Closely Spaced Pregnancies Are Associated With Increased Odds of Autism in California Sibling Births

Robert Wood Johnson Foundation Health and Society Scholars, Columbia University, New York, New York, USA.
PEDIATRICS (Impact Factor: 5.47). 02/2011; 127(2):246-53. DOI: 10.1542/peds.2010-2371
Source: PubMed


To determine whether the interpregnancy interval (IPI) is associated with the risk of autism in subsequent births.
Pairs of first- and second-born singleton full siblings were identified from all California births that occurred from 1992 to 2002 using birth records, and autism diagnoses were identified by using linked records of the California Department of Developmental Services. IPI was calculated as the time interval between birth dates minus the gestational age of the second sibling. In the primary analysis, logistic regression models were used to determine whether odds of autism in second-born children varied according to IPI. To address potential confounding by unmeasured family-level factors, a case-sibling control analysis determined whether affected sibling (first versus second) varied with IPI.
An inverse association between IPI and odds of autism among 662 730 second-born children was observed. In particular, IPIs of <12, 12 to 23, and 24 to 35 months were associated with odds ratios (95% confidence intervals) for autism of 3.39 (3.00-3.82), 1.86 (1.65-2.10), and 1.26 (1.10-1.45) relative to IPIs of ≥ 36 months. The association was not mediated by preterm birth or low birth weight and persisted across categories of sociodemographic characteristics, with some attenuation in the oldest and youngest parents. Second-born children were at increased risk of autism relative to their firstborn siblings only in pairs with short IPIs.
These results suggest that children born after shorter intervals between pregnancies are at increased risk of developing autism; the highest risk was associated with pregnancies spaced <1 year apart.

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Available from: Peter S Bearman, Jan 25, 2015
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    • "Variations in early maternal care could affect behavioral responses in the offspring by altering at least the methylation status of the glucocorticoid receptor gene promoter [95]. Maternal stress due to the first child developing autism may also contribute to children born within a year from this first child having a much higher ASD risk [96]. ASD patients have high anxiety levels and are unable to handle stress appropriately [97]. "
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    ABSTRACT: Background Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes. Discussion We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells. Summary Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.
    BMC Pediatrics 07/2012; 12(1):89. DOI:10.1186/1471-2431-12-89 · 1.93 Impact Factor
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    • "An interval of less than one year between pregnancies was found in an initial report to be associated with more than a threefold increase in autism risk compared to intervals of three or more years (OR = 3.4, 95% CI = 3.00 to 3.82). If short interpregnancy interval is an autism risk factor, it could implicate the intrauterine environment through nutritional depletion mechanisms [81]. Indeed, researchers in a large case-control investigation have reported intake of prenatal vitamin supplements in the periconception period (three months prior and one month after conception) to confer nearly a 40% reduction in risk (OR = 0.62, 95% CI = 0.42 to 0.93) [82]. "
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    ABSTRACT: Infant sibling studies have been at the vanguard of autism spectrum disorders (ASD) research over the past decade, providing important new knowledge about the earliest emerging signs of ASD and expanding our understanding of the developmental course of this complex disorder. Studies focused on siblings of children with ASD also have unrealized potential for contributing to ASD etiologic research. Moving targeted time of enrollment back from infancy toward conception creates tremendous opportunities for optimally studying risk factors and risk biomarkers during the pre-, peri- and neonatal periods. By doing so, a traditional sibling study, which already incorporates close developmental follow-up of at-risk infants through the third year of life, is essentially reconfigured as an enriched-risk pregnancy cohort study. This review considers the enriched-risk pregnancy cohort approach of studying infant siblings in the context of current thinking on ASD etiologic mechanisms. It then discusses the key features of this approach and provides a description of the design and implementation strategy of one major ASD enriched-risk pregnancy cohort study: the Early Autism Risk Longitudinal Investigation (EARLI).
    Journal of Neurodevelopmental Disorders 04/2012; 4(1):7. DOI:10.1186/1866-1955-4-7 · 3.27 Impact Factor
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    • "It has long been recognized that short interbirth interval (the time since the immediately preceding birth) is associated with increased risk of adverse pregnancy outcomes such as preterm birth and low birth weight (5). Recently, studies have shown associations between short interbirth interval and an increased risk of diseases in the offspring including childhood autism (6) and schizophrenia (7) and a reduced risk of childhood leukemia (8). The mechanism behind these findings is unknown, but researchers have suggested that short interbirth intervals may not allow complete restoration of maternal micronutrients at the time of conception (7,9), may lead to increased maternal stress (7), and may increase exposure to childhood infections from immediately older siblings (7). "
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    ABSTRACT: Short interbirth interval has been associated with maternal complications and childhood autism and leukemia, possibly due to deficiencies in maternal micronutrients at conception or increased exposure to sibling infections. A possible association between interbirth interval and subsequent risk of childhood type 1 diabetes has not been investigated. A secondary analysis of 14 published observational studies of perinatal risk factors for type 1 diabetes was conducted. Risk estimates of diabetes by category of interbirth interval were calculated for each study. Random effects models were used to calculate pooled odds ratios (ORs) and investigate heterogeneity between studies. Overall, 2,787 children with type 1 diabetes were included. There was a reduction in the risk of childhood type 1 diabetes in children born to mothers after interbirth intervals <3 years compared with longer interbirth intervals (OR 0.82 [95% CI 0.72-0.93]). Adjustments for various potential confounders little altered this estimate. In conclusion, there was evidence of a 20% reduction in the risk of childhood diabetes in children born to mothers after interbirth intervals <3 years.
    Diabetes 03/2012; 61(3):702-7. DOI:10.2337/db11-1000 · 8.10 Impact Factor
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