Familial confounding of the association between maternal smoking in pregnancy and autism spectrum disorder in offspring

Amy E. Kalkbrenner, Sandra M. Meier, Paul Madley-Dowd, Christine Marie Ladd-Acosta, Daniele Daniele Fallin, Erik Parner, Diana Schendel

Research output: Contribution to journalArticle

Abstract

Evidence supports no link between maternal smoking in pregnancy and autism spectrum disorder (autism) overall. To address remaining questions about the unexplained heterogeneity between study results and the possibility of risk for specific autism sub-phenotypes, we conducted a whole-population cohort study in Denmark. We followed births 1991–2011 (1,294,906 persons, including 993,301 siblings in 728,271 families), from 1 year of age until an autism diagnosis (13,547), death, emigration, or December 31, 2012. Autism, with and without attention deficit hyperactivity disorder (ADHD) and with and without intellectual disability (ID) were based on ICD-8 and ICD-10 codes from Danish national health registers, including 3,319 autism + ADHD, 10,228 autism − no ADHD, 2,205 autism + ID, and 11,342 autism − no ID. We estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) between any maternal smoking (from birth records) and autism (or sub-phenotypes) using survival models with robust standard errors, stratifying by birth year and adjusting for child sex, parity, and parental age, education, income, and psychiatric history. To additionally address confounding using family designs, we constructed a maternal cluster model (adjusting for the smoking proportion within the family), and a stratified sibling model. Associations with maternal smoking and autism were elevated in conventional adjusted analyses (HR of 1.17 [1.13–1.22]) but attenuated in the maternal cluster (0.98 [0.88–1.09]) and sibling (0.86 [0.64–1.15]) models. Similarly, risks of autism sub-phenotypes with maternal smoking were attenuated in the family-based models. Together these results support that smoking in pregnancy is not linked with autism or select autism comorbid sub-phenotypes after accounting for familial confounding. Autism Res 2019.

Original languageEnglish (US)
JournalAutism Research
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Autistic Disorder
Smoking
Mothers
Pregnancy
Attention Deficit Disorder with Hyperactivity
Intellectual Disability
Phenotype
Siblings
International Classification of Diseases
Autism Spectrum Disorder
Parturition
Birth Certificates
Emigration and Immigration
Denmark
Parity
Psychiatry
Cohort Studies
Parents

Keywords

  • attention deficit hyperactivity disorder
  • autism
  • autism spectrum disorder
  • confounding
  • family-based designs
  • intellectual disability
  • maternal smoking
  • neurodevelopment
  • tobacco

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Genetics(clinical)

Cite this

Familial confounding of the association between maternal smoking in pregnancy and autism spectrum disorder in offspring. / Kalkbrenner, Amy E.; Meier, Sandra M.; Madley-Dowd, Paul; Ladd-Acosta, Christine Marie; Fallin, Daniele Daniele; Parner, Erik; Schendel, Diana.

In: Autism Research, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "Evidence supports no link between maternal smoking in pregnancy and autism spectrum disorder (autism) overall. To address remaining questions about the unexplained heterogeneity between study results and the possibility of risk for specific autism sub-phenotypes, we conducted a whole-population cohort study in Denmark. We followed births 1991–2011 (1,294,906 persons, including 993,301 siblings in 728,271 families), from 1 year of age until an autism diagnosis (13,547), death, emigration, or December 31, 2012. Autism, with and without attention deficit hyperactivity disorder (ADHD) and with and without intellectual disability (ID) were based on ICD-8 and ICD-10 codes from Danish national health registers, including 3,319 autism + ADHD, 10,228 autism − no ADHD, 2,205 autism + ID, and 11,342 autism − no ID. We estimated hazard ratios (HRs) and 95{\%} confidence intervals (95{\%} CIs) between any maternal smoking (from birth records) and autism (or sub-phenotypes) using survival models with robust standard errors, stratifying by birth year and adjusting for child sex, parity, and parental age, education, income, and psychiatric history. To additionally address confounding using family designs, we constructed a maternal cluster model (adjusting for the smoking proportion within the family), and a stratified sibling model. Associations with maternal smoking and autism were elevated in conventional adjusted analyses (HR of 1.17 [1.13–1.22]) but attenuated in the maternal cluster (0.98 [0.88–1.09]) and sibling (0.86 [0.64–1.15]) models. Similarly, risks of autism sub-phenotypes with maternal smoking were attenuated in the family-based models. Together these results support that smoking in pregnancy is not linked with autism or select autism comorbid sub-phenotypes after accounting for familial confounding. Autism Res 2019.",
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