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The concept of biological identity has been traditionally a central issue in immunology. The assumption that entities foreign to a specific organism should be rejected by its immune system, while self-entities do not trigger an immune response is challenged by the expanded immunotolerance observed in pregnancy. To explain this "immunological paradox", as it was first called by Sir Peter Medawar, several mechanisms have been described in the last decades. Among them, the intentional transfer and retention of small amounts of cells between a mother and her child have gained back attention. These microchimeric cells contribute to expanding allotolerance in both organisms and enhancing genetic fitness, but they could also provoke aberrant alloimmune activation. Understanding the mechanisms used by microchimeric cells to exert their function in pregnancy has proven to be challenging as per definition they are extremely rare. Profiting from studies in the field of transplantation and cancer research, a synergistic effect of microchimerism and cellular communication based on the secretion of extracellular vesicles (EVs) has begun to be unveiled. EVs are already known to play a pivotal role in feto-maternal tolerance by transferring cargo from fetal to maternal immune cells to reshape their function. A further aspect of EVs is their function in antigen presentation either directly or on the surface of recipient cells. Here, we review the current understanding of microchimerism in the feto-maternal tolerance during human pregnancy and the potential role of EVs in mediating the allorecognition and tropism of microchimeric cells.

The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this review, we summarize the current knowledge of drug transporters in the human placenta. We only refer to human data since the placenta demonstrates great diversity among species. In addition, we describe the experimental models that have been used in human placental transport studies and discuss their availability. A better understanding of placental drug transporters will be beneficial for the health of pregnant women who need drug treatment and their fetuses.

Members of the innate immune system, innate lymphoid cells (ILCs), encompass five major populations (Natural Killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells) whose functions include defense against pathogens, surveillance of tumorigenesis, and regulation of tissue homeostasis and remodeling. ILCs are present in the uterine environment of humans and mice and are dynamically regulated during the reproductive cycle and pregnancy. These cells have been repurposed to support pregnancy promoting maternal immune tolerance and placental development. To accomplish their tasks, immune cells employ several cellular and molecular mechanisms. They have the capacity to remember a previously encountered antigen and mount a more effective response to succeeding events. Memory responses are not an exclusive feature of the adaptive immune system, but also occur in innate immune cells. Innate immune memory has already been demonstrated in monocytes/macrophages, neutrophils, dendritic cells, and ILCs. A population of decidual NK cells characterized by elevated expression of NKG2C and LILRB1 as well as a distinctive transcriptional and epigenetic profile was found to expand during subsequent pregnancies in humans. These cells secrete high amounts of interferon-γ and vascular endothelial growth factor likely favoring placentation. Similarly, uterine ILC1s in mice upregulate CXCR6 and expand in second pregnancies. These data provide evidence on the development of immunological memory of pregnancy. In this article, the characteristics, functions, and localization of ILCs are reviewed, emphasizing available data on the uterine environment. Following, the concept of innate immune memory and its mechanisms, which include epigenetic changes and metabolic rewiring, are presented. Finally, the emerging role of innate immune memory on reproduction is discussed. Advances in the comprehension of ILC functions and innate immune memory may contribute to uncovering the immunological mechanisms underlying female fertility/infertility, placental development, and distinct outcomes in second pregnancies related to higher birth weight and lower incidence of complications.

Developmental toxicity testing urgently requires the implementation of human-relevant new approach methodologies (NAMs) that better recapitulate the peculiar nature of human physiology during pregnancy, especially the placenta and the maternal/fetal interface, which represent a key stage for human lifelong health. Fit-for-purpose NAMs for the placental–fetal interface are desirable to improve the biological knowledge of environmental exposure at the molecular level and to reduce the high cost, time and ethical impact of animal studies. This article reviews the state of the art on the available in vitro (placental, fetal and amniotic cell-based systems) and in silico NAMs of human relevance for developmental toxicity testing purposes; in addition, we considered available Adverse Outcome Pathways related to developmental toxicity. The OECD TG 414 for the identification and assessment of deleterious effects of prenatal exposure to chemicals on developing organisms will be discussed to delineate the regulatory context and to better debate what is missing and needed in the context of the Developmental Origins of Health and Disease hypothesis to significantly improve this sector. Starting from this analysis, the development of a novel human feto–placental organ-on-chip platform will be introduced as an innovative future alternative tool for developmental toxicity testing, considering possible implementation and validation strategies to overcome the limitation of the current animal studies and NAMs available in regulatory toxicology and in the biomedical field.

Tobacco smoking is an important public health issue recognized by the world health organization as one of the most serious, preventable risk factors for developing a series of pregnancy pathologies. Maternal smoking is positively associated with intrauterine growth restriction (IUGR) and gestational diabetes (GDM), but negatively associated with preeclampsia (PE). In this review, we examine epidemiological, clinical and laboratory studies of smoking effects on immunoregulation during pregnancy, trophoblast function, and placental vasculature development and metabolism. We aim to identify effects of tobacco smoke components on specific placental compartments or cells, which may contribute to the understanding of the influences of maternal smoking on placenta function in normal and pathological pregnancies. Data corroborates that in any trimester, smoking is unsafe for pregnancy and that its detrimental effects outweigh questionable benefits. The effects of maternal smoking on the maternal immune regulation throughout pregnancy and the impact of different tobacco products on fetal growth have not yet been fully understood. Smoking cessation rather than treatment with replacement therapies is recommended for future mothers because also single components of tobacco and its smoke may have detrimental effects on placental function.

This opinion paper briefly presents arguments that support the unlikelihood of an impact on female fertility from current covid-19 vaccines.

ZusammenfassungDas Mammakarzinom gehört zu den am häufigsten in der Schwangerschaft auftretenden Malignomen. Da Frauen zunehmend erst in fortgeschrittenem Alter gebären, ist anzunehmen, dass die Inzidenz schwangerschaftsassoziierter Mammakarzinome zukünftig weiter steigen wird. Aufgrund schwangerschaftsbedingter Veränderungen und zurückhaltender Diagnostik kommt es häufig dazu, dass diese Karzinome erst in fortgeschrittenen Stadien detektiert werden und somit meist einer systemischen adjuvanten Therapie bedürfen. Verfügbare Daten bezüglich des optimalen chemotherapeutischen Managements sind limitiert. Insbesondere zur Anwendung des Target-Agents Trastuzumab, das in der Therapie des HER2-überexprimierenden Mammakarzinoms der nicht schwangeren Frau einen entscheidenden Beitrag zur Verbesserung der Prognose leisten konnte, fehlen dezidierte Informationen bezüglich des Wirk- und Sicherheitsprofils in der Schwangerschaft sowie auch hinsichtlich etwaiger Langzeiteffekte auf das Kind. Innerhalb der derzeit verfügbaren Literatur konnten 38 Schwangerschaften unter Trastuzumab zur Therapie eines Mammakarzinoms analysiert werden. Es lassen sich daraus Informationen gewinnen und Rückschlüsse ziehen, die zukünftig die Therapieoptionen der schwangeren Mammakarzinompatientin individualisieren und entscheidend verbessern können.

The cynomolgus monkey is increasingly considered in toxicological research as the most appropriate model for humans due to the species' close physiological contiguity, including reproductive physiology. Here, literature on the cynomolgus monkey placenta is reviewed in regards to its similarity to the human placenta and particularly for its immunological role, which is not entirely mirrored in humans. Pertinent original data are included in this article. The cynomolgus monkey placenta is evaluated based on three aspects: first, morphological development; second, the spatial and temporal appearance of maternal and fetal immune cells and certain immune cell products of the innate and adaptive immune systems; and third, the expression of relevant immune tolerance-related molecules including the homologs of anti-human leucocyte antigen, indoleamine 2,3-dioxygenase, FAS/FAS-L, annexin II, and progesterone. Parameters relevant to the immunological role of the placenta are evaluated from the immunologically immature stage of gestational day (GD) 50 until more mature stages close to birth. Selected comparisons are drawn with human and other laboratory animal placentas. In conclusion, the cynomolgus monkey placenta has a high degree of morphological and physiological similarity to the human placenta. However, there are differences in the topographical distribution of cell types and immune tolerance-related molecules. Three basic features are recognized: (1) the immunological capacity of the placenta changes throughout the lifetime of the organ; (2) these immunological changes include multiple parameters such as morphological adaptations, cell type involvement, and changes in immune-relevant molecule expression; and (3) the immune systems of two genetically disparate individuals (mother and child) are functionally intertwined at the maternal-fetal interface.

