Amniotic Fluid Embolism: An Update of the Evidence

This article reviews the current evidence on amniotic fluid embolism (AFE), focusing on epidemiology, pathogenesis, clinical presentation, diagnosis and treatment. AFE is a rare and life-threatening obstetric condition, occurring in 2 to 8 per 100 000 births. With a mortality of 0.5 to 1.7 deaths per 100,000 deliveries in the developed world and 1.9 to 5.9 deaths per 100,000 deliveries in the developing world, it is among the leading direct causes of maternal death. Furthermore, persistent neurological impairment has been reported in 6-61% of survivors. Even though there is no shared pathogenetic theory for AFE, the transfer of amniotic fluid components in the maternal circulation may lead either to an inflammatory-mediated anaphylactoid response or to complement activation. There is great variability in the presentation of AFE from classical cardiopulmonary collapse with coagulopathy to minor and subclinical presentations. In severe cases, AFE should be distinguished from other acute and life-threatening emergencies, such as pulmonary embolism, myocardial infarction and peripartal cardiomyopathy. Thus, the diagnosis is one of exclusion, very often on post-mortem report. In fact, several diagnostic biomarkers have been proposed, but they have not been established in routine clinical diagnosis. Prompt recognition of the symptoms and immediate interdisciplinary management are pivotal for prognosis. The traditional treatment is supportive and aimed at treating cardiovascular, pulmonary, and coagulation derangements. Recently, novel treatment strategies have been proposed in the field of invasive hemodynamic support and C1 esterase inhibitors represent a potential therapeutic option. However, due to the lack of specific diagnostic tests, the difficulty of establishing the diagnosis and excluding competing diagnoses, and the complex treatment required, AFE still remains a major clinical challenge.


Introduction
Amniotic fluid embolism (AFE) is a rare and incompletely understood condition that is unique to pregnancy. This disease is characterized by the sudden onset of maternal compromise generally involving the cardio-respiratory and haematological systems, which can rapidly progress to cardiac arrest and profound coagulopathy, leading to death [1]. In this review we aim to extend our previous work, by summarizing the current evidence concerning epidemiology, pathogenesis, diagnosis, and management for AFE [2].

Epidemiology
Provided the fact that reliable data are difficult to obtain due to heterogeneous diagnostic criteria, the incidence rate is estimated to range from 2 to 8 per 100 000 births in different countries [3,4]. However, a lower incidence (1.7 per 100 000 births) has been reported in a prospective population-based study, collecting data of 7001438 maternities in the period between 1 February 2005 and 31 January 2014 in the United Kingdom [5].
AFE is one of the leading causes of death resulting directly from childbirth, as it accounts for 5% to 15% of cases worldwide [3]. It is a more frequent cause of death in the developed countries, while it is not dominant in developing ones [6]. The case-related maternal mortality is estimated to range between 0.5 to 1.7 deaths per 100,000 deliveries in the developed world and 1.9 to 5.9 deaths per 100,000 deliveries in the developing world [6]. Based on the recent United Kingdom Obstetric Surveillance System (UKOSS) report, maternal mortality rate is even lower and accounts for 0.3 per 100 000 maternities5. On the grounds of previous data, the rate of perinatal mortality seemed to range between 7% and 38%, but it has been recently estimated to be 6.7% in the UK. This datum is still significantly higher than the national perinatal mortality rate of 0.75% [5,7].
Between 24% and 50% of surviving children suffer from persistent neurological deficits [8]. As compared to AFE being diagnosed before or at delivery, diagnosis of AFE in the postpartum period seems to predispose significantly to perinatal death, need for intensive neonatal care and major complications [5].

