Grand-Maternal Smoking during Pregnancy and Autism Spectrum Disorder/Attention-Deficit/Hyperactivity Disorder in Grandchildren
Animal experiments indicate that environmental factors can alter gene expression to induce multigenerational transmission of biological traits to subsequent generations through the germline. However, there is very little data on such effects in humans. Cigarette smoke is one exposure that is known to alter germline DNA methylation patterns, but only a single study has investigated the association between grand-maternal smoking in pregnancy and grandchild’s diagnosed autism, using data from the Avon Longitudinal Study of Parents and Children (ALSPAC).
To examine the associations between grandmother smoking while pregnant and risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in her grandchildren.
We analyzed data reported by nurses in The Nurses’ Health Study (NHS) II, the participants of which were born between 1946 and 1964. In 1999, nurses (F1) were asked whether their mother (F0) smoked during her pregnancy with them. ASD and ADHD cases were identified according to the nurses’ report of whether or not they had ever had a child (F2) diagnosed with ASD (2009) or ADHD (2013).
In NHS II, each nurse can have more than one child causing clustering of the outcome in the F2 generation. Because the exposure (F0 smoking) could affect the number of children (F2) per nurse (F1), and neurodevelopmental deficits in the F2 generation could affect the number of children a nurse has, the clustering could be informative. To address the correlated data structure and possible informative clustering simultaneously, the associations of maternal in utero exposure to smoking and ASD and ADHD were analyzed using cluster-weighted generalized estimating equations with a logit link. Models were adjusted for several potential confounders. Additionally, sensitivity analyses were conducted by repeating our main analyses adjusting for potential mediators (i.e., F1 smoking during pregnancy with F2).
For ASD, N=44,660 F1 mothers had data on exposure, outcome, and confounders, and for ADHD, N=42,218 F1 mothers had complete data. For both outcomes, the prevalence of F0 smoking during the pregnancy with the F1 nurses was similar (24.9% and 24.7% for ASD and ADHD outcomes, respectively). Of 100,670 and 95,218 F2 children, 1,272 (1.26%) were diagnosed with ASD and 7,173 (7.53%) were diagnosed with ADHD. Grand-maternal smoking during the pregnancy with the nurses was associated with an increased risk of ADHD among the grandchildren with adjusted odds ratio (aOR) of 1.18 (95% CI, 1.11-1.27), whereas an association was not observed between F0 smoking during the pregnancy with F1 and a risk of ASD among the F2 generation (aOR = 0.97; 95% CI, 0.85-1.12). Controlling for the F1 level potential mediators did not substantially change the findings. When the analyses were repeated as performed in ALSPAC, the results for the outcome of ASD diagnosis remained the same.
Maternal prenatal exposure to smoking is associated with an increased risk of ADHD, but not with ASD. Further exploration of these third generation associations is needed in other epidemiological study settings.