Pregnant women have been carefully observed during the COVID-19 pandemic, as the pregnancy-specific immune adaptation is known to increase the risk for infections. Recent evidence indicates that even though most pregnant have a mild or asymptomatic course, a severe course of COVID-19 and a higher risk of progression to diseases have also been described, along with a heightened risk for pregnancy complications. Yet, vertical transmission of the virus is rare and the possibility of placental SARS-CoV-2 infection as a prerequisite for vertical transmission requires further studies. We here assessed the severity of COVID-19 and onset of neonatal infections in an observational study of women infected with SARS-CoV-2 during pregnancy. Our placental analyses showed a paucity of SARS-CoV-2 viral expression ex vivo in term placentae under acute infection. No viral placental expression was detectable in convalescent pregnant women. Inoculation of placental explants generated from placentas of non-infected women at birth with SARS-CoV-2 in vitro revealed inefficient SARS-CoV-2 replication in different types of placental tissues, which provides a rationale for the low ex vivo viral expression. We further detected specific SARS-CoV-2 T cell responses in pregnant women within a few days upon infection, which was undetectable in cord blood. Our present findings confirm that vertical transmission of SARS-CoV-2 is rare, likely due to the inefficient virus replication in placental tissues. Despite the predominantly benign course of infection in most mothers and negligible risk of vertical transmission, continuous vigilance on the consequences of COVID-19 during pregnancy is required, since the maternal immune activation in response to the SARS-CoV2 infection may have long-term consequences for children’s health.

Regeneration of the endometrial stromal compartment in premenopausal women is likely maintained by the perivascular endometrial mesenchymal stem/stromal cells (eMSC) expressing sushi domain containing 2 (SUSD2). The fate of SUSD2+ eMSC during pregnancy and their role in decidualization is not fully known. The aim of our study was to determine the effect of progesterone on the stemness of the SUSD2+ eMSC isolated from non-pregnant uterine samples. Secondary objectives were to characterize the functional capacity including differentiation and clonogenicity assays of SUSD2+ eMSC isolated from decidua at full term and compare it to the capacity of those isolated from non-pregnant uterine samples. Progesterone treatment induced changes in the decidual gene expression profile in non-pregnant SUSD2+ eMSC. Data analysis of a publicly available single cell RNA-seq data set revealed differential expression of several mesenchymal and epithelial signature genes between the SUSD2+ eMSC and the decidual stromal cells, suggesting mesenchymal-to-epithelial transition occurs during decidualization. Histological analysis revealed a significantly lower abundance of SUSD2+ eMSC in 1st trimester and full term samples compared to non-pregnant samples, p = 0.0296 and 0.005, respectively. The differentiation and the colony forming capacity did not differ significantly between the cells isolated from non-pregnant and pregnant uterine samples. Our results suggest that SUSD2+ eMSC undergo decidualization in vitro, while maintaining MSC plasma membrane phenotype. Human eMSC seem to play an important role in the course of endometrial decidualization and embryo implantation. Pregnancy reduced the abundance of SUSD2+ eMSC, however eMSC function remains intact.

Evolution of spectroscopic properties of a soda–lime silicate glass with different thermal history and under applied uniaxial stress was investigated using Raman and Brillouin spectroscopies as well as Nd3+ photoluminescence techniques. Samples of soda–lime silicate with a cooling rate from 6 × 10−4 to 650 K/min were prepared either by controlled cooling from the melt using a differential scanning calorimeter or by a conventional annealing procedure. Uniaxial stress effects in a range from 0 to −1.3 GPa were investigated in situ by compression of the glass cylinders. The spectroscopic observations of rearrangements in the network structure were related to the set cooling rates or the applied uniaxial stress to calculate an interrelated set of calibrations. Comparing the results from Raman and Brillouin spectroscopy with Nd3+ photoluminescence analysis, we find a linear dependence that can be used to identify uniaxial stress and cooling rate in any given combination concurrently. The interrelated calibrations and linear dependence models are established and evaluated, and equations relating the change of glass network due to effects of cooling rate or uniaxial stress are given.

In Fibre-to-the-X, fibre is used to connect new active optic equipment at a certain location. In most cases, a connection to an existing network is required. Costs can be saved by using existing infrastructure, like empty ducts and spare fibres. Often, restrictions are given by municipalities to only use certain tracks or to only follow street patterns. This means that planners have to work with the combination of several networks to design the new network. In this article we propose a new algorithm that finds a low cost-path between two points, using multiple available networks. The given points do not have to be connected to one of the networks from the start. We split the problem in three sub-problems: connecting the points with the network, find the transition points between the networks, and finally find the low cost-path between the given points. For each sub-problems an algorithm is proposed and the combination of those is tuned for optimal performance. The algorithm is applied to a problem in telecommunication: it quickly finds low-cost paths in complex urban environments.