Heterogeneity of the placenta in health and disease explored through integrated histology, gene expression and modelling

Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. Altered placental formation and functional capacity are major contributors to FGR pathogenesis. Relating placental structure to function across the placenta in healthy and FGR pregnancies remains largely unexplored but could improve understanding of placental diseases. We investigated integration of these parameters spatially in the term human placenta using predictive modelling. Systematic sampling was able to overcome heterogeneity in placental morphological and molecular features. Defects in villous development, elevated fibrosis, and reduced expression of growth and functional marker genes (IGF2, VEGA, SLC38A1, SLC2A3) were seen in age-matched term FGR versus healthy control placentas. Characteristic histopathological changes with specific accompanying molecular signatures could be integrated through computational modelling to predict if the placenta came from a healthy or FGR pregnancy. Our findings yield new insights into the spatial relationship between placental structure and function and the aetiology of FGR. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement ANSP received funding for this work via an Academy of Medical Sciences Springboard Grant, Dorothy Hodgkin Research Fellowship (DH130036/RG74249), MRC New Investigator Grant (MR/R022690/1/RG93186) and Lister Institute of Preventative Medicine Research Prize (RG93692). TN and AZ are supported by a Medical Research Council grant (MR/R02524X/1). HEJY was supported by an A*STAR International Fellowship from the Agency for Science, Technology and Research. KM was supported by UCLH Charity. SLH received funding for this work via an Academy of Medical Sciences Clinical Lecturer Starter Grant (AMS-SGL015\ 1011) and the UCLH EGA Obstetric Charity. ### 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: Subjects were recruited from University College London Hospital NHS Foundation Trust, London, UK with ethics approval from the South-Central Oxford A research ethics committee (17/SC/0432) and the Stanmore research ethics committee (13/LO/1254). Written informed consent was received prior to participation. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors