Implementation challenges in preeclampsia care: perspectives from health care professionals in urban Uganda.

Background: Sub-Saharan Africa bears the burden of 70% of maternal deaths worldwide, of which ∼10% are attributable to hypertensive disorders of pregnancy, primarily complications of preeclampsia. In other global settings, outcomes of pregnancies affected by preeclampsia are improved with timely and effective medical care.

Objective: This study aimed to explore the perspectives of local health care professionals on how preeclampsia care is currently delivered in the study setting and what challenges they experience in providing prompt and safe care.

Trophoblast organoid systems to study human placentation.

Human trophoblast organoids provide a valuable in vitro system to investigate human placental development and function. In this issue of Developmental Cell, Shannon et al. benchmark two organoid models against primary trophoblast at single-cell resolution, identifying their strengths and limitations.

Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy.

In humans, balanced invasion of trophoblast cells into the uterine mucosa, the decidua, is critical for successful pregnancy. Evidence suggests that this process is regulated by uterine natural killer (uNK) cells, but how they influence reproductive outcomes is unclear. Here, we used our trophoblast organoids and primary tissue samples to determine how uNK cells affect placentation.

Barriers and facilitators to maternal death surveillance and response at a busy urban National Referral Hospital in Uganda.

Preventable maternal and newborn deaths remain a global concern, particularly in low- and- middle-income countries (LMICs) Timely maternal death surveillance and response (MDSR) is a recommended strategy to account for such deaths through identifying contextual factors that contributed to the deaths to inform recommendations to implement in order to reduce future deaths. Implementation of MDSR is still suboptimal due to barriers such as inadequate skills and leadership to support MDSR. With the leadership of WHO and UNFPA, there is momentum to roll out MDSR, however, the barriers and enablers for implementation have received limited attention.

Primitive haematopoiesis in the human placenta gives rise to macrophages with epigenetically silenced HLA-DR.

The earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis. Although this process is thought to be spatially restricted to the yolk sac in the mouse, in humans, it remains poorly understood. Human foetal placental macrophages, or Hofbauer cells (HBC), arise during the primitive haematopoietic wave ~18 days post conception and lack expression of human leukocyte antigen (HLA) class II.

Spatial multiomics map of trophoblast development in early pregnancy.

The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia.

Natural Killer Cells in the Human Uterine Mucosa.

The presence of granulated lymphocytes in the human uterine mucosa, known as decidua during pregnancy, or endometrium otherwise, was first noted in the nineteenth century, but it was not until 1990 that these cells were identified as a type of natural killer (NK) cell. From the outset, uterine NK (uNK) cells were found to be less cytotoxic than their circulating counterparts, peripheral NK (pNK) cells. Recently, unbiased approaches have defined three subpopulations of uNK cells, all of which cluster separately from pNK cells.

Why mothers die at a busy tertiary urban hospital in Kampala, Uganda: a comprehensive review of maternal deaths 2016-2018 and implications for quality improvement to reduce deaths.

Background: Reviewing maternal deaths and drawing out lessons for clinical practice is part of an effective cohesive intervention strategy to reduce future deaths.

Objective: To review maternal deaths at the National Referral hospital in Kampala over a 3-year period (2016-2018) to determine causes of death, extent of preventability, proportion of deaths notified and audited as per national guidelines.

Methods: Trained-multidisciplinary panels (obstetricians and senior midwives) conducted retrospective reviews of maternal deaths that occurred.

Learning from maternal deaths due to uterine rupture: review of cases from peri-urban Uganda.

Background: Maternal deaths from uterine rupture continue to occur globally, with particularly high rates in sub-Saharan Africa. Maternal death reviews have been shown to be an effective part of cohesive strategies to prevent future deaths.

Objective: This study aimed to conduct maternal death reviews for all deaths following uterine rupture in the study center, to assess preventability, and to synthesize key learning points that may help to prevent future maternal deaths following uterine rupture.

Local immune recognition of trophoblast in early human pregnancy: controversies and questions.

The role of the maternal immune system in reproductive success in humans remains controversial. Here we focus on the events that occur in the maternal decidua during the first few weeks of human pregnancy, because this is the site at which maternal leukocytes initially interact with and can recognize fetal trophoblast cells, potentially involving allorecognition by both T cells and natural killer (NK) cells. NK cells are the dominant leukocyte population in first-trimester decidua, and genetic studies point to a role of allorecognition by uterine NK cells in establishing a boundary between the mother and the fetus.

