Inhibitory effects of amniotic fluid on the activated protein C anticoagulation system in maternal plasma.

Pulmonary thromboembolism (PTE) is one of the leading causes of maternal mortality. We previously reported that possible contamination of amniotic fluid (AF) into maternal circulation accelerated thrombin production and activated platelet function in maternal blood through the extrinsic pathway, which may be associated with the high incidence of PTE in early puerperium. However, it remains unclear whether the maternal anticoagulation system, e.g., the activated protein C (APC) pathway, contributes to the hypercoagulable condition induced by AF. Our previous study using an endogenous thrombin potential (ETP)-based assay revealed that sensitivity to APC was reduced during the postpartum first day, i.e., immediately after delivery, when parturients were supposed to be exposed to AF. Our aim is to investigate the susceptibility of maternal plasma to APC when mixed with AF. We collected plasma from 51 pregnant females and mixed with AF as well as APC. APC-sensitivity ratio (APC-sr) was calculated using the ETP-based assay. Addition of AF to maternal plasma showed a significant increase of ETP in the presence of APC. APC-sr was significantly increased, indicating decreased sensitivity to APC, after AF mixture to maternal plasma. The present APC-sr difference with AF contamination was smaller than that we reported previously in venous thromboembolism cases. The inhibitory effects of AF on the APC anticoagulation pathway may contribute, at least partly, to further promotion of thrombin production induced by AF. Combined with other classical thrombophilic risk factors, the present findings support possible involvements of AF exposure in the high incidence of PTE in early puerperium.

Term Newborns with relatively low Tissue Oxygen Saturation Levels soon after Birth are predisposed to Neonatal Respiratory Disorders in Low-risk, Elective Cesarean Sections.

Background: Neonatal respiratory disorders, such as transient tachypnea of the newborn and respiratory distress syndrome, occur frequently after an elective cesarean delivery. Although conventional pulse oximetry is recommended for neonatal resuscitation, it often requires several minutes after birth to obtain a reliable signal. In a previous study, we used novel tissue oximetry equipment to detect fetal and neonatal early tissue oxygen saturation (StO2) before and immediately after vaginal delivery. Therefore, we hypothesized that low neonatal StO2 levels measured by tissue oximetry may lead to neonatal respiratory disorder after a scheduled cesarean delivery. Hence, this study aimed to evaluate the StO2 levels measured by tissue oximetry in neonates with or without a respiratory disorder subsequently diagnosed after an elective cesarean delivery. Materials and methods: We enrolled 78 pregnant Japanese women who underwent an elective cesarean section at ≥36 weeks' gestation. After combined spinal and epidural anesthesia were administered to the mother, fetal StO2 levels were measured by tissue oximetry using an examiner's finger-mounted sensor during a pelvic examination immediately before the cesarean section. We measured the neonatal StO2 levels at 1, 3, and 5 minutes after birth and retrospectively compared the fetal and neonatal StO2 levels with the incidence of subsequent diagnoses of neonatal respiratory disorders. Results: The data of StO2 levels in 35 neonates were collected. Seven neonates (respiratory disorder (RD) group) were subsequently diagnosed with respiratory disorders by neonatal medicine specialists, whereas the 28 remaining neonates (NR group) were not. The median fetal StO2 (interquartile range) of the RD and NR groups was 52.0% (41.8%-60.8%) and 42.5% (39.0%-52.5%), respectively (P = 0.12). The median neonatal StO2 (interquartile range) of the RD and NR groups at 1 minute after birth was 42.0% (39.0%-44.0%) and 46.0% (42.0%-49.0%), respectively (P = 0.091). At 3 minutes after birth, the median neonatal StO2 (interquartile range) of the RD and NR groups was 41.0% (39.0%-46.0%) and 47.0% (44.3%-53.5%), respectively (P = 0.004). Finally, at 5 minutes after birth, the median neonatal StO2 (interquartile range) of the RD and NR groups was 45.0% (44.0%-52.0%) and 54.0% (49.3%-57.0%), respectively (P = 0.007). Conclusions: The StO2 values in the RD group were lower than those in the NR group at 3 and 5 minutes after birth, suggesting that neonates with low StO2 levels soon after birth may be predisposed to clinically diagnosed neonatal respiratory disorders.

