Showing papers on "Fetus published in 2023"

Questioning the fetal microbiome illustrates pitfalls of low-biomass microbial studies

Abstract: Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.

Perinatal Outcome in Meconium Stained Amniotic Fluid

Abstract: This prospective study was conducted to evaluate the perinatal outcome in meconium stained amniotic fluid. The study group consists of 300 patients in labour with meconium stained amniotic fluid. Among these patients, 50.7% had thick meconium stained liquor, 35% of the patients had thin meconium stained liquor and 14.3% of the patients had moderate meconium stained liquor. The control group consists of 100 patients in labour with clear liquor. • Meconium stained liquor was detected in the latent phase in 59% of the patients. Most of the patients (64.3%) in the study group were delivered within 1 hour of detection of meconium. • In the study group, 52.3% of patients had reactive NST and 47.6% had non reactive NST. Whereas in the control group, 86% of patients had reactive NST and only 14% had non – reactive NST. This shows that the incidence of non reassuring cardiotocography is significantly higher in women with meconium stained liquor in labour (47.6% vs 14%) P = 0.001. • In thin meconium group of patients, majority (74.2%) of the patients had reactive NST. Whereas in patients with thick meconium stained liquor, majority (60.5%) had non – reactive NST. This indicates a significant linear association between the thickness of meconium and abnormal fetal heart rate pattern during labour. • In the study group, almost half of the patients were delivered by cesarean section (52.7% vs 37% in the control group) P = 0.001. This higher rate of cesarean section in the meconium group is mainly contributed by patients in thick meconium group with non – reactive NST (36.7%). Fetal distress is the commonest indication for cesarean section in the study group (70.2% vs 18.9% in control group) p = 0.001. There was 31 cases of repeat LSCS in the study group and 14 cases of repeat LSCS in the control group. • In the meconium group with reactive NST 94.9% of babies had good mean Apgar score of ³ 7/10 at 1 and 5mins. With non – reactive NST, only 61.5% of babies had good mean Apgar score of ³ 7/10. In other words, 39.5% of babies had meand Apgar score of < 7/10. This shows that the incidence of low Apgar score at 1 and 5 minutes in meconium stained amniotic fluid was significantly higher when associated with fetal heart rate abnormalities. 39.5% vs 4.1%. • In the study group, 31.7% of the babies were admitted for NICU care. In patients with reactive NST only 13.4% of the babies were admitted, but in those patients with non – reactive NST 51.8% of the babies were admitted to NICU. (51.8% vs 13.4%); P = 0.001. Majority of the NICU admission is constituted by babies from thick meconium group with non – reactive NST (58.94%). • The commonest reason for NICU admission was mild respiratory distress (34.7%). The second most common reason was meconium aspiration syndrome (32.6%). The incidence of meconium aspiration syndrome in the study group was 10.3%. In the control group, only 5% of the babies were admitted. • The perinatal mortality in the study group was 3.3% as compared to no neonatal death in the control group. (3.3% Vs 0); P = 0.17. There were total of 10 neonatal deaths. 3 babies died in the thin meconium group, 1 baby died in moderate meconium group and 6 babies died in the thick meconium group. All neonatal deaths has occurred in those patients with non reactive NST (7% Vs0) P = 0.003, 95% CI = 7%, (2 – 12%). CONCLUSION : The incidence of non reassuring fetal heart rate pattern is significantly higher in women with meconium stained amniotic fluid in labour. There is a significant linear association between the thickness of meconium and abnormal fetal heart rate pattern during labour. • The perinatal outcome is good in patients with meconium stained amniotic fluid and reactive NST. • The cesarean section rate, low Apgar Score, neonatal admissions and perinatal mortality were significantly higher with meconium stained amniotic fluid and non reactive NST. So, meconium in the amniotic fluid is associated with obstetric hazard and significantly increased risk of adverse neonatal outcomes, only when it is associated with fetal heart rate abnormalities. The main clinical value of meconium stained amniotic fluid is to alert the obstetrician to look for further signs of fetal compromise.

Ionizable Lipid Nanoparticles for In Vivo mRNA Delivery to the Placenta during Pregnancy.

Abstract: Ionizable lipid nanoparticles (LNPs) are the most clinically advanced nonviral platform for mRNA delivery. While they have been explored for applications including vaccines and gene editing, LNPs have not been investigated for placental insufficiency during pregnancy. Placental insufficiency is caused by inadequate blood flow in the placenta, which results in increased maternal blood pressure and restricted fetal growth. Therefore, improving vasodilation in the placenta can benefit both maternal and fetal health. Here, we engineered ionizable LNPs for mRNA delivery to the placenta with applications in mediating placental vasodilation. We designed a library of ionizable lipids to formulate LNPs for mRNA delivery to placental cells and identified a lead LNP that enables in vivo mRNA delivery to trophoblasts, endothelial cells, and immune cells in the placenta. Delivery of this top LNP formulation encapsulated with VEGF-A mRNA engendered placental vasodilation, demonstrating the potential of mRNA LNPs for protein replacement therapy during pregnancy to treat placental disorders.

Spatial multiomics map of trophoblast development in early pregnancy

Abstract: 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 vessels1. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia2. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids3,4 and trophoblast stem cells5. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.

Prenatal perfluoroalkyl substances exposure and maternal sex steroid hormones across pregnancy.

Abstract: Poly- and perfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants that may act as endocrine disruptors in utero, but the specific endocrine pathways are unknown. We examined associations between maternal serum PFAS and sex steroid hormones at three time points during pregnancy. Pregnant women participating in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaire, and medical record data in each trimester (n = 285). PFAS (including perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA)) were analyzed in second-trimester serum samples by high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Total testosterone [TT], free testosterone [fT], estrone [E1], estradiol [E2], and estriol [E3]) were measured by LC-MS/MS in serum samples from each trimester. Linear mixed models with random intercepts were used to examine associations between log-transformed PFAS concentrations and hormone levels, adjusting for covariates, and stratifying by fetal sex. Results are presented as the mean percentage difference (Δ%) in hormone levels per ln-unit increase in PFAS concentration. In adjusted models, PFHxS was associated with higher TT (%Δ = 20.0, 95%CI: 1.7, 41.6), particularly among women carrying male fetuses (%Δ = 15.3, 95%CI: 1.2, 30.7); this association strengthened as the pregnancy progressed. PFNA (%Δ = 7.9, 95%CI: 3.4, 12.5) and PFDA (%Δ = 7.2, 95%CI: 4.9, 9.7) were associated with higher fT, with associations again observed only in women carrying male fetuses. PFHxS was associated with higher levels of E2 and E3 in women carrying female fetuses (%Δ = 13.2, 95%CI: 0.5, 29.1; %Δ = 17.9, 95%CI: 3.2, 34.8, respectively). No associations were observed for PFOS and PFOA. PFHxS, PFNA, and PFDA may disrupt androgenic and estrogenic pathways in pregnancy in a sex-dependent manner.

Cesarean Scar Pregnancy and Successful Ultrasound-Guided Removal after Uterine Artery Ligation

Abstract: A correct management of cesarean scar pregnancy (CSP) is mandatory to avoid further complications. There is no consensus for the standard therapy and the most frequent methods used are not free from failures and sequelae. A 38-year-old woman was admitted referring amenorrhea lasting 9 weeks, pelvic pain, and vaginal bleeding. She had three previous cesarean sections. Transvaginal ultrasound showed a gestational sac of 16 mm in the cervico-isthmic site and inside the thickness of the uterine wall, and the dosage of beta-human chorionic gonadotropin was 12,770 mU/mL. A diagnosis of CSP was done, and an ultrasound-guided removal after uterine artery cervical branch ligation was performed. The follow-up was uneventful. Even if not yet codified in the literature, our therapeutic procedure should be considered in other similar cases in the future, as it potentially limits the possible iatrogenic problems and reduces intraoperative and postoperative bleeding to a minimum.

BPDE, the Migration and Invasion of Human Trophoblast Cells, and Occurrence of Miscarriage in Humans: Roles of a Novel <i>lncRNA-HZ09</i>

Abstract: Recurrent miscarriage (RM) affects 1%-3% of pregnancies. However, in almost 50% of cases, the cause is unknown. Increasing evidence have shown that benzo(a)pyrene [B(a)P], a representative of polycyclic aromatic hydrocarbons (PAHs), is correlated with miscarriage. However, the underlying mechanisms of B(a)P/benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE)-induced trophoblast cell dysfunctions and miscarriage remain largely unknown.The objective was to discover the role(s) of a novel lncRNA, lnc-HZ09, in the regulation of BPDE-inhibited migration and invasion of trophoblast cells and the occurrence of miscarriage.Human trophoblast cells were treated with 0, 0.25, 0.5, 1.0, or 1.5μM BPDE with or without corresponding lnc-HZ09 silencing or overexpression. Using these cells, we evaluated cell migration and invasion, the mRNA and protein levels of members of the PLD1/RAC1/CDC42 pathway, the regulatory roles of lnc-HZ09 in PLD1 transcription and mRNA stability, and lnc-HZ09 transcription and stability. Human villous tissues were collected from RM (n=15) group and their matched healthy control (HC, n=15) group. We evaluated the levels of BPDE-DNA adducts, lnc-HZ09, and the mRNA and protein expression of members of the PLD1/RAC1/CDC42 pathway, and correlated their relative expression levels. We further constructed 0, 0.05 or 0.2mg/kg B(a)P-induced mouse miscarriage model (each n=6), in which the mRNA and protein expression of members of the Pld1/Rac1/Cdc42 pathway were measured.We identified a novel lnc-HZ09. Human trophoblast cells treated with lnc-HZ09 exhibited less cell migration and invasion. In addition, the levels of this lncRNA were higher in villous tissues from women with recurrent miscarriage than those from healthy individuals. SP1-mediated PLD1 mRNA levels were lower, and HuR-mediated PLD1 mRNA stability was less in trophoblast cells overexpressing lnc-HZ09. However, trophoblast cells treated with MSX1 had higher levels of lnc-HZ09, and METTL3-mediated m6A methylation on lnc-HZ09 resulted in greater lnc-HZ09 RNA stability. In BPDE-treated human trophoblast cells and in RM villous tissues, MSX1-mediated lnc-HZ09 transcription and METTL3-mediated lnc-HZ09 stability were both greater. In our mouse miscarriage model, B(a)P-treated mice had lower mRNA and protein levels of members of the Pld1/Rac1/Cdc42 pathway.These results suggest that in human trophoblast cells, BPDE exposure up-regulated lnc-HZ09 level, suppressed PLD1/RAC1/CDC42 pathway, and inhibited migration and invasion, providing new insights in understanding the causes and mechanisms of unexplained miscarriage. https://doi.org/10.1289/EHP10477.

Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B

Abstract: DNA methylation is a repressive epigenetic modification that is essential for development, exemplified by the embryonic and perinatal lethality observed in mice lacking de novo DNA methyltransferases (DNMTs). Here we characterise the role for DNMT3A, 3B and 3L in gene regulation and development of the mouse placenta. We find that each DNMT establishes unique aspects of the placental methylome through targeting to distinct chromatin features. Loss of Dnmt3b results in de-repression of germline genes in trophoblast lineages and impaired formation of the maternal-foetal interface in the placental labyrinth. Using Sox2-Cre to delete Dnmt3b in the embryo, leaving expression intact in placental cells, the placental phenotype was rescued and, consequently, the embryonic lethality, as Dnmt3b null embryos could now survive to birth. We conclude that de novo DNA methylation by DNMT3B during embryogenesis is principally required to regulate placental development and function, which in turn is critical for embryo survival.

Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction

Abstract: Preeclampsia and fetal growth restriction (FGR) are both associated with an increased ratio of sFLT1 (soluble fms-like tyrosine kinase-1) to PlGF (placenta growth factor) in maternal serum. In preeclampsia, it is assumed that increased placental release of sFLT1 results in PlGF being bound and inactivated. However, direct evidence for this model is incomplete, and it is unclear whether the same applies in FGR.We conducted a prospective cohort study where we followed 4212 women having first pregnancies from their dating ultrasound, obtained blood samples serially through the pregnancy, and performed systematic sampling of the placenta after delivery. The aim of the present study was to determine the relationship between protein levels of sFLT1 and PlGF in maternal serum measured at ≈36 weeks and placental tissue lysates obtained after term delivery in 82 women with preeclampsia, 50 women with FGR, and 132 controls.The sFLT1:PlGF ratio was increased in both preeclampsia and FGR in both the placenta and maternal serum. However, in preeclampsia, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental sFLT1 level (r=0.45; P<0.0001) but not placental PlGF level (r=-0.17; P=0.16). In contrast, in FGR, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental PlGF level (r=-0.35; P=0.02) but not sFLT1 level (r=0.04; P=0.81).We conclude that the elevated sFLT1:PlGF ratio is primarily driven by increased placental sFLT1 in preeclampsia, whereas in FGR, it is primarily driven by decreased placental PlGF.

Elateriospermum tapos Yogurt Supplement in Maternal Obese Dams during Pregnancy Modulates the Body Composition of F1 Generation

Abstract: Maternal obesity is a key predictor of childhood obesity and a determining factor for a child’s body composition. Thus, any form of maternal nutrition during the gestational period plays a vital role in influencing the growth of the fetus. Elateriospermum tapos (E. tapos) yogurt has been found to comprise many bioactive compounds such as tannins, saponins, α-linolenic acid, and 5′-methoxy-bilobate with apocynoside I that could cross the placenta and exhibit an anti-obesity effect. As such, this study aimed to investigate the role of maternal E. tapos yogurt supplementation on offspring body composition. In this study, 48 female Sprague Dawley (SD) rats were induced with obesity using a high-fat diet (HFD) and were allowed to breed. Upon confirmation of pregnancy, treatment was initiated with E. tapos yogurt on the obese dams up to postnatal day 21. The weaning offspring were then designated into six groups according to their dam’s group (n = 8) as follows; normal food and saline (NS), HFD and saline (HS), HFD and yogurt (HY), HFD and 5 mg/kg of E. tapos yogurt (HYT5), HFD and 50 mg/kg of E. tapos yogurt (HYT50), and HFD and 500 mg/kg of E. tapos yogurt (HYT500). The body weight of the offspring was accessed every 3 days up to PND 21. All the offspring were euthanized on PND 21 for tissue harvesting and blood sample collection. The results showed that both male and female offspring of obese dams treated with E. tapos yogurt showed growth patterns similar to NS and reduced levels of triglycerides (TG), cholesterol, LDL, non-HDL, and leptin. Liver enzymes such as ALT, ALP, AST, GGT, and globulin, and renal markers such as sodium, potassium, chloride, urea, and creatinine levels significantly reduced (p < 0.05) in the offspring of E. tapos yogurt-treated obese dams with the normal histological architecture of the liver, kidney, colon, RpWAT, and visceral tissue that is comparable to NS. In toto, E. tapos yogurt supplementation of obese dams exerted an anti-obesity effect by preventing intergenerational obesity by reversing HFD-induced damage in the fat tissue of the offspring.

Prenatal thyroid hormones accelerate postnatal growth and telomere shortening in wild great tits

Abstract: The early-life environment is known to affect later-life health and disease, which could be mediated by the early-life programming of telomere length, a key hallmark of ageing. According to the fetal programming of telomere biology hypothesis, variation in prenatal exposure to hormones is likely to influence telomere length. Yet, the contribution of key metabolic hormones, i.e. thyroid hormones (THs), has been largely ignored. We recently showed that in contrast to predictions, exposure to elevated prenatal THs increased postnatal telomere length in wild collared flycatchers, but the generality of such effect, the underlying proximate mechanisms and consequences for survival have not been investigated. We therefore conducted a comprehensive study evaluating the impact of THs on potential drivers of telomere dynamics (growth, post-natal THs, mitochondria and oxidative stress), telomere length and medium-term survival using wild great tits as a model system. While prenatal THs did not significantly affect telomere length a week after hatching (i.e. day 7), they influenced postnatal telomere shortening (i.e. shorter telomeres at day 14 and the following winter) but not apparent survival. Circulating THs, mitochondrial density or oxidative stress biomarkers were not significantly influenced, whereas the TH-supplemented group showed accelerated growth, which may explain the observed delayed effect on telomeres. We discuss several alternative hypotheses that may explain the contrast with our previous findings in flycatchers. Given that shorter telomeres in early life tend to be carried until adulthood and are often associated with decreased survival prospects, the effects of prenatal THs on telomeres may have long-lasting effects on senescence.

Study of the Embryonic Toxicity of TiO2 and ZrO2 Nanoparticles

Abstract: Currently, the widespread use of TiO2 and ZrO2 nanoparticles (NPs) in various industries poses a risk in terms of their potential toxicity. A number of experimental studies provide evidence of the toxic effect of TiO2 and ZrO2 NPs on biological objects. In order to supplement the level of knowledge and assess the risks of toxicity and danger of TiO2 and ZrO2 NPs, we decided to conduct a comprehensive experiment to study the embryonic toxicity of TiO2 and ZrO2 NPs in pregnant rats. For the experiment, mongrel white rats during pregnancy received aqueous dispersions of powders of TiO2 and ZrO2 NPs at a dose of 100 mg/kg/day. To characterize the effect of TiO2 and ZrO2 NPs on females and the postnatal ontogenesis of offspring, a complex of physiological and biochemical research methods was used. The results of the experiment showed that TiO2 NPs as ZrO2 NPs (100 mg/kg per os) cause few shifts of similar orientation in the maternal body. Neither TiO2 NPs nor ZrO2 NPs have an embryonic and teratogenic effect on the offspring in utero, but both modify its postnatal development.

SARS-CoV-2 variant-related abnormalities detected by prenatal MRI: a prospective case–control study

Abstract: There are known complications for fetuses after infection with SARS-CoV-2 during pregnancy. However, previous studies of SARS-CoV-2 in pregnancy have largely been limited to histopathologic studies of placentas and prenatal studies on the effects of different SARS-CoV-2 variants are scarce to date. To examine the effects of SARS-CoV-2 variants on the placenta and fetus, we investigated fetal and extra-fetal structures using prenatal MRI. For this prospective case–control study, two obstetric centers consecutively referred pregnant women for prenatal MRI after confirmed SARS-CoV-2 infection. Thirty-eight prenatal MRI examinations were included after confirmed infection with SARS-CoV-2 and matched 1:1 with 38 control cases with respect to sex, MRI field strength, and gestational age (average deviation 1.76 ± 1.65, median 1.5 days). Where available, the pathohistological examination and vaccination status of the placenta was included in the analysis. In prenatal MRI, the shape and thickness of the placenta, possible lobulation, and vascular lesions were quantified. Fetuses were scanned for organ or brain abnormalities. Of the 38 included cases after SARS-CoV-2 infection, 20/38 (52.6%) were infected with pre-Omicron variants and 18/38 (47.4%) with Omicron. Prenatal MRIs were performed on an average of 83 days (±42.9, median 80) days after the first positive PCR test. Both pre-Omicron (P = .008) and Omicron (P = .016) groups showed abnormalities in form of a globular placenta compared to control cases. In addition, placentas in the pre-Omicron group were significantly thickened (6.35, 95% CI .02–12.65, P = .048), and showed significantly more frequent lobules (P = .046), and hemorrhages (P = .002). Fetal growth restriction (FGR) was observed in 25% (n = 5/20, P = .017) in the pre-Omicron group. SARS-CoV-2 infections in pregnancy can lead to placental lesions based on vascular events, which can be well visualized on prenatal MRI. Pre-Omicron variants cause greater damage than Omicron sub-lineages in this regard. Vienna Science and Technology Fund.

Transgene-Free Ex Utero Derivation of A Human Post-Implantation Embryo Model Solely from Genetically Unmodified Naïve PSCs

Abstract: Our ability to study early human post-implantation development remains highly limited due to the ethical and technical challenges associated with intrauterine development of the human embryo after implantation. Despite the great progress made on human gastruloids, axioloids and in vitro cultured blastoids, such elegant models do not constitute an integrated Stem cell-derived Embryo Models (SEMs) that includes all the key extra-embryonic tissues of the early post-implantation human conceptus (e.g., hypoblast, yolk-sac, trophoblasts, amnion, and extraembryonic mesoderm), and thus, do not recapitulate post-implantation epiblast development within the context of these extra-embryonic compartments. Mouse naïve pluripotent stem cells (PSCs) have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation mouse SEMs, while bypassing the blastocyst-like stage, and eventually initiating organogenesis ex utero. Here, we implement critical adaptations to extend these finding to humans, while using only genetically unmodified human naïve PSCs, thus circumventing the need for ectopic expression of lineage promoting transgenes. Such integrated human SEMs recapitulate the organization of all known compartments of early post-implantation stage human embryos, including epiblast, hypoblast, extra-embryonic mesoderm, and trophoblast surrounding the latter layers. The organized human SEMs recapitulate key hallmarks of post-implantation stage embryogenesis up to 13-14 days post-fertilization (dpf, Carnegie stage 6a), such as bilaminar disk formation, epiblast lumenogenesis, amniogenesis, anterior-posterior symmetry breaking, PGC specification, primary and secondary yolk sac formation, and extra-embryonic mesoderm expansion that defines a chorionic cavity and a connective stalk. This new platform constitutes a tractable stem cell-based model for experimentally interrogating previously inaccessible windows of human peri- and early post-implantation development.

Effectiveness of ambulatory non‐invasive fetal electrocardiography: impact of maternal and fetal characteristics

Abstract: Non‐invasive fetal electrocardiography (NIFECG) has potential benefits over the computerized cardiotocography (cCTG) that may permit its development in remote fetal heart‐rate monitoring. Our study aims to compare signal quality and heart‐rate detection from a novel self‐applicable NIFECG monitor against the cCTG, and evaluate the impact of maternal and fetal characteristics on both devices.

Evaluating the Clinical Utility of a Long-Read Sequencing-Based Approach in Prenatal Diagnosis of Thalassemia.

Abstract: BACKGROUND The aim is to evaluate the clinical utility of a long-read sequencing-based approach termed comprehensive analysis of thalassemia alleles (CATSA) in prenatal diagnosis of thalassemia. METHODS A total of 278 fetuses from at-risk pregnancies identified in thalassemia carrier screening by PCR-based methods were recruited from 9 hospitals, and PCR-based methods were employed for prenatal diagnosis. CATSA was performed retrospectively and blindly for all 278 fetuses. RESULTS Among the 278 fetuses, 263 (94.6%) had concordant results and 15 (5.4%) had discordant results between the 2 methods. Of the 15 fetuses, 4 had discordant thalassemia variants within the PCR detection range and 11 had additional variants identified by CATSA. Independent PCR and Sanger sequencing confirmed the CATSA results. In total, CATSA and PCR-based methods correctly detected 206 and 191 fetuses with variants, respectively. Thus, CATSA yielded a 7.9% (15 of 191) increment as compared with PCR-based methods. CATSA also corrected the predicted phenotype in 8 fetuses. Specifically, a PCR-based method showed one fetus had homozygous HBB c.52A > T variants, while CATSA determined the variant was heterozygous, which corrected the predicted phenotype from β-thalassemia major to trait, potentially impacting the pregnancy outcome. CATSA additionally identified α-globin triplicates in 2 fetuses with the heterozygous HBB c.316-197C > T variant, which corrected the predicted phenotype from β-thalassemia trait to intermedia and changed the disease prognosis. CONCLUSIONS CATSA represents a more comprehensive and accurate approach that potentially enables more informed genetic counseling and improved clinical outcomes compared to PCR-based methods.

MRI Findings in Third-Trimester Opioid-Exposed Fetuses, With Focus on Brain Measurements: A Prospective Multicenter Case-Control Study

Abstract: BACKGROUND. The opioid epidemic has profoundly affected infants born in the United States, as in utero opioid exposure increases the risk of cognitive and behavioral problems in childhood. Scarce literature has evaluated prenatal brain development in fetuses with opioid exposure in utero (hereafter opioid-exposed fetuses). OBJECTIVE. The purpose of this study is to compare opioid-exposed fetuses and fetuses without opioid exposure (hereafter unexposed fetuses) in terms of 2D biometric measurements of the brain and additional pregnancy-related assessments on fetal MRI. METHODS. This prospective case-control study included patients in the third trimester of pregnancy who underwent investigational fetal MRI at one of three U.S. academic medical centers from July 1, 2020, through December 31, 2021. Fetuses were classified as opioid exposed or unexposed in utero. Fourteen 2D biometric measurements of the fetal brain were manually assessed and used to derive four indexes. Measurements and indexes were compared between the two groups by use of multivariable linear regression models, which were adjusted for gestational age (GA), fetal sex, and nicotine exposure. Additional pregnancy-related findings on MRI were evaluated. RESULTS. The study included 65 women (mean age, 29.0 ± 5.5 [SD] years). A total of 28 fetuses (mean GA at the time of MRI, 32.2 ± 2.5 weeks) were opioid-exposed, and 37 fetuses (mean GA at the time of MRI, 31.9 ± 2.7 weeks) were unexposed. In the adjusted models, seven measurements were smaller (p < .05) in opioid-exposed fetuses than in unexposed fetuses: cerebral frontooccipital diameter (93.8 ± 7.4 vs 95.0 ± 8.6 mm), bone biparietal diameter (79.0 ± 6.0 vs 80.3 ± 7.1 mm), brain biparietal diameter (72.9 ± 7.7 vs 74.1 ± 8.6 mm), corpus callosum length (37.7 ± 4.0 vs 39.4 ± 3.7 mm), vermis height (18.2 ± 2.7 vs 18.8 ± 2.6 mm), anteroposterior pons measurement (11.6 ± 1.4 vs 12.1 ± 1.4 mm), and transverse cerebellar diameter (40.4 ± 5.1 vs 41.4 ± 6.0 mm). In addition, in the adjusted model, the frontoocccipital index was larger (p = .02) in opioid-exposed fetuses (0.04 ± 0.02) than in unexposed fetuses (0.04 ± 0.02). Remaining measures and indexes were not significantly different between the two groups (p > .05). Fetal motion, cervical length, and deepest vertical pocket of amniotic fluid were not significantly different (p > .05) between groups. Opioid-exposed fetuses, compared with unexposed fetuses, showed higher frequencies of both breech position (21% vs 3%, p = .03) and increased amniotic fluid volume (29% vs 8%, p = .04). CONCLUSION. Fetuses with opioid exposure in utero had a smaller brain size and altered fetal physiology. CLINICAL IMPACT. The findings provide insight into the impact of prenatal opioid exposure on fetal brain development.

Ingested Polystyrene Nanospheres Translocate to Placenta and Fetal Tissues in Pregnant Rats: Potential Health Implications

Abstract: Recent studies in experimental animals found that oral exposure to micro- and nano-plastics (MNPs) during pregnancy had multiple adverse effects on outcomes and progeny, although no study has yet identified the translocation of ingested MNPs to the placenta or fetal tissues, which might account for those effects. We therefore assessed the placental and fetal translocation of ingested nanoscale polystyrene MNPs in pregnant rats. Sprague Dawley rats (N = 5) were gavaged on gestational day 19 with 10 mL/kg of 250 µg/mL 25 nm carboxylated polystyrene spheres (PS25C) and sacrificed after 24 h. Hyperspectral imaging of harvested placental and fetal tissues identified abundant PS25C within the placenta and in all fetal tissues examined, including liver, kidney, heart, lung and brain, where they appeared in 10–25 µm clusters. These findings demonstrate that ingested nanoscale polystyrene MNPs can breach the intestinal barrier and subsequently the maternal–fetal barrier of the placenta to access the fetal circulation and all fetal tissues. Further studies are needed to assess the mechanisms of MNP translocation across the intestinal and placental barriers, the effects of MNP polymer, size and other physicochemical properties on translocation, as well as the potential adverse effects of MNP translocation on the developing fetus.

Assessment of fetal thymus size and BMI in pregnant women with diabetes

Abstract: The study group consisted of 63 pregnant women admitted to the Department of Perinatology, Obstetrics and Gynaecology. Inclusion criteria included patients with PGDM - 11 pregnancies, GDM1- 23 pregnancies, and GDM2 - 29 pregnancies. Exclusion criteria included pregnant women with gestational diabetes and history of other comorbidities as well as multiple pregnancies, fetal developmental abnormalities and genetic disorders. Each patient received a detailed fetal ultrasound performed by the team of ultrasound experts specialising in obstetric ultrasonography. Fetal thymus measurements were obtained between 14+5 and 40+0 weeks of gestational age. After the three-vessel view was clearly displayed we assessed longitudinal dimensions of the thymus. The obtained measurements were juxtaposed with nomograms for thymus size in healthy foetuses whose mothers had no history of diabetes. Prior to ultrasound examination the participants were asked to complete a questionnaire regarding their body weight status before 10 weeks of gestational age.The Mann-Whitney U test was used for comparison of two groups, i.e. diabetic pregnancies and non-diabetic pregnancies, whereas Kruskal-Wallis H test was used to compare multiple groups. A linear regression model was used to determine the correlation between the type of diabetes and fetal thymus size as well as between maternal BMI and fetal thymus size. The significance level α was set at 0.05. Thymus size is statistically smaller in foetuses of diabetic mothers when compared to healthy controls. Overweighted and obese pregnancy is not a factor affecting fetal thymus size.

A systematic review and meta‐analysis of cell‐free DNA testing for detection of fetal sex chromosome aneuploidy

Abstract: The aim was to determine the accuracy of cell‐free DNA testing (cfDNA) for detecting sex chromosome aneuploidies (SCA) in singleton pregnancies.

Similar Pro- and Antiangiogenic Profiles Close to Delivery in Different Clinical Presentations of Two Pregnancy Syndromes: Preeclampsia and Fetal Growth Restriction

Abstract: The purpose of this study was to evaluate serum levels of anti- and pro-angiogenic substances measured using enzyme-linked immunosorbent assays and their ratios in pregnancies complicated by different clinical subsets of placental ischemic syndrome: preeclampsia and/or fetal growth restriction. A prospective case-control study was performed consisting of 77 singleton pregnancies complicated by preeclampsia, preeclampsia with concurrent fetal growth restriction (FGR), and isolated normotensive FGR pairwise matched by gestational age with healthy pregnancies. The entire study cohort was analyzed with respect to adverse pregnancy outcomes that occurred. In all investigated subgroups, placental growth factor (PlGF) was lower and soluble endoglin (sEng), the soluble fms-like tyrosine kinase-1—sFlt-1/PlGF and sFlt-1*sEng/PlGF ratios were higher than in the control group. The differences were most strongly pronounced in the PE with concurrent FGR group and in the sFlt-1/PlGF ratio. The highest sFlt-1 values in preeclamptic patients suggest that this substance may be responsible for reaching the threshold needed for PE to develop as a maternal manifestation of ischemic placental disease. The FGR is characterized by an elevated maternal sFlt-1/PlGF ratio, which boosts at the moment of indicated delivery due to fetal risk. We concluded that angiogenic imbalance is reflective of placental disease regardless of its clinical manifestation in the mother, and may be used as support for the diagnosis and prognosis of FGR.

Cell-Free DNA Fragmentomics: The Novel Promising Biomarker

Abstract: Cell-free DNA molecules are released into the plasma via apoptotic or necrotic events and active release mechanisms, which carry the genetic and epigenetic information of its origin tissues. However, cfDNA is the mixture of various cell fragments, and the efficient enrichment of cfDNA fragments with diagnostic value remains a great challenge for application in the clinical setting. Evidence from recent years shows that cfDNA fragmentomics’ characteristics differ in normal and diseased individuals without the need to distinguish the source of the cfDNA fragments, which makes it a promising novel biomarker. Moreover, cfDNA fragmentomics can identify tissue origins by inferring epigenetic information. Thus, further insights into the fragmentomics of plasma cfDNA shed light on the origin and fragmentation mechanisms of cfDNA during physiological and pathological processes in diseases and enhance our ability to take the advantage of plasma cfDNA as a molecular diagnostic tool. In this review, we focus on the cfDNA fragment characteristics and its potential application, such as fragment length, end motifs, jagged ends, preferred end coordinates, as well as nucleosome footprints, open chromatin region, and gene expression inferred by the cfDNA fragmentation pattern across the genome. Furthermore, we summarize the methods for deducing the tissue of origin by cfDNA fragmentomics.

Characteristics of the antiulcerogenic activity of cryopreserved placenta extract in acute and chronic lesions of the stomach

Abstract: To date, Ukraine has registered about 5 million patients with ulcer disease, and the market of drugs with proven anti-ulcer activity exceeds 500 names, but the problem of effective therapy is far from being solved. Cryoextract of the placenta attracted our attention as a new domestic biotechnological anti-ulcer agent. The purpose of the study. To characterize the antiulcer activity of cryoextract of human placenta in acute and chronic ulcerogenesis. Materials and methods. Studies of antiulcer activity were carried out on 56 male rats weighing 200–220 g in two stages: on the model of acute serotonin ulcerogenesis (28 rats) under the therapeutic and prophylactic regimen of placenta cryoextract and on the model of chronic acetic acid damage to the stomach (28 rats) under the therapeutic regimen application of the specified cryoextract. Results and discussion. The study showed that the therapeutic and prophylactic injection of the cryoextract of the placenta shows a pronounced antiulcer activity in the model of serotonin-induced gastric damage, which was indicated by a decrease in the ulcer index by 13.7 times compared to a similar indicator in the group of untreated animals and was 0.3 and 4, respectively. 1. Hemorrhagic lesions of the gastric mucosa occurred twice as often against the background of placenta cryoextract administration, respectively, against the background of esomeprazole administration – in 57.1% of rats, and against the background of placenta cryoextract administration – in 28.6% of rats. It was established that the investigated cryoextract has a cytoprotective effect on the mucous membrane of the stomach against the background of acetic acid damage. This was indicated by a statistically significant (p<0.05) decrease in the ulcer index by 30.0% compared to the indicators of untreated animals. Conclusions. It was established that the cryoextract of the human placenta has pronounced antiulcer activity both in acute and chronic experimental ulcerogenesis, which was indicated by a statistically significant decrease in erosions and ulcers of the gastric mucosa.

Markers of placental function correlate with prevalence and quantity of nucleated fetal cells in maternal circulation in normotensive term pregnancies

Abstract: Transplacental fetal cell transfer results in the engraftment of fetal‐origin cells in the pregnant woman's body, a phenomenon termed fetal microchimerism. Increased fetal microchimerism measured decades postpartum is implicated in maternal inflammatory disease. Understanding which factors cause increased fetal microchimerism is therefore important. During pregnancy, circulating fetal microchimerism and placental dysfunction increase with increasing gestational age, particularly towards term. Placental dysfunction is reflected by changes in circulating placenta‐associated markers, specifically placental growth factor (PlGF), decreased by several 100 pg/mL, soluble fms‐like tyrosine kinase‐1 (sFlt‐1), increased by several 1000 pg/mL, and the sFlt‐1/PlGF ratio, increased by several 10 (pg/mL)/(pg/mL). We investigated whether such alterations in placenta‐associated markers correlate with an increase in circulating fetal‐origin cells.

Ambulatory antenatal fetal electrocardiography in high-risk pregnancies (AMBER): protocol for a pilot prospective cohort study

Abstract: Introduction Fetal heart rate (FHR) monitoring is a vital aspect of fetal well-being assessment, and the current method of computerised cardiotocography (cCTG) is limited to the hospital setting. Non-invasive fetal ECG (NIFECG) has the ability to produce FHR patterns through R wave detection while eliminating confusion with maternal heart rate, but is presently limited to research use. Femom is a novel wireless NIFECG device that is designed to be placed without professional assistance, while connecting to mobile applications. It has the ability to achieve home FHR monitoring thereby allowing more frequent monitoring, earlier detection of deterioration, while reducing hospital attendances. This study aims to assess the feasibility, reliability, and accuracy of femom (NIFECG) by comparing its outputs to cCTG monitoring. Methods and analysis This is a single-centred, prospective pilot study, taking place in a tertiary maternity unit. Women with a singleton pregnancy over 28+0 weeks’ gestation who require antenatal cCTG monitoring for any clinical indication are eligible for recruitment. Concurrent NIFECG and cCTG monitoring will take place for up to 60 min. NIFECG signals will be postprocessed to produce FHR outputs such as baseline FHR and short-term variation (STV). Signal acceptance criteria is set as <50% of signal loss for the trace duration. Correlation, precision and accuracy studies will be performed to compare the STV and baseline FHR values produced by both devices. The impact of maternal and fetal characteristics on the effectiveness of both devices will be investigated. Other non-invasive electrophysiological assessment parameters will be assessed for its correlation with the STV, ultrasound assessments and maternal and fetal risk factors. Ethics and dissemination Approval has been obtained from South-East Scotland Research Ethics Committee 02 and MHRA. The results of this study will be published in peer-reviewed journals, and presented at international conferences. Trial registration number NCT04941534.

Transmission of SARS-CoV-2 from mother to fetus or neonate: What to know and what to do?

Abstract: SARS-CoV-2 can be vertically transmitted from the mother to the fetus and the neonate. This transmission route is rare compared to the environmental or horizontal spread and therefore, the risk can be deemed inconsequential by some medical providers. However, severe, although just as rare, feto-neonatal consequences are possible: fetal demise, severe/critical neonatal COVID-19 and multi-inflammatory syndrome (MIS-N) have been described. Therefore, it is important for the clinicians to know the mechanism of vertical transmission, how to recognize this, and how to deal with neonatal COVID-19 and MIS-N. Our knowledge about this field has significantly increased in the last three years. This is a summary of the pathophysiology, diagnostics, and therapeutics of vertical SARS-CoV-2 transmission that clinicians apply in their clinical practice.

Myeloidderived suppressor cells: Escorts at the maternal–fetal interface

Abstract: Myeloid-derived suppressor cells (MDSCs) are a novel heterogenous group of immunosuppressive cells derived from myeloid progenitors. Their role is well known in tumors and autoimmune diseases. In recent years, the role and function of MDSCs during reproduction have attracted increasing attention. Improving the understanding of their strong association with recurrent implantation failure, pathological pregnancy, and neonatal health has become a focus area in research. In this review, we focus on the interaction between MDSCs and other cell types (immune and non-immune cells) from embryo implantation to postpartum. Furthermore, we discuss the molecular mechanisms that could facilitate the therapeutic targeting of MDSCs. Therefore, this review intends to encourage further research in the field of maternal–fetal interface immunity in order to identify probable pathways driving the accumulation of MDSCs and to effectively target their ability to promote embryo implantation, reduce pathological pregnancy, and increase neonatal health.