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Background mRNA vaccination is an effective, safe, and widespread strategy for protecting pregnant women against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, information on factors such as perinatal outcomes, safety, and coverage of mRNA vaccinations among pregnant women is limited in Japan. Therefore, this study aimed to investigate the perinatal outcomes, coverage, adverse effects, and short-term safety of mRNA vaccination as well as vaccine hesitancy among pregnant women. Methods We conducted a multicenter online survey of postpartum women who delivered their offspring at 15 institutions around Tokyo from October 2021 to March 2022. Postpartum women were divided into vaccinated and unvaccinated groups. Perinatal outcomes, COVID-19 prevalence, and disease severity were compared between the two groups. Adverse reactions in the vaccinated group and the reasons for being unvaccinated were also investigated retrospectively. Results A total of 1,051 eligible postpartum women were included. Of these, 834 (79.4%) had received an mRNA vaccine, while 217 (20.6%) had not, mainly due to concerns about the effect of vaccination on the fetus. Vaccination did not increase the incidence of adverse perinatal outcomes, including fetal morphological abnormalities. The vaccinated group demonstrated low COVID-19 morbidity and severity. In the vaccinated group, the preterm birth rate, cesarean section rate, and COVID-19 incidence were 7.2%, 33.2%, and 3.3%, respectively, compared with the 13.7%, 42.2%, and 7.8% in the unvaccinated group, respectively. Almost no serious adverse reactions were associated with vaccination. Conclusions mRNA vaccines did not demonstrate any adverse effects pertaining to short-term perinatal outcomes and might have prevented SARS-CoV-2 infection or reduced COVID-19 severity. Concerns regarding the safety of the vaccine in relation to the fetus and the mother were the main reasons that prevented pregnant women from being vaccinated. To resolve concerns, it is necessary to conduct further research to confirm not only the short-term safety but also the long-term safety of mRNA vaccines.

Uterine necrosis is a rare complication in uterine artery embolization (UAE) for postpartum hemorrhage (PPH). Preeclampsia (PE) is a condition characterized with systemic endothelial damage and intravascular volume depletion. Whether a patient with PE is at high risk for uterine necrosis after UAE for PPH has been unknown. A 30-year-old primipara woman was diagnosed with PE based on hypertension and proteinuria during delivery. UAE was performed for PPH after forceps delivery. After UAE, the patient presented with pleural effusion and massive ascites as well as persistent fever unresponsive to antibiotics. Ultrasonography and contrast-enhanced magnetic resonance imaging (MRI) led to the diagnosis of uterine necrosis, for which we performed total laparoscopic hysterectomy. It should be kept in mind that patients with PE associated with massive ascites may be at high risk for uterine necrosis after UAE due to decreased uterine perfusion. Therefore, it is important to pay attention to persistent symptoms such as fever and abdominal pain after UAE to diagnose uterine necrosis.

Intrapartum transperineal ultrasound is considered useful in judging fetal head descent; however, the inability to detect ischial spines on ultrasound images has been a drawback to its legitimacy. The current study aimed to determine the anatomical location of ischial spines, which can be directly applied to intrapartum transperineal ultrasound images. Based on magnetic resonance imaging (MRI) of 67 pregnant women at 33+2 [31+6-34+0] weeks gestation (median [interquartile range: IQR]), we calculated the angle between the pubic symphysis and the midpoint of ischial spines (midline symphysis-ischial spine angle; mSIA), which is theoretically equivalent to the angle of progression at fetal head station 0 on ITU, by determining spatial coordinates of pelvic landmarks and utilizing spatial vector analysis. Furthermore, we measured symphysis-ischial spine distance (SID), defined as the distance between the vertical plane passing the lower edge of the pubic symphysis and the plane that passes the ischial spines. As a result, mSIA was 109.6° [105.1–114.0] and SID 26.4 mm [19.8–30.7] (median, [IQR]). There was no correlation between mSIA or SID and maternal characteristics, including physique. We established a novel method to measure the components of the pelvic anatomy by analyzing the three-dimensional coordinates of MRI data and identified the anatomical location of ischial spines which can be applied to ultrasound images. Our results provide valuable evidence to enhance the reliability of intrapartum transperineal ultrasound in assessing fetal head descent by considering the location of ischial spines.

