Maternal germline factors associated with aneuploid pregnancy loss: a systematic review

BACKGROUND: Miscarriage describes the spontaneous loss of pregnancy before the threshold of viability; the vast majority occur before 12 weeks of gestation. Miscarriage affects one in four couples and is the most common complication of pregnancy. Chromosomal abnormalities of the embryo are identified in ∼50% of first trimester miscarriages; aneuploidy accounts for 86% of these cases. The majority of trisomic miscarriages are of maternal origin with errors occurring during meiotic division of the oocytes. Chromosome segregation errors in oocytes may be sporadic events secondary to advancing maternal age; however, there is increasing evidence to suggest possible maternal germline contributions to this. OBJECTIVE AND RATIONALE: The objective of this review was to appraise critically the existing evidence relating to maternal germline factors associated with pregnancy loss secondary to embryo aneuploidy, identify limitations in the current evidence base and establish areas requiring further research. SEARCH METHODS: The initial literature search was performed in September 2019 and updated in January 2021 using the electronic databases OVID MEDLINE, EMBASE and the Cochrane Library. No time or language restrictions were applied to the searches and only primary research was included. Participants were women who had suffered pregnancy loss secondary to numerical chromosomal abnormalities of the embryo. Study identification and subsequent data extraction were performed by two authors independently. The Newcastle-Ottawa Scale was used to judge the quality of the included studies. The results were synthesized narratively. OUTCOMES: The literature search identified 2198 titles once duplicates were removed, of which 21 were eligible for inclusion in this systematic review. They reported on maternal germline factors having variable degrees of association with pregnancy loss of aneuploid origin. The Online Mendelian Inheritance in Man (OMIM) gene ontology database was used as a reference to establish the functional role currently attributed to the genes reported. The majority of the cases reported and included were secondary to the inheritance of maternal structural factors such as Robertsonian translocations, deletions and insertions. Germline factors with a plausible role in aneuploid pregnancy loss of maternal origin included skewed X-inactivation and CGG repeats in the fragile X mental retardation (FMR1) gene. Studies that reported the association of single gene mutations with aneuploid pregnancy loss were conflicting. Single gene mutations with an uncertain or no role in aneuploid pregnancy loss included mutations in synaptonemal complex protein 3 (SYCP3), mitotic polo-like kinase 4 (PLK4) and meiotic stromal antigen 3 (STAG3) spindle integrity variants and 5,10-methylenetetrahydrofolate reductase (MTHFR). WIDER IMPLICATIONS: Identifying maternal genetic factors associated with an increased risk of aneuploidy will expand our understanding of cell division, non-disjunction and miscarriage secondary to embryo aneuploidy. The candidate germline factors identified may be incorporated in a screening panel for women suffering miscarriage of aneuploidy aetiology to facilitate counselling for subsequent pregnancies.