Amniotic fluid embolism.

Amniotic fluid embolism (AFE) is an unpredictable and as-of-yet unpreventable complication of maternity. With its low incidence it is unlikely that any given practitioner will be confronted with a case of AFE. However, this rare occurrence carries a high probability of serious sequelae including cardiac arrest, ARDS, coagulopathy with massive hemorrhage, encephalopathy, seizures, and both maternal and infant mortality. In this review the current state of medical knowledge about AFE is outlined including its incidence, risk factors, diagnosis, pathophysiology, and clinical manifestations. Special attention is paid to the modern aggressive supportive care that resulted in an overall reduction in the still alarmingly high mortality rate of this devastating entity. The key factors for successful management and resolution of this disease process continue to be sharp vigilance, a high level of clinical suspicion, and rapid all-out resuscitative efforts on the part of all clinicians involved in the medical care of the parturient.

INTRODUCTION

Amniotic fluid embolism (AFE) is a rare event that affects parturients during delivery or in the immediate postpartum period. Clinical sequelae of this unpredictable and unpreventable entity are often devastating with significant associated morbidity and mortality.[1] Its first modern description was published in the 1920's[2] with a further report recognizing AFE as a syndrome in the 1940s.[34] The reported incidence of AFE is between 0.001% and 0.013% among patients admitted for delivery.[56] Due to the uncommon occurrence of AFE the need exists for a high level of clinical suspicion among practitioners. Although specialists in obstetrics are the most likely to encounter this clinical entity; emergency medicine physicians, surgeons, anesthesiologists, and intensivists should also be familiar with the diagnosis and management of AFE. In this review we discuss the pathophysiology, clinical presentation, and diagnostic and therapeutic considerations associated with AFE. We also highlight the critical care aspects of affected patient care, and focus on the high index of clinical suspicion required to promptly recognize and treat this cause of 10-26% of maternal deaths.[378]

INCIDENCE OF AMNIOTIC FLUID EMBOLISM

The reported incidence of AFE varies because of a wide spectrum of presenting signs and symptoms, as well as lack of a standardized approach to diagnostic evaluation of patients with suspected AFE. As previously enumerated, the incidence of AFE is fortunately low, between 1.9 and 11 per 100,000 admissions for delivery.[35] This translates roughly into a relatively broad range of 1 in 4,500 to 1 in 80,000 pregnancies.[56] The incidence of AFE was reported to be significantly higher in patients who had cesarean section (22/100,000 deliveries) than in patients who had vaginal delivery (8/100,000).[6] The incidence is also significantly higher in women aged 30-39 years (17/100,000) than in women aged 15-29 years (8/100,000).[6] Despite relatively unchanged incidence, it has been noted that the mortality associated with AFE has decreased significantly in the recent past.[7]

Pathophysiology of amniotic fluid embolism

Amniotic fluid embolism syndrome is thought to occur through three different pathophysiologic mechanisms. These three contributory pathways are: (a) mechanical obstruction of vessels caused by AFE; (b) a subsequent inflammatory effect by AFE on the maternal circulatory system; and (c) an as of yet poorly understood immunologic mechanism.

The clinical syndrome itself is precipitated when amniotic fluid is able to breach the physical barrier between the maternal and fetal environments as a result of uterine trauma. Autopsy reports from fatal cases of AFE report epithelial squamous cells, lanugo hair, and fat from vernix or infantile mucin in the maternal pulmonary vasculature. Commonly suspected sites of amniotic fluid entry into the maternal circulation are small tears in the endocervix and lower uterine segment – both frequently seen during labor and delivery.[9] Amniotic fluid, once forced into the maternal systemic circulation, may lead to circulatory obstruction, including that of the pulmonary circulation.[4910]

There is evidence that once AFE has occurred certain biochemical mediators associated with it can trigger systemic inflammatory responses. Clinical manifestations of AFE may be similar to that of anaphylactic or septic shock. In fact, Clark et al.[11] proposed changing the name of the syndrome from “amniotic fluid embolus” to “anaphylactoid syndrome of pregnancy”. Amniotic fluid has both vasoactive and procoagulant characteristics that have been proposed to be mediated by prostaglandins, endothelin, platelet activating factor, leukotrienes, bradykinin and tissue factor.[910] Consequently, clinical manifestations of AFE including coagulopathy, increased vascular permeability, vasoconstriction of pulmonary, systemic and coronary vessels, and bronchospasm could all be seen to proceed by a humoral mechanism.[10]

A possible immunologic mechanism has been proposed as a third contributing factor, based on the many similarities that exist between clinical and hemodynamic findings of AFE and anaphylactic shock.[12] The complement system may play a role in this mechanism of the AFE syndrome.[1314] However, our understanding of the immunologic pathophysiology of AFE is in its early stages and further work needs to be done.

