Paternal age and the risk of spontaneous miscarriage

Published 03 June 2020

A new systematic review finds that advanced paternal age beyond 40 years is significantly associated with an increased risk of spontaneous miscarriage when adjusted for maternal age, especially in the first trimester of pregnancy.

The trend of delayed childbearing has been rising since the 1970s in developed countries; here too the number of couples seeking ART because of age-related infertility is increasing. One major hazard in older couples following both spontaneous and ART conceptions is miscarriage before 24 weeks gestation, which occurs in about 30% of all pregnancies. Although advanced maternal age is intrinsically associated with a higher risk of spontaneous miscarriage, the significant contribution of paternal age has only now been unequivocally demonstrated in the first systematic review and meta-analysis.(1)

As background to this review the authors report that spontaneous miscarriage is a consequence of various underlying pathologies, with chromosomal abnormalities of the conceptus accounting for more than half of all cases recorded during the course of first trimester. There is solid evidence, they note, that women over 35 years of age are more likely to conceive a non-viable embryo, which can be a result of aberrant fertilisation and/or impaired division of embryonic cells during preimplantation development. These genetic abnormalities in the embryo may originate in the ageing oocyte which loses its DNA integrity, thus directly reflecting the impact of maternal age, or in the embryo during its first stages of cell division. The ageing sperm cell, which carries 50% of an embryo’s genetic material, could account for some of these later occurring errors.

Indeed, ten studies so far have efficiently addressed the theory that advanced paternal age contributes to the incidence of spontaneous miscarriage following natural or ART conception. These studies were included in the meta-analysis because their link between paternal age and spontaneous miscarriage was adjusted for maternal age in order to negate the co-linearity between paternal and maternal age.

However, these studies did not use the same definition of miscarriage with regard to gestational age, prompting the authors to perform two separate analyses putting the threshold for spontaneous fetal demise first at 20 weeks (nine studies) and then at 13 weeks (four studies) of pregnancy. Thus, fathers between 40-44 years of age were 23% more likely to contribute to the incidence of spontaneous miscarriage before 20 weeks of gestation than their younger peers. Similarly, when the paternal age was over 45 years the risk for pregnancy loss before 20 weeks was increased by 43% and before 13 weeks by 74%.

While the strength of the outcomes from the individual studies was limited by the small sample representation in the advanced paternal age groups, pooling the data in the meta-analysis increased the statistical power and consolidated the conclusion that older fathers, independently of maternal age, do introduce a small but considerable risk for miscarriage in spontaneous and ART pregnancies. The authors argue that residual confounding by maternal age is difficult to exclude and acknowledge that clinical research has so far failed to report a strong link between age-related decline in conventional sperm parameters and miscarriage.

Nonetheless, a confidence in their findings stems from the vast amount of basic research that associates sperm DNA integrity to ageing and specifically DNA fragmentation, which has been repeatedly linked directly to recurrent miscarriage. These studies inspired the authors to launch a new prospective case-control study (REMI III project) to assess the impact and predictive value of various paternal factors, including age and sperm DNA integrity, on recurrent pregnancy loss.(2) The first results are expected later at the end of the year, with a follow up pending in 2025.

1. Du Fossé NA, Van der Hoorn MP, Van Lith JMM, et al. Advanced paternal age is associated with an increased risk of spontaneous miscarriage: A systematic review and meta-analysis. Hum Reprod Update 2020; doi: 10.1093/humupd/dmaa010.
2. Du Fossé NA, Van der Hoorn MP, Eikmans M, et al. Evaluating the role of paternal factors in aetiology and prognosis of recurrent pregnancy loss: study protocol for a hospital-based multicentre case–control study and cohort study (REMI III project). BMJ Open 2019; 9: e033095. doi: 10.1136/b

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