional 200 compounds possessing neurotoxic properties, and more than 1000 other compounds suspected to also disrupt central nervous system development based on experimental findings (Fig. 1) (Grandjean and Landrigan, 2006). This is particularly concerning given the continuing rise in reported cases of neurodevelopmental disorders (Schieve et al., 2010). In many cases, environmental effects on brain development are preventable if vulnerable segments of the population can be identified.
To better study the role of genetics in autism, mouse models have been developed which mimic the genetics of specific autism spectrum and related disorders. These models have facilitated research on the role genetic susceptibility factors in the pathogenesis of autism in the absence of environmental factors. Inbred mouse strains have been similarly studied to assess the role of environmental agents on neurodevelopment, typically without the complications of genetic heterogeneity of the human population. What has not been as actively pursued, however, is the methodical study of the interaction between these factors (e.g., gene and environmental interactions in neurodevelopment). This review suggests that a genetic predisposition paired with exposure to environmental toxicants plays an important role in the etiology of neurodevelopmental disorders including autism, and may contribute to the largely unexplained rise in the number of children diagnosed with autism worldwide. Specifically, descriptions of the major mouse models of autism and toxic mechanisms of prevalent environmental chemicals are provided followed by a discussion of current and future research strategies to evaluate the role of gene and environment interactions in neurodevelopmental disorders.
Gestational age at birth and risk of autism spectrum disorders in Alberta, Canada
2013, Journal of Pediatrics
Citation Excerpt :
The prevalence of singleton live preterm births (<37 weeks gestation) in our study cohort was 8.2%, and although this rate is slightly higher than the 1996 reported prevalence for Canada of 7.1%,18 results are likely commensurate given the trend toward increasing rates of preterm birth in Canada each year.18,19 Although some previous studies have examined the prevalence of ASD exclusively in preterm populations29,31,32,35,36 or the frequency of preterm birth in a population of children already diagnosed with an ASD,30 the majority of studies have compared GA and the frequency of ASD in previously selected cohorts.9,11,25,27,46 Preterm birth is most commonly defined as birth at <37 weeks GA; thus, cohorts are divided based on this cutoff.
To examine the association between autism spectrum disorders (ASD) and each completed week of gestation using a graphical method of presenting results at all possible categorizations of gestational age (GA).
The risk of ASD in a total of 218 110 singleton live births with complete data from Alberta, Canada between 1998 and 2004 was examined through linkage to health insurance records. The relative risk of developing ASD according to the 21 dichotomizations of shorter gestation (GA ≤23 weeks vs >23 weeks to ≤43 weeks vs >43 weeks, in 1-week increments) was calculated using log-binomial regression and adjusted for fetal sex, socioeconomic status, and birth year.
We observed a gradual increased risk of ASD with shorter gestation. Cutoffs only between 29 and 40 weeks clearly denoted an elevated risk of developing ASD compared with longer gestation, and the risk increased with earlier GA cutoff. The results were not affected by sex or measures of fetal growth.
Our data confirm the role of shortened gestation in ASD risk. We warn against the use of prespecified or a data-driven GA cutoff, however; instead, we recommend systematically examining all plausible cutoffs for GA to avoid overstating the homogeneity of risk in children on either side of a given cutoff, as well as to increase the comparability of studies.

View all citing articles on Scopus

: Financial disclosure: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease and Control and Prevention. Dr. Rice conducts a limited number of training sessions to professionals on the diagnosis of the autism spectrum disorders as an approved outside activity separate from employment with the federal government. The other authors report no conflicts of interest.

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Research PaperRisk for cognitive deficit in a population-based sample of U.S. children with autism spectrum disorders: Variation by perinatal health factors

Abstract

Background

Objective/Hypotheses

Methods

Results

Conclusions

Section snippets

Study sample

Results

Discussion

Conclusion

Ann Epidemiol

Res Dev Disabil

Prevalence of autism spectrum disorders—Autism and Developmental Monitoring Network, 14 sites, United States, 2002

MMWR Morb Mortal Wkly Rep

The epidemiology of mental retardation: challenges and opportunities in the new millennium

Ment Retard Dev Disabil Res Rev

Birth weight, childhood socioeconomic environment, and cognitive development in the 1958 British birth cohort study

BMJ

Neurodevelopmental outcome at 8 months and 4 years among infants born full-term small-for-gestational-age

J Perinatol

Longitudinal neurology follow-up in neonatal intensive care unit survivors with various neonatal morbidities

Pediatrics

Academic achievement of small-for-gestational-age children at age 10 years

Arch Pediatr Adolesc Med

Cognitive and behavioral outcomes of school-aged children who were born preterm

JAMA

Birth weight and cognitive ability in childhood: a systematic review

Psychol Bull

Neighbourhood socioeconomic status and maternal factors at birth as moderators of the association between birth characteristics and school attainment: a population study of children attending government schools in Western Australia

J Epidemiol Community Health

Correlations between socioeconomic status, IQ and aetiology in mental retardation: a population-based study of Norwegian children

Soc Psychiatry Psychiatr Epidemiol

Black-white achievement gap and family wealth

Child Dev

Determinants of cognitive function in childhood: a cohort study in a middle income context

BMC Public Health

Socioeconomic position, maternal IQ, home environment, and cognitive development

J Pediatr

Family processes as pathways from income to young children's development

Dev Psychol

Socioeconomic status modifies heritability of IQ in young children

Psychol Sci

Genotype by environment interaction in adolescents' cognitive aptitude

Psychol Rev

Relation between intrauterine growth and subsequent intellectual disability in a ten-year population cohort of children in Western Australia

Am J Epidemiol

Revisiting parental concerns in the age of autism spectrum disorders

Arch Pediatr Adolesc Med

Research Paper
Risk for cognitive deficit in a population-based sample of U.S. children with autism spectrum disorders: Variation by perinatal health factors