du Fossé, N. A., van der Hoorn, M. P., van Lith, J. M. M., le Cessie, S., & Lashley, E. E. L. O. (2020). Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Human reproduction update. https://doi.org/10.1093/humupd/dmaa010
du Fossé NA, van der Hoorn MP, van Lith JMM, le Cessie S, Lashley EELO. Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Human reproduction update. 2020. doi:10.1093/humupd/dmaa010
du Fossé, Nadia A., et al. "Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis." Human reproduction update, 2020.
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Free full text on PubMed Central (PMC7456349)
RRM Academy Synopsis
Paternal age of 40 and older is linked to higher miscarriage risk
A meta-analysis of nine studies that adjusted for the mother's age found that miscarriage risk was higher among pregnancies fathered by men aged 40 or older. Pooled risk estimates were 1.23 at ages 40 to 44 and 1.43 at 45 and older, against fathers aged 25 to 29.
Study at a glance, meta-analysis of nine studies: Paternal age of 40 and older is linked to higher miscarriage risk. Source: du Fossé NA et al., 2020, PMID 32358607.
Key Findings
Of 975 articles screened, ten studies (four cohort, six case-control) met the inclusion criteria, and nine of them entered the meta-analysis.
Against fathers aged 25 to 29, pooled estimates were 1.04 (95% CI 0.90, 1.21) at ages 30 to 34 and 1.15 (0.92, 1.43) at 35 to 39, neither statistically significant.
The pooled estimate was 1.23 (95% CI 1.06, 1.43) at ages 40 to 44 and 1.43 (95% CI 1.13, 1.81) at 45 and older.
In the four studies limited to first trimester miscarriage, the pooled estimate at 45 and older was 1.74 (95% CI 1.26, 2.41), with similar estimates in the three younger categories.
Dropping the study with the most extreme estimates lowered the pooled estimates for ages 35 to 39 and 40 to 44 slightly (−8%), and the overall pattern stayed similar.
Interpretation
The authors pooled adjusted results from observational studies, mostly population-based, and left out studies of ART pregnancies. Seven of the ten studies found a significant paternal age effect. The authors report that the effect is smaller than the maternal age effect and that residual confounding by maternal age may remain.
RRM Context
The male partner supplies half of the embryo's genetic material. The authors suggest that paternal age may act through sperm DNA damage, which is higher in older men. They note that recurrent miscarriage stays unexplained in most cases and that paternal age could account for a share of them. Restorative reproductive medicine treats unexplained loss as undiagnosed loss and looks for the cause in both partners.
Our editorial summary of this paper, not the article's abstract.
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 the first three age categories and a slightly higher pooled risk estimate for age category ≥45 years (1.74; 95% CI 1.26, 2.41).
Wider Implications of the Findings
Over the last decades, childbearing at later ages has become more common. It is known that frequencies of adverse reproductive outcomes, including spontaneous miscarriage, are higher in women with advanced age. We show that advanced paternal age is also associated with an increased risk of spontaneous miscarriage. Although the paternal age effect is less pronounced than that observed with advanced maternal age and residual confounding by maternal age cannot be excluded, it may have implications for preconception counselling of couples comprising an older aged male.