Amniotic fluid embolism: Risk factors

The United Kingdom Obstetric Surveillance System [UKOSS] reported that elevated risk for AFE is associated with the following factors: (a) induction of labor (relative risk of 3.86); (b) Caesarean section (relative risk of 12.5); (c) placenta previa and placental abruption (3-10 times greater risk); (d) eclampsia; (e) multiple pregnancies; and (f) maternal age ≥35 years (possibly related to abnormal placental invasion and predisposition to disruption of the uterine vasculature).[15] These findings suggest that if induction and caesarean section were avoided the incidence AFE could be significantly reduced. It has also been observed that patient age <19 years may confer a protective effect against the syndrome. Direct attribution of AFE to any one of these factors is probably an oversimplification and other variables are likely involved.

Clinical manifestations

Amniotic fluid embolism can take a variety of clinical presentations [Table 1], making it truly a “great mimicker” of various other disease states. The sequelae of AFE can be truly devastating, and it can affect many organ systems. There may be little to no warning signs preceding the full-blown syndrome. It usually occurs as a complication of childbirth, presenting during delivery, immediately postpartum, or as late as 48 hours after. It can also occur at other points during pregnancy, including during transabdominal amniocentesis, cervical suture removal, and as a result of blunt abdominal trauma.[1516]

Table 1

Common signs and symptoms associated with amniotic fluid embolism

Classic presenting signs and symptoms may include sudden anxiety, agitation, dyspnea, hypotension, cyanosis, cardiopulmonary arrest, coagulopathy, and seizures.[15] It is not uncommon for AFE to progress rapidly from a sudden decrease in oxygen saturation and end-tidal carbon dioxide, to the development of cardiovascular collapse. In the later phase, coagulopathy and hemorrhage can occur. Disseminated intravascular coagulation (DIC) should also be considered, though it is not seen universally among patients with AFE. Finally, tissue injury and multi organ failure occur. Currently, no reliable preventive approaches for AFE are known, but the authors strongly encourage practitioners to be familiar with established risk factors and implement this knowledge in their practices.

Atypical manifestations of AFE can take a number of forms. One such form includes isolated coagulopathy with either a sudden or a gradual onset. The report of maternal deaths within the UK found that parturients who died from AFE frequently had premonitory symptoms before complete collapse including feeling cold, restlessness, and respiratory distress. This may give a clue to diagnosis, before cardiac arrest and DIC occur.[17]

Progression of systemic changes in AFE

The acute phase

Occurs within the initial 30 minutes. Amniotic fluid and fetal cells in the circulation can cause severe pulmonary hypertension secondary to pulmonary vasoconstriction with resulting right heart failure, hypotension and hypoxemia. In AFE hypoxemia is the most common manifestation of respiratory failure. This occurs because of severe ventilation/perfusion (V/Q) mismatch associated with acute pulmonary hypertension, although hypoventilation can also occur.[1819] The initial acute hypoxemia can lead to ischemic myocardial injury and this can be aggravated by the effect of direct myocardial depressant factors present in the amniotic fluid. The influence of humoral factors can contribute to inflammatory capillary leak, leading to non-cardiogenic pulmonary edema and bronchospasm.[1120] Victims of AFE frequently succumb during the acute phase of the insult.[21]

The late phase

This phase is seen in survivors of the acute phase. The acute insult of AFE can be followed by the development of left heart failure within an hour. This left heart failure is likely secondary to the leftward shift of the interventricular septum because of right heart failure/strain. Severe hypotension results - compounded by the active vasodilatory process, and hemorrhage (if present). Primary lung injury (from mechanical circulatory obstruction or inflammatory/immunologic mechanisms) often leads to acute respiratory distress syndrome (ARDS).[22]

Coagulopathy is related to either a consumptive process or massive fibrinolysis. Lockwood et al. found a procoagulant tissue factor in the amniotic fluid that can trigger the coagulation cascade.[23] Coagulopathy may be one of the most prominent signs of AFE, it usually appears within 4 hours of the initial presentation. The end result may be massive bleeding similar to that seen in disseminated intravascular coagulation, which may in fact be present. The development of hemorrhagic shock is a distinct possibility.

