Background: Recurrent miscarriage (RM) is traditionally described as three or more consecutive pregnancy losses and remains a challenging condition, affecting 1-3% of couples trying to conceive. Although factors such as uterine abnormalities, maternal hypothyroidism and parental balanced translocations are associated with RM, in most situations the aetiology is unknown. The coexistence of RM and live births in many families suggests a potential association with an underlying recessive, X-linked or imprinted condition. Indeed, placental function and fetal growth and development are intricately linked. The main steroid needed to maintain pregnancy is progesterone. In humans, progesterone synthesis occurs from the maternal corpus luteum in the first 6-8 weeks of gestation at which point the fetally-derived placenta takes over progesterone production (luteal-placental shift). The progesterone receptor (PGR) is the only classic liganded nuclear receptor without an associated disorder in humans. Furthermore, prematurity is reported in a child with disruption of CYP11A1 (encoding P450scc) but no bi-allelic loss-of-function variants in FDX1 or HSD3B1 have been described.
Aims: We hypothesised that disruption of placental steroidogenesis is associated with recurrent pregnancy loss.
Methods: DNA from 123 couples with RM of unknown aetiology and 22 products of conception (POC) was obtained with ethical approval and consent from the Baby Bio Bank. Custom HaloPlex HS targeted panels were designed to capture 256 genes involved in placental function, novel components of steroidogenesis from transcriptomic analysis, and fetal growth. DNA libraries were prepared, and next-generation sequencing performed using NextSeq platforms. Analysis focused on several inheritance models including rare variants (MAF<0.1) co-segregating in couples (recessive model) as well as imprinted genes, X-linked genes, and non-filtered singleton global gene enrichment analysis. In addition, human placental single-cell RNA sequencing data were analysed to study clustering of factors involved in progesterone and growth pathways (https://maternal-fetal-interface.cellgeni.sanger.ac.uk).
Results: Most placental genes involved in progesterone synthesis (e.g., CYP11A1, HSD3B1, FDX1) were strongly localised in the syncytiotrophoblastic cells of the fetal placenta whereas the progesterone receptor was expressed in maternally-derived decidua, as expected. No likely pathogenic variants were found in key components of progesterone synthesis and action that were studied in this RM/POC cohort.
Conclusions: The luteal-placental shift is a key event in progesterone synthesis and the maintenance of pregnancy past the first trimester in humans. However, defects in core components of placental progesterone synthesis and action are not likely to be a common cause of pregnancy loss in couples with a history of recurrent miscarriage.
22 Sep 2021 - 26 Sep 2021