Placental biomarkers in second trimester maternal serum are associated with postpartum hemorrhage: a secondary analysis of the NuMoM2b dataset

Abstract Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide, which is often attributed to retained placenta (RP) after delivery. There are no biomarkers currently used to predict a risk of developing RP/PPH prior to labor. The objective of this study was to determine relationships between placental biomarkers measured in the first and second trimesters and proxy measures of postpartum blood loss relative to preeclampsia status in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) dataset. 2,192 participants had placental analytes drawn during the first and second trimesters (9-13 and 16-22 weeks gestation, respectively); the outcome was a composite of retained placenta and/or PPH requiring blood transfusion (RP/PPH). Using Kruskal-Wallis tests, median differences in levels of soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), sFlt-1/PlGF ratio, soluble endoglin (sEng), beta subunit of human chorionic gonadotropin (β-hCG), inhibin A (INHA), and pregnancy-associated protein-A (PAPP-A) were assessed between women with (n=67) and without (n=2125) RP/PPH overall and stratified by preeclampsia status. Women with RP/PPH had significantly higher median levels of sEng, β-hCG, INHA, PAPP-A in the second trimester and sFlt-1was higher in both first and second trimesters, which was observed again when stratifying by preeclampsia status. Our findings indicate that biomarkers associated with angiogenesis, particularly when measured in the second trimester, are important targets for further study of RP and/or PPH pathophysiology and potential risk screening development. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by the University of Arizona College of Nursing (JNR, PI) and R00NR019596 (EE, PI; EG, Postdoctoral Research Fellow). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board (IRB) approval for the parent nuMoM2b study was obtained from Columbia University Human Subjects Institutional Review Board and the City University of New York (IRB-AAAR9413 and .HRPP/IRB 2019-0855 respectively). Each site reviewed and approved all study procedures. All participants (or their legal guardian(s)) provided written informed consent before participating in the study. All methods in the parent study and this secondary analysis were carried out in accordance with relevant guidelines and regulations. This secondary analysis of deidentified data is exempt from IRB approval beyond that granted to the parent study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes There was an error regarding the sample size in the abstract. It was 2,192, not 2,188. Further clarification was added to the figure. No substantive changes were made. Data Availability nuMoM2B data can be obtained through application to the National Institute of Child Health and Human Development Data and Specimen Hub.