HIF-1α is essential for the augmentation of myometrial contractility during labor†.

Uterine contraction is crucial for a successful labor and the prevention of postpartum hemorrhage. It is enhanced by hypoxia; however, its underlying mechanisms are yet to be elucidated. In this study, transcriptomes revealed that hypoxia-inducible factor-1alpha was upregulated in laboring myometrial biopsies, while blockade of hypoxia-inducible factor-1alpha decreased the contractility of the myometrium and myocytes in vitro via small interfering RNA and the inhibitor, 2-methoxyestradiol. Chromatin immunoprecipitation sequencing revealed that hypoxia-inducible factor-1alpha directly binds to the genome of contraction-associated proteins: the promoter of Gja1 and Ptgs2, and the intron of Oxtr. Silencing the hypoxia-inducible factor-1alpha reduced the expression of Ptgs2, Gja1, and Oxtr. Furthermore, blockade of Gja1 or Ptgs2 led to a significant decrease in myometrial contractions in the hypoxic tissue model, whereas atosiban did not remarkably influence contractility. Our study demonstrates that hypoxia-inducible factor-1alpha is essential for promoting myometrial contractility under hypoxia by directly targeting Gja1 and Ptgs2, but not Oxtr. These findings help us to better understand the regulation of myometrial contractions under hypoxia and provide a promising strategy for labor management and postpartum hemorrhage treatment.

Effects of skin-to-skin contact on afterpain and postpartum hemorrhage: A randomized controlled trial.

This study determined the effects of skin-to-skin contact between the mother and the infant during the third stage of labor on postpartum hemorrhage and pain. This assessor-blinded randomized controlled trial was conducted with primiparous women. Skin-to-skin contact interventions between the infants and their mothers occurred for 30 min after birth (n = 34), whereas the infants in the control group were provided routine care (n = 34). Data were gathered using a Personal Information Form, the Visual Analog Scale-Pain, postpartum bleeding follow-up bags, and records of blood oxytocin and beta endorphin levels. There was no significant difference in beta-endorphin levels in both groups (p = 0.771), whereas it was determined that the 30th min oxytocin level was significantly higher in the intervention group (The Visual Analog Scale-Pain score at the postpartum sixth hour was significantly lower in the intervention group. It was found that skin-to-skin contact made at the third stage of labor reduced the amount of postpartum hemorrhage. The results of this study suggested that skin-to-skin contact intervention may have beneficial effects on postpartum pain and postpartum hemorrhage in the early postpartum period.

Two Zn(II)-based Coordination Polymers: Fe3+ Ion and Prevention Activity Detection On Postpartum Hemorrhage By Regulating Anticoagulant Factor Activity.

Two new Zn(II)-based coordination polymers {[Zn3(L1)6(H2O)]∙(H2O)4}n (1, HL1 = 4-(tetrazol-5-yl)phenyl-4,2':6',4″-terpyridine) and [Zn2Cl2(L2)2H2O]n (2, HL2 = 4-([2,2':6',2″'-terpyridin]-4'-yl)benzoic acid) have been successfully prepared using two similar organic ligands with distinct donor groups under similar reaction conditions. The distinct structural features and donor atoms make the two complexes show different water stability, and the complex 1 with good water stability, which can be utilized as the sensor for Fe3+ ion detection in water. The value of Stern-Volmer quenching constant of 1 to the Fe3+ is 5.77 × 104 M- 1, which lies in the top region of the reported CP-based sensors. The mechanism investigation reveals that the energy transfer of resonance from the complex 1 to the Fe3+ ion can account for its fluorescent quenching behavior. The treatment activity of compounds 1 and 2 on the postpartum hemorrhage (PPH) was assessed. First, the cytotoxicity of compounds 1 and 2 on human umbilical vein endothelial cells was assessed with Cell Counting Kit-8 detection kit. Then, to evaluate the prevention of compounds 1 and 2 on the PPH, we conducted the Lowry method and detected the clotting factor IX and anticoagulant factor III contents after the indicated treatment. Finally, the inflammatory response in mice was determined by ELISA method, and the IL-6 and IL-8 levels were determined.

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.

A Common OXTR Risk Variant Alters Regulation of Gene Expression by DNA Hydroxymethylation in Pregnant Human Myometrium.

Postpartum hemorrhage, or excessive bleeding after birth, is a leading cause of maternal morbidity. A major cause of postpartum hemorrhage is uterine atony, tiring of the uterus which leads to ineffective contractions. Uterine contractions depend on oxytocin signaling in the myometrium, which in turn depends on expression of the oxytocin receptor (OXTR). Both genetic and epigenetic factors related to the oxytocin receptor are associated with risk of postpartum hemorrhage, but a mechanism relating these factors to oxytocin receptor activity in myometrium remains unclear. We report a genetic by epigenetic interaction whereby the relationship between DNA hydroxymethylation and OXTR gene expression depends on a common OXTR gene variant (rs53576). We also provide evidence that a similar genetic by epigenetic interaction using blood-derived DNA methylation is associated with relevant clinical outcomes: quantity of oxytocin administration and odds for postpartum hemorrhage. These results provide new avenues for predicting how women will respond to pharmacological agents in the prevention and treatment of postpartum hemorrhage.

The effect of placental removal method on perioperative hemorrhage at cesarean delivery; a randomized clinical trial.

PURPOSE: The aim of this prospective randomized clinical study is to compare whether the removal methods of placenta during cesarean section have an impact on perioperative hemorrhage. METHODS: One hundred women with singleton term pregnancies undergoing elective cesarean section through lower segment transverse incision under general anesthesia were included in this study. They were randomly allocated to two groups according to the type of removal of the placenta from the uterus after childbirth; manually or spontaneously. The main outcome measures were change in hemoglobin levels after cesarean section. The secondary outcomes were operative time, required transfusions and postcesarean endometritis. RESULTS: Fifty patients were randomized to the manual removal group and 50 to the spontaneous group. The demographic characteristics of the two groups were similar. There were no difference in terms of change in hemoglobin levels after cesarean section between two groups (1.6 ± 1.0 and 1.5 ± 1.0, respectively; P = 0.711). In addition, none of the patients required blood transfusion and showed postpartum infections. CONCLUSION: There is not an association between the method of removal of the placenta and postpartum blood loss in cesarean section deliveries.

Effects of maternal subclinical hypothyroidism on obstetrical outcomes during early pregnancy.

BACKGROUND: Maternal hypothyroidism [overt hypothyroidism and subclinical hypothyroidism (SCH)] during early pregnancy is suspected to associate with adverse obstetrical outcomes. AIM: The aim of the present study was to investigate whether maternal SCH during the early stage of pregnancy increase obstetrical complications and whether treatment results in an improvement in these outcomes. SUBJECTS AND METHODS: A total of 756 women in the 1st trimester (≤12 weeks) of pregnancy were enrolled through 10 hospitals in Shenyang from 2007 to 2009. All participants underwent thyroid function testing in early pregnancy and their obstetrical outcomes were studied following delivery. RESULTS: The incidence of spontaneous abortions in the SCH group was higher than the normal TSH group (15.48% vs 8.86%, p=0.03). No significant association was observed between SCH and other obstetrical complications including gestational hypertension, premature delivery, anemia, post-partum hemorrhage, low neonatal Apgar scores and low birth weight. Although levo-T4 (L-T4) treatment decreased the incidence of spontaneous abortions in women with SCH, it was not statistically significant when compared to women who did not receive treatment in the SCH group. None of the 28 women who received L-T4 treatment had premature delivery, low birth weight, hemorrhage, and low Apgar score. CONCLUSIONS: The incidence of spontaneous abortion in pregnant women with SCH increases in early pregnancy.

Fibrinogen may aid in the early differentiation between amniotic fluid embolism and postpartum haemorrhage: a retrospective chart review.

This study aimed to determine whether blood loss and fibrinogen can differentiate amniotic fluid embolism (AFE) from postpartum haemorrhage (PPH). This retrospective case-control study included nine patients with clinical AFE ("AFE group") and 78 patients with PPH managed at our tertiary care perinatal centre between January 2014 and March 2016. Patients meeting the Japanese diagnostic criteria for AFE were stratified into cardiopulmonary collapse-type AFE and disseminated intravascular coagulation (DIC)-type AFE groups. The relationship between blood loss and fibrinogen at onset was examined to compare DIC severity. Vital signs at onset were not significantly different. The AFE group had significantly less blood loss at onset (1506 mL vs 1843 mL, P = 0.0163), significantly more blood loss 2 h post-onset (3304 mL vs 1996 mL, P < 0.0001) and more severe coagulopathy and fibrinolysis. The blood loss/fibrinogen (B/F) ratio at onset was significantly higher in the DIC-type AFE group (23.15 ± 8.07 vs 6.28 ± 3.35 mL dL/mg, P < 0.0001). AFE was complicated by catastrophic DIC irrespective of blood loss at onset. Fibrinogen exhibited the strongest correlation among test findings at onset. The B/F ratio may help differentiate PPH from DIC-type AFE and diagnose clinical AFE, facilitating optimal replacement of coagulation factors during the early stages.

Exploration of the potential mechanism of the Tao Hong Si Wu Decoction for the treatment of postpartum blood stasis based on network pharmacology and in vivo experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Tao Hong Si Wu Decoction (THSWD) is a traditional prescription for blood management in traditional Chinese medicine, THSWD consists of Paeoniae Radix Alba (Paeonia lactiflora Pall.), Rehmanniae Radix Praeparata (Rehmannia glutinosa (Gaertn.) DC.), Angelicae Sinensis Radix (Angelica sinensis (Oliv.) Diels), Chuanxiong Rhizoma (Conioselinum anthriscoides 'Chuanxiong'), Persicae Seman (Prunus persica (L.) Batsch) and Carthami Flos (Carthamus tinctorius L.) at a weight ratio of 3: 4: 3: 2: 3: 2. THSWD is a commonly used prescription in the treatment of postpartum blood stasis disease. AIM OF THE STUDY: To explore the potential mechanism of THSWD for the treatment of postpartum blood stasis using network pharmacology and experimental research. MATERIALS AND METHODS: We extracted the active ingredients and targets in THSWD from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and constructed a herbs-ingredients-targets-disease-network, devised a protein-protein interaction (PPI) network, performed GO enrichment analysis, and performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to discover potential treatment mechanisms. A postpartum blood stasis model was established in rats, and the results of network pharmacology were verified by in vivo experiments. RESULTS: The results showed that 69 potential active ingredients and 207 THSWD target genes for the treatment of postpartum blood stasis disease were obtained after ADME filtering analysis. The targets were enriched in multiple gene functions and different signaling pathways. By exploring various different signaling pathways, it was found that mitochondrial regulation of oxidative stress plays a potentially important role in the treatment of postpartum blood stasis with THSWD. Compared to model group, THSWD alleviated mitochondrial damage, decreased levels of oxidative stress in the rat model of postpartum blood stasis and reduced apoptosis in uterine cells. CONCLUSION: The therapeutic effect of THSWD on postpartum blood stasis is likely related to mitochondrial regulation of oxidative stress, which paves the way for further research investigating its mechanisms.

Early potential metabolic biomarkers of primary postpartum haemorrhage based on serum metabolomics.

OBJECTIVES: Postpartum hemorrhage (PPH) is the leading cause of maternal death, accounting for 1/4 of maternal deaths worldwide. Determining sensitive biomarkers in the peripheral blood to identify postpartum haemorrhage (PPH) is essential for the early diagnosis and management of PPH. The purpose of this study is to identify predictive serum metabolic biomarkers of PPH. Thirty healthy pregnant women and 30 cases of postpartum hemorrhage were studied for our research. MATERIAL AND METHODS: The serum metabolites of all pregnant were detected by liquid chromatography-quadruple time-of-flight mass spectrometry (LC-QTOFMS) and the corresponding biomarkers were identified. RESULTS: 34 significantly altered metabolites in PPH-pre-group were identified. They were mainly involved in fatty acid, and glycerophospholipid metabolism. CONCLUSIONS: The LysoPCs, PCs, PGs, PIs were effective biomarkers for identifying PPH. The disturbed signaling pathways, mTOR signaling, acute phase response signaling, AMPK signaling and eNOS signaling pathways might be related to the etiopathogenesis of PPH. Our study provided a valuable attempt to screen early diagnostic markers of PPH and to further understand its pathogenesis.

Expression of ß-catenin in human trophoblast and its role in placenta accreta and placenta previa.

OBJECTIVES: To investigate the expression of ß-catenin in chorionic villi, and to explore its roles in placenta accreta and placenta previa. METHODS: We compared ß-catenin expression in the control group, placenta accreta group (lesion area and normal zones), and placenta previa group (placental central and placental edge zones) by immunohistochemistry, Western blotting, and RT-PCR techniques. RESULTS: Compared with the normal group, the placenta accreta group had a longer length of stay, greater bleeding volume, and lower newborn birth weight. Further, the expression of ß-catenin was lower in both placenta previa and placenta accreta groups than in the control group, as measured by immunohistochemistry. Compared with the control group, expression of ß-catenin was significantly lower in the placenta previa and placenta accreta groups by Western blotting and RT-PCR. Importantly, the level of placental ß-catenin was significantly different when compared between the lesion and normal zones of placenta. CONCLUSION: The expression of ß-catenin in placenta accreta might play an important role in the regulation of placental cell invasion; low expression of ß-catenin in placenta accreta might be responsible for excessive trophoblastic invasion.

Severe secondary postpartum hemorrhage 3 weeks after cesarean section: alternative etiologies of uterine scar non-union.

A case of secondary postpartum hemorrhage that occurred 3 weeks after cesarean section requiring total abdominal hysterectomy is reported. The patient's history and pathologic features of the removed uterus did not allow the authors to clearly recognize a previous reported cause of this potentially life-threatening complication. Alternative causes of the non-union of the uterine incision are suggested.

[Spontaneous post-partum inhibitor to factor VIII clotting anti- gen--a cause of life-threatening hemorrhage]. / Spontaner Gerinnungsfaktor-VIII: C-Inhibitor post partum--Ursache lebensbedrohlicher Blutung.

Pathologic inhibitors of blood coagulation as cause of acquired haemostatic failure are rare. We report about a 23 years old primigravida with a life-threatening haemorrhage post partum. Analysis of coagulation parameters showed the presence of inhibitor to factor VIII. We reacted successfully with cyclophosphamid and cryoprecipitated factor VIII. References to diagnostic and therapy of pathologic clotting factor inhibitors are described.

Actualización en el uso de uterotónicos / Update on the use of uterotonic agents

La hemorragia posparto supone la pérdida de más de 500 ml de sangre tras un parto vaginal o de más de 1.000 ml tras una cesárea en las primeras 24 h posparto. Aunque la incidencia de muerte materna por hemorragia posparto ha disminuido, esta continúa siendo la causa más frecuente de muerte materna por hemorragia obstétrica. La incidencia de atonía uterina, primera causa de hemorragia posparto, va en aumento tanto en el parto vaginal como en la cesárea. Aunque en más de dos terceras partes las hemorragias posparto tienen lugar en pacientes sin factores de riesgo identificables, el tercer estadio del parto prolongado es el principal factor de riesgo. El manejo activo de este periodo incluye la administración de uterotónicos, fármacos que producen una contracción uterina adecuada, tras el nacimiento del neonato. Se puede administrarlos de forma profiláctica o terapéutica. Se ha comprobado que la administración profiláctica se relaciona con un tercer estadio más corto, menor riesgo de hemorragia y menor necesidad de uterotónicos adicionales. Actualmente existen cuatro fármacos o grupos de fármacos con actividad uterotónica: oxitocina, carbetocina, alcaloides del cornezuelo del centeno y prostaglandinas. Aunque la literatura es heterogénea, la oxitocina es el uterotónico de elección en la profilaxis y el tratamiento de la hemorragia posparto, pero se debe disminuir la dosis; la metilergometrina es uterotónico de segunda línea en la profilaxis y el tratamiento; a pesar de los efectos secundarios, el carboprost (prostaglandina F2alfa) es la prostaglandina de elección en el tratamiento de la hemorragia; el misoprostol puede ser una alternativa a la oxitocina, y el uso profiláctico de carbetocina debe individualizarse(AU)

Postpartum haemorrhage (PPH) is defined by the WHO as a blood loss >500 mL after vaginal delivery or >1000 mL after caesarean section during the first 24 hours post-delivery. Although the incidence of maternal mortality caused by PPH has decreased, it continues to be the major cause of maternal mortality due to obstetric haemorrhage. Furthermore, the incidence of uterine atony, which is the most prevalent cause of PPH, is still increasing in both vaginal delivery and caesarean section. Although PPH occurs in more than two thirds of patients without any identifiable risk factor, a prolonged third stage of labour is the main risk factor. Active management of the third stage of labour has been postulated to reduce the risk of bleeding in this period. It includes the administration of uterotonic agents after the birth of the baby. Uterotonic agents are defined as drugs that produce adequate uterine contraction. These drugs can be used as prophylactic therapy or treatment. The prophylactic use of uterotonic agents has been reported to be associated with a shorter third stage of labour, less risk of PPH and less need of additional uterotonic agents. There are currently four drugs or groups of drugs with uterotonic action: oxytocin, carbetocin, ergot derivatives and prostaglandins. The literature on this subject is extensive, heterogeneous and sometimes discordant. Oxytocin is still the first-line uterotonic drug for prophylaxis and treatment of uterine atony. There is a common trend to use high doses of uterotonics for fear of inadequate uterine contraction, but the current literature recommends its reduction. Methylergonovine continues being the second-line uterotonic agent in the prophylaxis and treatment of PPH, because of its side effects. Despite carboprost (PGF2alpha) side effects, it is still the first-line prostaglandin for PPH treatment. Misoprostol may be an alternative to oxytocin when it is not available, although it needs further studies to support this. Finally, the prophylactic use of carbetocin should be individualised(AU)