Consumptive Coagulopathy Involving Amniotic Fluid Embolism: The Importance of Earlier Assessments for Interventions in Critical Care.

OBJECTIVES: Amniotic fluid embolism is a rare disease that induces fatal coagulopathy; however, due to its rarity, it has not yet been examined in detail. The strict diagnostic criteria by Clark for amniotic fluid embolism include severe coagulopathy complicated by cardiopulmonary insufficiency, whereas the Japanese criteria also include postpartum hemorrhage or Disseminated Intravascular Coagulation in clinical practice. Amniotic fluid embolism cases with preceding consumptive coagulopathy may exist and are potential clinical targets for earlier assessments and interventions among amniotic fluid embolism cases fulfilling the Japanese, but not Clark criteria. The present study was performed to compare coagulopathy in the earlier stage between the amniotic fluid embolism patients diagnosed by Clark criteria (Clark group, n = 6), those by the Japanese criteria (Non-Clark group, n = 10), and peripartum controls and identify optimal clinical markers for earlier assessments of amniotic fluid embolism-related consumptive coagulopathy. DESIGN: Retrospective case-control study. SETTING: A single university-based center. Our amniotic fluid embolism registry program has accumulated clinical information and blood samples since 2003. PATIENTS: Amniotic fluid embolism patients in the Clark and Non-Clark groups between 2009 and 2017 and peripartum controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical information was collected on hemoglobin levels, platelet counts, and coagulation- and fibrinolysis-related variables. Fibrinolytic parameters were also measured and compared among the three groups before blood transfusion. Fibrinogen levels in all patients in the Clark group and most in the Non-Clark group decreased earlier than hemoglobin levels, which was consistent with the high hemoglobin/fibrinogen ratio and, thus, is a promising clinical marker for the earlier assessment of amniotic fluid embolism-related consumptive coagulopathy. CONCLUSIONS: Earlier evaluations of consumptive coagulopathy and hyperfibrinolysis using the hemoglobin/fibrinogen ratio following preemptive treatment may reduce the occurrence or prevent the aggravation of severe coagulopathy in amniotic fluid embolism patients.

Comparison of three classification systems of Prepregnancy Body Mass Index with Perinatal Outcomes in Japanese Obese Pregnant Women: A retrospective study at a single center.

In Japan, pregnant women are diagnosed as obese if the prepregnancy body mass index (BMI) is ≥25 kg/m2. However, this is different from other countries. The Institute of Medicine (IOM) classifies prepregnancy BMI as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obese (BMI ≥30 kg/m2). In addition to these four categories, the American College of Obstetricians and Gynecologists (ACOG) classifies prepregnancy BMI as obesity class I (BMI 30.0-34.9 kg/m2), obesity class II (BMI 35.0-39.9 kg/m2), and obesity class III (BMI ≥40 kg/m2). We conducted a retrospective cohort study to compare obstetric outcomes by the three different categorizations in 6,066 pregnant women who gave birth between 2010 and 2019. According to Japanese classification, 668 (11%) pregnant women were classified as obese, and significant odds ratios (OR) were observed for hypertensive disorders of pregnancy (HDP; 3.32), gestational diabetes mellitus (GDM; 3.39), large for gestational age (LGA; 2.91), and macrosomia (4.01). According to the classification of IOM, 474 (7.8%) and 194 (3.1%) were classified as overweight and obese pregnant women, respectively. Specifically, a high OR was observed in obese pregnant women for HDP (5.85) and GDM (5.0). ACOG classification categorized 474 (7.8%) pregnant women as overweight, 141 (2.3%) as obesity class I, 41 (0.6%) as obesity class II, and 12 (0.2%) as obesity class III. In obesity class III, a significantly high OR was observed for HDP (12.89), GDM (8.37), and LGA (5.74). The Japanese classification may be useful for low-risk pregnancies, whereas IOM classification may be applicable to identify high-risk pregnancies. ACOG criteria may be useful for step-wise assessments of HDP and GDM risks in Japanese pregnant women; however, the number of class II and III obese pregnant women was small.

