Journal of Obstetrics and Gynaecology, October 2014; 34: 580–584 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2014.919996
OBSTETRICS
Incidence, diagnosis and pathophysiology of amniotic fluid embolism F. Ito, J. Akasaka, N. Koike, C. Uekuri, A. Shigemitsu & H. Kobayashi
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Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
Amniotic fluid embolism (AFE) is a rare clinical entity, sometimes fatal. A review was conducted to describe the frequency, diagnosis and pathophysiology of AFE. The reported incidences ranged from 1.9 cases per 100,000 maternities (UK) to 6.1 per 100,000 maternities (Australia), which can vary considerably, depending on the period, region of study and the definition. Although the development of amniotic fluid-specific markers would have an impact on early diagnosis, definition of AFE based on these markers is not widely accepted. To date, immunological mechanisms, amniotic fluid-dependent anaphylactic reaction and complement activation, have been proposed as potential pathogenetic and pathophysiological mechanisms. Immune cell activation induced through complement activation may be associated with the mechanism that immediately initiates maternal death, only in susceptible individuals. This review will focus on advances in the field of AFE biology and discuss the prevalence, diagnosis and pathophysiology of AFE. Keywords: Amniotic fluid embolism, anaphylaxis, complement activation, incidence, pathophysiology
Introduction Amniotic fluid embolism (AFE) is a rare obstetric emergency, with potentially catastrophic consequences. AFE patients develop one or more of three key signs: cardiovascular collapse, respiratory distress and/or coagulopathy. This disorder may most commonly occur during labour, delivery, caesarean section, dilatation and evacuation, or in the immediate postpartum period (within 30 min postpartum) (Rudra et al. 2009; Tuffnell 2005). AFE accounts for an estimated 5–15% of all maternal deaths in developed countries. There are variations in the definitions of AFE used between countries (Moore and Baldisseri 2005). Since the underlying mechanism is still poorly understood, AFE remains a clinical diagnosis with potential errors in diagnosis (Gist et al. 2009; O’Shea and Eappen 2007). Therefore, it is difficult to obtain reliable information about incidence, risk factors, outcomes, management, pathophysiology and pathogenesis. The aim of this study is to review the definition, frequency, causes, pathophysiology and pathogenesis of AFE and raise awareness towards recent advancement in AFE research.
Materials and methods This present paper reviews the literature for clinical, biological, pathogenetic and pathophysiological studies on AFE. For studies
that reported data on other obstetric disorders, only data pertaining to AFE were included. A computerised literature search was performed to identify relevant studies reported in the English language. We initially searched PubMed MEDLINE electronic databases (www.ncbi.nlm.nih.gov/sites/entrez) for a 30-year period (1980–2010), combining the keywords ‘definition’, ‘incidence’, ‘pathogenesis’, ‘pathophysiology’ and ‘marker’ with ‘amniotic fluid embolism’. All abstracts were reviewed by two investigators to identify papers for full-text review. Additionally, references in each article were searched to identify potentially missed studies. Abstracts were not included.
Incidence and case fatality rate of AFE The reported incidences can vary considerably between studies and these differences may relate to the differences in the criteria used to define AFE (Moore and Baldisseri 2005). Amniotic fluid embolism remains an important public health concern and an emerging obstetric catastrophe in developed nations. It presents with one or more of the cardinal signs of acute hypotension or cardiac arrest, acute hypoxia, respiratory distress and coagulation defects, with onset during labour, caesarean section or within 30 min of delivery (Tuffnell 2005). The diagnosis must be made clinically and exclude other potential illnesses and entities with similar clinical presentation. There are variations in the definitions of AFE used between countries. AFE is often mistaken for sepsis, thromboembolic pulmonary embolism, acute coronary syndromes, because of the considerable overlap in their clinical features, making early diagnosis difficult. There are no universal criteria that include a clinical case definition and an algorithm for diagnosing suspected disease. Several investigators have reviewed the incidence of AFE using different definitions and various methods of case identification, including data-entry and medical coding, data-validation identification and discrepancy management (Moore and Baldisseri 2005). The incidence varied substantially in each country; it was approximately three times higher in the USA and Australia (5.5– 6.1 cases per 100,000 maternities) than in Europe (1.9–2.5 cases per 100,000 maternities) (Knight et al. 2012). The populationbased registration studies and death certificates may provide unreliable estimates of mortality, because the routinely registered cases were not designed to re-examine the clinical status to reduce false-positive diagnoses of this disorder (Knight et al. 2012). Cause-specific mortality ratios more accurately reflect the true rates than population-based study methods. The medicolegal autopsy databases from Japan confirmed that AFE was the
Correspondence: H. Kobayashi, Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara, 634–8522, Japan. E-mail, [email protected]
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Incidence, diagnosis and pathophysiology of amniotic fluid embolism most common cause of maternal death, accounting for 25% of maternal mortalities (Kanayama et al. 2011). AFE was the first, second and third leading cause of maternal deaths in Australia, the USA and Canada/France, respectively (Conde-Agudelo and Romero 2009). Internationally, sudden cardiopulmonary collapse and coagulopathy are the underlying medical conditions in most cases of AFE. Limitations of this study are that the incidence is dependent on efforts to detect and exclude the disease and multiple different entry criteria have existed for a long time due to the absence of an internationally recommended consensus. Database studies without case validation may include a number of false-positive cases. The validated case identification studies provide a detailed assessment of errors and the estimates may define more severe cases. For example, exclusion criteria of the UK surveillance studies included maternal haemorrhage as the first presenting feature. The quality of the database was validated. In contrast, the entry criteria in Japan were: onset of all of the signs and symptoms developed during pregnancy, labour, caesarean section or within 12 h postpartum. False-positive cases or over-estimation of incidence may include atonic postpartum haemorrhage and subsequent disseminated intravascular coagulation (DIC). The published incidence data might be changed when altered information regarding the timing of the event was added to entry criteria of AFE. In addition, depending on the definition, the reported AFE mortality rates ranged from 0.1 cases per 100,000 maternities (the Netherlands) to 1.1 per 100,000 maternities (Australia). The AFE case fatality rates also varied from 11% (the Netherlands) to 43% (Australia). Of the registered cases, maternal mortality was 61% in the USA in 1995 (Clark et al. 1995). Recent reports showed that maternal fatality rate was 35%, 27%, 20% and 11% in Australia (Roberts et al. 2010), Canada (Kramer et al. 2012), UK (Knight et al. 2010) and the Netherlands (Stolk et al. 2012), respectively. Decreasing rates of mortality likely reflect early recognition and high-quality aggressive supportive care (Rudra et al. 2009). Since atypical presentation, limitations in diagnostic scope, uncertain clinical diagnosis and clinical diagnostic errors may lead to underdiagnosis, the accuracy of death certificates issued for maternal deaths has been questioned. This finding consistently stressed the important role of autopsy in improving clinical practice in direct maternal mortality.
Comparison of clinical and autopsy diagnoses There may be substantial discrepancy between antemortem clinical diagnoses and postmortem pathological findings. To address this hypothesis, Kanayama et al. (2011) retrospectively assessed the accuracy of clinical diagnosis using 193 cases of autopsy results registered during the period 1989–2004 in the series of Annual of pathological autopsy cases in Japan. Despite an acceptable correspondence between clinical diagnosis and autopsy findings, some patients who were clinically diagnosed with non-AFE did actually show pathological signs of AFE (Kanayama et al. 2011). An interesting issue is that squamous cells in the pulmonary arterial circulation have been identified in 60% of pregnant women without AFE (Kuhlman et al. 1985), and even in non-pregnant women (Clark et al. 1986; Giampaolo et al. 1987), rendering the detection of squamous cells in the maternal pulmonary arterial circulation not sufficient for the diagnosis of AFE. Interestingly, the death certificate diagnosis, rendered before autopsy, was often atonic postpartum haemorrhage or DIC of unknown cause (Kanayama et al. 2011). Although common causes of excessive haemorrhage associated with parturition are uterine atony, abnormal placentation and uterine trauma, atonic
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postpartum haemorrhage and DIC are also devastating complications of AFE. Thus, some patients diagnosed with uterine atony could actually have AFE, leading to under-diagnosis of AFE in cases of uterine atony. One limitation is that the frequency cannot be accurately assessed because most patients were described in reports of a few selected patients and the number of cases reported was small. It is also unclear whether the atonic postpartum haemorrhage leading to the diagnosis of DIC preceded the signs and symptoms of AFE or was a consequence of AFE, i.e. occurred after its onset. Patients meeting entry criteria for AFE and proven pathological signs of fetal and amniotic fluid material contamination at autopsy could be diagnosed with AFE. The diagnosis of AFE depends on the clinical presentation rather than on histopathological examination. Therefore, some patients may be clinically diagnosed with AFE who did not actually show the pathological signs of AFE. If a patient meeting entry criteria for AFE had neither fetal antigens (e.g. squamous cells) nor amniotic fluid materials (e.g. mucin) at autopsy, one may diagnose that this patient died of non-AFE. Furthermore, if a patient, who had an antemortem clinical diagnosis of AFE, showed pathological signs of mucin contamination detected by Alcian blue staining, without apparent evidence of fetal antigens, could this patient meet criteria for AFE? The diagnosis with non-AFE might be made in the fetal antigen-negative case, because definite diagnosis can be confirmed by identification of lanugo, fetal hair and fetal squamous cells. On the other hand, if a patient who had a premortem clinical diagnosis of uterine rupture and subsequent DIC, showed pathological signs of fetal and amniotic fluid material contamination at autopsy, could the diagnosis of AFE be made? A single diagnosis of AFE based on histological findings would be risky because there is a possibility of it being misdiagnosed as AFE. Therefore, there remains some degree of over-diagnosis of AFE. It is unlikely that clinical management might have been different if the diagnosis of AFE had been made premortem.
Fetal and amniotic fluid materials contamination in uterine vasculatures Tsunemi et al. (2012) proposed tentatively classifying AFE into three subtypes designated: the classical subtype, the anaphylactoid subtype and the DIC subtype, each having a distinct pattern of clinical symptoms and disease severity. Since amniotic fluid leakage is a very serious complication of pregnancy, AFE may occur after entry of amniotic fluid through endocervical veins or through lacerations of the uterus or cervix. Many obstetricians in Japan believe that the survivors of AFE with pathological signs of fetal material contamination in uterine vasculatures at the time of peripartum hysterectomy samples should be diagnosed with AFE (Kobayashi 2010). Although cytological findings of fetal material in uterine vasculatures of survivors are assumed to be pathological, no histological studies have been reported in the uterus of patients diagnosed with non-AFE. More careful attention should be paid to the mechanism of amniotic fluid leakage into the uterine vasculatures and maternal circulation. Surprisingly, the entry of amniotic fluid components into the uterine vessel circulation was the common physiological mechanism during labour (Kobayashi 2012). Support for this hypothesis came from the works of several investigators. The vascular lumen of uterine endothelial cells contained amniotic squamous cells and mucoid material at term parturition (Leong et al. 2008). Fetal nucleated red blood cells were normally identified in maternal circulation in all pregnancies, indicating that intact fetal cells can migrate to the maternal circulation from placenta (Kobayashi
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2012; Ahmed and Abdullatif 2011). Populations of fetal cells and cell-free fetal DNA in maternal peripheral blood increased as gestation progressed (Kobayashi 2012). Furthermore, Benson et al. (2012) showed that maternal intravascular fetal materials were detected in the specimens of peripartum hysterectomy for haemorrhage. Fetal material and amniotic fluid passage into the maternal circulation may probably cause cardiopulmonary symptoms or coagulopathy through vasoactive chemical mediators causing pulmonary vascular constriction and immune mediators and coagulation factors, such as tissue factor, but does not invariably result in AFE or DIC. Several investigators reported that fetal antigens (squamous cells) and amniotic fluid materials were identified in blood sampled from the maternal pulmonary arterial circulation, irrespective of cases with and without the diagnosis of AFE (Kuhlman et al. 1985; Clark et al. 1986; Giampaolo et al. 1987). The introduction of an autopsy study would require careful assessment of clinical signs and symptoms for excluding sources of amniotic fluid leakage different to that of AFE. Although histological diagnosis is still the criterion standard for its detection, the diagnosis depends on the clinical presentation. A careful clinical history is basic. At present, there is no appropriate explanation for the mechanism of how AFE is triggered by the physiological entry of amniotic fluid and fetal material. One possible explanation for this could be that the cause of AFE-associated reactions seems to be classified by two hypotheses: an effect of amniotic fluid itself or a host idiosyncrasy (‘hypersensitivity’ reaction) (Tsunemi et al. 2012). AFE-associated reactions may depend on the causative components, including the meconium-stained or infectious bacteria in amniotic fluid. Host idiosyncrasy may be a major cause of hypersensitivity reaction, which is related to a combination of immunological and vasospastic factors.
and 97%, respectively. Furthermore, the ZnCP-1 assay yielding 73% specificity would still detect 46% of AFE cases. The ZnCP-1 method was more sensitive (46% vs 26%) and less specific (73% vs 97%) than the STN assay. The STN test had an excellent specificity, but false-positive results should be expected in the non-AFE cases, such as uterine dehiscence and rupture. Taken together, false-negative and false-positive results in certain populations are the main limitations to its clinical use. One major impediment to diagnose AFE is the current lack of biomarker with sufficient sensitivity and specificity. Several investigators have recently evaluated the diagnostic power of amniotic fluid-specific proteins and peptides as reliable and non-invasive diagnostic tests of obstetrical disorders, including not only AFE but also premature rupture of membranes (PROM). PROM, one of the most common complications of pregnancy, also has a major impact on pregnancy outcomes. Proteomic technologies have been predominantly used in the research to discover new amniotic fluid-specific biomarkers and establish a diagnostic pattern. This approach allowed us to identify several peptides as possible candidate biomarkers. In a recent study, the six antigens: interleukin (IL)-6, squamous cell carcinoma (SCC) antigen, insulin-like growth factor-binding protein (IGFBP)-1, osteopontin (OPN), CA125 and STN, were specifically overexpressed in amniotic fluid (Oi et al. 2010; Kobayashi et al. 2011). Among these candidate markers, the tests based on IL-6 or SCC seem to be more sensitive and specific bedside tests compared with the conventional STN and ZnCP-1 tests for the detection of entry of amniotic fluid into maternal circulation (Naruse et al. 2012). The maternal serum levels of IL-6 and SCC antigen should not be regarded as a useful marker to detect AFE, but rather, some of many candidates for specific laboratory tests. However, redefinition of AFE based on amniotic fluid-specific markers is not universally accepted.
Diagnostic value of amniotic fluid-specific markers The diagnosis of AFE is currently based on clinical signs and symptoms, because there is no blood marker available for its detection. An early detection for amniotic fluid leakage may help in predicting AFE and is crucial for effective triage and management of patients with suspected AFE. For this, a diagnostic tool that is non-invasive, specific, quick and reproducible is needed. In Japan, both zinc coproporphyrin-1 (ZnCP-1) and sialyl-Tn structure (STN, NeuAc alpha 2–6GalNAc alpha 1–O-Ser/Thr) that are characteristic components of amniotic fluid and meconium have been used for a long time as markers of amniotic fluid leakage into maternal circulation. Gourley et al. (1990) for the first time discovered ZnCP-1 in human meconium, a chelate of coproporphyrin I with Zn2⫹, as a meconium-specific substance. In 1992, the Terao’s group described the clinical usefulness of ZnCP-1 as a new indicator of the presence of meconium in the maternal circulation (Kanayama et al. 1992). The maternal serum levels of ZnCP-1 have been determined by high-pressure liquid chromatography. Furthermore, Kobayashi’s group for the first time discovered that STN is a specific and characteristic component in meconium and amniotic fluid in 1993 (Kobayashi et al. 1993). The STN concentration was determined by an immunoradiometric competitive inhibition assay. The STN assay, but not the ZnCP-1 measurement, can allow AFE to be diagnosed immediately after onset of clinical symptoms. Japan Association of Obstetricians and Gynecologists (JAOG) has recommended the use of ZnCP-1 and STN assays in patients with suspected AFE. The method for STN assay is simple, inexpensive and the results are reproducible (Kobayashi et al. 1993; Oi et al. 2010). The sensitivity and specificity of STN for detecting AFE was 26%
Pathophysiology and pathogenesis of AFE The literature dealing with the pathophysiology and pathogenesis of AFE is scattered among different clinicians and medical specialities. There are several phases of AFE. The initial wave of the entry of fetal antigens and amniotic fluid components into uterine vasculatures and maternal circulation would be followed by the second big wave of acute dyspnoea or hypotension. Coagulopathy and multiple end-organ system failure might comprise the last phase of AFE. Pathogenesis of the disease is still unclear, with the theories of the direct mechanical occlusion, anaphylactic reaction and complement activation. Historically, the theory of mechanical occlusion or physical obstruction attributes the symptoms of AFE to embolisation to the pulmonary circulation caused by a wide range of fetal antigens and amniotic fluid debris. Embolisation of a massive amount of amniotic fluid material may result in pulmonary hypertension and right-heart failure, often resulting in sudden cardiovascular collapse. Some studies demonstrated that this syndrome might result from the various chemical mediators, humoral factors and immunological reactions (Rudra et al. 2009). In 1956, Attwood for the first time proposed anaphylaxis as a mechanism of AFE. In 1985, Mulder gave an overview of AFE that was due to not only the mechanical obstruction but apparently also to an anaphylactoid reaction. In 1993, Benson suggested that AFE actually results from systemic anaphylaxis induced by small quantities of fetal materials leaking into the maternal circulation. Immediate hypersensitivity reaction in a patient presenting with anaphylaxis usually occurs in the form of acute urticaria, mucocutaneous swelling, angioedema, rhinitis and conjunctivitis. However, these
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Incidence, diagnosis and pathophysiology of amniotic fluid embolism symptoms are uncommon clinical problems even in confirmed AFE cases. The major part of AFE was thought to be the result of mast cell activation, a central feature of anaphylaxis (Fineschi et al. 1998). The known mediators include: tryptase, histamine, bradykinin, endothelin, leukotriene and arachidonic acid metabolites. A case report showed that postmortem serum of an AFE case showed an elevated tryptase level (Nishio et al. 2002). However, other studies did not support the hypothesis that anaphylaxis-dependent mast cell degranulation plays a central role in the pathophysiology of AFE (Benson 2012). Nor did Benson et al. (2001) find evidence to support the role of mast cell degranulation. Therefore, results of the tryptase assay were the subject of much controversy. Although parts of the clinical presentation suggested anaphylaxis, laboratory testing did not support this. In 1982 however, Vercellotti et al., in an experimental study, found that amniotic fluid could activate complement. The complement system plays a central role in the first-line of defence against invading pathogens, and its activation involves the release of potent pro-inflammatory mediators, such as anaphylatoxins C3a, C4a and C5a. Benson et al. (2001) in a small series reported that patients with AFE had abnormally low C3 and C4 complement concentrations, and defined the central role of the complement system in the pathophysiology of the disease in humans. This hypothesis remains to be proved in a large-scale study or in clinical practice. Similar to AFE, cardiac anaphylaxis is a severe, dangerous and life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs (Szebeni et al. 2006). Systemic complement activation can underlie cardiac anaphylaxis, because mast cells are abundant in the human heart and express receptors for C3a and C5a. Activated mast cells triggered by a variety of stimuli, including anaphylatoxins, which can induce the release of a variety of inflammatory mediators and vasoactive molecules. Cardiac mast cells express chymase and renin, which induce arteriolar vasoconstriction (Tsunemi et al. 2012). Interestingly, anaphylatoxins induced by complement activation were generated during hypersensitivity reactions clinically associated with cardiopulmonary collapse (del Balzo et al. 1989). These data suggest that amniotic fluid-induced complement activation functions as an amplification system in cardiac anaphylaxis of AFE (Tsunemi et al. 2012). We should explore the immunohistochemical trafficking of anaphylatoxins and their receptors within the uterus, heart and lung in the AFE cases. The process of AFE may consist of at least two steps. The first step is an induction of barrier breach between amniotic fluid and maternal blood, which can promote the entry of amniotic fluid components into the uterine vessel circulation during labor. The constituents of amniotic fluid include fetal antigens and amniotic fluid components, such as squamous cells, lanugo, debris and meconium mucins. Amniotic fluid influx to the maternal circulatory system may occur through the uterine cervical vein, placental site and damaged uterine site, such as cervical laceration. The second step is an immune and complement activation with the release of chemical mediators only in a very small fraction of patients. Fetal antigens and amniotic fluid materials may induce systemic complement activation, which can underlie cardiac anaphylaxis. It is presumed that entry of amniotic fluid into the maternal circulation occurs commonly, and the rarity of AFE strongly suggests a genetically determined immunemediated hypersensitivity reaction. The conventional thinking about the mechanisms of AFE has centred on the hypothesis that the idiosyncrasy arises from a specific immune response to the amniotic fluid material (Tsunemi et al. 2012). The term
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‘idiosyncrasy’ became ‘hypersensitivity’. Undetermined episodes or factors during parturition may decrease the threshold for hypersensitivity reaction and thereby render an individual susceptible to hypersensitivity reaction or idiosyncratic response that would not otherwise occur. During parturition, several events such as inflammation and tissue damage occur in many women. Inflammation may render only some individuals more sensitive. Injured tissue during parturition produces danger signals that evoke a toxic response in which neither fetal antigens nor amniotic fluid materials are necessary elements. Furthermore, hypersensitivity reactions may be influenced by genetic predisposition or polymorphisms of the mast cell-dependent complement activation in the heart. In conclusion, the pathophysiology of AFE is poorly understood at present. Although the similarities in clinical presentation between cardiac anaphylaxis and AFE exist, there is no direct evidence linking cardiac anaphylaxis to the initiation of AFE, especially in humans. One leading proposal suggests that the initial wave of the entry of amniotic fluid components into uterine vasculatures would be followed by the second big wave of complement activation and subsequent maternal death that occurs only in susceptible individuals. Pulmonary vascular constriction as a result of complement activation process may explain sudden hypoxia and respiratory arrest.
Conclusion This paper reviews the definition, incidence and diagnostic laboratory evaluation, along with the pathophysiological mechanisms of amniotic fluid embolism (AFE). There is still no universally accepted definition. The reported incidences vary depending on period, region of study and the definition. Although the pathogenic mechanisms underlying immediate reactions are not defined clearly, AFE is a severe, life-threatening, generalised or systemic hypersensitivity reaction. Necessary elements for AFE are fetal antigens and amniotic fluid materials, and their interplay with the immune system. Maternal mortality and morbidity occur only in susceptible individuals. AFE hypersensitivity appears to be an uncommon idiosyncratic clinical syndrome. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Supported by Grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan to the Department of Obstetrics and Gynecology, Nara Medical University (H. Kobayashi).