One of the most devastating long-term consequences of AFE is neurologic dysfunction. As many as 85% of survivors demonstrate residual neurologic deficits.[3] In fact, neurologic complications often represent the most severe of post-AFE sequelae. It is thought that both the encephalopathy and seizures associated with AFE are secondary to hypoxia.[24]

Clinical diagnosis

The clinical description of AFE has remained fairly constant over the past four decades [Tables 1 and 2]. Amniotic fluid embolism essentially remains a diagnosis of exclusion; however, a more detailed examination of many AFE cases does show certain common themes. The diagnosis usually relies on the presence of one or more of four otherwise unexplained events occurring during parturience[1525] [Tables 1 and 3]. These diagnostic indicators are (a) acute hypotension, (b) cardiac arrest, (c) acute hypoxemia or respiratory distress and (d) severe hemorrhage or coagulopathy. Any episodes that occur during labor, caesarean deliveries, dilation and evacuation, or within 30 minutes postpartum without other explanations should alert the practitioner to the possibility of AFE.

Table 2

Modern strategies for the treatment of amniotic fluid embolism

Table 3

Differential diagnosis of amniotic fluid embolism

Most patients initially present with abrupt cardiac and respiratory failure. Early signs such as dyspnea, altered consciousness and restlessness may be associated with hypoxia and impending cardiopulmonary failure. Furthermore, some case reports have described fetal bradycardia occurring early at the onset of AFE.[26-28] Other signs may be severe hemorrhage and coagulopathy.[29] It should also be noted that uterine atony has been reported by some authors.[3031] Again, many of the signs and symptoms of AFE are non-specific, and alternative diagnoses need to be ruled out.

Laboratory abnormalities associated with AFE

Several diagnostic tests have been put forth as useful in the diagnosis of AFE. However, no single diagnostic test can confirm or disprove the presence of AFE. Clinically useful but non-specific laboratory data includes: (a) arterial blood gas analysis to determine adequacy of ventilation and degree of hypoxemia; (b) comprehensive blood cell count including platelet count; (c) coagulation profile to assess platelet function, prothrombin time, International Normalized Ratio (INR), activated partial thromboplastin time, and fibrinogen levels. Thromboelastography (TEG) may also be useful.

The finding of amniotic fluid debris in the maternal pulmonary microvasculature is considered highly suggestive, especially when fetal squamous cells/debris and neutrophils are found in blood samples collected through the distal port of a pulmonary artery catheter.[3233] One investigator found transient intracardiac thrombi to be associated with AFE.[34] Kanayama et al. reported an association between AFE and increases in zinc coproporphyrin (an amniotic fluid component) in cytological analysis of maternal plasma.[35] Other investigators have demonstrated that TKH-2 antibody and serum sialyl-Tn (STN) assays have a good sensitivity for supporting the diagnosis of AFE.[36] Furthermore, Nishio et al hint that AFE may be associated with elevated serum tryptase levels, pointing to potential mechanistic similarities between AFE and anaphylaxis.[37] This evidence while supportive is not definitive, as some investigators describe the amniotic fluid components to be commonly present in maternal circulation without clinical evidence of AFE syndrome.[3839] Additionally, obstetric hemorrhage patients receiving autotransfusion containing up to 1% fetal squamous cells in approximately 20% of cases demonstrated no obvious association with AFE.[40]

Other diagnostic adjuncts in AFE

Adjunctive tests may be helpful with the diagnosis and treatment of AFE. An electrocardiogram may show right heart strain and arrhythmia. Chest X-ray findings will detect evidence of pulmonary edema with interstitial and alveolar infiltrates distributed bilaterally. Transesophageal echocardiography (TEE) is beneficial to demonstrate regional wall motion abnormalities, evaluate valve function, ejection fraction, right-sided pressures, chamber size, and visualization of debris. In two case reports during the acute phase of AFE, TEE findings revealed severe pulmonary hypertension and acute right ventricular failure with a leftward deviation of the interatrial and interventricular septa.[1819]

