Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis

• Published in: Human reproduction update 2020-09, Vol.26 (5), p.650-669
• Main Authors: du Fossé, Nadia A, van der Hoorn, Marie-Louise P, van Lith, Jan M M, le Cessie, Saskia, Lashley, Eileen E L O
• Format: Article
• Language: English
• Subjects: Abortion, Spontaneous - epidemiology; Abortion, Spontaneous - etiology; Adult; Aged; Fathers - statistics & numerical data; Female; Humans; Male; Maternal Age; Middle Aged; Paternal Age; Pregnancy; Pregnancy Outcome - epidemiology; Prenatal Care - methods; Prenatal Care - statistics & numerical data; Reviews; Risk Factors; Young Adult
• ISSN: 1355-4786; 1460-2369
• DOI: 10.1093/humupd/dmaa010

Abstract BACKGROUND Although spontaneous miscarriage is the most common complication of human pregnancy, potential contributing factors are not fully understood. Advanced maternal age has long been recognised as a major risk factor for miscarriage, being strongly related with fetal chromosomal abnormalities. The relation between paternal age and the risk of miscarriage is less evident, yet it is biologically plausible that an increasing number of genetic and epigenetic sperm abnormalities in older males may contribute to miscarriage. Previous meta-analyses showed associations between advanced paternal age and a broad spectrum of perinatal and paediatric outcomes. This is the first systematic review and meta-analysis on paternal age and spontaneous miscarriage. OBJECTIVE AND RATIONALE The aim of this systematic review and meta-analysis is to evaluate the effect of paternal age on the risk of spontaneous miscarriage. SEARCH METHODS PubMed, Embase and Cochrane databases were searched to identify relevant studies up to August 2019. The following free text and MeSH terms were used: paternal age, father’s age, male age, husband’s age, spontaneous abortion, spontaneous miscarriage, abortion, miscarriage, pregnancy loss, fetal loss and fetal death. PRISMA guidelines for systematic reviews and meta-analysis were followed. Original research articles in English language addressing the relation between paternal age and spontaneous miscarriage were included. Exclusion criteria were studies that solely focused on pregnancy outcomes following artificial reproductive technology (ART) and studies that did not adjust their effect estimates for at least maternal age. Risk of bias was qualitatively described for three domains: bias due to confounding, information bias and selection bias. OUTCOMES The search resulted in 975 original articles. Ten studies met the inclusion criteria and were included in the qualitative synthesis. Nine of these studies were included in the quantitative synthesis (meta-analysis). Advanced paternal age was found to be associated with an increased risk of miscarriage. Pooled risk estimates for miscarriage for age categories 30–34, 35–39, 40–44 and ≥45 years of age were 1.04 (95% CI 0.90, 1.21), 1.15 (0.92, 1.43), 1.23 (1.06, 1.43) and 1.43 (1.13, 1.81) respectively (reference category 25–29 years). A second meta-analysis was performed for the subgroup of studies investigating first trimester miscarriage. This showed similar pooled risk estimates for