Dataset Information

Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.

ABSTRACT: Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes, HAND2, TBX3, and RAP2C/FRMD7, at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR). Furthermore, there were strong genetic correlations with birth weight, gestational duration, and uterine fibroids. Early bleeding during pregnancy (28,898 cases and 302,894 controls) yielded no genome-wide association signals, but showed strong genetic correlation with a variety of human traits, indicative of polygenic and pleiotropic effects. Our results suggest that postpartum bleeding is related to myometrium dysregulation, whereas early bleeding is a complex trait related to underlying health and possibly socioeconomic status.

SUBMITTER: Westergaard D

PROVIDER: S-EPMC10462219 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.

Westergaard David D Steinthorsdottir Valgerdur V Stefansdottir Lilja L Rohde Palle Duun PD Wu Xiaoping X Geller Frank F Tyrmi Jaakko J Havulinna Aki S AS Navais Pol Sole PS Flatley Christopher C Ostrowski Sisse Rye SR Pedersen Ole Birger OB Erikstrup Christian C Sørensen Erik E Mikkelsen Christina C Brun Mie Topholm MT Jensen Bitten Aagaard BA Brodersen Thorsten T Ullum Henrik H Magnus Per P Andreassen Ole A OA Njolstad Pål R PR Kolte Astrid Marie AM Krebs Lone L Nyegaard Mette M Hansen Thomas Folkmann TF Fenstra Bjarke B Daly Mark M Lindgren Cecilia M CM Thorleifsson Gudmar G Stefansson Olafur A OA Sveinbjornsson Gardar G Gudbjartsson Daniel F DF Thorsteinsdottir Unnur U Banasik Karina K Jacobsson Bo B Laisk Triin T Laivuori Hannele H Stefansson Kari K Brunak Søren S Nielsen Henriette Svarre HS

medRxiv : the preprint server for health sciences 20230815

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation an ...[more]

PMID: 37645979

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Project description:IntroductionPostpartum hemorrhage (PPH) is recognized as a leading cause of obstetric morbidity and mortality. Population-wide studies have used International Classification of Diseases (ICD) diagnostic codes to track and report the prevalence of PPH. Although the 10th revision (ICD-10) was introduced in Sweden in 1997, the accuracy of ICD-10 codes for PPH is not known. Thus, the aim was to determine the accuracy of diagnostic coding for PPH in the Swedish Pregnancy Register.Material and methodsWe performed a retrospective cohort study of 609 807 deliveries in Sweden between 2014 and 2019. Information on ICD-10 codes for PPH and estimated blood loss were extracted from the Swedish Pregnancy Register. Using an estimated blood loss >1000 mL as the reference standard, we evaluated the diagnostic accuracy of ICD-10 codes for PPH by estimating sensitivity, specificity, positive predictive value and negative predictive value with exact binomial 95% confidence intervals (CIs). In our secondary analysis, we assessed the ICD-10 coding accuracy for severe PPH, defined as an estimated blood loss >1000 mL and transfusion of at least 1 unit of red blood cells registered in the Scandinavian Donations and Transfusion database.ResultsOf the 609 807 deliveries, 43 312 (7.1%) had an ICD-10 code for PPH and 45 071 (7.4%) had an estimated blood loss >1000 mL. The ICD codes had a sensitivity of 88.5% (95% CI 88.2-88.7), specificity of 99.4% (95% CI 99.4-99.4), positive predictive value of 92.0% (95% CI 91.8-92.3) and negative predictive value of 99.1% (95% CI 99.1-99.1). In our secondary analysis, on deliveries with severe PPH, the sensitivity for an ICD code was 91.3% (95% CI 90.7-91.9), whereas specificity was 83.5% (95% CI 82.3-84.6).ConclusionsOur findings indicate that ICD-10 codes for PPH in Sweden have moderately high sensitivity and excellent specificity. These results suggest that PPH diagnostic codes in medical records and linked pregnancy and birth registers can be used for research, quality improvement and reporting PPH prevalence in Sweden.

