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Rationale: Amniotic fluid embolism (AFE) is a fatal obstetric condition that often rapidly leads to severe respiratory and circulatory failure. It is complicated by obstetric disseminated intravascular coagulation (DIC) with bleeding tendency; therefore, the introduction of venoarterial extracorporeal membrane oxygenation (VA-ECMO) is challenging. We report the case of a patient with AFE requiring massive blood transfusion, rescued using VA-ECMO without initial anticoagulation., Patients Concerns: A 39-year-old pregnant patient was admitted with a complaint of abdominal pain. An emergency cesarean section was performed because a sudden decrease in fetal heart rate was detected in addition to DIC with hyperfibrinolysis. Intra- and post-operatively, the patient had a bleeding tendency and required massive blood transfusions. After surgery, the patient developed lethal respiratory and circulatory failure, and VA-ECMO was introduced., Diagnosis: Based on the course of the illness and imaging findings, the patient was diagnosed with AFE., Interventions: By controlling the bleeding tendency with a massive transfusion and tranexamic acid administration, using an antithrombotic ECMO circuit, and delaying the initiation of anticoagulation and anti-DIC medication until the bleeding tendency settled, the patient was managed safely on ECMO without complications., Outcomes: By day 5, both respiration and circulation were stable, and the patient was weaned off VA-ECMO. Mechanical ventilation was discontinued on day 6. Finally, she was discharged home without sequelae., Lessons: VA-ECMO may be effective to save the lives of patients who have AFE with lethal circulatory and respiratory failure. For safe management without bleeding complications, it is important to start VA-ECMO without initial anticoagulants and to administer anticoagulants and anti-DIC drugs after the bleeding tendency has resolved., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

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., (© 2024. The Author(s).)

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.

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.

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., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: This study aimed to investigate the rate of coagulopathy progression in amniotic fluid embolism (AFE), using the level of fibrinogen., Methods: We examined all cases of maternal death (46 cases) related to AFE between 2010 and 2013 in Japan (total number of deliveries: 4,291,459). Fibrinogen, blood loss from AFE onset to fibrinogen measurement, and time from onset to fibrinogen measurement were investigated. The correlations of fibrinogen with time from onset to fibrinogen measurement and blood loss at fibrinogen measurement were analyzed., Results: Fibrinogen was undetectable (less than 50 mg/dL) in 14 cases (93%) and 65 mg/dL in one case (7%). All the cases involving not less than 1000 mL of blood loss or within 60 min from onset to fibrinogen measurement demonstrated low levels of fibrinogen., Conclusions: Coagulopathy in AFE was not directly proportional to bleeding. Furthermore, coagulopathy in AFE developed in a remarkably short length of time. If AFE is suspected, fibrinogen level should be measured rapidly for favoring a more AFE to decrease the risk of death from AFE. And, rapid treatment of coagulopathy can help reduce mortality from AFE.

Amniotic fluid embolism (AFE) is recognized as a type of syndrome characterized by the abrupt onset of hypoxia, hypotension, seizures, or disseminated intravascular coagulopathy (DIC), occurring during labor, delivery, or immediately postpartum, caused by the inflow of amniotic components into the maternal circulation. AFE is a rare condition but one of the most serious obstetrical complications, resulting in a high mortality rate among pregnant women. Despite earlier recognition and intensive critical management, we often encounter patients who unfortunately do not recover from the exacerbation of AFE-related conditions. A major concern is that there are no effective evidence-based therapies for AFE, because its pathophysiology is still not well understood. This article reviewed AFE, focusing on the pathology and currently proposed pathophysiology., (© 2017 Japan Society of Obstetrics and Gynecology.)

Background: The Japan Association of Obstetricians and Gynecologists (JAOG) recommends transfusion with a fresh-frozen plasma (FFP):red blood cell (RBC) ratio of 1 or more in postpartum hemorrhage. However, no global consensus exists concerning this, and little is known regarding the impact of FFP:RBC ratio on maternal mortality. This study evaluates the efficacy of transfusion with FFP:RBC ratio of 1 or more for amniotic fluid embolism (AFE) with coagulopathy., Study Design and Methods: The Maternal Death Exploratory Committee, established by the JAOG, conducted this retrospective nationwide case-control study in Japan. Women with AFE and coagulopathy were included in the study and were stratified into survival and death groups. Obstetric variables and therapy methods (hysterectomy, uterine artery embolism, and transfusion with FFP:RBC ratio ≥ 1) were compared between the survival and death groups., Results: A total of 54 women had AFE and coagulopathy (death group, n = 22; survival group, n = 32). Only nine (40.9%) women in the death group were transfused with FFP:RBC ratio of 1 or more, whereas 29 (90.6%) women in the survival group were transfused with FFP:RBC ratio of 1 or more. FFP:RBC ratio of 1 or more was found to be associated with better survival rate (adjusted odds ratio, 28.32; 95% confidence interval, 4.26-188.37). No difference was found in obstetric variables, hysterectomy, and uterine artery embolism between survival and death groups., Conclusion: Transfusion with FFP:RBC ratio of 1 or more is associated with higher survival rate in women with AFE with coagulopathy., (© 2016 AABB.)

The registry program of amniotic fluid embolism (AFE) in Japan started in 2003. More than 400 hundred clinical diagnosed amniotic fluid embolism has been accumulated. Those data showed that there were two etiologies of AFE: the fetal materials create physical obstructions in the maternal microvessels in various organs, such as the lung; and (ii) the liquids cause an anaphylactoid reaction that leads to pulmonary vasospasm and activation of platelets, white blood cells and/or complements. The clinical findings showed that AFE was characterized mainly by cardiopulmonary collapse, the other involves the presence of disseminated intravascular coagulation (DIC) and atonic bleeding. Zinc coproporphyrin-1, sialyl Tn antigen (STN), complement C3, C4 and interleukin-8 have been used as serum markers of AFE. The levels of zinc coproporphyrin-1 and STN were increased in cardiopulmonary collapse type AFE, and a marked reduction of C3 and C4 was observed in DIC type AFE. At the primary medical institution, initial treatments for shock airway management, vascular management, fluid replacement, administration of anti-DIC therapy such as antithrombin, and administration of fresh frozen plasma should be provided. C1 esterase inhibitor activity in AFE cases was significantly lower than those of normal pregnant women. C1 esterase inhibitor may be a promising candidate of treatment of AFE., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

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.

Aim: The purpose of this study was to evaluate the possibility of establishing predictors of mortality in women with amniotic fluid embolism., Methods: Our previous report identified eight factors associated with amniotic fluid embolism (AFE) fatality: dyspnea, cardiac arrest, loss of consciousness, serum sialyl Tn greater than 47 U/mL, serum interleukin-8 greater than 100 pg/mL, vaginal delivery, multiparity and term delivery. The ratio of the number of positive fatal factors to the number of possible fatal factors in the same case was calculated as the abundance ratio, which was used because information regarding all eight factors was not retrievable for all the patients at the time of registration. The patient group was divided into four quartiles based on this abundance ratio, and the mortality rate in each quartile was compared with the overall mortality rate among the 130 patients with AFE enrolled between 1992 and 2006. The validity of this approach was confirmed in another dataset from a cohort of 38 patients with AFE in 2007., Results: A statistically significant positive correlation was observed between the abundance ratio and the mortality in each quartile (P<0.01) for the patients with AFE enrolled between 1992 and 2006. This result was also found in the AFE patients enrolled in 2007 (P<0.05). Thus, an increased in the abundance ratio of the eight fatal factors resulted in an increased case fatality rate., Conclusion: These data suggested that the abundance ratio of fatal factors may be a useful predictor of mortality and therefore may be expected to improve prognostic accuracy in the future., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Amniotic fluid embolism (AFE) is a rare, high-risk obstetric complication primarily found in the lungs and potentially related to anaphylaxis. Tryptase release from the mast cell reflects anaphylaxis. Case report and findings: A female, aged over 40 years, presented with uterine atony and lethal hemorrhage after induced vaginal labor. Cervical laceration was accompanied by severe hemorrhage. Stromal edema and myometrial swelling were consistent with uterine atony. Alcian blue staining and zinc coproporphyrin immunostaining disclosed AFE, which was more prominent in the uterus than in the lungs. Tryptase immunostaining was diffuse and prominent around the activated mast cells (halos) in the uterus, including the cervix. Similar distribution of findings on the AFE markers, tryptase halos, complement receptor C5aR, and atony in the uterus suggested the causality of AFE to anaphylaxis, complement activation and atony. It is probable that disseminated intravascular coagulation (DIC), induced by AFE, uterine atony and cervical laceration, caused the lethal hemorrhage. It is likely that AFE, in association with cervical laceration, induces uterine anaphylaxis, complement activation, atony, DIC and lethal hemorrhage., (© 2014 S. Karger AG, Basel.)

Despite the decrease in maternal mortality rate, amniotic fluid embolism (AFE) is still one of the most feared complications of pregnancy due to the high rate of mortality in Japan. The authors present a fatal case of a healthy 39-year-old woman who died during delivery after a normal 40-week second pregnancy. Shortly after the arrival at hospital, an abrupt drop of foetal heart rate was observed, followed by deterioration of consciousness and cardiac arrest of the patient. Prompt cardiopulmonary resuscitation (CPR) was performed but the patient died about an hour and a half after her arrival at hospital. Forensic autopsy confirmed the pathohistological diagnosis of amniotic fluid embolism supported by histochemical analysis results and excluded other possible causes of death. This paper stresses the fundamental importance of autopsy in an unexpected maternal death in conjunction with the significance of data accumulation on maternal death., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Aim: To clarify the cause of maternal deaths, an autopsy is essential. However, there has been no systemic analysis of maternal death in Japan based on autopsy cases., Material & Methods: Maternal death reports were retrieved from a large amount of registered autopsy data on maternal death in the series of 'Annual of pathological autopsy cases in Japan'. These files contain 468,015 autopsy records from 1989 to 2004. We collected 193 cases of maternal death due to direct obstetric causes. We recorded all the data into Excel files. Then we analyzed the causes of death and classified them into 11 categories., Results: The causes of maternal death were as follows: amniotic fluid embolism (AFE), 24.3%; disseminated intravascular coagulation (DIC) related to pregnancy-induced hypertension, 21.2%; pulmonary thromboembolism, 13.0%; injury to the birth canal, 11.4%; medical and surgical complications, 9.8%; and atonic bleeding or DIC of unknown cause, 8.3%. A discrepancy between the clinical diagnosis and pathological diagnosis was frequently observed in cases of AFE, septic DIC and injury to the birth canal. AFE diagnosed by autopsy was often clinically diagnosed as atonic bleeding or DIC of unknown cause before death. Half of the cases of AFE diagnosed by autopsy were associated with DIC., Conclusion: We found that AFE, DIC related to pregnancy-induced hypertension, pulmonary thromboembolism and injury to the birth canal were the major causes of maternal death in Japan. AFE had various clinical features such as uterine atony and DIC in addition to pulmonary cardiac collapse., (© 2010 The Authors. Journal of Obstetrics and Gynaecology Research © 2010 Japan Society of Obstetrics and Gynecology.)

Aims: To identify factors leading to fatality of patients with amniotic fluid embolism (AFE)., Methods: Patients who had fatal or nonfatal AFE were registered at the Hamamatsu University School of Medicine in the Department of Obstetrics and Gynecology from 1992 to 2006. Data collected included information about demographics and clinical characteristics. The fatal factors among these data were identified using chi(2) analysis and the Mann-Whitney test., Results: One hundred and thirty-five patients met the criteria, which included fatal (n = 65) and nonfatal AFE (n = 70). Maternal full-term gestational weeks, multiparous and noncesarean sections were the risk factors for death found in this study (p < 0.01). Sialyl Tn levels (mean +/- SD) in the serum of patients with fatal AFE (69.7+/- 126.4 U/ml) were higher compared to those with nonfatal AFE (48.3+/- 161.8 U/ml; p = 0.003). Each of three items (cardiac arrest, dyspnea or loss of consciousness) was more common in fatal AFE (p < 0.01). Maternal pregnancy and labor complications were not associated with the distinction between fatal and nonfatal AFE., Conclusion: Factors associated with patients with fatal AFE were identified. These included multiparity, noncesarean section at full-term and the three symptoms mentioned above. Sialyl Tn levels could be a possible prognostic fatality factor., (Copyright 2010 S. Karger AG, Basel.)

The early pathogenesis of amniotic fluid embolism is not completely understood. The entrance of amniotic fluid (AF) into the systemic circulation leads to an initial phase of pulmonary vasospasm, pulmonary hypertension and cor pulmonale. We studied the effect of AF on endothelin (ET) production in vivo and in vitro. Injection of rabbits (pregnant and nonpregnant) with meconium-stained AF, raw AF and supernatant AF led to a significant increase in serum ET. This result was confirmed by using human umbilical vein endothelial cell cultures incubated with the same types of AFs. After infusion of rabbits with AFs, we observed that the lung, heart and kidney were positively stained for ET and von Willebrand factor. AF was found to have an injurious effect on endothelial cells measured by using fura-2. The maximal injurious effect of AFs was observed for the meconium-stained AF. We hypothesized that the early pathological changes in AF embolism may be mediated by ET.

We measured the concentration of zinc coproporphyrin I (ZnCP-I), a characteristic component of meconium, in maternal plasma by fluorometry after HPLC. We obtained plasma samples from 89 women: 35 at weeks 10-40 of normal pregnancy, 41 shortly after normal delivery, 4 from patients with amniotic fluid embolism (AFE), and 9 from non-AFE patients with intra- or postpartum shock caused by genital bleeding. The plasma ZnCP-I concentration was 97 (SD 83, range 38-240) nmol/L in the AFE patients, 11 (SD 9.2) nmol/L in the non-AFE patients, 12 (SD 7.9) nmol/L during normal pregnancy, and 26 (SD 10) nmol/L shortly after normal delivery. We suggest that measuring ZnCP-I in maternal plasma by fluorometry on HPLC is a rapid, noninvasive, and sensitive method for diagnosing AFE and propose 35 nmol/L as the cutoff value for the ZnCP-I concentration in maternal plasma for the diagnosis of AFE.