The U-shaped relationship between parental age and the risk of bipolar disorder in the offspring: A systematic review and meta-analysis.

Parenthood age may affect the risk for the development of different psychiatric disorders in the offspring, including bipolar disorder (BD). The present systematic review and meta-analysis aimed to appraise the relationship between paternal age and risk for BD and to explore the eventual relationship between paternal age and age at onset of BD. We searched the MEDLINE, Scopus, Embase, PsycINFO online databases for original studies from inception, up to December 2021. Random-effects meta-analyses were conducted. Sixteen studies participated in the qualitative synthesis, of which k = 14 fetched quantitative data encompassing a total of 13,424,760 participants and 217,089 individuals with BD. Both fathers [adjusted for the age of other parent and socioeconomic status odd ratio - OR = 1.29(95%C.I. = 1.13-1.48)] and mothers aged ≤ 20 years [(OR = 1.23(95%C.I. = 1.14-1.33)] had consistently increased odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Fathers aged ≥ 45 years [adjusted OR = 1.29 (95%C.I. = 1.15-1.46)] and mothers aged 35-39 years [OR = 1.10(95%C.I. = 1.01-1.19)] and 40 years or older [OR = 1.2(95% C.I. = 1.02-1.40)] likewise had inflated odds of BD diagnosis in their offspring compared to parents aged 25-29 years. Early and delayed parenthood are associated with an increased risk of BD in the offspring. Mechanisms underlying this association are largely unknown and may involve a complex interplay between psychosocial, genetic and biological factors, and with different impacts according to sex and age range. Evidence on the association between parental age and illness onset is still tentative but it points towards a possible specific effect of advanced paternal age on early BD-onset.

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Copyright © 2022. Published by Elsevier B.V.

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Declaration of Competing Interest EV has received grants and served as consultant, advisor, or CME speaker unrelated to the present work for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, Sunovion, and Takeda. GF has received CME-related honoraria, or consulting fees from Angelini, Janssen-Cilag and Lundbeck. MSV has received financial support for CME activities or travel funds from Janssen-Cilag and Lundbeck, and has served as a speaker for Casen Recordati. She reports no financial or other relationship relevant to the subject of this article. AM has received funding unrelated to the present work for research projects and/or honoraria as a consultant or speaker from the following entities: Angelini, Janssen, Lundbeck, Otsuka, Sanofi-Aventis and Spanish Ministry of Science and Innovation- Instituto de Salud Carlos III. SGC has received CME-related honoraria, or consulting fees from Janssen-Cilag, Italfarmaco, Angelini and Lundbeck and reports no financial or other relationship relevant to the subject of this article. AS is or has been a consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier.