A spatially resolved timeline of the human maternal-fetal interface.

Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR)1-3. However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.

Luteal phase support in fresh and frozen embryo transfers.

Context: Luteal phase support (LPS) has become an essential component of IVF protocols following both fresh and frozen embryo transfers, yet there is still controversy with regards to the optimal protocol of LPS to enhance treatment outcome. Search strategy: A search via PubMed for all the selected topics was limited to publications from the past 10 years and to English language. We subsequently searched the reference lists of retrieved articles. Where available, RCTs were chosen over non-randomized studies. Here we provide an updated review of the current literature on various issues relating to LPS, in both fresh and frozen embryo transfers. The timing of LPS initiation as well as the route of administration and dosing are discussed for both fresh and frozen transfers. A separate discussion for frozen thawed embryo transfer in natural cycles and non-ovulatory cycles is presented. Conclusions: We present data that supports the use of Progesterone LPS in fresh and frozen embryo transfers. No benefits were found to the addition of hCG or estradiol to progesterone LPS in fresh transfers, however GnRH agonist may have a role. IM Progesterone was not advantageous over vaginal progesterone in fresh transfers but was superior in frozen transfers. The timing of LPS introduction, the interval to embryo transfer, as well as the serum concentration of progesterone, have significant effects on the success of the treatment.

Whole-cell segmentation of tissue images with human-level performance using large-scale data annotation and deep learning.

A principal challenge in the analysis of tissue imaging data is cell segmentation-the task of identifying the precise boundary of every cell in an image. To address this problem we constructed TissueNet, a dataset for training segmentation models that contains more than 1 million manually labeled cells, an order of magnitude more than all previously published segmentation training datasets. We used TissueNet to train Mesmer, a deep-learning-enabled segmentation algorithm. We demonstrated that Mesmer is more accurate than previous methods, generalizes to the full diversity of tissue types and imaging platforms in TissueNet, and achieves human-level performance. Mesmer enabled the automated extraction of key cellular features, such as subcellular localization of protein signal, which was challenging with previous approaches. We then adapted Mesmer to harness cell lineage information in highly multiplexed datasets and used this enhanced version to quantify cell morphology changes during human gestation. All code, data and models are released as a community resource.

MAUI (MBI Analysis User Interface)-An image processing pipeline for Multiplexed Mass Based Imaging.

Mass Based Imaging (MBI) technologies such as Multiplexed Ion Beam Imaging by time of flight (MIBI-TOF) and Imaging Mass Cytometry (IMC) allow for the simultaneous measurement of the expression levels of 40 or more proteins in biological tissue, providing insight into cellular phenotypes and organization in situ. Imaging artifacts, resulting from the sample, assay or instrumentation complicate downstream analyses and require correction by domain experts. Here, we present MBI Analysis User Interface (MAUI), a series of graphical user interfaces that facilitate this data pre-processing, including the removal of channel crosstalk, noise and antibody aggregates. Our software streamlines these steps and accelerates processing by enabling real-time and interactive parameter tuning across multiple images.

The Society for Immunotherapy of Cancer statement on best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) staining and validation.

OBJECTIVES: The interaction between the immune system and tumor cells is an important feature for the prognosis and treatment of cancer. Multiplex immunohistochemistry (mIHC) and multiplex immunofluorescence (mIF) analyses are emerging technologies that can be used to help quantify immune cell subsets, their functional state, and their spatial arrangement within the tumor microenvironment. METHODS: The Society for Immunotherapy of Cancer (SITC) convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the optimization and validation of mIHC/mIF assays across platforms. RESULTS: Representative outputs and the advantages and disadvantages of mIHC/mIF approaches, such as multiplexed chromogenic IHC, multiplexed immunohistochemical consecutive staining on single slide, mIF (including multispectral approaches), tissue-based mass spectrometry, and digital spatial profiling are discussed. CONCLUSIONS: mIHC/mIF technologies are becoming standard tools for biomarker studies and are likely to enter routine clinical practice in the near future. Careful assay optimization and validation will help ensure outputs are robust and comparable across laboratories as well as potentially across mIHC/mIF platforms. Quantitative image analysis of mIHC/mIF output and data management considerations will be addressed in a complementary manuscript from this task force.