Elevated bradykinin receptor type 1 expression in postpartum acute myometritis: Possible involvement in augmented interstitial edema of the atonic gravid uterus.

AIM: Uterine atony is a major cause of postpartum hemorrhage. We recently proposed a new concept for the histopathophysiology of refractory uterine atony, postpartum acute myometritis (PAM), characterized by acute inflammatory changes with massive stromal edema, increased numbers of complement C5a receptors and diffuse mast cell activation in the myometrium. We herein focused on the possible involvement of the kinin-kallikrein system in the rapid development of interstitial edema in PAM, particularly bradykinin receptor type 1 (B1R), which is up-regulated under inflammatory conditions. The present study investigated B1R expression with uterine interstitial edema in PAM. METHODS: Our institution plays an important role in a Japanese amniotic fluid embolism registry project. We selected PAM cases from uterine samples delivered to us for further analyses between 2012 and 2017. Control tissues were collected during cesarean section and planned hysterectomy. B1R expression was semi-quantitatively measured by immunohistochemistry, while uterine interstitial edema was estimated by semi-quantitative measurements of the alpha smooth muscle actin-negative area using immunohistochemistry. RESULTS: There were 36 and 8 cases in the PAM and control groups, respectively. The alpha smooth muscle actin-negative area was increased in the PAM group, concomitant with the significant up-regulation of B1R expression in uterine smooth muscle cells, vascular endothelial cells, and neutrophils. A positive correlation was observed between these two factors. CONCLUSION: We demonstrated the up-regulated expression of B1R in the myometrium and its positive correlation with histologically estimated interstitial edema, suggesting the contribution of the kinin-kallikrein-B1R system to the development of interstitial edema in PAM cases.

Reevaluation of intrapartum fetal monitoring using fetal oximetry: A review.

AIM: Although several studies reported the measurement of fetal oxygen saturation using fetal pulse oximetry (FPO) for evaluation of the fetal intrapartum condition, a systematic review of the seven randomized controlled trials (RCTs) provided no evidence to support FPO for intrapartum fetal monitoring. In the present review, we re-evaluate an overview for the use of FPO and seven RCTs of FPO. METHODS: We reviewed numerous previous reports on FPO and seven RCTs of intrapartum FPO. RCTs were conducted with the main outcome measure being a reduction in the cesarean section rate. RESULTS: The largest trial with 5341 entries failed to show any reduction. The negative result from this RCT may be explained by the use of a different cutoff value for fetal oxygen saturation compared to the other RCT; in addition, there were differences in the indications for cesarean section due to dystocia and in the definition of non-reassuring fetal status (NRFS). An abnormal FPO value, defined as the fetal oxygen saturation value <30% for at least 10 min, is useful for making a diagnosis of fetal acidosis. A newly developed device, an examiner's finger-mounted tissue oximetry, accurately measures tissue oxygen saturation while overcoming the drawbacks of FPO, such as infection risk and slipping off of the sensor during descent of the fetal head. CONCLUSION: FPO (including the new device) with fetal heart rate monitoring in selected cases of NRFS may reduce the cesarean section rate.

Tissue oxygen saturation levels from fetus to neonate.