Preventing death following unsafe abortion: a case series from urban Uganda.

Background: Maternal deaths from unsafe abortion continue to occur globally, with particularly high rates in Sub-Saharan Africa where most abortions are classified as unsafe. Maternal death reviews are an effective part of cohesive strategies to prevent future deaths while abortion remains illegal.

Objective: This study aimed to conduct maternal death reviews for all deaths occurring following unsafe abortion during the study period, to assess preventability, and to synthesize key learning points that may help to prevent future maternal deaths following unsafe abortions.

Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro.

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments.

Characterization of primary models of human trophoblast.

Two recently developed models, trophoblast organoids and trophoblast stem cells (TSCs), are useful tools to further the understanding of human placental development. Both differentiate from villous cytotrophoblast (VCT) to either extravillous trophoblast (EVT) or syncytiotrophoblast (SCT). Here, we compare the transcriptomes and miRNA profiles of these models to identify which trophoblast they resemble in vivo.

How Do Uterine Natural Killer and Innate Lymphoid Cells Contribute to Successful Pregnancy?

Innate lymphoid cells (ILCs) are the most abundant immune cells in the uterine mucosa both before and during pregnancy. Circumstantial evidence suggests they play important roles in regulating placental development but exactly how they contribute to the successful outcome of pregnancy is still unclear. Uterine ILCs (uILCs) include subsets of tissue-resident natural killer (NK) cells and ILCs, and until recently the phenotype and functions of uILCs were poorly defined.

BAP1/ASXL complex modulation regulates epithelial-mesenchymal transition during trophoblast differentiation and invasion.

Normal function of the placenta depends on the earliest developmental stages when trophoblast cells differentiate and invade into the endometrium to establish the definitive maternal-fetal interface. Previously, we identified the ubiquitously expressed tumour suppressor BRCA1-associated protein 1 (BAP1) as a central factor of a novel molecular node controlling early mouse placentation. However, functional insights into how BAP1 regulates trophoblast biology are still missing.

Menstrual flow as a non-invasive source of endometrial organoids.

Assessment of the endometrium often necessitates a biopsy, which currently involves an invasive, transcervical procedure. Here, we present an alternative technique based on deriving organoids from menstrual flow. We demonstrate that organoids can be derived from gland fragments recovered from menstrual flow.

The CD94/NKG2A inhibitory receptor educates uterine NK cells to optimize pregnancy outcomes in humans and mice.

The conserved CD94/NKG2A inhibitory receptor is expressed by nearly all human and ∼50% of mouse uterine natural killer (uNK) cells. Binding human HLA-E and mouse Qa-1, NKG2A drives NK cell education, a process of unknown physiological importance influenced by HLA-B alleles. Here, we show that NKG2A genetic ablation in dams mated with wild-type males caused suboptimal maternal vascular responses in pregnancy, accompanied by perturbed placental gene expression, reduced fetal weight, greater rates of smaller fetuses with asymmetric growth, and abnormal brain development.

Diversity of KIR genes and their HLA-C ligands in Ugandan populations with historically varied malaria transmission intensity.

Background: Malaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity.

Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.

Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI).

Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells.

Hofbauer cells (HBCs) are a population of macrophages found in high abundance within the stroma of the first-trimester human placenta. HBCs are the only fetal immune cell population within the stroma of healthy placenta. However, the functional properties of these cells are poorly described.

Establishment and differentiation of long-term trophoblast organoid cultures from the human placenta.

The human placenta is essential for successful reproduction. There is great variation in the anatomy and development of the placenta in different species, meaning that animal models provide limited information about human placental development and function. Until recently, it has been impossible to isolate trophoblast cells from the human placenta that proliferate in vitro.

Parental human leukocyte antigen-C allotypes are predictive of live birth rate and risk of poor placentation in assisted reproductive treatment.

Objective: To study the pregnancy, miscarriages, and live birth rates (LBRs) according to maternal killer cell immunoglobulin-like receptor (KIR) genes expressed by uterine natural killer cells and paternal or oocyte donor human leukocyte antigen-C (HLA-C) genes expressed by trophoblast cells in patients with recurrent reproductive failure.

Design: Prospective observational cohort study.

Setting: Private infertility center.