Perinatal and Neonatal Risk Factors for Autism: A Comprehensive Meta-analysis
Open accessAbstract
BACKGROUND: The etiology of autism is unknown, although perinatal and neonatal exposures have been the focus of epidemiologic research for over 40 years. OBJECTIVE: To provide the first review and meta-analysis of the association between perinatal and neonatal factors and autism risk. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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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Autism etiology is most likely polygenic and potentially epistatic, and environmental factors may interact with genetic factors to increase risk.
“Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model.”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [8]
Summer birth was significantly associated with an elevated risk of autism, RR: 1.14, P = 0.02.
“Interestingly, summer season [summer birth was significantly associated with an elevated risk of autism, RR: 1.14, P = 0.02; (8)] corresponds to the longest days of the year.”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [8]
AD might be due mainly to genetic factors in some cases or mainly to environmental factors in other cases with possible cumulative effects mediated by different environmental factors and/or genetic factors.
“AD might be due mainly to genetic factors in some cases [for example, neonatal congenital malformations are significantly associated with an increased risk for autism; (8)] or mainly to environmental factors in other cases (for example, in utero exposure to valproate) with possible cumulative effects mediated by different environmental factors and/or genetic factors”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [8]
The perinatal factors with the strongest evidence against a role in autism risk included anesthesia use during delivery, assisted vaginal delivery, post-term birth, high birth weight, or head circumference.
“Finally, the perinatal factors with the strongest evidence against a role in autism risk included anesthesia use during delivery, assisted vaginal delivery, post-term birth, high birth weight, or head circumference (8).”
From Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms (2014) · cites this paper as [8]
Another meta-analysis focusing on the perinatal and neonatal period identified several potential risk factors, the main being fetal presentation, umbilical-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, low 5-minute Apgar score, meconium aspiration, neonatal anemia, ABO or Rh incompatibilty
“In another meta-analysis focusing on the perinatal and neonatal period,83 the same authors identified several potential risk factors, the main being fetal presentation, umbilieal-cord complications, fetal distress, birth injury or trauma, multiple birth, maternal hemorrhage, summer birth, low birth weight, small for gestational age, low 5minute Apgar score, meconium aspiration, neonatal anemia, AB”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [83]
Overall, preterm birth was not associated with the risk of autism.
“Overall, preterm birth was not associated with the risk of autism”
From Autism risk factors: genes, environment, and gene-environment interactions (2012) · cites this paper as [83]
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- Authors
- Gardener, H., Spiegelman, D., & Buka, S. L.
- Affiliations
- Department of Epidemiology and
- Harvard University (US)
- Brown University (US)
- Venue
- Pediatrics
- Publisher
- American Academy of Pediatrics (AAP)
- Published
- 2011-08-01
- Volume
- 128
- Issue
- 2
- Pages
- 344-355
- ISSN
- 0031-4005 (ISSN-L)
- 1098-4275
- PMC
- PMC3387855
- OpenAlex
- W2142647774
- Cited by
- 665
- References
- 11
- Citations by year
- 2026: 24 · 2025: 42 · 2024: 43 · 2023: 49 · 2022: 49 · 2021: 57 · 2020: 57 · 2019: 42 · 2018: 49 · 2017: 50 · 2016: 53 · 2015: 43 · 2014: 44 · 2013: 37 · 2012: 22
- FWCI
- 17.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- PEDIATRICS (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institute of Mental Health (T32 MH 17119, T32MH017119)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Infant Development and Preterm Care
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- autism spectrum disorder, perinatal risk factors, neonatal risk factors, autism etiology, birth trauma, fetal distress, umbilical cord complications, low birth weight, Apgar score, meconium aspiration syndrome, ABO incompatibility, Rh incompatibility, hyperbilirubinemia, congenital malformations, multiple births
- MeSH terms
- Autistic Disorder, Female, Humans, Infant, Newborn, Pregnancy, Pregnancy Complications, Risk Factors, Neonatal Screening, Perinatal Care
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