A Canadian survey of patients' attitudes toward donation of products of conception for research at the time of their aspiration abortion.

OBJECTIVE: We explored patients' attitudes toward donating products of conception for research at the time of their aspiration abortion. STUDY DESIGN: We surveyed patients presenting for first or second trimester aspiration abortion to the abortion service at British Columbia Women's Hospital over a 6-month period in 2018. Questions explored demographics, attitudes toward tissue donation, willingness to donate products of conception for research, and how the option of donating tissue influenced patients' perception of their abortion. We analyzed quantitative data using descriptive statistics and answers to open-ended questions using content analysis. RESULTS: The partially tracked response rate to our survey was n = 35 of 46 (76%). Of 98 respondents included for analysis 77 (79%) were willing to donate their products of conception to research. Most respondents (n = 85, 93%), 49 (54%) of whom had ever been offered to actually donate tissue, reported that tissue donation would either positively change (n = 33, 36%) or not change (n = 52, 57%) how they felt at the time of their abortion. The majority of respondents (n = 25, 60%) who were not invited to donate their products of conception would have liked the opportunity to do so. Content analysis of open-ended responses from those willing to donate identified the categories of helping others, contributing to research and providing meaning beyond the respondents' individual experience. CONCLUSION: Patients' willingness to donate products of conception to research and their associated positive attitudes provide important support for researchers and clinicians who are involved in research that uses products of conception. IMPLICATIONS: Our data may inform research programs and abortion clinics involved in research using products of conception by better understanding the patient experience of being involved in this type of research.

Failure of Decidualization and Maternal Immune Tolerance Underlies Uterovascular Resistance in Intra Uterine Growth Restriction.

Failure of uterine vascular transformation is associated with pregnancy complications including Intra Uterine Growth Restriction (IUGR). The decidua and its immune cell populations play a key role in the earliest stages of this process. Here we investigate the hypothesis that abnormal decidualization and failure of maternal immune tolerance in the second trimester may underlie the uteroplacental pathology of IUGR. Placental bed biopsies were obtained from women undergoing elective caesarian delivery of a healthy term pregnancy, an IUGR pregnancy or a pregnancy complicated by both IUGR and preeclampsia. Decidual tissues were also collected from second trimester terminations from women with either normal or high uterine artery Doppler pulsatile index (PI). Immunohistochemical image analysis and flow cytometry were used to quantify vascular remodeling, decidual leukocytes and decidual status in cases vs. controls. Biopsies from pregnancies complicated by severe IUGR with a high uterine artery pulsatile index (PI) displayed a lack of: myometrial vascular transformation, interstitial, and endovascular extravillous trophoblast (EVT) invasion, and a lower number of maternal leukocytes. Apoptotic mural EVT were observed in association with mature dendritic cells and T cells in the IUGR samples. Second trimester pregnancies with high uterine artery PI displayed a higher incidence of small for gestational age fetuses; a skewed decidual immunology with higher numbers of; CD8 T cells, mature CD83 dendritic cells and lymphatic vessels that were packed with decidual leukocytes. The decidual stromal cells (DSCs) failed to differentiate into the large secretory DSC in these cases, remaining small and cuboidal and expressing lower levels of the nuclear progesterone receptor isoform B, and DSC markers Insulin Growth Factor Binding protein-1 (IGFBP-1) and CD10 as compared to controls. This study shows that defective progesterone mediated decidualization and a hostile maternal immune response against the invading endovascular EVT contribute to the failure of uterovascular remodeling in IUGR pregnancies.

Identification of a novel neutrophil population: proangiogenic granulocytes in second-trimester human decidua.

The maternal leukocytes of the first-trimester decidua play a fundamental role in implantation and early development of the fetus and placenta, yet little is known regarding the second-trimester decidual environment. Our multicolor flow cytometric analyses of human decidual leukocytes detected an elevation in tissue resident neutrophils in the second trimester. These cells in both human and murine samples were spatially restricted to decidua basalis. In comparison with peripheral blood neutrophils (PMNs), the decidual neutrophils expressed high levels of neutrophil activation markers and the angiogenesis-related proteins: vascular endothelial growth factor-A, Arginase-1, and CCL2, similarly shown in tumor-associated neutrophils. Functional in vitro assays showed that second-trimester human decidua conditioned medium stimulated transendothelial PMN invasion, upregulated VEGFA, ARG1, CCL2, and ICAM1 mRNA levels, and increased PMN-driven in vitro angiogenesis in a CXCL8-dependent manner. This study identified a novel neutrophil population with a physiological, angiogenic role in human decidua.

Vascular-leukocyte interactions: mechanisms of human decidual spiral artery remodeling in vitro.

Transformation of uterine spiral arteries is critical for healthy human pregnancy. We recently proposed a role for maternal leukocytes in decidual spiral artery remodeling and suggested that matrix metalloprotease (MMP) activity contributed to the destruction of the arterial wall. In the current study we used our first trimester placental-decidual co-culture (PDC) model to define the temporal relationship and test the mechanistic aspects of this process. PDC experiments were assessed by image analysis over a six-day time-course for degree of vascular transformation and leukocyte distribution around progressively remodeled arterioles. We observed rapid transformation in PDCs associated with loss of vascular smooth muscle cells, widening of the vessel lumen, and significant accumulation of uterine Natural Killer cells and macrophages within the vascular wall (P < 0.001) before trophoblast presence in the vessel lumens. These events did not occur in decidua-only cultures. Active MMP-9 was detected in leukocytes and vascular cells of remodeling arterioles, and inhibition of MMP-2/9 activity in PDC resulted in failure of decidual vascular remodeling compared with vehicle-treated PDCs. Apoptosis of vascular cells, macrophage-mediated phagocytosis, and vascular smooth muscle cell dedifferentiation contributed to the remodeling observed. The PDC model indicates that placental presence is required to initiate decidual spiral artery remodeling but that uterine Natural Killer cells and macrophages mediate the early stages of this process at the cellular level.

Promotion of angiogenesis by human endometrial lymphocytes.

The human endometrium is a unique tissue that undergoes dramatic monthly remodeling during the menstrual cycle in preparation for an implanting conceptus. This remodeling involves sequential proliferation and differentiation of endometrial stromal and epithelial cells, coupled with extensive angiogenesis and infiltration of a specific specialized immune cell subset. Increasing evidence points to an essential role for these maternal leukocytes in stimulating the endometrial angiogenesis, and we propose that they also play a key role in the decidual vascular transformation. Aberrant endometrial angiogenesis, decidualisation and vascular transformation is thought to underlie many pathologies of pregnancy, from infertility to the development of preeclampsia and Intra Uterine Growth Restriction. In this chapter we review the cellular processes associated with each stage of endometrial and decidual transformation, detailing the role of the immune cell populations and the angiogenic and chemotactic factors secreted by them.

Aberrant endometrial features of pregnancy in diabetic NOD mice.

OBJECTIVE: Pregnant diabetic women are at a 4-12 times higher risk for preeclampsia, an urgent acute-onset complication of mid- to late gestation, than normal pregnant women. Hallmarks of preeclampsia are hypertension, proteinuria, and incomplete modification of endometrial spiral arteries. Transient proangiogenic lymphocytes called uterine natural killer (uNK) cells are implicated in human and rodent spiral artery modification. We studied mid- to late gestations in spontaneously type 1 diabetic NOD mice to investigate whether diabetes alters uNK cell homing and/or function. RESEARCH DESIGN AND METHODS: Normoglycemic, pre-diabetic, and diabetic NOD mice and controls were mated. Lymphocytes and endometrial endothelium and decidua were studied histologically and in functional assays. RESULTS: Conception accelerated progression to overt diabetes in NOD females who had limited spiral artery development, heavier placentas, and lighter fetuses displaying numerous birth defects compared with controls. UNK cell numbers were reduced in the decidua basalis of diabetic females, whereas interferon-gamma production was elevated. In diabetic NOD mice, decidual expression of the mucosal vascular addressin cell adhesion molecule (MAdCAM)-1 was aberrant in position, whereas vascular cell adhesion molecule (VCAM)-1 expression was reduced. Assays of lymphocyte adhesion to tissue sections under shear forces indicated that diabetes compromises the potential homing functions of both endometrial endothelium and peripheral NK cells. CONCLUSIONS: In diabetes, gestational endometrium has immune and vascular defects that likely contribute to murine fetal loss and birth defects. Analogous problems and preeclampsia in diabetic women may involve similar mechanisms.