Project description:Background Pregnant persons with bleeding disorders and their potentially affected newborns are at a higher risk of peripartum bleeding complications. The safest mode of delivery for persons with bleeding disorders remains debated, leading to uncertainties in decision-making between the patient and her multidisciplinary team. Objectives This study aimed to describe maternal outcomes for pregnant persons with bleeding disorders by mode of delivery and to examine whether postpartum hemorrhage (PPH) and neonatal hemorrhagic manifestations are associated with the mode of delivery. Methods We collected retrospective data on pregnant persons with bleeding disorders who delivered at a single center from 2010 to 2021. Descriptive statistics, Fisher exact test, and odds ratios were used for analysis. Results A total of 82 pregnancies in 56 subjects were included. Hemophilia A and von Willebrand disease represented the largest cohort, at 30% (17/56) each. Overall rates of primary and secondary PPH were 7.3% (6/82) and 17.4% (12/69), respectively. We did not find a statistically significant difference between mode of delivery and PPH. Upon comparing vaginal and cesarian deliveries, we found an odds ratio of 0.7 (95% CI, 0.1-3.4) for primary PPH and 2.6 (95% CI, 0.4-16.4) for secondary PPH. One male newborn with severe hemophilia A was treated for a suspected intracranial hemorrhage. Conclusion In our cohort, high rates of PPH remained an important complication for pregnant persons with bleeding disorders. There was no significant difference in PPH based on modes of delivery. The small sample size likely limited the power of our study, and consequently, future larger studies are needed. Essentials • Peripartum management of persons with bleeding disorders requires additional research efforts.• We described maternal and neonatal outcomes from a single Canadian tertiary care center.• Persons with bleeding disorders had high rates of secondary postpartum hemorrhage.• We found no significant difference between rates of postpartum hemorrhage and mode of delivery.

Project description:IntroductionDuring the peripartum, women undergo significant hormonal changes that are crucial for fetal development and a healthy pregnancy and postpartum period for mother and infant. Although several studies have determined healthy norm ranges of estradiol and progesterone, there are discrepancies among the reports, rendering it unclear which hormone levels are linked to adverse health outcomes. To account for the impact of sex steroid patterns on health outcomes in mothers and children, a longitudinal assessment of different parameters is needed.Materials and methodsWe longitudinally assessed a cohort of 130 women over five months during pregnancy and postpartum. The women provided saliva samples and completed psychosocial questionnaires. Hormone analyses were conducted using enzyme-linked immunosorbent assay (ELISA). Different parameters of estradiol and progesterone were analyzed and evaluated in relation to psychometric variables. To examine the presence of heterogenous hormonal trajectories in the peripartum, we applied group-based trajectory modelling as a special case of latent-class group analysis.ResultsEstradiol and progesterone levels rose towards the end of pregnancy and dropped sharply after birth, with considerable individual variation, particularly during pregnancy. However, their ratio remained stable. We identified three estradiol trajectory subgroups and two progesterone subgroups. Age influenced progesterone levels, with older pregnant women having higher levels than younger women. Anxiety and depressive symptoms had a predictive value for trajectories of specific subgroups of women. The study also revealed two distinct subgroups regarding the course of estradiol and progesterone fluctuations as well as their ratio.ConclusionThis study provides insights into the course and fluctuation of salivary estradiol and progesterone levels among healthy women during the peripartum period, highlighting significant variations in hormone levels but stability in their ratio during this time. The finding of distinct sex steroid courses in the peripartum is new and suggests the need for further research to explore their impact on health outcomes. Our preliminary results suggest that hormonal fluctuations at the end of pregnancy appear to be a normal occurrence and might even be a protective factor for associated psychological symptoms and sleep disturbances in women.

Dataset Information

Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.

Publications

Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.

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