Background Adenomyosis is known to be associated with unfavorable perinatal outcomes, but the patient population among women with adenomyosis who is at high risk for adverse perinatal outcomes remains unclear. Recent case reports show that some women with adenomyosis experience pain at the adenomyosis lesion during pregnancy and have detrimental perinatal outcomes. However, the prevalence of pain onset in women with adenomyosis has not been studied, nor has its influence on perinatal outcomes. This study aimed to clarify the clinical characteristics of pain developing in adenomyosis lesions during pregnancy and the perinatal outcomes associated with this phenomenon. Methods This was a single-center retrospective analysis of a cohort of women with adenomyosis who delivered between 2011 and 2021. The incidence of pain onset at adenomyosis lesions among women with adenomyosis during pregnancy was analyzed retrospectively from medical records. Pain during pregnancy was defined as persistent pain at the adenomyosis site with administration of analgesics for pain relief, and its association with perinatal outcomes was analyzed. Results Among 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2%) presented with pain at the adenomyosis site during pregnancy. In total, 5 of the 12 pregnancies (41.7%) developed preeclampsia, which resulted in preterm delivery, and only 3 of the 12 pregnancies (25.0%) achieved term delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those who did not (41.7% vs. 13.9%; p p p

Introduction Disturbance in placental epigenetic regulation contributes to the pathogenesis of preeclampsia (PE). Although aberrant placental DNA methylation status in PE has been thoroughly studied, the role of histone modifications, including histone methylation, in PE remains unclear. Moreover, no study has ever reported the association between PE and placental histone methylation status by focusing on histone methyltransferases. The present study aimed to investigate the possible involvement of placental epigenetic regulation by histone methylation via histone methyltransferases in the pathophysiology of PE. Methods Placental mRNA expression of histone methyltransferases was examined using quantitative RT-PCR. Protein expression of histone methyltransferases and histone methylation status in placentas and trophoblast cell lines were assessed by immunoblotting and immunohistochemistry. Results Expression profile of histone methyltransferases in the placentas using quantitative RT-PCR revealed that the mRNA expression levels of histone 3 lysine 4 (H3K4) methyltransferases, SETD1A and SMYD3, were significantly increased in placentas from PE patients. Immunoblotting and immunohistochemistry revealed that not only protein expression levels of SETD1A and SMYD3, but also H3K4 methylation status was increased in the trophoblasts from PE placentas. In vitro studies using HTR-8/SV-neo and BeWo cells showed that hypoxia induced the expression levels of SETD1A and SMYD3, and subsequently enhanced H3K4 methylation. Furthermore, the overexpression of SETD1A and SMYD3 in HTR-8/SV-neo cells enhanced H3K4 methylation in response to hypoxia. Discussion Our study results suggest that placental epigenetic alteration by enhanced histone H3K4 methylation through upregulated SETD1A and SMYD3 might play a role in the pathophysiological process of PE associated with hypoxia.

Since fetal presentation is an essential factor for planning mode of delivery, the estimation of fetal presentation at delivery is important in prenatal management. This study aimed to clarify the transition of fetal presentation during pregnancy and to propose practical strategy to predict final fetal presentation.During the period of 2 years, fetal presentations were analyzed using ultrasonography during the prenatal visits at and after 22 weeks of gestation in a single facility. The relationship between the transition of fetal presentation and final presentation at delivery was analyzed. Further, a prediction model was developed to predict the final fetal presentation at birth.Among 1737 singleton pregnancies with full-term delivery, non-cephalic delivery occurred in 76 pregnancies (4.4%). Non-cephalic presentation in later half of the gestational period was associated with low incidence of spontaneous cephalic version. Furthermore, we found that in 46% of women with a final non-cephalic delivery, the non-cephalic presentation continued during whole of the observational period without spontaneous cephalic version. Based on the analyzed data of this cohort, we show that in a group of women with non-cephalic presentation at 35/36 weeks, the best predictability for spontaneous cephalic version depended on whether the cephalic presentation was observed at least once at and after 30 weeks of gestation.Our findings suggest that information on the changes in fetal presentation during gestation contributes to the prediction of the fetal presentation at delivery and planning mode of delivery.

Objective To clarify the clinical characteristics of pain developing in adenomyosis lesions during pregnancy and the perinatal outcomes associated with this phenomenon. Study Design Retrospective cohort study. Setting A tertiary hospital in Japan. Patients and methods Ninety one singleton pregnancies with adenomyosis who delivered between 2011 and 2021 were retrospectively analyzed. Pain during pregnancy was defined as persistent pain at the adenomyosis site with analgesics administration, and its association with perinatal outcomes was analyzed. Main outcome measures Pain at the adenomyosis lesion and its onset and duration, maximum C-reactive protein level during pain, and perinatal outcomes such as preterm delivery, preeclampsia, and blood loss. Results Among 91 singleton pregnancies with adenomyosis, 12 pregnancies (13.2%) presented with pain at the adenomyosis site. In total, 5 of the 12 pregnancies (41.7%) developed preeclampsia, which resulted in preterm delivery. The incidence of preeclampsia and preterm delivery was higher in those who experienced pain than in those without (41.7% vs. 13.9%; p

Objective We experienced a case of 22q11.2 deletion syndrome (22qDS), with severe polyhydramnios, and dysphagia, which prompted us to review prognosis in neonates with 22qDS, with a focus on dysphagia. Case report A patient was referred to our hospital at 35 gestational weeks because of polyhydramnios. After amniotic fluid reduction, labor was induced at 38 weeks. The neonate had serious dysphagia, and 22qDS was diagnosed postnatally by fluorescent in situ hybridization analysis. This prompted a retrospective analysis of 9 cases with 22qDS experienced in our facility. Three out of these nine cases showed polyhydramnios, and had severe dysphagia postnatally. In total, 4 cases had dysphagia, while mortality was observed in 2 of these 4 cases. Additionally, 5 cases without dysphagia had normal development and no major complications. Conclusion Polyhydramnios associated with postnatal dysphagia might be a risk factor related to short-term prognostic outcomes in newborns with 22qDS.

Objective: Additional risk factors for preterm delivery in pregnant women with cervical shortening are not fully understood; however, mid-trimester cervical shortening is accepted as a risk factor for preterm delivery. This study aimed to identify risk factors associated with subsequent preterm delivery among patients with short cervix detected after late mid-trimester. Materials and methods: This was a retrospective study of medical data from a single perinatal tertiary facility. We identified 134 asymptomatic women with singleton pregnancies where cervical shortening (≤25 mm) was detected during routine universal screening at 22–33 weeks. Statistical analyses were conducted to identify causal relationships between the incidence of preterm delivery and known risk factors for preterm delivery. Results: Incidence of preterm delivery was 27.6% (37/134) and preterm premature rupture of membrane was preceded in 46.0% (17/37) of the women with preterm delivery. Using logistic regression analysis, we identified uterine contractions [aOR 4.25, 95% confidence intervals (CI):1.68–12.1] and increased C-reactive protein (CRP) and increased white blood cell (WBC) in blood test (CRP: aOR 3.45, 95% CI:1.50–9.71; WBC: aOR 1.28, 95% CI: 1.08–1.55) as risk factors which significantly increased the risk of preterm delivery among women diagnosed with short cervix. Preterm delivery occurred in 91% of women positive for both uterine contractions and CRP >0.5 mg/dl. Conclusions: Uterine contraction and elevated CRP were additional risk factors for preterm delivery among women with short cervix. These results might be clinically useful to evaluate subsequent risk for preterm delivery in asymptomatic pregnant women presenting with short cervix in mid-pregnancy. Keywords: Preterm labor, Cervical length, Inflammation, Pregnancy

Recent evidence indicates that elevated placental adenosine signaling contributes to preeclampsia (PE). However, the molecular basis for the chronically enhanced placental adenosine signaling in PE remains unclear. Here, we report that hypoxia-inducible factor-1α (HIF-1α) is crucial for the enhancement of placental adenosine signaling. Utilizing a pharmacologic approach to reduce placental adenosine levels, we found that enhanced adenosine underlies increased placental HIF-1α in an angiotensin receptor type 1 receptor agonistic autoantibody (AT1 -AA)-induced mouse model of PE. Knockdown of placental HIF-1α in vivo suppressed the accumulation of adenosine and increased ecto-5'-nucleotidase (CD73) and adenosine A2B receptor (ADORA2B) in the placentas of PE mouse models induced by AT1 -AA or LIGHT, a TNF superfamily cytokine (TNFSF14). Human in vitro studies using placental villous explants demonstrated that increased HIF-1α resulting from ADORA2B activation facilitates the induction of CD73, ADORA2B, and FLT-1 expression. Overall, we demonstrated that (a) elevated placental HIF-1α by AT1 -AA or LIGHT upregulates CD73 and ADORA2B expression and (b) enhanced adenosine signaling through upregulated ADORA2B induces placental HIF-1α expression, which creates a positive feedback loop that promotes FLT-1 expression leading to disease development. Our results suggest that adenosine-based therapy targeting the malicious cycle of placental adenosine signaling may elicit therapeutic effects on PE.

Loeys-Dietz syndrome (LDS) is a connective tissue disorder with a high incidence of aortic dissection (AD). After treating two previously reported cases of postpartum AD in women with LDS following prophylactic aortic root replacement (ARR), we succeeded in managing a 30-year-old primigravida with no AD during her peripartum period. On the basis of the patient's stated desire to conceive during preconception counseling, a multidisciplinary team was assembled. She conceived naturally after receiving prophylactic ARR and beta-blocker treatment. Multidisciplinary patient care included precise blood pressure management, continuation of beta-blocker treatment, cardiovascular assessment with echocardiogram, regional anesthesia during labor, prevention of lactation, and resumption of angiotensin II receptor blocker therapy immediately after delivery. On the basis of our assessment of three cases, including this case, and a literature review, we propose a peripartum management strategy for patients with LDS following prophylactic ARR.

No previous study has evaluated the transitions of intrapartum transperineal ultrasound parameters during labor progression in cephalic malposition.We aimed to quantitate the characteristic trends of fetal head position and descent in cephalic malposition by analyzing the transitions of intrapartum transperineal ultrasound parameters and explore an indicator associated with the degree of cephalic malposition.We retrospectively analyzed pregnant women who delivered at term from January 2018 to December 2020 at the University of Tokyo Hospital. The fetal occipital position was classified as occiput anterior and nonocciput anterior according to the fetal occipital angle of 0° to 75° and 75° to 180°, respectively. Fetal occipital angle was defined by the midline angle and position of the ocular orbit. The differences in the trends of head direction, head-symphysis distance, and progression distance relative to the angle of progression between occiput anterior and nonocciput anterior cases were evaluated. In addition, the parameters that showed differences were analyzed to evaluate their relationship to the degree of cephalic malposition.A total of 502 images (occiput anterior, 319; nonocciput anterior, 183) met the inclusion criteria. The distribution of head direction values relative to the angle of progression was smaller in the nonocciput anterior group than in the occiput anterior group, whereas the head-symphysis distance and progression distance values relative to the angle of progression showed no difference in their distribution between the occiput anterior and nonocciput anterior groups. The ratio of head direction to the angle of progression was significantly smaller in the nonocciput anterior group than in the occiput anterior group (median [interquartile range], 0.03 [-0.02 to 0.10] vs 0.21 [0.12-0.28]; P.0001). Furthermore, this ratio was negatively correlated with fetal occipital angle (Spearman correlation coefficient, -0.66).Our results indicated that the head direction to angle of progression ratio reflects the deviation in the fetal head direction toward the maternal dorsal side, and decreases in proportion to the degree of cephalic malposition. This concept of deviation in the head direction as an indicator for evaluating cephalic malposition with intrapartum transperineal ultrasound may contribute to improving labor management in the case of cephalic malposition.

We aimed to assess the impact of fetal growth restriction (FGR) as a diagnostic criterion for preeclampsia (PE) on the severity of maternal preeclamptic features by comparing it with other diagnostic criteria for PE, maternal organ dysfunction.We performed a retrospective cohort study of singleton pregnancies. Based on the status at diagnosis, PE cases preceded by FGR without maternal organ dysfunction (Group F; n = 28) and those preceded by maternal organ dysfunction without FGR (Group M; n = 87) were analyzed.Group F had an earlier PE diagnosis (32.5 ± 4.9 vs. 36.7 ± 3.5 weeks, p 0.01) and delivery (33.7 ± 4.5 vs. 37.5 ± 3.1 weeks, p 0.01) than Group M. No significant differences in maternal morbidities were observed between the groups, including severe hypertension (75.0 vs. 60.0%), need for intravenous antihypertensives (42.9 vs. 48.3%) or magnesium sulfate (60.7 vs. 54.5%), or a composite of major maternal complications (17.9 vs. 21.8%). When limited to early-onset PE diagnosed before 34 weeks of gestation (17 and 17 cases in Group F and M, respectively), the frequencies of maternal morbidities (severe hypertension: 70.6 vs. 52.9%, intravenous antihypertensives: 35.3 vs. 35.3%, magnesium sulfate: 58.8 vs. 47.1%, major complications: 29.4 vs. 23.5%) and the duration from diagnosis until delivery (11.2 ± 14.7 vs. 16.5 ± 21.7 days) were comparable between two groups.Our results suggest that the presence of FGR on PE diagnosis is associated with the development of severe maternal symptoms as much as that of maternal organ dysfunction at diagnosis, and it may be reasonable to include FGR in PE diagnostic criteria.