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OBSTETRICS
Incidence, diagnosis and pathophysiology of amniotic fluid embolism F. Ito, J. Akasaka, N. Koike, C. Uekuri, A. Shigemitsu & H. Kobayashi
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Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan
Amniotic fluid embolism (AFE) is a rare clinical entity, sometimes fatal. A review was conducted to describe the frequency, diagnosis and pathophysiology of AFE. The reported incidences ranged from 1.9 cases per 100,000 maternities (UK) to 6.1 per 100,000 maternities (Australia), which can vary considerably, depending on the period, region of study and the definition. Although the development of amniotic fluid-specific markers would have an impact on early diagnosis, definition of AFE based on these markers is not widely accepted. To date, immunological mechanisms, amniotic fluid-dependent anaphylactic reaction and complement activation, have been proposed as potential pathogenetic and pathophysiological mechanisms. Immune cell activation induced through complement activation may be associated with the mechanism that immediately initiates maternal death, only in susceptible individuals. This review will focus on advances in the field of AFE biology and discuss the prevalence, diagnosis and pathophysiology of AFE. Keywords: Amniotic fluid embolism, anaphylaxis, complement activation, incidence, pathophysiology
Introduction Amniotic fluid embolism (AFE) is a rare obstetric emergency, with potentially catastrophic consequences. AFE patients develop one or more of three key signs: cardiovascular collapse, respiratory distress and/or coagulopathy. This disorder may most commonly occur during labour, delivery, caesarean section, dilatation and evacuation, or in the immediate postpartum period (within 30 min postpartum) (Rudra et al. 2009; Tuffnell 2005). AFE accounts for an estimated 5–15% of all maternal deaths in developed countries. There are variations in the definitions of AFE used between countries (Moore and Baldisseri 2005). Since the underlying mechanism is still poorly understood, AFE remains a clinical diagnosis with potential errors in diagnosis (Gist et al. 2009; O’Shea and Eappen 2007). Therefore, it is difficult to obtain reliable information about incidence, risk factors, outcomes, management, pathophysiology and pathogenesis. The aim of this study is to review the definition, frequency, causes, pathophysiology and pathogenesis of AFE and raise awareness towards recent advancement in AFE research.
Materials and methods This present paper reviews the literature for clinical, biological, pathogenetic and pathophysiological studies on AFE. For studies
that reported data on other obstetric disorders, only data pertaining to AFE were included. A computerised literature search was performed to identify relevant studies reported in the English language. We initially searched PubMed MEDLINE electronic databases (www.ncbi.nlm.nih.gov/sites/entrez) for a 30-year period (1980–2010), combining the keywords ‘definition’, ‘incidence’, ‘pathogenesis’, ‘pathophysiology’ and ‘marker’ with ‘amniotic fluid embolism’. All abstracts were reviewed by two investigators to identify papers for full-text review. Additionally, references in each article were searched to identify potentially missed studies. Abstracts were not included.
Incidence and case fatality rate of AFE The reported incidences can vary considerably between studies and these differences may relate to the differences in the criteria used to define AFE (Moore and Baldisseri 2005). Amniotic fluid embolism remains an important public health concern and an emerging obstetric catastrophe in developed nations. It presents with one or more of the cardinal signs of acute hypotension or cardiac arrest, acute hypoxia, respiratory distress and coagulation defects, with onset during labour, caesarean section or within 30 min of delivery (Tuffnell 2005). The diagnosis must be made clinically and exclude other potential illnesses and entities with similar clinical presentation. There are variations in the definitions of AFE used between countries. AFE is often mistaken for sepsis, thromboembolic pulmonary embolism, acute coronary syndromes, because of the considerable overlap in their clinical features, making early diagnosis difficult. There are no universal criteria that include a clinical case definition and an algorithm for diagnosing suspected disease. Several investigators have reviewed the incidence of AFE using different definitions and various methods of case identification, including data-entry and medical coding, data-validation identification and discrepancy management (Moore and Baldisseri 2005). The incidence varied substantially in each country; it was approximately three times higher in the USA and Australia (5.5– 6.1 cases per 100,000 maternities) than in Europe (1.9–2.5 cases per 100,000 maternities) (Knight et al. 2012). The populationbased registration studies and death certificates may provide unreliable estimates of mortality, because the routinely registered cases were not designed to re-examine the clinical status to reduce false-positive diagnoses of this disorder (Knight et al. 2012). Cause-specific mortality ratios more accurately reflect the true rates than population-based study methods. The medicolegal autopsy databases from Japan confirmed that AFE was the
Correspondence: H. Kobayashi, Department of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara, 634–8522, Japan. E-mail, [email protected]
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Incidence, diagnosis and pathophysiology of amniotic fluid embolism most common cause of maternal death, accounting for 25% of maternal mortalities (Kanayama et al. 2011). AFE was the first, second and third leading cause of maternal deaths in Australia, the USA and Canada/France, respectively (Conde-Agudelo and Romero 2009). Internationally, sudden cardiopulmonary collapse and coagulopathy are the underlying medical conditions in most cases of AFE. Limitations of this study are that the incidence is dependent on efforts to detect and exclude the disease and multiple different entry criteria have existed for a long time due to the absence of an internationally recommended consensus. Database studies without case validation may include a number of false-positive cases. The validated case identification studies provide a detailed assessment of errors and the estimates may define more severe cases. For example, exclusion criteria of the UK surveillance studies included maternal haemorrhage as the first presenting feature. The quality of the database was validated. In contrast, the entry criteria in Japan were: onset of all of the signs and symptoms developed during pregnancy, labour, caesarean section or within 12 h postpartum. False-positive cases or over-estimation of incidence may include atonic postpartum haemorrhage and subsequent disseminated intravascular coagulation (DIC). The published incidence data might be changed when altered information regarding the timing of the event was added to entry criteria of AFE. In addition, depending on the definition, the reported AFE mortality rates ranged from 0.1 cases per 100,000 maternities (the Netherlands) to 1.1 per 100,000 maternities (Australia). The AFE case fatality rates also varied from 11% (the Netherlands) to 43% (Australia). Of the registered cases, maternal mortality was 61% in the USA in 1995 (Clark et al. 1995). Recent reports showed that maternal fatality rate was 35%, 27%, 20% and 11% in Australia (Roberts et al. 2010), Canada (Kramer et al. 2012), UK (Knight et al. 2010) and the Netherlands (Stolk et al. 2012), respectively. Decreasing rates of mortality likely reflect early recognition and high-quality aggressive supportive care (Rudra et al. 2009). Since atypical presentation, limitations in diagnostic scope, uncertain clinical diagnosis and clinical diagnostic errors may lead to underdiagnosis, the accuracy of death certificates issued for maternal deaths has been questioned. This finding consistently stressed the important role of autopsy in improving clinical practice in direct maternal mortality.
Comparison of clinical and autopsy diagnoses There may be substantial discrepancy between antemortem clinical diagnoses and postmortem pathological findings. To address this hypothesis, Kanayama et al. (2011) retrospectively assessed the accuracy of clinical diagnosis using 193 cases of autopsy results registered during the period 1989–2004 in the series of Annual of pathological autopsy cases in Japan. Despite an acceptable correspondence between clinical diagnosis and autopsy findings, some patients who were clinically diagnosed with non-AFE did actually show pathological signs of AFE (Kanayama et al. 2011). An interesting issue is that squamous cells in the pulmonary arterial circulation have been identified in 60% of pregnant women without AFE (Kuhlman et al. 1985), and even in non-pregnant women (Clark et al. 1986; Giampaolo et al. 1987), rendering the detection of squamous cells in the maternal pulmonary arterial circulation not sufficient for the diagnosis of AFE. Interestingly, the death certificate diagnosis, rendered before autopsy, was often atonic postpartum haemorrhage or DIC of unknown cause (Kanayama et al. 2011). Although common causes of excessive haemorrhage associated with parturition are uterine atony, abnormal placentation and uterine trauma, atonic
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postpartum haemorrhage and DIC are also devastating complications of AFE. Thus, some patients diagnosed with uterine atony could actually have AFE, leading to under-diagnosis of AFE in cases of uterine atony. One limitation is that the frequency cannot be accurately assessed because most patients were described in reports of a few selected patients and the number of cases reported was small. It is also unclear whether the atonic postpartum haemorrhage leading to the diagnosis of DIC preceded the signs and symptoms of AFE or was a consequence of AFE, i.e. occurred after its onset. Patients meeting entry criteria for AFE and proven pathological signs of fetal and amniotic fluid material contamination at autopsy could be diagnosed with AFE. The diagnosis of AFE depends on the clinical presentation rather than on histopathological examination. Therefore, some patients may be clinically diagnosed with AFE who did not actually show the pathological signs of AFE. If a patient meeting entry criteria for AFE had neither fetal antigens (e.g. squamous cells) nor amniotic fluid materials (e.g. mucin) at autopsy, one may diagnose that this patient died of non-AFE. Furthermore, if a patient, who had an antemortem clinical diagnosis of AFE, showed pathological signs of mucin contamination detected by Alcian blue staining, without apparent evidence of fetal antigens, could this patient meet criteria for AFE? The diagnosis with non-AFE might be made in the fetal antigen-negative case, because definite diagnosis can be confirmed by identification of lanugo, fetal hair and fetal squamous cells. On the other hand, if a patient who had a premortem clinical diagnosis of uterine rupture and subsequent DIC, showed pathological signs of fetal and amniotic fluid material contamination at autopsy, could the diagnosis of AFE be made? A single diagnosis of AFE based on histological findings would be risky because there is a possibility of it being misdiagnosed as AFE. Therefore, there remains some degree of over-diagnosis of AFE. It is unlikely that clinical management might have been different if the diagnosis of AFE had been made premortem.
Fetal and amniotic fluid materials contamination in uterine vasculatures Tsunemi et al. (2012) proposed tentatively classifying AFE into three subtypes designated: the classical subtype, the anaphylactoid subtype and the DIC subtype, each having a distinct pattern of clinical symptoms and disease severity. Since amniotic fluid leakage is a very serious complication of pregnancy, AFE may occur after entry of amniotic fluid through endocervical veins or through lacerations of the uterus or cervix. Many obstetricians in Japan believe that the survivors of AFE with pathological signs of fetal material contamination in uterine vasculatures at the time of peripartum hysterectomy samples should be diagnosed with AFE (Kobayashi 2010). Although cytological findings of fetal material in uterine vasculatures of survivors are assumed to be pathological, no histological studies have been reported in the uterus of patients diagnosed with non-AFE. More careful attention should be paid to the mechanism of amniotic fluid leakage into the uterine vasculatures and maternal circulation. Surprisingly, the entry of amniotic fluid components into the uterine vessel circulation was the common physiological mechanism during labour (Kobayashi 2012). Support for this hypothesis came from the works of several investigators. The vascular lumen of uterine endothelial cells contained amniotic squamous cells and mucoid material at term parturition (Leong et al. 2008). Fetal nucleated red blood cells were normally identified in maternal circulation in all pregnancies, indicating that intact fetal cells can migrate to the maternal circulation from placenta (Kobayashi
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2012; Ahmed and Abdullatif 2011). Populations of fetal cells and cell-free fetal DNA in maternal peripheral blood increased as gestation progressed (Kobayashi 2012). Furthermore, Benson et al. (2012) showed that maternal intravascular fetal materials were detected in the specimens of peripartum hysterectomy for haemorrhage. Fetal material and amniotic fluid passage into the maternal circulation may probably cause cardiopulmonary symptoms or coagulopathy through vasoactive chemical mediators causing pulmonary vascular constriction and immune mediators and coagulation factors, such as tissue factor, but does not invariably result in AFE or DIC. Several investigators reported that fetal antigens (squamous cells) and amniotic fluid materials were identified in blood sampled from the maternal pulmonary arterial circulation, irrespective of cases with and without the diagnosis of AFE (Kuhlman et al. 1985; Clark et al. 1986; Giampaolo et al. 1987). The introduction of an autopsy study would require careful assessment of clinical signs and symptoms for excluding sources of amniotic fluid leakage different to that of AFE. Although histological diagnosis is still the criterion standard for its detection, the diagnosis depends on the clinical presentation. A careful clinical history is basic. At present, there is no appropriate explanation for the mechanism of how AFE is triggered by the physiological entry of amniotic fluid and fetal material. One possible explanation for this could be that the cause of AFE-associated reactions seems to be classified by two hypotheses: an effect of amniotic fluid itself or a host idiosyncrasy (‘hypersensitivity’ reaction) (Tsunemi et al. 2012). AFE-associated reactions may depend on the causative components, including the meconium-stained or infectious bacteria in amniotic fluid. Host idiosyncrasy may be a major cause of hypersensitivity reaction, which is related to a combination of immunological and vasospastic factors.
and 97%, respectively. Furthermore, the ZnCP-1 assay yielding 73% specificity would still detect 46% of AFE cases. The ZnCP-1 method was more sensitive (46% vs 26%) and less specific (73% vs 97%) than the STN assay. The STN test had an excellent specificity, but false-positive results should be expected in the non-AFE cases, such as uterine dehiscence and rupture. Taken together, false-negative and false-positive results in certain populations are the main limitations to its clinical use. One major impediment to diagnose AFE is the current lack of biomarker with sufficient sensitivity and specificity. Several investigators have recently evaluated the diagnostic power of amniotic fluid-specific proteins and peptides as reliable and non-invasive diagnostic tests of obstetrical disorders, including not only AFE but also premature rupture of membranes (PROM). PROM, one of the most common complications of pregnancy, also has a major impact on pregnancy outcomes. Proteomic technologies have been predominantly used in the research to discover new amniotic fluid-specific biomarkers and establish a diagnostic pattern. This approach allowed us to identify several peptides as possible candidate biomarkers. In a recent study, the six antigens: interleukin (IL)-6, squamous cell carcinoma (SCC) antigen, insulin-like growth factor-binding protein (IGFBP)-1, osteopontin (OPN), CA125 and STN, were specifically overexpressed in amniotic fluid (Oi et al. 2010; Kobayashi et al. 2011). Among these candidate markers, the tests based on IL-6 or SCC seem to be more sensitive and specific bedside tests compared with the conventional STN and ZnCP-1 tests for the detection of entry of amniotic fluid into maternal circulation (Naruse et al. 2012). The maternal serum levels of IL-6 and SCC antigen should not be regarded as a useful marker to detect AFE, but rather, some of many candidates for specific laboratory tests. However, redefinition of AFE based on amniotic fluid-specific markers is not universally accepted.
Diagnostic value of amniotic fluid-specific markers The diagnosis of AFE is currently based on clinical signs and symptoms, because there is no blood marker available for its detection. An early detection for amniotic fluid leakage may help in predicting AFE and is crucial for effective triage and management of patients with suspected AFE. For this, a diagnostic tool that is non-invasive, specific, quick and reproducible is needed. In Japan, both zinc coproporphyrin-1 (ZnCP-1) and sialyl-Tn structure (STN, NeuAc alpha 2–6GalNAc alpha 1–O-Ser/Thr) that are characteristic components of amniotic fluid and meconium have been used for a long time as markers of amniotic fluid leakage into maternal circulation. Gourley et al. (1990) for the first time discovered ZnCP-1 in human meconium, a chelate of coproporphyrin I with Zn2⫹, as a meconium-specific substance. In 1992, the Terao’s group described the clinical usefulness of ZnCP-1 as a new indicator of the presence of meconium in the maternal circulation (Kanayama et al. 1992). The maternal serum levels of ZnCP-1 have been determined by high-pressure liquid chromatography. Furthermore, Kobayashi’s group for the first time discovered that STN is a specific and characteristic component in meconium and amniotic fluid in 1993 (Kobayashi et al. 1993). The STN concentration was determined by an immunoradiometric competitive inhibition assay. The STN assay, but not the ZnCP-1 measurement, can allow AFE to be diagnosed immediately after onset of clinical symptoms. Japan Association of Obstetricians and Gynecologists (JAOG) has recommended the use of ZnCP-1 and STN assays in patients with suspected AFE. The method for STN assay is simple, inexpensive and the results are reproducible (Kobayashi et al. 1993; Oi et al. 2010). The sensitivity and specificity of STN for detecting AFE was 26%
Pathophysiology and pathogenesis of AFE The literature dealing with the pathophysiology and pathogenesis of AFE is scattered among different clinicians and medical specialities. There are several phases of AFE. The initial wave of the entry of fetal antigens and amniotic fluid components into uterine vasculatures and maternal circulation would be followed by the second big wave of acute dyspnoea or hypotension. Coagulopathy and multiple end-organ system failure might comprise the last phase of AFE. Pathogenesis of the disease is still unclear, with the theories of the direct mechanical occlusion, anaphylactic reaction and complement activation. Historically, the theory of mechanical occlusion or physical obstruction attributes the symptoms of AFE to embolisation to the pulmonary circulation caused by a wide range of fetal antigens and amniotic fluid debris. Embolisation of a massive amount of amniotic fluid material may result in pulmonary hypertension and right-heart failure, often resulting in sudden cardiovascular collapse. Some studies demonstrated that this syndrome might result from the various chemical mediators, humoral factors and immunological reactions (Rudra et al. 2009). In 1956, Attwood for the first time proposed anaphylaxis as a mechanism of AFE. In 1985, Mulder gave an overview of AFE that was due to not only the mechanical obstruction but apparently also to an anaphylactoid reaction. In 1993, Benson suggested that AFE actually results from systemic anaphylaxis induced by small quantities of fetal materials leaking into the maternal circulation. Immediate hypersensitivity reaction in a patient presenting with anaphylaxis usually occurs in the form of acute urticaria, mucocutaneous swelling, angioedema, rhinitis and conjunctivitis. However, these
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Incidence, diagnosis and pathophysiology of amniotic fluid embolism symptoms are uncommon clinical problems even in confirmed AFE cases. The major part of AFE was thought to be the result of mast cell activation, a central feature of anaphylaxis (Fineschi et al. 1998). The known mediators include: tryptase, histamine, bradykinin, endothelin, leukotriene and arachidonic acid metabolites. A case report showed that postmortem serum of an AFE case showed an elevated tryptase level (Nishio et al. 2002). However, other studies did not support the hypothesis that anaphylaxis-dependent mast cell degranulation plays a central role in the pathophysiology of AFE (Benson 2012). Nor did Benson et al. (2001) find evidence to support the role of mast cell degranulation. Therefore, results of the tryptase assay were the subject of much controversy. Although parts of the clinical presentation suggested anaphylaxis, laboratory testing did not support this. In 1982 however, Vercellotti et al., in an experimental study, found that amniotic fluid could activate complement. The complement system plays a central role in the first-line of defence against invading pathogens, and its activation involves the release of potent pro-inflammatory mediators, such as anaphylatoxins C3a, C4a and C5a. Benson et al. (2001) in a small series reported that patients with AFE had abnormally low C3 and C4 complement concentrations, and defined the central role of the complement system in the pathophysiology of the disease in humans. This hypothesis remains to be proved in a large-scale study or in clinical practice. Similar to AFE, cardiac anaphylaxis is a severe, dangerous and life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs (Szebeni et al. 2006). Systemic complement activation can underlie cardiac anaphylaxis, because mast cells are abundant in the human heart and express receptors for C3a and C5a. Activated mast cells triggered by a variety of stimuli, including anaphylatoxins, which can induce the release of a variety of inflammatory mediators and vasoactive molecules. Cardiac mast cells express chymase and renin, which induce arteriolar vasoconstriction (Tsunemi et al. 2012). Interestingly, anaphylatoxins induced by complement activation were generated during hypersensitivity reactions clinically associated with cardiopulmonary collapse (del Balzo et al. 1989). These data suggest that amniotic fluid-induced complement activation functions as an amplification system in cardiac anaphylaxis of AFE (Tsunemi et al. 2012). We should explore the immunohistochemical trafficking of anaphylatoxins and their receptors within the uterus, heart and lung in the AFE cases. The process of AFE may consist of at least two steps. The first step is an induction of barrier breach between amniotic fluid and maternal blood, which can promote the entry of amniotic fluid components into the uterine vessel circulation during labor. The constituents of amniotic fluid include fetal antigens and amniotic fluid components, such as squamous cells, lanugo, debris and meconium mucins. Amniotic fluid influx to the maternal circulatory system may occur through the uterine cervical vein, placental site and damaged uterine site, such as cervical laceration. The second step is an immune and complement activation with the release of chemical mediators only in a very small fraction of patients. Fetal antigens and amniotic fluid materials may induce systemic complement activation, which can underlie cardiac anaphylaxis. It is presumed that entry of amniotic fluid into the maternal circulation occurs commonly, and the rarity of AFE strongly suggests a genetically determined immunemediated hypersensitivity reaction. The conventional thinking about the mechanisms of AFE has centred on the hypothesis that the idiosyncrasy arises from a specific immune response to the amniotic fluid material (Tsunemi et al. 2012). The term
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‘idiosyncrasy’ became ‘hypersensitivity’. Undetermined episodes or factors during parturition may decrease the threshold for hypersensitivity reaction and thereby render an individual susceptible to hypersensitivity reaction or idiosyncratic response that would not otherwise occur. During parturition, several events such as inflammation and tissue damage occur in many women. Inflammation may render only some individuals more sensitive. Injured tissue during parturition produces danger signals that evoke a toxic response in which neither fetal antigens nor amniotic fluid materials are necessary elements. Furthermore, hypersensitivity reactions may be influenced by genetic predisposition or polymorphisms of the mast cell-dependent complement activation in the heart. In conclusion, the pathophysiology of AFE is poorly understood at present. Although the similarities in clinical presentation between cardiac anaphylaxis and AFE exist, there is no direct evidence linking cardiac anaphylaxis to the initiation of AFE, especially in humans. One leading proposal suggests that the initial wave of the entry of amniotic fluid components into uterine vasculatures would be followed by the second big wave of complement activation and subsequent maternal death that occurs only in susceptible individuals. Pulmonary vascular constriction as a result of complement activation process may explain sudden hypoxia and respiratory arrest.
Conclusion This paper reviews the definition, incidence and diagnostic laboratory evaluation, along with the pathophysiological mechanisms of amniotic fluid embolism (AFE). There is still no universally accepted definition. The reported incidences vary depending on period, region of study and the definition. Although the pathogenic mechanisms underlying immediate reactions are not defined clearly, AFE is a severe, life-threatening, generalised or systemic hypersensitivity reaction. Necessary elements for AFE are fetal antigens and amniotic fluid materials, and their interplay with the immune system. Maternal mortality and morbidity occur only in susceptible individuals. AFE hypersensitivity appears to be an uncommon idiosyncratic clinical syndrome. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Supported by Grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan to the Department of Obstetrics and Gynecology, Nara Medical University (H. Kobayashi).
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