Do Grandchildren whose Grandmother Smoked while Pregnant with the Mother have a Higher Risk of Childhood Asthma? A Protocol for a Systematic Review

Background: Mothers smoking while pregnant is known to increase the offspring risk of subsequent wheezing or asthma. It is less well known whether this phenomenal occurs trans-generationally, which would suggest potential epigenetic transfer. If a link is identified, this would strengthen the need for anti-smoking strategies during pregnancy and would direct further research towards understanding the epigenetic mechanisms. We aim to perform a systematic review and meta-analysis to determine whether or not grandchildren of grandmothers who smoked while pregnant with their mother have a higher risk of childhood wheeze or asthma. Methods: The systematic review will use the Preferred Reporting items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist. To identify relevant studies, we will search databases including Medline, PubMed, Embase, Web of Science and Scopus. The exposure being investigated is whether the maternal grandmother smoked in pregnancy and the outcome being measured is recurrent wheeze and/or asthma in the grandchild.Studies will be screened according to inclusion and exclusion criteria to include primary cohort studies of any study design type. Eligible studies will then be evaluated for quality and assessed for bias independently by three reviewers using the “Grading of Recommendations, Assessment, Development and Evaluation” (GRADE) approach. The results of the studies will be extracted into 2x2 outcome tables and a meta-analysis will be carried out. The statistical software used will be StatsDirect.Discussion: This review will help determine whether there is transgenerational inheritance of wheeze and asthma, beyond the risk of direct in utero exposure. Systematic Review Registration: PROSPERO REG: CRD42021234346