Preeclampsia (PE) is a hypertensive obstetric disorder with poor prognosis for both the mother and offspring. Infants born to mothers with PE are known to be at increased risk of developing higher brain dysfunction, such as autism. However, how maternal PE can affect the environment in the fetal brain has not been fully elucidated. Here, we examined the impact of PE on the fetal brain in a mouse model of PE induced by angiotensin II (Ang II), focusing on changes in the inflammatory condition. We confirmed that pregnant mice which were continuously administered Ang II exhibited PE phenotypes, including high blood pressure, proteinuria, and fetal growth restriction. Quantitative RT-PCR analysis demonstrated that the brain of fetuses on embryonic day 17.5 (E17.5) in the Ang II-administered pregnant mice showed increased expression of cytokines, interleukin (IL)- 6, IL-17a, tumor necrosis factor-α, interferon-γ, IL-12, IL-4, and IL-10. Immunohistochemical analysis over a wide area, from the tip of the frontal lobe to the posterior cerebral end, on E17.5 revealed that the microglia in the fetal brain of the Ang II-administered group displayed higher solidity and circularity than those of the control group, indicating that the microglia had transformed to an amoeboid morphology and were activated. Our findings suggest that maternal PE may cause altered inflammatory conditions in the fetal brain, which might be associated with the pathological mechanism connecting maternal PE and brain dysfunction in the offspring.

Placenta-specific molecular basis that is responsible for the pathophysiology of preeclampsia (PE) remains to be fully understood. Adenosine, an endogenous nucleoside, is a signaling molecule that is induced under pathological conditions such as hypoxia and is involved in various diseases. Recent evidence on humans and animal models has demonstrated that enhanced placental adenosine signaling contributes to the development of PE. This review is to summarize current progress and discuss the significance of adenosine signaling in the pathophysiology of PE and future perspectives of therapeutic possibilities targeting adenosine signaling.

Objectives: To investigate the spontaneous outcomes of vascularized retained products of conception (RPOC) detected by ultrasonography after second-trimester abortion, and to identify the predictiv...

Insufficient O(2) supply is frequently associated with fetal growth restriction (FGR), a leading cause of perinatal mortality and morbidity. Although the erythrocyte is the most abundant and only cell type to deliver O(2) in our body, its function and regulatory mechanism in FGR remain unknown. Here, we report that genetic ablation of mouse erythrocyte equilibrative nucleoside transporter 1 (eENT1) in dams, but not placentas or fetuses, results in FGR. Unbiased high-throughput metabolic profiling coupled with in vitro and in vivo flux analyses with isotopically labeled tracers led us to discover that maternal eENT1–dependent adenosine uptake is critical in activating AMPK by controlling the AMP/ATP ratio and its downstream target, bisphosphoglycerate mutase (BPGM); in turn, BPGM mediates 2,3-BPG production, which enhances O(2) delivery to maintain placental oxygenation. Mechanistically and functionally, we revealed that genetic ablation of maternal eENT1 increases placental HIF-1α; preferentially reduces placental large neutral aa transporter 1 (LAT1) expression, activity, and aa supply; and induces FGR. Translationally, we revealed that elevated HIF-1α directly reduces LAT1 gene expression in cultured human trophoblasts. We demonstrate the importance and molecular insight of maternal eENT1 in fetal growth and open up potentially new diagnostic and therapeutic possibilities for FGR.

OBJECTIVE To investigate pregnancy outcomes, especially the risk of pregnancy-related aortic dissection (AD), in patients with Marfan syndrome (MFS) after prophylactic aortic root replacement (ARR). DESIGN Retrospective case series study. SETTING Tertiary perinatal care centre at a university hospital. POPULATION Pregnant women fulfilling the revised Ghent nosology (2010) criteria for MFS who were managed at our institute. METHODS The pregnancy outcomes of all patients with MFS managed at our institute between 1982 and September 2016 were reviewed retrospectively based on medical records. MAIN OUTCOME MEASURES Obstetrical management and complication including the incidence of AD throughout the peripartum period. RESULTS Among 22 patients (28 pregnancies) who had been managed as potential MFS or related disorders, 14 (17 pregnancies) fulfilled the revised Ghent nosology (2010) criteria for MFS and were enrolled in this study. Five patients (five pregnancies) had received ARR before conception: three (60%) developed type B aortic dissection [AD(B)] during the peripartum period, compared with only one of 10 patients (12 pregnancies) without ARR (P

Hydatidiform moles are known to pose an extremely high risk of severe early-onset preeclampsia if left untreated. TNF superfamily cytokine, LIGHT has recently been reported to contribute to pathophysiology of preeclampsia. The present study aimed to investigate the involvement of LIGHT in hydatidiform moles. We measured the serum levels of LIGHT and sFlt-1 by ELISA in 17 women with complete hydatidiform mole (HM) and 20 gestational-age-matched normal pregnant women (control). As a result, the serum LIGHT levels were significantly higher in HM as compared with those in control (69.9 ± 9.6 pg/ml vs 25.4 ± 5.3 pg/ml, p = 0.0001) and the serum levels of LIGHT were significantly positively correlated with those of sFlt-1 in HM (r = 0.68, p = 0.0029). Immunohistochemical analysis revealed that the expression levels of LIGHT were increased in HM placentas as compared with controls, and LIGHT and sFlt-1 were co-localized in the trophoblast cells of HM. In vitro studies using primary syncytiotrophoblast cells demonstrated that LIGHT directly induced sFlt-1 expression in trophoblast cells. Our results indicated that elevated LIGHT in the trophoblast cells of hydatidiform mole induces sFlt-1, which might underlie the pathogenic mechanism of early-onset preeclampsia developing secondary to molar pregnancies.

Secretory leukocyte protease inhibitor (SLPI) and progranulin (PGRN) are secretory proteins with an anti-inflammatory property. Their involvement in cervical remodeling in pregnant uterus is not yet elucidated. Thus, this study aimed to explore the significance of SLPI and PGRN in the maintenance of pregnancy by investigating the factors associated with their expression levels at the cervix. Concentrations of SLPI and PGRN proteins were measured in cervical mucus samples collected from asymptomatic pregnant women at 24-26 weeks of gestation (n = 166). The concentrations of those molecules were analyzed with clinical parameters related to risk for preterm delivery (PD). In pregnant mice, we evaluated the effect of lipopolysaccharide-induced inflammation and progesterone effect modulation on cervical mRNA expression of SLPI and PGRN. The cervical PGRN level was significantly lower in women with short cervix (

To evaluate the potential impact of adenomyosis on the pregnancy outcomes by retrospectively investigating adenomyosis-complicated pregnancy cases.We performed a retrospective case-control study. Forty-nine singleton pregnancy cases complicated with adenomyosis were included in this study. The controls (n = 245) were singleton pregnant women without adenomyosis and were frequency matched to adenomyosis cases by age, parity, and the need for assisted reproductive technology for this conception. The incidence of obstetrical complications and delivery and neonatal outcomes were examined.Patients in the adenomyosis group were significantly more likely to have a second trimester miscarriage (12.2% versus 1.2%, odds ratio (OR): 11.2, 95% confidence interval (95% CI): 2.2-71.2), preeclampsia (18.3% versus 1.2%, OR: 21.0, 95% CI: 4.8-124.5), placental malposition (14.2% versus 3.2%, OR: 4.9, 95% CI: 1.4-16.3), and preterm delivery (24.4% versus 9.3%, OR: 3.1, 95% CI: 1.2-7.2), compared with the control group.Adenomyosis was associated not only with an increased incidence of preterm delivery, as previously reported, but also with an increased risk of second trimester miscarriage, preeclampsia, and placental malposition, which could lead to poor perinatal outcomes.

Background: Insufficient oxygen supply is associated with the pathophysiology of fetal growth restriction (FGR). Although the erythrocyte (RBC) is the most abundant and only cell type to deliver oxygen, its function and regulatory mechanism in FGR remains unknown. Recently, adenosine uptake by equilibrative nucleoside transporter 1 (ENT1), a key adenosine transporter expressed in RBCs, was reported to be crucial for RBCs to deliver oxygen. We aimed to investigate the involvement of RBCs' oxygen delivering capacity in maintaining fetal growth by focusing on RBC ENT1. Methods and Results: The mating strategy was to delete ENT1 only on the maternal RBCs but not in the placentas or fetuses to assess the effect of maternal RBC ENT1 on fetal growth. Specifically, EpoR-Cre+ (EPO) female mouse was used as a control and Ent1f/f-EpoR-Cre+ (E1FE) female mouse as an experimental mouse and mated with WT male mouse. As a result, E1FE dams showed FGR phenotype with reduction of 12.9% in fetal weight compared to EPO group. The maternal RBCs showed decrease in p50 and 2,3-BPG in E1FE, indicating decreased oxygen delivery in E1FE RBCs. To determine the molecular basis underlying the FGR phenotype seen in EIFE dams, we conducted a metabolomics screening of the RBCs isolated from controls and EIFE dams. It showed that adenosine metabolism inside the RBCs is the most impacted pathway. Specifically, it showed decrease in adenosine, AMP, and hypoxanthine, but adenine, ADP, and ATP did not show any reduction, implicating that ENT1-mediated uptake of adenosine is largely converted to AMP. We then incubated either WT or ENT1 KO RBCs with isotopically 13C15N labeled adenosine and traced the metabolism of intracellular adenosine derived from labeled adenosine. Indeed, adenosine was rapidly phosphorylated to AMP upon uptake, and 13C15N labeled AMP levels were lower in the ENT1 KO RBCs compared to controls. These findings provide evidence that 1) the most affected metabolic pathway in the RBCs of EIFE dam is adenosine metabolism; 2) ENT1-mediated uptake of extracellular adenosine is largely converted to AMP but not ATP. We hypothesized that decreased AMP/ATP ratio underlies the reduced 2,3-BPG production by lowering AMPK activity and subsequently decreasing BPG mutase (BPGM) activity. We measured AMPK phosphorylation and BPGM activity in the RBCs from E1FE and EPO dams. Both AMPK and BPGM activity were decreased in RBCs of E1FE dams compared to controls. Thus, we conclude that i) adenosine derived from uptake via ENT1 is largely converted to AMP; ii) lack of maternal RBC ENT1 lowers AMP/ATP ratio and activity of AMPK and BPGM in maternal RBC. We conducted immunofluorescence staining to assess hypoxia in the placentas, and confirmed the increased expression of HIF-1α in the placentas from E1FE dams. To determine functional changes of these placentas, we conducted metabolomics profiling in both the placenta and maternal plasma. Of all the metabolites altered, amino acids (AA) were the most reduced metabolites in E1FE placentas. In contrast, AA were the most accumulated in maternal plasma. We then injected isotopically labelled 13C15N AA mix in both controls and EIFE dams 24 hours prior to sacrifice. 13C15N AA level was decreased in the placentas in EIFE compared to the controls, while it was accumulated in plasma of EIFE, indicating reduced AA transporter function in the placentas of EIFE. Finally, we performed real time PCR to quantify the mRNA of the known main transporters of AA in the mouse placenta. It showed reduction of LAT1 mRNA in E1FE placenta, where there was no difference in LAT2, SNAT1, or SNAT2. Western blot of the placenta lysates confirmed the expression of LAT1 was indeed reduced. To validate our mouse finding and determine if HIF-1α elevation directly induces LAT1 mRNA in humans, we treated cultured human trophoblast cell line (HTR-8/SVneo cells) with or without DMOG, a cell permeable prolyl-4-hydroxylase inhibitor. After confirming DMOG upregulated HIF-1α, we found stabilized HIF-1α induced LAT1 mRNA levels. Thus, we conclude that elevated HIF-1α underlies the reduction of LAT1 mRNA in cultured human trophoblasts. Conclusion: Our findings suggest that maternal RBCs' oxygen delivering capacity mediated by ENT1 is essential for maintaining adequate placental oxygenation to support fetal growth via AA transporter function. Strategies to improve RBCs' function to deliver oxygen may provide new therapeutic possibilities for FGR. Figure Disclosures No relevant conflicts of interest to declare.

In human pregnancy, CD14 + decidual macrophages (DMs) are the dominant professional antigen-presenting cells in the decidua, comprising 20–30% of the local leukocyte population. Although the relevance of DMs to feto-maternal immune tolerance has been described, the molecular mechanisms underlying these functions have not been fully elucidated. B7-H1, a costimulatory ligand in the B7 family, negatively modulates T cell activity by binding to its corresponding receptor, PD-1. The present study aimed to investigate the functional significance of costimulatory interactions between DMs and T cells, with a particular focus on B7-H1:PD-1 signaling. An analysis of the expression profile of B7 ligands on human DMs revealed that B7-H1 was present on DMs isolated from early but not term pregnancies. B7-H1 was not expressed on the peripheral monocytes (PMs) of pregnant women. In response to IFN-γ, B7-H1 expression was induced on PMs and was enhanced on DMs, suggesting that this cytokine might be a key factor in the control of B7-H1 expression in the decidua. The majority of decidual T cells were noted to exhibit robust expression of PD-1, whereas the expression was limited to a small subpopulation of circulating T cells. Functional assays demonstrated that DMs are able to suppress T cell IFN-γ production via B7-H1:PD-1 interactions. This suppressive property was not observed for PMs, which lack B7-H1. B7-H1 on DMs may function as a key regulator of local IFN-γ production and thereby contribute to the development of appropriate maternal immune responses to the fetus in early pregnancy.

Citation Iwasawa Y, Kawana K, Fujii T, Schust DJ, Nagamatsu T, Kawana Y, Sayama S, Miura S, Matsumoto J, Adachi K, Hyodo H, Yamashita T, Kozuma S, Taketani Y. A possible coagulation-independent mechanism for pregnancy loss involving β2glycoprotein 1-dependent antiphospholipid antibodies and CD1d. Am J Reprod Immunol 2012; 67: 54–65 Problem β2glycoprotein1 (β2GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-β2GP1 antibodies can interact with phosphatidylserine (PS)-bearing CD1d on trophoblast cells and induce local inflammation. Methods CD1d-bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross-linking. Cytokine production during co-culture of decidual lymphocytes with CD1d-bearing cells was also examined. Results Trophoblast surface-expressed CD1d forms a complex with PS-bound β2GP1. Anti-β2GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-β2GP1 mAb to co-cultures resulted in a three-fold increase in IL12p70 secretion. IFNγ secretion from decidual lymphocytes was also induced during co-culture with anti-β2GP1 mAbs. Conclusions β2GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism.

Problem This study explored the possibility of evaluating cervical maturation using swabbed cervical cell samples at term pregnancy, and aimed to develop a novel approach to predict labor onset. Method of study Women with uncomplicated pregnancies (n=117 from 62 women at term pregnancy) were recruited. Messenger RNA expression levels of cervical cells for ten genes were quantified by qPCR. Principal component analysis (PCA) was conducted, and principal components that significantly contributed to the prediction of days to delivery were determined. Results PCA demonstrated that 76% of the expression information from the ten genes can be represented by three principal components (PC1-3). By the multiple regression analysis, PC2 and Bishop score but not PC1 or PC3 were significant variables in the prediction of days to delivery. Conclusion These findings support the concurrent assessment of multiple gene activities in cervical cells as a promising approach to predict the initiation of labor.

Problem Elafin and secretory leukocyte peptidase inhibitor (SLPI) are unique among antimicrobial peptides (AMPs). This study aimed to determine the expression levels of these AMPs at the cervix during pregnancy and to investigate their association with preterm labor. Method of study Cervical epithelial cells were swabbed from normal pregnant women to evaluate the physiological expression of elafin and SLPI. Cross-sectional analysis was conducted to compare cervical expression levels for SLPI and elafin among three women's groups, controls (n = 26), women with threatened preterm labor who delivered at term (t-TPL, n = 23) and TPL who ended in preterm labor (p-TPL, n = 19). Results Elafin and SLPI proteins were detected in the squamous and glandular cells of the cervix. Cervical SLPI expression levels increased over the course of pregnancy, whereas elafin levels remained unchanged. Cervical mRNA expression levels of elafin and SLPI were significantly higher in p-TPL compared with t-TPL and control groups. Conclusion Constitutive expression of elafin and SLPI in cervical cells during pregnancy suggests their essential roles in local tissue homeostasis and immune defense. The elevations in cervical elafin and SLPI expression in the women with preterm delivery might reflect the local response to the pathogen invasion into the cervix preceding preterm labor.

PROBLEM β(2) glycoprotein1 (β(2) GP1)-dependent antiphospholipid antibodies (aPL) increase the risk for recurrent pregnancy loss. We address whether anti-β(2) GP1 antibodies can interact with phosphatidylserine (PS)-bearing CD1d on trophoblast cells and induce local inflammation. METHODS CD1d-bearing choriocarcinoma cells were used in flow cytometry and immunoprecipitation experiments. CD1d-mediated cytokine induction was assessed using antibody cross-linking. Cytokine production during co-culture of decidual lymphocytes with CD1d-bearing cells was also examined. RESULTS Trophoblast surface-expressed CD1d forms a complex with PS-bound β(2) GP1. Anti-β(2) GP1 mAb cross-linking causes IL12p70 release from CD1d-bearing cells. IL12p70 release from CD1d-bearing trophoblast cells was also induced during co-culture with human decidual lymphocytes. The addition of anti-β2GP1 mAb to co-cultures resulted in a three-fold increase in IL12p70 secretion. IFNγ secretion from decidual lymphocytes was also induced during co-culture with anti-β2GP1 mAbs. CONCLUSIONS β(2) GP1-dependent IL12 release from CD1d-bearing trophoblast in the presence of aPL may link the antiphospholipid syndrome to pregnancy loss via an inflammatory mechanism.