Clinical management

At our present level of understanding all recommendations are treatment oriented, as there are no effective prophylactic options to prevent the development of AFE. Early recognition and prompt initiation of proper management is critical in optimizing outcomes for the patient with AFE. The treatment is supportive. The airway should be rapidly controlled and therapy undertaken to prevent or correct hypoxemia. Aggressive resuscitative efforts should be pursued to support and maintain hemodynamic sufficiency, and ensure adequate tissue perfusion. In the face of severe hemorrhage coagulopathies must be treated [Table 4].

Table 4

Amniotic fluid embolism: Key points

To reduce the impact of aorto-caval compression on venous return, left uterine displacement should be done either manually or by placing a wedge under the parturient's right hip. Moreover, the Managing Obstetric Emergencies and Trauma (MOET) course recommends that fetal delivery (i.e., perimortem caesarean section or PMCS) be undertaken within 5 minutes of maternal cardiac arrest to decrease fetal toxicity and improve resuscitation efforts by removing aorto-caval compression. This will also potentially facilitate the efficacy of cardiopulmonary resuscitation.[4142] The fetus should be continuously monitored for any signs of hypoxia or distress.

In general, an approach based on traditional A-B-Cs (i.e., airway-breathing-circulation) of life support is the safest way to proceed. Immediate administration of high flow oxygen to prevent hypoxia is critical. Depending on patient status, this may be accomplished via high flow nasal cannula, face-mask, non-invasive positive pressure ventilation, or bag-valve mask ventilation. Most patients will require endotracheal intubation and positive pressure ventilation with 100% oxygen – at least initially. The decision to intubate is better made earlier than later. In severe cases, advanced ventilatory strategies may be required to treat severe hypoxia, non-cardiogenic pulmonary edema or ARDS. Besides lung protective strategies with use of a conventional ventilator, other approaches such as high frequency oscillatory ventilation, or even extracorporeal membrane oxygenation (ECMO) may be required. Veno-venous ECMO intervention for purely pulmonary support and veno-arterial EMCO intervention for cardiac support (with or without pulmonary decompensation) should be considered.[43] The potential airway difficulties present in a parturient should be kept in mind and physicians should be ready to secure the airway by use of a fiberoptic scope or even tracheotomy.

After the airway and respiratory status have been addressed, management focuses on treatment of hypotension and restoration of maternal circulation. Besides two large bore intravenous lines, central venous access should be established with serious consideration given to the use of a pulmonary artery catheter. Also, an arterial line and a urinary catheter should be placed to help guide therapy. Recent reports suggest that the use of transthoracic echocardiography or TEE may be beneficial when evaluating left ventricular contractility and filling. These modalities may also be useful in guiding the administration of intravenous fluid therapy and/or vasopressor/inotrope administration.[1819]

The physician should rapidly administer isotonic solutions to maximize preload. Vasopressors and inotropes will usually be needed, as refractory hypotension is highly probable. In the early phases of AFE circulatory vasodilation occurs. Phenylephrine and vasopressin may be appropriate therapies. Inotropic support, including dobutamine, dopamine, epinephrine, or norepinephrine may be required to treat ventricular contractile impairment. Milrinone may be an appropriate choice for right heart support through its positive effect on inotropy as a phosphodiesterase inhibitor, and through its vasodilatory effect on the pulmonary vasculature. Inhaled nitric oxide or inhaled epoprostenol should be considered for pulmonary vasodilation to treat refractory hypoxemia and to unload the right ventricle. Should this strategy fail, an intraaortic balloon pump, right ventricular assist device and/or ECMO (see above) should be considered.[182026]

