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Perinatal and Neonatal Risk Factors for Autism: A Comprehensive Meta-analysis

Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
PEDIATRICS (Impact Factor: 5.3). 08/2011; 128(2):344-55. DOI: 10.1542/peds.2010-1036
Source: PubMed

ABSTRACT The etiology of autism is unknown, although perinatal and neonatal exposures have been the focus of epidemiologic research for over 40 years.
To provide the first review and meta-analysis of the association between perinatal and neonatal factors and autism risk.
PubMed, Embase, and PsycInfo databases were searched for studies that examined the association between perinatal and neonatal factors and autism through March 2007. Forty studies were eligible for the meta-analysis. For each exposure, a summary effect estimate was calculated using a random-effects model. Heterogeneity in effect estimates across studies was examined, and, if found, a meta-regression was conducted to identify measured methodological factors that could explain between-study variability.
Over 60 perinatal and neonatal factors were examined. Factors associated with autism risk in the meta-analysis were abnormal presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, congenital malformation, low 5-minute Apgar score, feeding difficulties, meconium aspiration, neonatal anemia, ABO or Rh incompatibility, and hyperbilirubinemia. Factors not associated with autism risk included anesthesia, assisted vaginal delivery, postterm birth, high birth weight, and head circumference.
There is insufficient evidence to implicate any 1 perinatal or neonatal factor in autism etiology, although there is some evidence to suggest that exposure to a broad class of conditions reflecting general compromises to perinatal and neonatal health may increase the risk. Methodological variations were likely sources of heterogeneity of risk factor effects across studies.

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    • "Risk for an ASD diagnosis increases in individuals who suffered fetal distress, were birthed via cesarean, or had a low Apgar score at birth (Hultman & Sparén, 2004). Furthermore, gestational complications, nuchal cord, edema, and fetal distress are also associated with increased ASD diagnoses (Gardener et al., 2011; Zhang et al., 2010). All of these complications put the infant at greater risk for oxidative stress, which in turn may lead to an increased risk for ASD, particularly in individuals who are not already genetically susceptible (Dodds et al., 2011). "
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    ABSTRACT: This study focused on prenatal and perinatal factors related to Autism Spectrum Disorder (ASD). We hypothesized that mothers who exposed their infants to intrauterine toxicity or who had complications with labor or delivery would be more likely to give birth to individuals with lower IQ scores, higher scores on a measure of ASD, and lower scores on a measure of adaptive functioning. This clinical sample consisted of 33 children who presented for neuropsychological assessment with symptoms of ASD. Results indicated that individuals with a history of intrauterine toxicity had lower IQ scores than individuals who did not have a history of intrauterine toxicity. However, no significant effects were found for intrauterine toxicity and ASD or adaptive functioning. Results indicated that individuals with a history of complications during labor and delivery had lower IQ scores, higher scores on a measure of ASD, and lower scores on a measure of adaptive functioning. Findings may lend support the oxidative stress theory of ASD.
    The Journal of Genetic Psychology 11/2014; In Press. DOI:10.1080/00221325.2014.987201
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    • "The etiology of autism is unknown, although perinatal and neonatal exposures have been the focus of recent epidemiologic research [57]. Exposure to certain medications such as perinatal medications, antiepileptic drugs, supplements, and SSRIs has been studied as well as drug exposure to cocaine and smoking. "
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    ABSTRACT: Autism is a neurodevelopmental disorder marked by severe deficits in social communication and interactions. It is a complex condition that lacks an established preventive method, warranting a need for research to identify possible environmental triggers. The identification of external factors particularly perinatal risk factors forms the initial critical step in preventing and alleviating risks. We conducted a literature review to assess evidence suggested in the worldwide literature. Perinatal risk factors that have a suggested association include íµí»½2 adrenergic receptor agonists, labor induction and augmentation, maternal infection and disease (i.e., antiphospholipid syndrome), antiepileptic drugs, cocaine use, and oral supplements. Smoking has not been found to have a direct association. Pollutants, selective serotonin reuptake inhibitors, artificial insemination, and fertility medications may have a link, but results are often conflicted. Factors related to the delivery room experience may be associated with meconium aspiration syndrome, birth weight, and labor time. Several risk factors during the pregnancy and labor periods have been associated with autism; yet further studies with large populations are needed to establish definitive associations. The fact that several risk factors during the prenatal and labor periods are implicated in autism should prompt the medical community to focus on the pregnancy and labor periods as preventive measures to curb the incidence of autism.
    International Scholarly Research Notices 10/2014; 2014(Article ID 290837). DOI:10.1155/2014/290837
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    • "It will be important to determine the exact rs4746-and ASDspecific mechanisms responsible for modulating GLO1 activity, although the latter may not be entirely ASD-specific. Oxidative stress, mitochondrial dysfunction and abnormal GLO1 activity are involved in the pathophysiology of other disorders, such as obesity, diabetes and associated vascular complications; interestingly, the presence of these disorders in mothers is associated with a twofold increased risk of autism in their offspring (Gardener et al., 2011; Lyall et al., 2011). The common C332 allele is clearly not a cause of ASD per se, as many unaffected individuals carry this common variant. "
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    ABSTRACT: Glyoxalase I (GLO1) is a homodimeric Zn(2+)-dependent isomerase involved in the detoxification of methylglyoxal and in limiting the formation of advanced glycation end-products (AGE). We previously found the rs4746 A332 (Glu111) allele of the GLO1 gene, which encodes for glyoxalase I, associated with "unaffected sibling" status in families with one or more children affected by Autism Spectrum Disorder (ASD). To identify and characterize this protective allele, we sequenced GLO1 exons and exon-intron junctions, detecting two additional SNPs (rs1049346, rs1130534) in linkage disequilibrium with rs4746. A family-based association study involving 385 simplex and 20 multiplex Italian families yielded a significant association with autism driven only by the rs4746 C332 (Ala111) allele itself (P < 0.05 and P < 0.001 under additive and dominant/recessive models, respectively). Glyoxalase enzymatic activity was significantly reduced both in leukocytes and in post-mortem temporocortical tissue (N = 38 and 13, respectively) of typically developing C332 allele carriers (P < 0.05 and <0.01), with no difference in Glo1 protein levels. Conversely, AGE amounts were significantly higher in the same C332 post-mortem brains (P = 0.001), with a strong negative correlation between glyoxalase activity and AGE levels (τ = -0.588, P < 0.01). Instead, 19 autistic brains show a dysregulation of the glyoxalase-AGE axis (τ = -0.209, P = 0.260), with significant blunting of glyoxalase activity and AGE amounts compared to controls (P < 0.05), and loss of rs4746 genotype effects. In summary, the GLO1 C332 (Ala111) allele confers autism vulnerability by reducing brain glyoxalase activity and enhancing AGE formation, but years after an autism diagnosis the glyoxalase-AGE axis appears profoundly disrupted, with loss of C332 allelic effects.
    Journal of Psychiatric Research 08/2014; 59. DOI:10.1016/j.jpsychires.2014.07.021
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