Pathogenesis and Pathophysiology
The pathogenesis of AFE has not been clarified yet. Amniotic fluid (AF) can enter the maternal circulation via endocervical veins, lesions of the uterus, or the site of placental attachment and was once thought to cause a purely mechanical obstruction of the pulmonary vessels [1]. Nowadays there are two current pathogenetic theories for AFE. According to the "anaphylactoid reaction hypothesis", AF contains vasoactive (bradykinin, histamine, and others) and procoagulant substances that can lead to endothelial activation and cause a massive inflammatory reaction [9]. Evidence supporting this hypothesis focuses on the role of β-tryptase, a serine protease contained into mast cell granules, whose levels rise both in anaphylaxis and in other allergic states. It has been proved that serum tryptase levels are not necessarily above the upper limit in fatal cases of AFE. However, the detection of a significantly higher number of mast cells and significantly higher levels of tryptase at pulmonary level in fatal AFE cases supports mast cell degranulation as the physiopathological mechanism of AFE [9]. On the other hand, the activation of complement could be responsible for the onset of AFE. In fact, complement levels are reported not to undergo a significant change during normal labour, even though they fall immediately after birth [9]. Therefore, abnormally low levels of C3 and C4 detected in AFE cases are suggestive of complement activation, either through the classical or alternative pathway [9,10]. The susceptibility of women to develop AFE after the transfer of AF or its components may depend on allergic diatheses or previous sensitization to specific fetal antigens [11]. Nevertheless, no related theory based on reliable evidence has been widely accepted nor have amniotic fluid-specific markers been developed, so far. AFE occurs during labor and delivery/Cesarean section (55% to 76% antenatally) or up to 48 h postpartum [12]. It may rarely occur during pregnancy following intrauterine surgery (e.g. abortion), blunt abdominal trauma or amniocentesis [3,13]. Several risk factors may predispose to AFE, including maternal age ≥ 35 years, placenta previa and multiple pregnancies [5,12]. Additionally, instrumental vaginal and caesarean deliveries are associated with the occurrence of AFE post-natally [5]. In fact, the rupture of the membranes followed by the inflow of amniotic fluid into maternal circulation occurs easily in cases of cesarean delivery, forceps/vacuum delivery, placenta previa, abruption placenta and eclampsia, because these conditions are ascribed to injury of the birth canal or injury of trophoblasts [14]. In keeping with this assumption, 91% women had ruptured membranes at or before AFE presentation in the recent UKOSS survey [5]. According to recent data, even labor induction seems to predispose to AFE [5,12]. Interestingly, there is no evidence of a temporal change in the incidence of or risk factors for AFE in recent times [5].
The first phase of AFE develops within 30-60 min after the onset of clinical symptoms. Pulmonary vasoconstriction and acute pulmonary hypertension lead to acute right heart failure with dilatation of the right ventricle and severe tricuspid insufficiency. Altered pulmonary perfusion and damage to the gas exchange surfaces caused by inflammation result in respiratory failure. In the second phase of AFE, reactive hypovolemia, cardiodepressive humoral factors from the AF and myo-cardial ischemia may cause acute left heart failure with consequent pulmonary edema (51% to 100%). Neurological sequelae and multi-organ failure depend from subsequent hypotension and hypoxia [3]. In 30% to 45% of patients coagulopathy develops with severe bleeding resulting from disseminated intravascular coagulation (DIC). Such a phenomenon may develop in two alternative ways: on the one hand, the procoagulant substances contained in the AF may activate the extrinsic coagulation cascade on the other hand, urokinase-like plasminogen activator and plasminogen activator 1 contained in the AF may trigger massive hyperfibrinolysis [9,11,15].
According to recent UKOSS data, AFE presented at or before delivery in 53% of women, at a median gestation of 39 weeks (range 28-42 weeks); 47% presented with AFE a median of 19 min after delivery (range 1 min to 6 h 27 min) having delivered at a median gestation of 39 weeks (range 28-42 weeks) [5].

Diagnosis
The diagnosis of AFE is based on clinical symptoms. In fact, zinc coproporphyrin, sialyl-Tn antigen, tryptase or C3 and C4 complement and detection of insulin-like growth factor binding protein-1 appear promising diagnostic markers for AFE, but they have not been established in routine clinical diagnosis [3]. Furthermore, hemodynamic parameters, ECG, blood gas analysis, chest X-ray and laboratory tests (including blood count,

ISSN 2471-9641
Vol.2 No.2:6 cardiac enzymes, and coagulation tests) and specific tests such as trans-esophageal echocardiography (TEE) and rotational thromboelastometry play a limited role in diagnosis and should be used instead for monitoring and treatment optimization. Thus, the diagnosis of AFE is one of exclusion and should be considered in every case of sudden maternal cardiovascular collapse and/or maternal death in childbirth with unexplained etiology. Although there are no general accepted criteria for diagnosis, reliable parameters were proposed by Benson et al. and later on by the UKOSS study12 (Table 1). According to recent data, at presentation, women had a median of four of the features of AFE and the diagnosis, including both antenatal and postnatal cases, was first considered a median of 33 min (range 0 min to 2 days) after presentation [5]. Differential diagnoses include pulmonary embolism (PTE), myocardial infarction and peripartal cardiomyopathy. The first differs most markedly from AFE in its typical risk factors, chest pain, rarer initial hypotension and usually the absence of coagulopathy. In fact, in PTE, fibrinogen level decreases and Ddimer level rises with increasing pulmonary occlusion rate, but hypofibrinogenemia (defined as <0.5 g/L) is seldom seen in patients with PTE [17].
Unfortunately, the diagnosis is very often a post-mortem report in case of sudden death during childbirth. In this case, careful histological examination reveals formed AF components such as usually lamellar, adjacent epidermal squames, meconium components, or lanugo hairs in the pulmonary blood flow [12]. AFE can be ruled out if no histological evidence of AF components in the lung is provided in the first three days following clinical manifestation of AFE and maternal death.

Management
A multidisciplinary team including anaesthesia, respiratory therapy, critical care, and maternal-fetal medicine is recommended. The mainstay of the treatment includes the following procedures: 1) Safeguard the airways: endotracheal intubation and early sufficient oxygenation should be performed using an optimized Fi02: PEEP (positive end-expiratory pressure) ratio. Reliable prevention against aspiration is essential.
3) Laboratory tests: coagulation tests, cross-matching, blood gas analysis, and -if available-rotational thromboelastometry (to distinguish between hemostatic disorders and assess their severity) should be checked.

7)
Maternal post-partum care is based on several procedures, including: I) prevention of atony through immediate administration of uterotonics and hysterectomy in case of treatment refractarity [7]; II) differentiated use of catecholamines optimized using TEE [16] and possible additional inotropy support; III) cardiac pump function monitoring [16]; IV) prompt optimization of coagulation status through initial administration of tranexamic acid to treat hyperfibrinolysis and subsequent use of fibrinogen concentrate (for fibrinogen levels below 2 g/L) possibly using rotational thromboelastometry [18]; V) Replacement of red blood cell concentrates and fresh-frozen plasma (FFP) according to blood loss/severity of bleeding and in line with the risk profile of the patient, paying attention to volume overload that can possibly lead to pulmonary oedema (Optimal RBC to FFP ratio 1:1-1.5 [14]; VI) administration of recombinant factor VIIa if the above treatments are ineffective for improving DIC [14].
In a scenario in which AFE management only includes supportive and palliative measures, novel treatment strategies have also been proposed. Antithrombin concentrates may improve outcomes in patients with AFE that develop coagulopathy [19]. On the contrary, heparin is not recommended because of the high risk of massive hemorrhage in the setting of AFE14. Invasive hemodynamic support may be considered when institutionally available in patients unresponsive to initial resuscitative interventions. . Therefore, the Authors proposed C1INH administration as a therapeutic option. In fact, C1INH is capable not only of inhibiting the complement system but also of modulating the coagulo-fibrinolytic kallikrein-kinin systems.
Recently, C1INH was successfully used in a patient presenting uterine atony, shock vitals and bleeding tendency. No anti-DIC agent (fibrinogen, antithrombin or FFP) was applied before the administration of C1INH concentrate; however, the levels of blood fibrinogen and antithrombin showed marginal change and increased, suggesting the independent effect of C1INH to cease the progression of DIC from AFE [28].
In addition to that, Evans and coll. achieved successful restoration of spontaneous circulation in a case of AFE complicated by pulseless electrical activity, through the use of sodium bicarbonate. On the grounds of their results, the Authors suggested to use sodium bicarbonate in the cases of suspected AFE that are characterized by evident right ventricular failure on TEE and acidosis and/or hypercarbia and do not respond to normal advanced life support measures. This substance is supposed to reduce the pulmonary vascular resistance directly, allowing the failing right ventricle to restore forward flow [29]. The efficacy of sodium bicarbonate had not been proved in previous reports, tough this could be due to the fact that TEE was never used during the initial resuscitation [30].

Prognosis
More than half of the patients (56%) die in the initial phase (0-23 h after initial clinical manifestations) [12], with death occurring a median of 1 h and 42 min after AFE presentation [5]. The leading causes of maternal death in the second phase are sudden cardiac arrest, hemorrhage resulting from coagulopathy or acute respiratory distress syndrome, and/or multiple organ failure [3]. Recently, the prognostic role of cardiac arrest has been emphasized: it seems to be significantly related to fatal outcome and permanent neurological injury, especially in the cases in which it is the first recognized symptom or sign of AFE5. Among survivors, persistent neurological impairment has been reported in 6-61% of women [8]. As pointed out by Fitzpatrick and coll., fatal outcome and permanent neurological injury are significantly related to cryoprecipitate administration, hysterectomy, shorter time interval between the AFE event and hysterectomy and ethnic provenance (black or other minority ethnic groups) [5].
Early diagnosis and aggressive treatment are the most critical factors associated with survival. The initial goal of the treatment is the rapid correction of maternal hemodynamic instability, ideally operated within an intensive care unit (ICU) by an interdisciplinary team. Accordingly, Fitzpatrick and coll reported that 90% of women who survived were admitted to an intensive therapy unit/high-dependency unit [5].

Conclusion
Despite a deeper understanding of its pathophysiology and risk factors, AFE still represents a diagnostic and therapeutic challenge. In the absence of reliable diagnostic markers, AFE should be diagnosed on the grounds of clinical manifestations that are often heterogeneous and unspecific. A prompt identification of the symptoms and a multidisciplinary management play a key role to prevent death and permanent neurological deficits. While supportive procedures constitute the mainstay of clinical management, novel treatment options are promising, but need further evaluation before being included in the therapeutic armamentarium.