BACKGROUND

背景

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.

尽管自然流产是人类妊娠最常见的并发症，但其潜在原因尚未阐明。长期以来，一直认为母亲高龄是流产的主要风险因素，因为这与胎儿染色体异常密切相关。父亲年龄与流产风险之间的关系尚不明确，尽管从生物学角度讲，高龄男性精子基因和表观遗传异常增多，可导致流产，这一观点是合理的。以往有多项荟萃分析显示，父亲高龄与多种围产期和儿科结局之间存在关联。这是首个关于父亲年龄与自然流产之间关系的系统综述和荟萃分析。

OBJECTIVE AND RATIONALE

目标及合理性

The aim of this systematic review and meta-analysis is to evaluate the effect of paternal age on the risk of spontaneous miscarriage.

本系统综述与荟萃分析旨在评估父亲年龄对自然流产风险的影响。

SEARCH METHODS

检索方法 

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.

我们检索了PubMed、Embase和Cochrane数据库，以查找截至2019年8月的相关研究。检索时使用了以下自由文本和医学主题词表（MeSH）术语：paternal age，father’s age，male age，husband’s age，spontaneous abortion，spontaneous miscarriage，pregnancy loss，fetal loss和fetal death。本研究遵循了系统综述与荟萃分析的优选报告项目（PRISMA）指南，纳入了以英文撰写的原始研究文章，这些文章探讨了父亲年龄与自然流产之间的关系。排除标准包括以下研究：仅关注辅助生殖技术（ART）后妊娠结局的研究，以及在进行效应估计时未对母体年龄等进行校正的研究。定性描述了三方面的偏倚风险：混杂偏倚、信息偏倚以及选择偏倚。

OUTCOMES

结果

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 metaanalysis 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).

检索出了975篇原始文章，其中有10项研究符合纳入标准，并被纳入定性综合分析中。在这10项研究中，有9项被纳入定量综合分析（即元分析）中。研究发现，父亲年龄较大与流产风险增加有关。对于30-34岁、35-39岁、40-44岁和≥45岁，这几个年龄段的流产风险合并估计值分别为1.04（95%置信区间：0.90, 1.21）、1.15（0.92, 1.43）、1.23（1.06, 1.43）和1.43（1.13, 1.81）（以25-29岁为参照组）。对于研究孕早期流产的亚组，进行了第二层元分析。结果显示，前三个年龄段的合并风险估计值相似，而≥45岁年龄段的合并风险估计值略高（1.74；95% 置信区间：1.26, 2.41）。

WIDER IMPLICATIONS:

更广泛的影响

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.

在过去几十年里，晚育变得越来越普遍。众所周知，女性年龄增加的不良生育结局（包括自然流产）的发生率更高。本文发现，父亲年龄也与自然流产风险增加有关。尽管父亲年龄的影响不如母亲年龄那么明显，而且目前不能排除母亲年龄带来的残余混杂效应，但是这一发现可能对高龄男性夫妇的孕前咨询具有启示意义。

参考文献：

Human Reproduction Update, Volume 26, Issue 5, September-October 2020, Pages 650–669, https://doi.org/10.1093/humupd/dmaa010