Group B Streptococcus maternal colonization and respiratory infections in the offspring: lessons learned from an analysis of a population-based cohort with 18-year follow-up.

OBJECTIVE: Group B Streptococcus (GBS) early onset disease is a major cause for neonatal morbidity and mortality. We aimed to determine whether maternal GBS and the associated intrapartum antibiotic prophylaxis impacts pediatric long-term respiratory infectious morbidity. STUDY DESIGN: A population-based cohort study was conducted, during the years 1991-2013, comparing the incidence of hospitalizations due to common respiratory infections (RI) in offspring of mothers with and without GBS. Univariate analysis and a Cox proportional hazard model were used to estimate un-adjusted and adjusted hazard ratios for pediatric RI risk. RESULTS: During the study period, 173,757 term vaginal deliveries took place, of which 2.4% (4252) were diagnosed as GBS + gravidas. In univariate and multivariate analyses for the entire study period, RI risk was increased in exposed offspring. In a sensitivity analysis investigating study periods with different health policies, both GBS diagnosis rates and pediatric infectious respiratory morbidity rates increased over time, but with no independent association between the two. CONCLUSION: When analyzing large data sets spanning over long time periods, a special attention must be paid to account for healthcare trends, to avoid erroneous conclusions, as demonstrated here.

Ecological dynamics of the vaginal microbiome in relation to health and disease.

The bacterial composition of the vaginal microbiome is thought to be related to health and disease states of women. This microbiome is particularly dynamic, with compositional changes related to pregnancy, menstruation, and disease states such as bacterial vaginosis. In order to understand these dynamics and their impact on health and disease, ecological theories have been introduced to study the complex interactions between the many taxa in the vaginal bacterial ecosystem. The goal of this review is to introduce the ecological principles that are used in the study of the vaginal microbiome and its dynamics, and to review the application of ecology to vaginal microbial communities with respect to health and disease. Although applications of vaginal microbiome analysis and modulation have not yet been introduced into the routine clinical setting, a deeper understanding of its dynamics has the potential to facilitate development of future practices, for example in the context of postmenopausal vaginal symptoms, stratifying risk for obstetric complications, and controlling sexually transmitted infections.

Maternal total cell-free DNA in preeclampsia and fetal growth restriction: Evidence of differences in maternal response to abnormal implantation.

OBJECTIVES: Preeclampsia and fetal growth restriction are obstetrical syndromes associated with abnormal placental implantation and changes in the activation status of maternal leukocytes. This study is aimed to determine by a simple, rapid fluorescent assay the changes in maternal serum total cell-free DNA (t-cfDNA) concentrations in women with preeclampsia and those with fetal growth restriction (FGR). STUDY DESIGN: A cross-sectional study was conducted measuring maternal serum t-cfDNA concentrations. Women were classified into the following groups: 1) patients with preeclampsia (n = 21); 2) FGR-estimated fetal weight below the 10thpercentile (n = 28); and 3) normal pregnancy (n = 39). Serum samples were directly assayed for t-cfDNA using a rapid fluorescent SYBR Gold assay. Elevated maternal serum t-cfDNA concentrations were defined as a cutoff>850ng/ml. Nonparametric statistics were used for analysis. RESULTS: Women with preeclampsia had a higher median maternal serum concentration (802 ng/ml, 400-2272 ng/ml) than women with a normal pregnancy (499 ng/ml, 0-1892 ng/ml, p = 0.004) and those with FGR (484 ng/ml, 72-2187 ng/ml, p = 0.012). Moreover, even patients with FGR <5th percentile and abnormal Doppler had a lower median maternal serum t-cfDNA than those with preeclampsia (median 487 ng/ml, 144-1971 ng/ml, p = 0.022). The median concentration of t-cfDNA did not differ between women with a normal pregnancy and those with FGR (p = 0.54), as well as those with fetuses <5th percentile and abnormal Doppler (p = 0.7). Women with preeclampsia had a higher proportion of elevated t-cfDNA than those with a normal pregnancy (p = 0.015) and patients with FGR (p = 0.025). CONCLUSIONS: Preeclampsia is associated with higher maternal serum t-cfDNA concentration than normal pregnancy or FGR. This observation may reflect an increased systemic activation of the maternal inflammation, rather than placental; this assumption is supported by the fact that we did not observe a significant change in the maternal serum t-cfDNA in patients with placental-mediated FGR.