AIM: Oxygen saturation during the term of delivery to the first cry, when fetal circulation dynamically changes, has not yet been examined. The aim of this study was therefore to determine whether the continuous measurement of regional tissue oxygen saturation (rSO2 ) from crowning until 5 min after delivery is possible using fetal tissue oximetry with a sensor attached to the examiner's finger. METHODS: Oxygen saturation levels in fetal cranial tissue between the second stage of delivery to crowning and up to 5 min after delivery were measured using fetal tissue oximetry with a sensor attached to the examiner's finger. Thirty-five deliveries were examined, and oxygen saturation was measured in seven infants from delivery of the head until 5 min after birth. Umbilical cord blood gas was measured in all cases. This clinical test was performed under the permission of the Ethics Committee of Hamamatsu University School of Medicine. RESULTS: Average tissue oxygen saturation in the second stage of delivery and at 5 min after delivery were 50.3 ± 16.3% and 56.8 ± 8.46%, respectively. In cases of continuous measurement, average rSO2 for crowning, immediately after delivery, and the first cry was 32.7 ± 9.5%, 30.0 ± 6.6%, and 31.6 ± 5.5%, respectively. CONCLUSION: We herein successfully measured oxygen saturation levels in fetal cranial tissue during crowning, delivery of the head, the first cry, and 5 min after delivery using fetal tissue oximetry with a sensor attached to the examiner's finger.

Examiner's finger-mounted fetal tissue oximetry: a preliminary report on 30 cases.

OBJECTIVE: To describe preliminary experience with a finger-mounted fetal tissue oximetry probe during the 2nd stage of labor. MATERIALS AND METHODS: A total of 30 term pregnant women without pregnancy complications were recruited. We measured fetal tissue oxygen saturation (FtO2) by using a finger-mounted fetal tissue oximetry during cervical examinations in the 2nd stage of labor. The data capturing rate of FtO2 and the interclass correlation coefficient were also examined. The mean FtO2 was compared to the neonatal condition assessed by the levels of umbilical cord blood. RESULTS: FtO2 was obtained in all cases, regardless of wetness, hair color, the part of the fetal head that was exposed, rotation of the fetus, color of amniotic fluid, and caput succedaneum. The mean FtO2 was 65.5%±8.58% in normal neonates [Apgar score >7 (1 min), n=25]. The mean FtO2 was significantly correlated with umbilical cord arterial pH (r=0.52, P=0.0030, n=30), but not with umbilical cord arterial partial pressure of oxygen. The interclass correlation coefficient was 0.94. CONCLUSIONS: Tissue oxygen saturation of the fetal head was obtained easily by the examiner's finger-mounted fetal tissue oximetry.

Randomized double-blind comparison of the effects of intramyometrial and intravenous oxytocin during elective cesarean section.

AIM: Obstetricians sometimes administer intramyometrial oxytocin to stimulate uterine contraction during cesarean section, but its effects have not been well investigated. We performed a randomized, double-blind study to test the hypothesis that a small dose of intramyometrial oxytocin would induce acceptable uterine contractility more quickly and with fewer hemodynamic side-effects than the same dose administered intravenously. METHODS: Forty women with a single fetus at ≥36 weeks of gestational age scheduled for elective cesarean section under spinal anesthesia were randomized to the intravenous and intramyometrial groups to receive oxytocin at 0.07 IU/kg. The drug was administered immediately after umbilical cord clamping. Systolic blood pressure, heart rate, intraoperative blood loss, uterine tone, total amount of intraoperative oxytocin, and additional uterotonic drugs administered in the first 24 h were compared. RESULTS: Maximum uterine contractility was achieved after 2 and 10 min for the intravenous and intramyometrial groups, respectively. The mean hemodynamic parameters of the intramyometrial group were stable. In contrast, the intravenous group showed a reduction in systolic blood pressure after 2-4 min and increased heart rate after 1-2 min. Intraoperative blood loss, total oxytocin dose, and frequency of additional uterotonic drugs were comparable between the two groups. CONCLUSION: Although intraoperative blood loss was comparable, a small dose of intramyometrial oxytocin was inappropriate to obtain a prompt and acceptable uterine contraction during cesarean section.

Measurement of maternal cerebral tissue hemoglobin on near-infrared time-resolved spectroscopy in the peripartum period.

AIM: To measure cerebral tissue hemoglobin in uncomplicated and complicated pregnant women during the peripartum period. METHODS: Time-resolved spectroscopy (TRS-20) can measure absolute concentration of oxygenated, deoxygenated, and total tissue hemoglobin based on the transit time of individual photons. Therefore, we used TRS-20 to measured tissue hemoglobin in the hemi-prefrontal lobes of normotensive pregnant women with (n = 51) or without (n = 19) epidural anesthesia, hypertensive pregnant women with pre-eclampsia (n = 10), a pregnant woman with acute onset of hypertension soon after delivery, and a hypertensive woman after hemorrhagic stroke in delivery. RESULTS: Cyclic labor concomitant with intra-abdominal pressure caused synergistic elevation in cerebral tissue hemoglobin. In contrast, epidural anesthesia reduced the amplitude of the cyclic increase of cerebral tissue hemoglobin in normotensive pregnant women. Hypertension in labor due to pre-eclampsia increased the amplitude of synergistic elevation of cerebral tissue hemoglobin caused by cyclic labor and intra-abdominal pressure. A prolonged high basal level of cerebral tissue hemoglobin was observed in a case of acute onset of hypertension soon after delivery. A decrease in cerebral tissue hemoglobin in the hemi-prefrontal lobe was observed in a woman 2 h after the onset of hemorrhagic stroke in labor. CONCLUSIONS: TRS-20 can detect specific changes in maternal cerebral tissue hemoglobin level in response to physiological and pathophysiological changes in delivery. Thus, it represents a promising new conventional tool for maternal cerebral monitoring in the peripartum period.

C1 esterase inhibitor activity in amniotic fluid embolism.

OBJECTIVES: Amniotic fluid embolism exhibits activation of the complement system and the kallikrein-kinin and coagulofibrinolytic systems. C1 esterase inhibitor is a major inhibitor of C1 esterase and can inhibit plasma kallikrein and also factors XIIa and XIa. Its activity has been shown to be significantly lower in pregnancy and labor than in the nonpregnant state. The purpose of this study was to determine C1 esterase inhibitor activity levels in amniotic fluid embolism. DESIGN: Retrospective study. SETTING: A single university-based center. PATIENTS: One hundred six cases with amniotic fluid embolism in a total of 194 singleton pregnant women between January 2010 and December 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred six cases of amniotic fluid embolism had applied to the Japan amniotic fluid embolism registration center in Hamamatsu University School of Medicine between January 2010 and December 2011. In amniotic fluid embolism cases, 85 cases were nonfatal and 21 cases were fatal. Eighty-eight women who delivered without amniotic fluid embolism were regarded as a control. C1 esterase inhibitor activity levels were significantly lower in amniotic fluid embolism patients (30.0% ± 1.8%) than in control women (62.0% ± 2.0%) (p < 0.0001). C1 esterase inhibitor activity levels in fatal amniotic fluid embolism cases (22.5% ± 3.4%) were significantly lower than those in nonfatal amniotic fluid embolism cases (32.0% ± 2.1%) (p < 0.05). CONCLUSIONS: These results demonstrated that low C1 esterase inhibitor activity levels were closely associated with the pathogenesis of amniotic fluid embolism suggesting that C1 esterase inhibitor activity levels have potential as a prognosis factor of amniotic fluid embolism.

Comparison between placental gene expression of 11ß-hydroxysteroid dehydrogenases and infantile growth at 10 months of age.

AIM: The local expression of two isoenzymes of 11ß-hydroxysteroid dehydrogenase, type 1 (11ßHSD-1) and type 2 (11ßHSD-2), regulates the access of glucocorticoid hormones to their target cells. Reports on the association between the placental expression of 11ßHSD and infantile growth are limited. The aim of the present study was to investigate if the placental gene expression of 11ßHSD affects infantile growth at 10 months of age. METHODS: Placentas and umbilical venous cord blood were obtained from 42 singleton cases of cesarean deliveries between 31 and 40 weeks of gestation at Hamamatsu University Hospital between March 2009 and June 2010. The gene expression of both 11ßHSD-1 and 11ßHSD-2 was measured by quantitative reverse transcription polymerase chain reaction. Adiponectin and leptin levels in umbilical cord blood were measured using enzyme-linked immunoassay. RESULTS: 11ßHSD-1 and 11ßHSD-2 gene expression in human placentas did not correlate with bodyweight or the ponderal index (PI) at 10 months of age, whereas the gene expression of 11ßHSD-1, but not 11ßHSD-2, correlated with birthweight as well as PI at birth. Adiponectin levels in umbilical cord blood significantly correlated with the placental gene expression of 11ßHSD-1 as well as bodyweight and PI at 10 months of age, although no direct correlation was observed between them. CONCLUSION: No direct correlation was observed between the placental gene expression of 11ßHSD and infantile growth at 10 months of age. However, the placental gene expression of 11ßHSD-1 may be indirectly connected with infantile growth via adiponectin-associated metabolic regulation represented by adiponectin levels in umbilical cord blood.

Postpartum acute myometritis suppresses expression of contraction-associated proteins in the gravid uterus.

Uterine atony is a major contributor to postpartum hemorrhage. We previously proposed the novel histological concept of postpartum acute myometritis (PAM) to elucidate the pathophysiology of uterine atony. This concept involves the infiltration of macrophages and neutrophils, as well as mast cell and complement activation in the myometrium. However, the pathological mechanism underlying uterine atony in the context of PAM remains unclear. Herein, we focused on uterine contraction-associated proteins (CAPs) including connexin 43 (Cx43), oxytocin receptors (OXR), prostaglandin receptors EP1, EP3, FP, and protease-activated receptor (PAR)-1. This follow-up study aimed to compare CAP expression between PAM and control groups. We selected 38 PAM subjects from the cases enrolled in our amniotic fluid embolism registry between 2011 and 2018. Control tissues from 10 parturients were collected during cesarean section. We stained the myometrial tissues with the following CAP markers, inflammatory cell markers, and other markers: Cx43, OXR, EP1, EP3, FP, PAR-1, C5a receptor, tryptase, neutrophil elastase, CD68, ß-actin, and Na+/K+-ATPase. The immunostaining-positive areas of Cx43, OXR, EP1, EP3, and FP standardized by ß-actin in the PAM tissue were significantly smaller than in the control group, whereas those of PAR-1 and Na+/K+-ATPase increased significantly in the PAM group. The Cx43- and OXR-positive areas correlated negatively with the immunostaining-positive cell numbers of CD68 and tryptase with halo, respectively. PAM may impair individual and synchronized myocyte contraction, leading to uterine atony refractory to uterotonics. Further cell-based studies are needed to elucidate the molecular mechanism by which inflammatory cells suppress CAP expression.

Comparative analysis of hyperfibrinolysis with activated coagulation between amniotic fluid embolism and severe placental abruption.

Amniotic fluid embolism (AFE) and placental abruption (PA) are typical obstetric diseases associated with disseminated intravascular coagulation (DIC). AFE is more likely to be complicated with enhanced fibrinolysis than PA. AFE may have an additional mechanism activating fibrinolytic cascade. We aimed to compare the coagulation/fibrinolysis factors among AFE, PA, and peripartum controls. We assessed AFE cases registered in the Japanese AFE Registry, and PA cases complicated with DIC (severe PA) and peripartum controls recruited at our hospital. The following factors in plasma were compared: prothrombin fragment 1 + 2 (PF1 + 2), plasmin α2-plasmin inhibitor complex (PIC), tissue factor (TF), tissue plasminogen activator (tPA), annexin A2 (AnnA2), total thrombin activatable fibrinolysis inhibitor (TAFI) including its activated form (TAFIa), and plasminogen activator inhibitor-type 1 (PAI-1). PF1 + 2 and PIC were markedly increased in both AFE (n = 27) and severe PA (n = 12) compared to controls (n = 23), without significant difference between those disease groups; however, PIC in AFE showed a tendency to elevate relative to PF1 + 2, compared with severe PA. AFE had significantly increased tPA and decreased total TAFI levels compared with severe PA and controls, which might be associated with further plasmin production in AFE and underlie its specific fibrinolytic activation pathway.

Reduction in maternal complement levels during delivery by cesarean section.

AIM: Primary elective cesarean sections are being carried out in considerable numbers in both developed and developing countries; however, little information is available concerning differences in maternal physiological responses associated with the mode of delivery. The aim of the present study was to compare the changes in the maternal complement and contact systems between delivery by cesarean section and vaginal delivery at term. METHODS: Maternal levels of complement 3 (C3), complement 4 (C4) and coagulation factor XII (FXII) were measured during primary elective cesarean (n=70) and vaginal (n=140) deliveries. RESULTS: The C3, C4 and FXII levels decreased significantly during delivery by cesarean section and remained low for two hours. By contrast, C3 levels, but not C4 levels, increased temporally during normal term delivery and FXII levels decreased two hours later. CONCLUSIONS: The changes in maternal C3, C4 and FXII levels during cesarean section were very different from those during delivery at term, suggesting that the maternal complement and contact systems respond differently.

Placental pathology predicts infantile neurodevelopment.

The aim of present study was to investigate the association of placental pathological findings with infantile neurodevelopment during the early 40 months of life. 258 singleton infants were enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) whose placentas were saved in our pathological division. To assess the infantile neurodevelopment, we used Mullen Scales of Early Learning (gross motor, visual reception, fine motor, receptive language, expressive language) at 10, 14, 18, 24, 32, and 40 months. For obtaining placental blocks, we carried out random sampling and assessed eleven pathological findings using mixed modeling identified 'Accelerated villous maturation', 'Maternal vascular malperfusion', and 'Delayed villous maturation' as significant predictors of the relatively lower MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. On the other hand, 'Avascular villi', 'Thrombosis or Intramural fibrin deposition', 'Fetal vascular malperfusion', and 'Fetal inflammatory response' were significant predictors of the relatively higher MSEL composite scores in the neurodevelopmental milestones by Mullen Scales of Early Learning. In conclusion, the present study is the first to report that some placental pathological findings are bidirectionally associated with the progression of infantile neurodevelopment during 10-40 months of age.

Comparative Analysis of Gene Expression Profiles in the Adipose Tissue of Obese Adult Mice With Rapid Infantile Growth After Undernourishment In Utero.

Rapid infantile growth (RG) markedly increases the risk of obesity and metabolic disorders in adulthood, particularly among neonates born small. To elucidate the molecular mechanisms by which RG following undernourishment in utero (UN) contributes to the deterioration of adult fat deposition, we developed a UN mouse model using maternal energy restriction, followed by RG achieved by adjustments to 4 pups per litter soon after birth. A high-fat diet (HFD) was fed to weaned pups treated or not (Veh) with tauroursodeoxycholic acid (TU). UN-RG pups showed the deterioration of diet-induced obesity and fat deposition, which was ameliorated by TU. We performed a microarray analysis of epididymal adipose tissue and two gene enrichment analyses (NN-Veh vs UN-RD-Veh and UN-RG-Veh vs UN-RG-TU). The results obtained identified 4 common gene ontologies (GO) terms of inflammatory pathways. In addition to the inflammatory characteristics of 4 GO terms, the results of heatmap and principal component analyses of the representative genes from 4 GO terms, genes of interest (GOI; Saa3, Ubd, S100a8, Hpx, Casp1, Agt, Ptgs2) selected from the 4 GO terms, and immunohistochemistry of macrophages collectively suggested the critical involvement of inflammation in the regulation of fat deposition in the responses to UN and TU. Therefore, the present results support the 'Developmental Origins of Metaflammation', the last word of which was recently proposed by the concept of metabolic disorders induced by low-grade systemic inflammation.

A case of spontaneous rupture of a uterine superficial varicose vein in midgestation.

A 25-year-old gravida two, nulliparous pregnant woman complained of a sudden onset of severe pain in the right lateral abdominal area and went to hospital at 28 weeks and 5 days' gestation. Since cyclic uterine contractions were observed, a diagnosis of preterm labor was made and tocolysis was carried out by the continuous venous infusion of ritodorine. She was transferred to Hamamatsu University Hospital and an emergency cesarean section was carried out due to non-reassuring fetal status. A hemoperitoneum of 850 mL was observed in the peritoneal cavity and an immature male baby weighing 1140 g was born. There was bleeding from a ruptured superficial varicose vein in the right lateral portion of the uterus, which was stopped by compression and the attachment of oxidized cellulose cotton. The clinical management and differential diagnosis were discussed.

Acute inflammation in the uterine isthmus coincides with postpartum acute myometritis in the uterine body involving refractory postpartum hemorrhage of unknown etiology after cesarean delivery.

Uterine atony is a major cause of postpartum hemorrhage. We recently proposed the new histological concept of postpartum acute myometritis (PAM) for the pathophysiology of refractory uterine atony of unknown etiology, which is characterized by the diffuse activation of mast cells and the complement system as well as the massive infiltration of macrophages and neutrophils into the uterine body. We herein focused on the uterine isthmus just adjacent to the body. The isthmus becomes significantly elongated throughout pregnancy. It is composed of myocytes and fibroblasts with an extracellular matrix that forms a passive lower segment during labor. The aim of this study was to histologically examine the uterine isthmus in cases of PAM in the uterine body. Under the amniotic fluid embolism-registry program in Japan, we selected PAM cases from uterine samples obtained by cesarean hysterectomy and delivered to us for analyses between 2011 and 2017. Control tissues were collected during elective cesarean section. We investigated the isthmus tissues of these cases and performed immunohistochemistry for inflammatory cell markers, i.e. neutrophil elastase, mast cell tryptase, CD68, CD3, and C5a receptor (C5aR). The numbers of tryptase-positive degranulating mast cells, elastase-positive neutrophils, CD68-positive macrophages, and C5aR-positive cells in the isthmus were significantly higher in uteri with PAM in the body than in controls without PAM. CD3 was negative in both groups. In conclusion, inflammation and an anaphylactoid reaction were histologically detected not only in the uterine body, but in the isthmus among cases of refractory PPH of unknown etiology after cesarean section.

The fetal/placental weight ratio is associated with the incidence of atopic dermatitis in female infants during the first 14 months: The Hamamatsu Birth Cohort for Mothers and Children (HBC Study).

BACKGROUND: Among atopic diseases, atopic dermatitis is the most common allergic disease in children and influences both infantile and parental quality of life. OBJECTIVE: The present study investigated the sex-specific relationship between the fetal/placental weight ratio and The incidence of atopic dermatitis in infants during the first 14 months of life. METHODS: Study participants were 922 infants (462 female and 460 male) from singleton pregnancies enrolled in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study) after the exclusion of 298 with missing data on atopic dermatitis. The enrollment of infants with atopic dermatitis was based on a positive response from parents regarding whether a physician had ever diagnosed their child with atopic dermatitis by 14 months of age. The two-sample Wilcoxon rank-sum test or χ2 test was adopted for descriptive analyses where appropriate. Unadjusted odds ratios and 95% confidence intervals for the infantile incidence of atopic dermatitis were compared using logistic regression analyses. RESULTS: Maternal and perinatal factors did not correlate with the incidence of infantile atopic dermatitis. Fetal/placental weight ratio, but not birth or placental weight, correlated with the incidence of atopic dermatitis in female, but not male, infants. A correlation was still observed after adjustments for maternal allergies, gestational age at birth, maternal smoking during pregnancy, and household income at birth (odds ratio: 1.57; 95% confidence interval, 1.05-2.33). CONCLUSION: We speculated that the intrauterine fetal environment, represented by a relatively small placenta, programs a predisposition in only female infants to atopic dermatitis during the first 14 months of life.