Hemorrhage in the setting of AFE should prompt early and aggressive blood product administration. Packed red blood cells and platelets should be administered to maintain oxygen carrying capacity and prevent thrombocytopenic bleeding. In cases of persistent bleeding, coagulopathy, or DIC treatment should proceed with a combination of fresh frozen plasma, cryoprecipitate, fibrinogen, and factor replacement. The exact products to be administered should be guided by laboratory studies, which may include fibrinogen levels, functional platelet counts, and thromboelastogram (TEG) as well as the standard INR and PTT. The use of recombinant activated factor VII has been reported in patients with AFE and bleeding unresponsive to conventional blood product therapy; however, due to significantly worse associated outcomes, factor VIIa should be restricted to cases where hemorrhage cannot be stopped by massive blood component replacement.[44] Antifibrinolytic drugs such as tranexamic acid or aminocaproic acid have been used in the past for obstetrical bleeding, but their efficacy in AFE is undetermined.[4546]

Medical therapy should be provided for uterine atony. If the bleeding cannot be controlled, hysterectomy may be necessary, but uterine artery embolization has been described in selected cases.[47] After initial stabilization, almost all patients with AFE require transfer to the intensive care unit. High-quality, modern maternal care using targeted approaches to potential sequelae and complications of AFE is the likely reason for improving outcomes associated with AFE.[15]

Prognosis and outcomes

Overall prognosis of patients with AFE, although significantly better since the advent of modern critical care capabilities and end-organ support, continues to be relatively poor. Mortality rate, although significantly lower than the previously reported range of approximately 60%, continues to be unacceptably high in the 20-40% range.[22] Chronic sequelae of end-organ dysfunction may be significant. Moreover, most of the survivors display some degree of neurologic impairment.[22] The perinatal death rate associated with AFE is also high (between 20-25%) with only 50% of surviving neonates being neurologically intact.[22] Among survivors, there are no data with regards to the risk for any subsequent AFE episodes in future pregnancies.

Pain and palliative considerations

Given potentially catastrophic nature of the AFE and the high risk for mortality, palliative critical care may be initiated concurrently with obstetrical critical care measures to relieve symptoms, distress, and facilitate communications between providers and the patient/family. The principles of palliative critical care can be applied by the obstetrical and intensivist team.[48] For patients with irreversible disease or uncertain prognosis, the complexities of palliative and end-of-life care warrant a consultation with specialist palliative care physicians, nurses, chaplains, and social workers. Optimal management requires teamwork, and obstetrical and critical care specialists should advise palliative care colleagues that of those maternal patients who do not survive, 25% die in the first hour, and approximately 80% succumb within the first 10 hours,[4950] with an associated high perinatal morbidity and mortality. As such, the consequences to the family are truly devastating. Interdisciplinary palliative care teams also have expertise in issues of grief, loss, and bereavement to support the complex needs of the family and clinicians experiencing the tragedy of a fatal AFE.

When providing palliation for a dying patient, opioids are the agents of choice to pharmacologically manage pain and dyspnea, and haloperidol to manage delirium of critical illness.[48] Terminal anxiety will usually respond to benzodiazepines in the majority of cases. The above symptoms are common to patients in critical care settings, should be assessed frequently, and are most distressing to both patients and families. Continuous symptoms warrant achieving a steady state utilizing regularly scheduled pharmacotherapy. Additional medications for acute exacerbations or refractory symptoms should be available in order for the bedside nurse to provide relief. Terminal anxiety and delirium are not relieved by opioid agents such as morphine injections or infusions, and high doses of opioids may actually worsen these symptoms. If withdrawal of futile technological support is indicated, then the pharmacological, staff training, and family communications need to become more complex and detailed.[5152] Loss of a family member, including critical care mortality, is often associated with post-traumatic stress symptoms among surviving relatives,[53] and these symptoms may be mitigated by optimization of palliative critical care communications via the facilitation of frequent family meetings with clinical teams.[54] Key competencies in the area of palliative critical care require active listening skills and compassion.[55] Enhanced bereavement care, with a high level of overall bereavement services given to family survivors in the obstetrical or critical care unit has the potential to improve general satisfaction with care.[56] Referral to counseling services and various support groups may be helpful as well.

CONCLUSIONS

AFE remains one of the most feared and devastating complications of pregnancy. Its presentation is variable and onset is unpredictable and largely non-preventable. Better knowledge of AFE on part of all members of the healthcare team is therefore crucial as it facilitates early recognition, aggressive management, and possibly improves the survival of both the mother and the child. Awareness of the syndrome and advances in intensive care medicine have been key to improving outcomes, although much needs to be done to further reduce both the morbidity and mortality associated with AFE.