Cesarean Delivery and Childhood Malignancies: A Single-Center, Population-Based Cohort Study.

Rising rates of cesarean deliveries worldwide prompt the evaluation of long-term morbidity to the offspring. In this retrospective cohort study, we evaluated whether cesarean delivery influences the development of childhood malignancies. We identified an association of cesarean delivery with acute lymphoblastic leukemia in children, suggesting prudence in the recommendation of cesarean delivery for nonmedically indicated cases.

Underlying mechanisms of retained placenta: Evidence from a population based cohort study.

OBJECTIVE: To determine risk factors for retained placenta, and to identify supporting epidemiologic evidence for the three previously-proposed mechanisms: (i) invasive placentation, (ii) placental hypo-perfusion, and (iii) inadequate uterine contractility. DESIGN: A retrospective population-based cohort study. SETTING AND POPULATION: Israeli population in the southern district. METHODS: Data were analyzed from a tertiary hospital database, between 1989 and 2014, using univariate tests and generalized estimating equation (GEE) multivariable models. MAIN OUTCOME MEASURES: Prevalence of retained placenta. RESULTS: The study population included 205,522 vaginal deliveries of which 4.8% (n=9870) were complicated with retained placenta. Previous intra-uterine procedures and placenta-related pregnancy complications were found to be significant risk factors for retained placenta (history of cesarean section aOR=8.82, 95%CI 8.35-9.31; history of curettage aOR=12.80, 95%CI 10.57-15.50; pre-eclampsia aOR=1.25, 95%CI 1.14-1.38; delivery of a small for gestational age neonate aOR=1.08, 95%CI 1.01-1.16; stillbirth aOR=2.34, 95%CI 1.98-2.77). During labour, the risk for retained placenta was increased in presence of arrest of dilatation (aOR=2.03, 95%CI 1.08-3.82) or arrest of descent (aOR=1.55, 95%CI 1.22-1.96). Infections of the uterine cavity during labour were also found to be strongly associated with increased risk of retained placenta (endometritis aOR=2.21, 95%CI 1.64-2.97; chorioamnionitis aOR=3.35, 95% CI 2.78-4.04). CONCLUSIONS: Supporting epidemiologic evidence were found for all three underlying mechanisms. In addition, there is evidence to suggest that intrauterine infection and inflammation may also be a possible pathology associated with retained placenta. TWEETABLE ABSTRACT: Risk factors for retained placenta support previously proposed mechanisms in a large cohort study.

Cerebral Palsy-Trends in Epidemiology and Recent Development in Prenatal Mechanisms of Disease, Treatment, and Prevention.

Cerebral palsy (CP) is the most common motor disability in childhood. This syndrome is the manifestation of intrauterine pathologies, intrapartum complications, and the postnatal sequel, especially among preterm neonates. A double hit model theory is proposed suggesting that an intrauterine condition along with intrapartum or postnatal insult lead to the development of CP. Recent reports demonstrated that treatment during the process of preterm birth such as magnesium sulfate and postnatal modalities such as cooling may prevent or reduce the prevalence of this syndrome. Moreover, animal models demonstrated that postnatal treatment with anti-inflammatory drugs coupled with nanoparticles may affect the course of the disease in pups with neuroinflammation. This review will describe the changes in the epidemiology of this disease, the underlying prenatal mechanisms, and possible treatments that may reduce the prevalence of CP and alter the course of the disease.

Escalating placenta invasiveness: repeated placenta accreta at the limit of viability.

Placenta percreta is an obstetric condition in which the placenta invades through the myometrium. This is the most severe form of placenta accreta and may result in spontaneous uterine rupture, a rare complication that threatens the life of both mother and fetus. In this case report, we describe a 32-year-old woman in her fourth pregnancy, diagnosed with repeated placenta accreta, which was eventually complicated by spontaneous uterine rupture at 24 weeks' gestation. This patient had a history of abnormal placentation in prior pregnancies and previous uterine injuries. This case demonstrates a pattern of escalating placental invasiveness, and raises questions regarding the process of abnormal placentation and the manifestation of uterine rupture in scarred uteri.