NEW YORK – An international team led by investigators at the University of Copenhagen has identified a handful of genetic loci linked to postpartum hemorrhage, highlighting apparent roles for progesterone signaling and other processes in the risky post-pregnancy bleeding condition.
In a paper published in Nature Genetics on Monday, University of Copenhagen researchers Henriette Svarre Nielsen and Soren Brunak and their colleagues called postpartum hemorrhage "a leading cause of maternal mortality, with approximately 100,000 young and otherwise healthy women dying every year worldwide."
"Despite affecting more than one in 10 births and being a heritable condition, [postpartum hemorrhage] remains unexplored at the genetic and molecular level," they explained, noting that "there is an urgent clinical need" to understand its molecular etiology and identify biomarkers that characterize high-risk women before labor to initiate preventive measures and monitoring.
With that in mind, Nielsen, Brunak, and their colleagues brought together data for 331,792 women from half a dozen northern European cohorts and performed a series of genome-wide association studies to delve into the genetic architecture of pregnancy-related bleeding conditions across and after pregnancy. The cohorts included 28,898 early bleeding cases, more than 3,200 cases of antepartum bleeding, and 21,521 postpartum hemorrhage cases.
"Bleeding in early pregnancy and postpartum hemorrhage bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health," the authors explained.
Using array-based and imputed variants for as many as 302,894 individuals per GWAS, the team searched for genetic variants with ties to early bleeding during the first and early second trimester, antepartum bleeding during the mid-to-late second trimester, or postpartum hemorrhage after pregnancy.
The GWAS analyses did not reveal variants with significant ties to early or antepartum bleeding, prompting speculation that these bleeding events may involve "complex, polygenic etiology." In contrast, their GWAS meta-analyses uncovered five postpartum hemorrhage-associated loci on chromosomes 4, 6, 10, and 12, as well as the X chromosome.
With the help of EpiMap enhancer element data and cis-regulatory element clues from the ENCODE effort, the investigators went on to investigate possible functional effects of postpartum hemorrhage-related loci. In the process, they tracked down candidate target genes at three of the five risk loci, while highlighting progesterone receptor binding sites that overlapped with postpartum hemorrhage-associated genetic variants.
The team also saw enrichment for postpartum hemorrhage-associated variants at transcription factor-binding sites active in smooth muscle cells and tissue, endometrial tissue, thyroid gland tissue, and other cell and tissue types.
While postpartum hemorrhage did not seem to show genetic correlation with bleeding during early pregnancy, the investigators reported, their phenotypic genetic correlation analyses pointed to genetic correlation between postpartum hemorrhage and traits ranging from positive correlations with maternal birth weight, fetal birth weight, or maternal gestational duration to an inverse correlation between postpartum hemorrhage and uterine fibroid risk.
Together, the results suggested that implantation-, contraction-, and progesterone signaling-related shifts contribute to postpartum hemorrhage, the authors explained, "whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified."