Implication of viruses in the etiology of preeclampsia.

Preeclampsia is one of the most common disorders that poses threat to both mothers and neonates and a major contributor to perinatal morbidity and mortality worldwide. Viral infection during pregnancy is not typically considered to cause preeclampsia; however, syndromic nature of preeclampsia etiology and the immunomodulatory effects of viral infections suggest that microbes could trigger a subset of preeclampsia. Notably, SARS-CoV-2 infection is associated with an increased risk of preeclampsia. Herein, we review the potential role of viral infections in this great obstetrical syndrome. According to in vitro and in vivo experimental studies, viral infections can cause preeclampsia by introducing poor placentation, syncytiotrophoblast stress, and/or maternal systemic inflammation, which are all known to play a critical role in the development of preeclampsia. Moreover, clinical and experimental investigations have suggested a link between several viruses and the onset of preeclampsia via multiple pathways. However, the results of experimental and clinical research are not always consistent. Therefore, future studies should investigate the causal link between viral infections and preeclampsia to elucidate the mechanism behind this relationship and the etiology of preeclampsia itself.

The COVID-19 pandemic affects pregnancy complications and delivery outcomes in Japan: a large-scale nationwide population-based longitudinal study.

The impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnancy outcomes in Japan at the national level is unclear. This study aimed to assess the impact of the pandemic on pregnancy complications and delivery outcomes in Japan using nationwide population-based longitudinal data. Secondary data from the Japan Society of Obstetrics and Gynecology from 2016 to 2020 were analyzed. Obstetric information, pregnancy complications, and delivery information of pregnant women over 22 weeks of gestation were compared before and during the pandemic. The trends of hypertensive disorder of pregnancy, fetal growth restriction, and APGAR < 7 increased, whereas those of preterm birth and low birth weight decreased during the COVID-19 pandemic. Pregnancy complications and delivery outcomes have worsened during the COVID-19 pandemic in Japan. Social changes caused by unprecedented situations may have massively influenced pregnancy in several ways. Our findings suggest that even in mild lockdowns like those in Japan, the introduction of social fear during the pandemic might negatively impact pregnancy outcomes.

Change in client choice under multiple prenatal genetic testing options including noninvasive prenatal testing (NIPT) after genetic counseling in a Japanese maternity hospital.

OBJECTIVE: This study examined how clients' selection and preference for noninvasive prenatal testing (NIPT) for aneuploidy changed with genetic counseling (GC) performed by certified geneticists at a primary hospital specializing in obstetrics, where other multiple prenatal genetic tests options were available. METHODS: A total of 334 couples who underwent GC between 2017 and 2019 were included in the study. The average age of the pregnant women who underwent GC was 35.1 years. RESULTS: Among the 95 couples (28.4%) who wanted NIPT at the start of GC, 10 (10.5%) switched to other tests, and 4 (4.2%) chose not to undergo any test. Among the 106 (31.7%) couples who wanted the combination of ultrasonography and the serum marker test, 12 (11.3%) chose not to undergo the test. Among the 92 (27.5%) couples who were undecided before GC, 21 (22.8%) wanted NIPT, 31 (33.7%) selected combined tests, and 18 (19.6%) did not undergo any test. CONCLUSION: We have demonstrated the significance of GC before prenatal genetic testing under widespread use of NIPT. Ideally, obstetric facilities should provide GC, or at least, pre-counseling at their own facilities, and offer multiple prenatal genetic testing options or refer to other facilities for the same.

Origin, prospective identification, and function of circulating endothelial colony-forming cells in mice and humans.

Most circulating endothelial cells are apoptotic, but rare circulating endothelial colony-forming cells (C-ECFCs), also known as blood outgrowth endothelial cells, with proliferative and vasculogenic activity can be cultured; however, the origin and naive function of these C-ECFCs remains obscure. Herein, detailed lineage tracing revealed murine C-ECFCs emerged in the early postnatal period, displayed high vasculogenic potential with enriched frequency of clonal proliferative cells compared with tissue-resident ECFCs, and were not committed to or derived from the BM hematopoietic system but from tissue-resident ECFCs. In humans, C-ECFCs were present in the CD34bright cord blood mononuclear subset, possessed proliferative potential and in vivo vasculogenic function in a naive or cultured state, and displayed a single cell transcriptome sharing some umbilical venous endothelial cell features, such as a higher protein C receptor and extracellular matrix gene expression. This study provides an advance for the field by identifying the origin, naive function, and antigens to prospectively isolate C-ECFCs for translational studies.

Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology and Japan Association of Obstetricians and Gynecologists 2020 edition.

The 2017 clinical guidelines for obstetrical practice by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists were revised and published as the 2020 edition (in Japanese). The aim of these guidelines is to present appropriate standard obstetric diagnosis and management procedures that have reached consensus among Japanese obstetricians. The 2020 guidelines include 113 clinical questions and an appendix, followed by answers (CQ&A; originally 112 in the 2017 edition), a discussion, list of references, and some tables and figures presenting common problems and questions encountered in obstetrical practice. Each answer comes with a recommendation level of A, B, or C and has been prepared based principally on evidence or a consensus among Japanese obstetricians in situations where "evidence" is weak or lacking. Answers with a recommendation level of A or B represent current standard care practices in Japan. All 113 CQ&As and the appendix are presented here to promote a better understanding of the current standard care practices for pregnant and lactating women in Japan.

A multicenter prospective study of home blood pressure measurement (HBPM) during pregnancy in Japanese women.

In the near future, hypertensive disorders of pregnancy (HDP) have been diagnosed by home blood pressure monitoring (HBPM) instead of clinic BP monitoring. A multicenter study of HBPM was performed in pregnant Japanese women in the non-high risk group for HDP. Participants were women (n = 218), uncomplicated pregnancy who self-measured and recorded their HBP daily. Twelve women developed HDP. HBP was appropriate (100 mmHg in systole and 63 mmHg in diastole), bottoming out at 17 to 21 weeks of gestation. It increased after 24 weeks of gestation and returned to non-pregnant levels by 4 weeks of postpartum. The upper limit of normal HBP was defined as the mean value +3 SD for systolic and mean +2 SD for diastolic with reference to the criteria for non-pregnant women. Using the polynomial equation, the hypertensive cut-off of systolic HBP was 125 mmHg at 15 weeks and 132 mmHg at 30 weeks of gestation, while it for diastolic HBP was 79 mmHg at 15 weeks and 81 mmHg at 30 weeks of gestation. Systolic HBP in women who developed HDP was higher after 24 weeks of gestation, and diastolic HBP was higher during most of the pregnancy compared to normal pregnancy. When the variability of individual HBP in women developed HDP compared to normal pregnant women was examined using the coefficient of variation (CV), the CV was lower in HDP before the onset of HDP. HBPM can be used not only for HDP determination, but also for early detection of HDP.

Hypoxia Promotes Extravillous Trophoblast Cell Invasion through the Hypoxia-Inducible Factor Urokinase-Type Plasminogen Activator Receptor Pathway.

OBJECTIVES: Hypoxia is a common feature of extravillous trophoblast (EVT) cells that promote invasion during the early stages of human placentation. This study aimed to examine whether hypoxia-induced an invasive phenotype in EVT cells in vitro and explore the underlying molecular mechanisms. DESIGN: The invasiveness of primary EVT cells isolated from the first trimester placental tissues during weeks 5-8 of gestation was examined under hypoxic (5% O2) and normoxic (20% O2) conditions. METHODS: Invasiveness was determined by transwell and wound-healing invasion assays using the IncuCyte ZOOM™ Live-Cell Imaging System. Protein expression of the urokinase plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor of hypoxia or normoxia-treated cells was measured using Western blot analysis. Knockdown of hypoxia-inducible factor-1 alpha (HIF-1α) was assessed using small interfering RNA (siRNA). RESULTS: Hypoxia enhanced EVT cell invasion but did not affect apoptosis. The stimulatory effect of hypoxia on EVT cell invasiveness was associated with induction of the uPA-uPAR pathway. The synthetic inhibitor of uPAR significantly inhibited hypoxia-induced EVT cell invasion. Silencing of HIF-1α by siRNA abolished the stimulatory effect of hypoxia and inhibited the upregulation of uPAR expression, suggesting that the HIF-1α-uPAR signal is the key mediator for hypoxia-induced EVT cell invasion. Further experiments need to be performed to elucidate the HIF-1α-uPAR signal pathways. CONCLUSIONS: The low oxygen-regulated early events of EVT invasion may be mediated by the HIF-1α-uPAR pathway.

Feasibility of a mobile cardiotocogram device for fetal heart rate self-monitoring in low-risk singleton pregnant women.

AIM: This study aimed to clarify the feasibility of a mobile cardiotocogram (CTG) device for self-monitoring fetal heart rate (FHR) in low-risk singleton pregnant women. METHODS: This study was conducted at six university hospitals and seven maternity clinics in Japan. Using a mobile cardiotocogram device (iCTG, Melody International Ltd., Kagawa, Japan), participants of more than 34 gestational weeks measured the FHR by themselves at least once a week until hospitalization for delivery. We evaluated the acquisition rate of evaluable FHR recordings and the frequency of abnormal FHR patterns according to the CTG classification system of the Japan Society of Obstetrics and Gynecology (JSOG). The participants also underwent a questionnaire survey after delivery to evaluate their satisfaction level of self-monitoring FHR using the mobile CTG device. RESULTS: A total of 1278 FHR recordings from 101 women were analyzed. Among them, 1276 (99.8%) were readable for more than 10 min continuously, and the median percentage of the total readable period in each recording was 98.9% (range, 51.4-100). According to the JSOG classification system, 1245 (97.6%), 9 (0.7%), 18 (1.4%), and four (0.3%) FHR patterns were classified as levels 1, 2, 3, and 4, respectively. The questionnaire survey revealed high participant satisfaction with FHR self-monitoring using the iCTG. CONCLUSION: The mobile CTG device is a feasible tool for self-monitoring FHR, with a high participant satisfaction level.

Congenital contractural arachnodactyly suspected by abnormally long extremities by fetal ultrasound.

Congenital contractural arachnodactyly (CCA) is a rare disease with the clinical features of limited extension of multiple joints, arachnodactyly, camptodactyly, thin and long extremities, and so on. In the point of long extremities, CCA resembles Marfan syndrome (MFS). CCA is easily differentiated from MFS after birth due to the flexion of multiple joints, including elbows, knees, hips and fingers. During the fetal period, observation of arachnodactyly and folded fingers by fetal ultrasound is the means of differential diagnosis between these two diseases. We report on a case of CCA diagnosed with prenatal symptoms of long extremities, and introduced physiotherapy in early childhood for a better physical prognosis.

Placental abruption in each hypertensive disorders of pregnancy phenotype: a retrospective cohort study using a national inpatient database in Japan.

We designed a retrospective cohort study using the Diagnosis Procedure Combination database, a national inpatient database for acute-care inpatients in Japan, to examine whether recent global diagnostic criteria for preeclampsia, phenotypes of hypertensive disorders of pregnancy (HDP) and features of the disease are useful as predictors of placental abruption and whether other risk factors are associated with the onset of placental abruption. A total of 85,858 hospitalized patients with a diagnosis of HDP who gave birth during hospitalization between July 2010 and March 2018 were included in this study. We examined the associations between the occurrence of placental abruption after hospitalization and several factors, including gestational age (GA) at placental abruption onset, HDP subtypes, GA on admission, maternal age, body mass index, smoking, multiple pregnancy, prelabor rupture of membranes, diabetes mellitus, emergency admission by ambulance, and consciousness, using a multivariate logistic regression analysis. Placental abruption occurred in 541 patients (0.63%) after hospital admission, and the occurrence increased acutely after 32 weeks GA. A decrease in abruption was significantly associated with maternal BMI on admission (≥30 kg/m2; odds ratio [OR], 0.54; 95% confidence interval [CI], 0.41-0.70) and multiple pregnancy (OR, 0.29; 95% CI, 0.18-0.46). An increase in abruption was associated with earlier GA on admission (<34 weeks' GA; OR, 3.77; 95% CI, 3.13-4.53) and emergency admission by ambulance (OR, 1.34; 95% CI, 1.09-1.65). Individual features of severe PE showed no significant associations with the occurrence of abruption. In conclusion, HDP at an earlier GA was suggested to be a risk factor for placental abruption, and we recommend hospitalization and careful management of such patients to improve their prognosis.

High-Quality Transmission of Cardiotocogram and Fetal Information Using a 5G System: Pilot Experiment.

BACKGROUND: A cardiotocogram (CTG) is a device used to perceive the status of a fetus in utero in real time. There are a few reports of its use at home or during emergency transport. OBJECTIVE: The aim of this study was to test whether CTG and other perinatal information can be transmitted accurately using an experimental station with a 5G transmission system. METHODS: In the research institute, real-time fetal heart rate waveform data from the CTG device, high-definition video ultrasound images of the fetus, and high-definition video taken with a video camera on a single line were transmitted by 5G radio waves from the transmitting station to the receiving station. RESULTS: All data were proven to be transmitted with a minimum delay of less than 1 second. The CTG waveform image quality was not inferior, and there was no interruption in transmission. Images of the transmitted ultrasound examination and video movie were fine and smooth. CONCLUSIONS: CTG and other information about the fetuses and pregnant women were successfully transmitted by a 5G system. This finding will lead to prompt and accurate medical treatment and improve the prognosis of newborns.

Involvement of Receptor for Advanced Glycation Endproducts in Hypertensive Disorders of Pregnancy.

Preeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially life-threatening disease. Recently, PE/HDP has been considered to cause adipose tissue inflammation, but the detailed mechanism remains unknown. We exposed human primary cultured adipocytes with serum from PE/HDP and healthy controls for 24 h, and analyzed mRNA expression of several adipokines, cytokines, and ligands of the receptor for advanced glycation endproducts (RAGE). We found that the mRNA levels of interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), high mobility group box 1 (HMGB1), and RAGE were significantly increased by the addition of PE/HDP serum. Among RAGE ligands, advanced glycation endproducts (AGE) and HMGB1 increased mRNA levels of IL-6 and CCL2 in SW872 human adipocytes and mouse 3T3-L1 cells. The introduction of small interfering RNA for RAGE (siRAGE) into SW872 cells abolished the AGE- and HMGB1-induced up-regulation of IL-6 and CCL2. In addition, lipopolysaccharide (LPS), a ligand of RAGE, increased the expression of IL-6 and CCL2 and siRAGE attenuated the LPS-induced expression of IL-6 and CCL2. These results strongly suggest that the elevated AGE, HMGB1, and LPS in pregnant women up-regulate the expression of IL-6 and CCL2 via the RAGE system, leading to systemic inflammation such as PE/HDP.

Prospective evaluation of screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population.

BACKGROUND: The administration of aspirin <16 weeks gestation to women who are at high risk for preeclampsia has been shown to reduce the rate of preterm preeclampsia by 65%. The traditional approach to identify such women who are at risk is based on risk factors from maternal characteristics, obstetrics, and medical history as recommended by the American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. An alternative approach to screening for preeclampsia has been developed by the Fetal Medicine Foundation. This approach allows the estimation of patient-specific risks of preeclampsia that requires delivery before a specified gestational age with the use of Bayes theorem-based model. OBJECTIVE: The purpose of this study was to examine the diagnostic accuracy of the Fetal Medicine Foundation Bayes theorem-based model, the American College of Obstetricians and Gynecologists, and the National Institute for Health and Care Excellence recommendations for the prediction of preterm preeclampsia at 11-13+6 weeks gestation in a large Asian population STUDY DESIGN: This was a prospective, nonintervention, multicenter study in 10,935 singleton pregnancies at 11-13+6 weeks gestation in 11 recruiting centers across 7 regions in Asia between December 2016 and June 2018. Maternal characteristics and medical, obstetric, and drug history were recorded. Mean arterial pressure and uterine artery pulsatility indices were measured according to standardized protocols. Maternal serum placental growth factor concentrations were measured by automated analyzers. The measured values of mean arterial pressure, uterine artery pulsatility index, and placental growth factor were converted into multiples of the median. The Fetal Medicine Foundation Bayes theorem-based model was used for the calculation of patient-specific risk of preeclampsia at <37 weeks gestation (preterm preeclampsia) and at any gestation (all preeclampsia) in each participant. The performance of screening for preterm preeclampsia and all preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and placental growth factor (triple test) was evaluated with the adjustment of aspirin use. We examined the predictive performance of the model by the use of receiver operating characteristic curve and calibration by measurements of calibration slope and calibration in the large. The detection rate of screening by the Fetal Medicine Foundation Bayes theorem-based model was compared with the model that was derived from the application of American College of Obstetricians and Gynecologists and National Institute for Health and Care Excellence recommendations. RESULTS: There were 224 women (2.05%) who experienced preeclampsia, which included 73 cases (0.67%) of preterm preeclampsia. In pregnancies with preterm preeclampsia, the mean multiples of the median values of mean arterial pressure and uterine artery pulsatility index were significantly higher (mean arterial pressure, 1.099 vs 1.008 [P<.001]; uterine artery pulsatility index, 1.188 vs 1.063[P=.006]), and the mean placental growth factor multiples of the median was significantly lower (0.760 vs 1.100 [P<.001]) than in women without preeclampsia. The Fetal Medicine Foundation triple test achieved detection rates of 48.2%, 64.0%, 71.8%, and 75.8% at 5%, 10%, 15%, and 20% fixed false-positive rates, respectively, for the prediction of preterm preeclampsia. These were comparable with those of previously published data from the Fetal Medicine Foundation study. Screening that used the American College of Obstetricians and Gynecologists recommendations achieved detection rate of 54.6% at 20.4% false-positive rate. The detection rate with the use of National Institute for Health and Care Excellence guideline was 26.3% at 5.5% false-positive rate. CONCLUSION: Based on a large number of women, this study has demonstrated that the Fetal Medicine Foundation Bayes theorem-based model is effective in the prediction of preterm preeclampsia in an Asian population and that this method of screening is superior to the approach recommended by American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. We have also shown that the Fetal Medicine Foundation prediction model can be implemented as part of routine prenatal care through the use of the existing infrastructure of routine prenatal care.

Preliminary evidence of a paternal-maternal genetic conflict on the placenta: Link between imprinting disorder and multi-generational hypertensive disorders.

There has been great research progress on hypertensive disorders in pregnancy (HDP) in the last few decades. Failure of placentation, especially a lack of uterine spiral artery remodeling, is the main pathological finding of HDP. Currently, members of the vascular endothelial growth factor family are used as markers for the early prediction of onset of HDP. Epidemiologic research has also shown that HDP can have effects on the next generation infants, representing a Development Origins of Health and Disease-related disease. However, the precise pathogenic mechanism and the effect of HDP on the offspring remain unclear. The group of strong pro-inflammatory molecules known as "danger signals" have been shown to be released from the placental trophoblast surface and increase in the maternal circulation in HDP, which are then possibly transported into the fetal circulation. These signals, including fatty acids or adipocytokines, may alter the offspring's health in later life. Moreover, a hypoxic condition alters placental methylation, and the change may be passed onto the fetus. Although the genetic origin of the disease is still unknown, a hypothesis has been put forward that a paternal-maternal genetic conflict, mainly at imprinting lesion sites, may be a key factor for disease initiation. In particular, an imbalance in paternal and maternal factors may impede proper placentation, trophoblast invasion, decidualization or immune moderation so as to achieve better nutrition for the fetus (paternal) versus ensuring safe delivery and further pregnancy (maternal). Here, we review this research progress on HDP and focus on this novel genetic conflict concept, which is expected to provide new insight into the cause, pathophysiology, and multi-generational effects of HDP.

Classification of factors involved in nonreportable results of noninvasive prenatal testing (NIPT) and prediction of success rate of second NIPT.

OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.

Fetal cell-free DNA fraction in maternal plasma for the prediction of hypertensive disorders of pregnancy.

OBJECTIVE: The purpose of this study is to compare the fetal fractions during non-invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP). STUDY DESIGN: This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed. RESULTS: A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP. CONCLUSION: A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult.