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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 9  |  Issue : 2  |  Page : 270-277

Amniotic fluid embolism: A narrative review of current concepts and future perspectives


Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

Date of Submission30-Sep-2020
Date of Decision06-Jun-2021
Date of Acceptance08-Jun-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Dr. Divyanu Jain
Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, 431-3192
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amhs.amhs_261_20

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  Abstract 


Amniotic fluid embolism (AFE) is a rare yet devastating complication of pregnancy. The outcomes are often poor, proving fatal for both mother and neonate. The incidence and mortality rate due to AFE is quite high even in developed countries and may be much higher in developing countries. Data from developing countries are unavailable. There is no uniform internationally accepted diagnostic criterion for AFE. No single diagnostic test has been found sufficient to suspect AFE in the early stages. Recently, complement system activation and an anaphylactoid reaction in the uterine tissue have been proposed in relation to its pathophysiology. In few cases, the use of complement C1 inhibitor with tranexamic acid, atropine, ondansetron, ketorolac therapy, and extracorporeal membrane oxygenation was observed to be very effective for early management. The studies on the pathophysiology of AFE are still limited. Further research is required to know the mechanism of this disease. Reliable rapid diagnostic tests are much needed at this stage. It is important to investigate the histopathology of tissues affected by AFE and find the origin of the disease in the maternal system. This review intends to highlight the best known and the unknown aspects of AFE relevant for future research purposes to minimize the fatality/mortality rate due to AFE, which remains an undiagnosed cause.

Keywords: Amniotic fluid embolism, anaphylactoid reaction, disseminated intravascular coagulation, maternal mortality, pregnancy


How to cite this article:
Jain D. Amniotic fluid embolism: A narrative review of current concepts and future perspectives. Arch Med Health Sci 2021;9:270-7

How to cite this URL:
Jain D. Amniotic fluid embolism: A narrative review of current concepts and future perspectives. Arch Med Health Sci [serial online] 2021 [cited 2022 Aug 19];9:270-7. Available from: https://www.amhsjournal.org/text.asp?2021/9/2/270/334014




  Introduction Top


Amniotic fluid embolism (AFE) is a life-threatening complication of pregnancy. In 1926, J. R. Meyer, a Brazilian pathologist, identified significant amounts of fetal materials in maternal pulmonary circulation at autopsy and first described the condition as AFE. Later, Steiner and Lushbaugh (1941) reported the presence of squamous cells and debris of fetal origin in maternal pulmonary circulation causing maternal death due to obstruction of airways. However, in the subsequent years, the involvement of the inflammatory mediators of the humoral immune response in maternal circulation was proposed, leading to an immunological reaction, termed as the “Anaphylactoid Syndrome of pregnancy.”[1] Since then, evidence of the presence of amniotic fluid components even in normal pregnant women has given way to incorporate further research strategies toward knowing the underlying pathophysiology of this condition.[2],[3],[4] It is often identified as a syndrome of pregnancy characterized by sudden onset of hypoxia, hypotension, and disseminated intravascular coagulation (DIC) associated with uterine atony resulting either from maternal pulmonary artery obstruction or an anaphylactic reaction to amniotic fluid components.[5]

Recent studies showed that humoral and immunological factors are more relevant to AFE.[6] In Japan, the condition is also recognized as postpartum hemorrhage (PPH) of unknown etiology because the exact cause is still unclear. Postpartum acute myometritis without an infectious pathological cause may be an important histopathological feature of PPH of unknown etiology identified by the Japanese AFE research group.[7] The histopathological evidence from human subjects to determine the pathophysiology of the disease seems promising for knowing better about the disease onset and the clinical–pathological course. Several experimental animal models were used to replicate the condition and to investigate the pathophysiology of the disease, but unfortunately yielded conflicting results.[8],[9] Recent investigations have disproved the old concept of pulmonary vascular obstruction caused by fetal squamous cells.[4] The results showed that even if the entire volume of amniotic fluid with squamous cells is introduced into maternal circulation, it is still incapable of obstructing the billions of pulmonary capillaries of each lung. These findings indicate that physical obstruction of pulmonary vasculature is not related to the pathogenesis of AFE.

AFE remains a clinical diagnosis until now, and very less information is available related to the pathophysiology involved in the sudden onset of the disease. Despite the timely diagnosis and intensive critical care including cardiopulmonary resuscitation (CPR), advanced cardiac life support (ACLS), anti-DIC therapy, and immediate delivery, maternal and perinatal outcomes are often poor. Even in developed countries, the case fatality due to AFE remains high and has been estimated to be between 11% and 43% with the highest being reported from Australia.[10] The clinical presentation of the disease is variable; there is a need for intensive research related to the exact pathophysiology for the disease onset leading to fatal outcomes. The aim of this narrative review is to provide a comprehensive and objective analysis of the existing literature on clinical and pathological aspects of AFE and helps in identifying the gaps in research in this field, which is crucial for ongoing and future studies.


  Materials and Methods Top


A literature search was performed through the databases PubMed, EMBASE, and Google Scholar using the terms: “amniotic fluid embolism,” “maternal mortality,” “disseminated intravascular coagulation,” “anaphylactoid reaction,” and “pregnancy.” The inclusion criteria were studies published until 2021 in the English language, all types of studies including case reports, systematic reviews, and committee guidelines, and relevance to the topic. Articles in a language other than English and unrelated to the research topic were excluded from this review. Additional studies older than 10 years with significant findings relevant for future research were manually retrieved from the cited references.


  Incidence Top


AFE is a rare complication of pregnancy with an estimated incidence of 0.8–1.8/100,000 deliveries.[11] In a majority of women who die unexpectedly during labor or delivery with cardiovascular collapse, respiratory arrest, and hemorrhagic shock with DIC, AFE remains the most likely diagnosis. The true incidence of AFE is quite difficult to estimate due to the disparity in the diagnostic criteria used by obstetricians worldwide. Moreover, the possibility of differences in reporting methods influenced by medicolegal reasons cannot be ruled out.[12] Available incidence data of mortality due to AFE from various countries are summarized in [Table 1].[12],[13],[14],[15],[16] The current incidence of AFE in Japan is approximately 5 in every 100,000 deliveries in a year, which is almost similar to the other developed countries.[17] According to the Maternal Death Exploratory Committee of Japan, among all the causes leading to pregnancy-associated deaths in Japan in 2014, AFE was the third most recurring cause, contributing to 12% of all the deaths after obstetric hemorrhage (23% including uterine type AFE) and brain disease (16%).[18] In a retrospective case study of 10 AFE cases in Japan, the case fatality rate was found to be 70%.[19]
Table 1: Incidence of amniotic fluid embolism in developed countries

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  Risk Factors for Amniotic Fluid Embolism Top


The understanding of the risk factors associated with AFE is still difficult because of the variations in the clinical presentations observed through case reports or maternal death consensus. Direct association of any of the suspicious risk factors is doubtful until date. However, in 2009, the data obtained from two large population-based cohort studies conducted in Canada and United States showed several factors to have a significant association with AFE such as advanced maternal age (>35 years of age), assisted vaginal deliveries (forceps and vacuum), cesarean delivery placenta previa, abruptio placenta, and fetal distress.[20],[21],[22] Induction of labor remained a conflicting result in both these studies; however, maternal age <20 years and dystocia were observed to be protective against AFE. The latest population-based study in Washington State, US, supported the previous finding that mothers >35 years of age had an elevated risk of severe morbidity from AFE.[23] According to UK Obstetric Surveillance System (UKOSS) report, the crucial risk factors associated with AFE are induction of labor (adjusted odds ratio [aOR] = 3.86), multiple pregnancies (aOR = 10.9), and cesarian section (aOR = 8.84).[24] A recent multicentric study reported that using the modified Clark criteria for the diagnosis of AFE, even women with gestational diabetes have a significantly increased risk of having AFE.[11] The authors also observed that the odds of having AFE were significantly higher in women induced with prostaglandin compared to women induced without it. Interestingly, both instrumental vaginal delivery and cesarean section were associated with increased risk of having postnatal AFE. [Table 2] summarizes the major risk factors associated with AFE.[7],[14],[15],[25],[26],[27],[28]
Table 2: Risk factors for amniotic fluid embolism

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The majority of these studies were based on the clinical diagnosis of the disease and the dissimilarity in the diagnostic criteria could have influenced the results. The probability of misdiagnosis cannot be ruled out, and therefore, there is a need for large prospective studies with uniform diagnostic criteria.


  Clinical Presentation Top


The classical presentation of AFE involves a triad of sudden onset of hypoxia, hypotension, followed by the development of coagulopathy during labor and delivery.[29],[30] AFE remains a diagnosis of exclusion and is often considered the differential diagnosis for pregnancy-related maternal deaths including cardiovascular collapse, extreme respiratory discomfort, and seizures along with coagulopathy.[31] The clinical picture is complex and may vary ranging from respiratory symptoms to cardiovascular insult, which is also reported to be preceded by premonitory signs such as the feeling of agitation and impending doom.[28] The average age of presentation is 35 ± 5 years.[32],[33] Few case studies reported the occurrence of AFE after early termination of pregnancy, transabdominal amniocentesis, and amnioinfusion with saline.[34],[35] However, the majority of the studies reported sudden systemic and local symptoms in the mother or fetus such as cardiac arrest/shock, hypotension, respiratory distress, seizures, coma, fetal distress, and restlessness.[36],[37] According to UKOSS data from 2000 to 2002, almost 47% of the women developed some premonitory signs or symptoms before collapsing such as tingling and numbness, feeling of agitation, pins and needles sensation in fingers, lightheadedness, chest pain, and breathlessness.[24],[38] The latest data from UK, Netherlands, Slovakia, Australia, and France using UKOSS case definition showed that among women who did not present with cardiac arrest, 60% presented with coagulopathy and 67% presented with maternal hemorrhage.[11] It was also noted that 77% of these patients had hypotension at presentation.

The systemic abnormalities that are frequently observed in these patients are DIC, atonic bleeding, hypoxemia, and acidosis.[37] However, the presence or the association of these symptoms has not yet been proved to be specific for AFE. To date, various diagnostic markers and biologic tests have been employed, but none has been proved reliable to accurately predict or confirm the diagnosis. In the clinical guidelines for the management of AFE, the Society for Maternal-Fetal Medicine does not recommend the use of any known laboratory test to either diagnose or refute the diagnosis for AFE, as it remains a clinical diagnosis.[31]

In a study on AFE cases conducted in the UK for 9 years from 2005 to 2014 using the UKOSS, it was observed that the AFE cases who either died or developed permanent neurological insult were more prone to present with cardiac arrest, more likely to receive hysterectomy, had short interval between diagnosis and hysterectomy, and were even less often recipients of cryoprecipitate.[39]


  Etiopathogenesis Top


The definite etiology for AFE has not yet been established. A number of theories proposed the entry of amniotic debris into the maternal pulmonary circulation leading to an obstructive pathological state; however, evidence of amniotic components even in females without AFE made this concept debatable.[3],[40],[41],[42] To date, the influx of amniotic fluid into maternal circulation and a pulmonary embolus associated with anaphylactoid reaction have been the accepted etiologies related to the onset of AFE.[12],[17],[27],[43],[44],[45],[46] Hammerschmidt et al. in 1984 first demonstrated that the mixing of amniotic fluid and plasma can activate the complement system.[47] Thereafter, significantly low levels of C3 and C4 were observed in experiments by Benson et al., suggesting their role in the anaphylactic response.[48] As mast cell degranulation and complement activation are closely related, it is difficult to ascertain the primary role of either of them in AFE. Kanayama and Tamura in 2014 postulated the development of AFE in the uterus due to the flow of amniotic fluid into the uterine tissues, leading to the production of bradykinin and inflammatory cytokines such as interleukin (IL8) resulting in an edematous and atonic uterus.[17],[49],[50] As the clinical picture and the pathological findings are enigmatic, the pathophysiology cannot be ascertained. However, there are several theories for the clinical and pathological diagnosis of AFE.[7],[46],[51],[52]

In recent times, physicians have extended their interest in the C1 esterase inhibitor pertaining to its ability to inhibit the complement system, thereby playing a major role in the coagulofibrinolytic and kallikrein–kinin systems. In a study involving 12 healthy pregnant women, it was observed that the levels of C3 and C4 complements significantly decreased by 15% and 11%, respectively, during labor and within an hour postpartum.[53] Benson in his study reported that complement levels significantly decreased in AFE patients, indicating a maternal immune activation due to contact with fetal materials.[48],[54] Tamura et al. in their study found a marked decline in the levels of C1INH in AFE cases compared to controls, indicating its key involvement in the pathophysiological mechanism of AFE.[55] They found that the C1INH activity in AFE patients was almost comparable to an “attack of angioedema” and suggested the predictive and prognostic potential of C1INH for AFE. In a recently published case report by Akasaka et al., the patient diagnosed as AFE had a facilitated recovery from the worsening symptoms and coagulopathy by the use of C1 inhibitor.[56]


  Diagnosis Top


Antemortem diagnosis of AFE is based primarily on the clinical findings and is usually one of exclusion. Most cases presenting with the classical triad of sudden hypoxia, hypotension, and coagulopathy occurring anytime during labor or after delivery and/or maternal death during childbirth are considered for the diagnosis of AFE[1],[33] However, on postmortem examination, the presence of fetal squames and amniotic fluid components in maternal pulmonary circulation remains the confirmatory evidence for establishing the diagnosis of AFE.[6] Autopsy findings of maternal lungs frequently reveal severe congestion, edema, and focal atelectasis with intravascular fetal squamous cells and pulmonary mast cells detected by immunohistochemistry.[57]

In the clinical setup, AFE closely mimics both anaphylactic reaction and embolism. It is now recognized as an immune-inflammatory reaction or an anaphylactoid syndrome of pregnancy.[1],[58] Often, two types of the clinical course of the disease are observed: first cardiopulmonary collapse type and second DIC type as described in [Figure 1].[1],[5],[12],[38] The cardiopulmonary collapse type is characterized by sudden cardiopulmonary collapse associated with chest pain and respiratory distress, whereas the sudden onset of atonic bleeding and DIC resulting in uncontrolled hemorrhage and shock is considered to be the DIC type of AFE. Under the AFE registry program in Japan, around two-thirds of the cases reported were considered to be DIC type.[17] The autopsy findings of the DIC type of AFE revealed marked edematous uterus along with pulmonary edema, which was absent in cardiopulmonary collapse type cases. However, in all cardiopulmonary collapse type cases, amniotic and fetal components were detected in pulmonary vessels, indicating their probable involvement in the development of embolus in the pulmonary artery.[59] A recent study has shown that the blood loss/fibrinogen ratio at onset may help distinguish between PPH and DIC-type AFE, which can improve the diagnostic accuracy and early intervention for consumptive coagulopathy in these patients.[60]
Figure 1: Types of AFE. AFE: Amniotic fluid embolism, DIC: Disseminated intravascular coagulation

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A diagnostic classification based on pathological findings is important for AFE as the clinical presentation of the disease is often unpredictable. Evident tissue findings provide a better understanding of the condition and more clarity about the pathophysiology related to its abrupt onset. It is known that the entry of fetal components into the uterine vessels is a normal physiological process during labor.[61] However, the anaphylactoid reaction occurring due to the same only in a few subjects is a matter of concern and a subject of further research. In Japan, another classification based on autopsy findings in AFE is proposed, which focuses on a pathological condition where classical amniotic/fetal components are absent in lungs but are found in uterine vessels along with uterine atony. They proposed this type as AFE of uterine type (Uterine type AFE).[17] The latest histopathological study from the Japanese AFE Registry investigated the uterine tissues from fatal and survived cases of “postpartum hemorrhage of unknown etiology,” one of the components of the Japanese diagnostic criteria of AFE.[62] The uterus was large and swollen and the tissue findings revealed an anaphylactoid reaction, complement system activation, massive interstitial edema associated with significant mast cell degranulation involving a major portion of the uterus including the uterine body as well as the uterine isthmus. Isthmus is the site for lower uterine incision during cesarean deliveries and the first maternal tissue, which comes in contact with amniotic fluid following cesarean delivery. Bradykinin Type 1 receptor was also expressed in these uterine myometrial tissues, suggesting the involvement of kinin–kallikrein system in the development of significant interstitial edema.[63] These histopathological findings provide an insight into the pathophysiology of this disease at the site of the uterus, which can be useful in developing a uniform diagnosis and treatment strategies.

For most of the developed countries, the criteria for diagnosing clinical AFE vary.[1],[24],[64],[65] Due to this fact, the lack of uniformity in the inclusion or exclusion of cases for research studies may affect the usefulness of the results obtained so far. In many AFE cases, few of these criteria are either absent or they are associated with manifestations that mimic other conditions. Often, the classical triad of hypoxia, hypotension, and coagulopathy in AFE is imperceptible. Interestingly, premonitory signs with a neurological involvement such as restlessness, agitation, and feeling of numbness or sensation of doom are more frequently observed irrespective of the criteria for diagnosis.[37] Therefore, it becomes obligatory to consider a differential diagnosis that mimics cardiorespiratory failure, hematological disorder, anaphylactic shock, pulmonary embolism, sepsis, or other pregnancy complications such as eclampsia. Of note, treatment should be initiated promptly and directed toward the correction of cardiopulmonary imbalance and coagulopathy. [Table 3] summarizes the various differential diagnoses, which can be considered for AFE.[9],[31]
Table 3: Differential diagnoses for cases with possible amniotic fluid embolism

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  Treatment and Management Top


AFE involves multiple organ dysfunctions and necessitates the involvement of a multidisciplinary team including critical care, anesthesia, respiratory medicine, pediatrics, and obstetrics–gynecology department. The prognosis of the patient mainly depends on the timely diagnosis and early effective intensive care with obstetric support.[38],[66],[67],[68] The management of cardiac arrest should not be delayed for an accurate diagnosis, rather immediate basic cardiac life support and ACLS should be initiated.[31] In case of recognizable symptoms and signs of AFE, obligatory diagnostic tests should be performed immediately such as complete blood count and platelet, blood grouping, blood coagulation profile, arterial blood gas, cardiac markers, electrocardiogram, echocardiogram, and chest X-ray. The aim of primary management is toward CPR and maintenance of deranged vascular perfusion.

Immediate management at the primary center requires oxygenation, intubation, blood transfusion including fresh frozen plasma (FFP), antithrombin (if available) for hemorrhage, and coagulopathy.[17] The decision to perform delivery at the primary or secondary center should depend on the expert judgment of the physician, keeping in mind the unstable condition of the patient. Upon arrival at the secondary center, the patient should be managed actively by the multidisciplinary team for hemodynamic stability after assuring cardiac resuscitation. Obstetric and neonatal care is of immense importance and should be taken care of simultaneously. An anticipated treatment and management plan are summarized in [Figure 2].
Figure 2: Treatment and management plan of AFE. AFE: Amniotic fluid embolism, ABG: Arterial blood gases, FFP: Fresh frozen plasma, CPR: Cardiopulmonary resuscitation, PPH: Postpartum hemorrhage, NICU: Neonatal intensive care unit

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Care should be taken to avoid acidosis, hypoxia, and hypercapnia as they rapidly lead to right heart failure.[21] Recently, a case was reported which was managed successfully by the team of anesthetists by incorporating 0.2 mg atropine, 8 mg ondansetron, and 15 mg ketorolac known as A-OK AFE protocol.[69] This protocol was initiated within 1 min of the onset of symptoms suggestive of AFE and all the three drugs were infused intravenously and led to the improvement of the symptoms within a few minutes. A-OK therapy might be a candidate for the initial active management of AFE. Excessive fluid administration is not recommended as it may worsen right ventricular function, leading to myocardial infarction. Vasopressors (norepinephrine and vasopressin) and inotropes (dobutamine and milrinone) should be administered to improve left ventricular function. Uterine atony should be managed intensively using uterotonics, uterine tamponade, or uterine balloons as required.[31] In the event of coagulopathy associated with AFE, massive transfusion protocol for blood components should be followed including FFP and cryoprecipitate before considering any surgical interventions.[70],[71] Measures to manage the rapidly progressing DIC include early measurement of fibrinogen levels, along with 3000I. U of Antithrombin, >15units of FFP (initial dose), and tranexamic acid 4 g div/h. Tranexamic acid has been proved to be very effective in the management of hereditary angioedema (HAE) and also to control blood loss in pregnant women who suffer PPH.[72],[73],[74] Therefore, tranexamic acid with fibrinogen concentrate should be used to treat the hyperfibrinolysis, using rotational thromboelastometry (ROTEM) is available.[75] Additionally, 500–5000 I. U. of plasma-derived C1INH concentrates can revert HAE in patients with C1INH deficiency, making it useful in the management of the anaphylactoid reaction associated with AFE.[76] The cytokines and chemical mediators of anaphylactoid reaction can be removed from maternal circulation with the help of hemofiltration and plasma exchange transfusion, further contributing to the prognosis of the patient.[77],[78]

Recombinant factor VII is also used in countries like Japan in cases with DIC. Recently the role of C1 esterase inhibitor (C1INH) has been proposed for its ability to inhibit complement activation and suppressing the anaphylactoid reaction.[55],[56] As C1INH is a component of FFP; administering FFP (≥10-15 units) would not only supplement coagulation factors but also C1INH. Often AFE associated with DIC results in severe and uncontrolled bleeding; therefore the use of heparin is not recommended.[17] Extracorporeal life support system may be used along with specific management. In a case report, veno-arterial extracorporeal membrane oxygenation was found to be very useful in the event of DIC where the patient regained consciousness within 2 h, with the improvement of ventricular dysfunction and pulmonary edema in the next 20–24 h.[79] After stabilization, the patient should be admitted to ICU. In case of unfortunate outcomes, an autopsy should be performed on all cases for further investigations and research.


  Prevention Top


The definite preventive measures for AFE are difficult to ascertain at this stage as the majority of the cases that have been reported and studied occurred in healthy individuals with no significant history. However, considering the associated anaphylactoid reaction, the surgeon must be cautious at the time of the rupture of membranes during cesarean section or induction of labor to prevent the contact of amniotic fluid to the myometrium as much as possible. Obstetricians must be vigilant during induced labor, vacuum delivery and must avoid laceration of the birth canal.


  Recurrence Top


The information regarding the recurrence risk of AFE is very limited and the available studies suggest that AFE is not a recurrent condition.[80],[81],[82] However, due to the lack of uniformity in the diagnosis of this condition, it is difficult to predict the possibility of recurrence. According to a report, considering the events of previous childbirth; the patients who fortunately survived were advised of the probability of recurrence and the risks involved, which affected their decisions for future pregnancies.[68]


  Discussion Top


It is apparent from this brief review that there is a lack of data on AFE from all over the world, especially from developing countries. The available data from few countries (USA, Japan, Australia and NZ, Canada, UK) indicate that critical challenges remain in this field of research. Therefore, it seems of utmost importance that scientific societies in other countries must take appropriate steps to generate awareness about AFE and conduct large population studies to establish a common consensus all over the world. Multicentric studies will help in knowing the real incidence and facilitate the development of effective treatment and management guidelines for AFE patients.

In majority of the fatal cases, the real cause may usually go undiagnosed which is one of the reasons for the variable incidence of AFE. A collaborative effort from all countries for the establishment of a uniform diagnostic criterion is required which should be acceptable worldwide so that the diagnosis is not missed and effective measures can be taken promptly to prevent any unfortunate outcome. The pathological findings of an anaphylactoid reaction need to be researched further with a larger sample size keeping in mind the importance of human tissue investigations for improving our approach towards this fatal complication of pregnancy.

Financial support and sponsorship

Nil.

Conflicts of interest

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