Amniotic fluid embolism

Amniotic fluid embolism (AFE, anaphylactoid syndrome of pregnancy) is one of the catastrophic complications of pregnancy, in which amniotic fluid, fetal cells, hair or other debris enter the mother's pulmonary circulation, causing sudden cardiorespiratory collapse and disseminated intravascular coagulation syndrome (DIC syndrome).

Amniotic fluid embolism differs from direct embolism or the presence of amniotic fluid itself.[ 1 ],[ 2 ]

The original description of AFE dates back to 1941, when Steiner and Lushbaugh found fetal cells in the pulmonary circulation of women who died during childbirth.[ 3 ] Data from the National Amniotic Fluid Embolism Registry indicate that the condition resembles anaphylaxis rather than a typical embolism. Notably, fetal tissue or amniotic fluid components are not always detected in women with signs and symptoms of AFE. Traditionally, the diagnosis of amniotic fluid embolism was made postmortem based on the presence of fetal squamous cells in the maternal pulmonary artery blood.[ 4 ] However, because fetal squamous cells are also found in the circulation of parturient women who do not develop AFE, the diagnosis is exclusionary and based on the clinical picture after other causes of hemodynamic instability have been excluded.

Epidemiology

The estimated incidence of EOI ranges from 1.9 to 6.1 per 100,000 births, although the exact prevalence remains uncertain due to imprecise diagnosis and underreporting of non-fatal cases.[ 5 ],[ 6 ] Notably, EOI was the leading cause of death during childbirth in Germany in 2011 and accounts for 24.3% of maternal mortality in Japan. In Australia, EOI is recognized as the leading direct cause of maternal mortality, affecting between 1 in 8,000 and 1 in 80,000 births. The incidence in the United Kingdom is estimated to be 2 per 100,000 births, while in the United States, the incidence of EOI is approximately 7.7 per 100,000 births.

The vast majority of cases of EOV, approximately 70%, present during labor, with approximately 19% occurring during cesarean section and 11% following vaginal delivery. Notably, EOV can occur up to 48 hours after delivery. Rare cases of EOV have been reported following termination of pregnancy, amniocentesis, injection of hypertonic saline into the uterus to induce abortion, and in the first or second trimester of pregnancy.[ 7 ]

Causes amniotic fluid embolism

Amniotic fluid embolism remains unpredictable, with an unknown origin. Its development is promoted by various factors, including maternal age (especially over 35–40 years), male fetus, early pregnancy, cervical ripening, polyhydramnios, multiple gestations, gestational diabetes, manual removal of the placenta, Asian and black race, asthma, illicit substance use, and trauma. Induction of labor and conditions such as cerebrovascular accidents and cardiac disease increase the risk of AFE, with a strong association seen with placenta previa, eclampsia, uterine rupture, fetal growth restriction, fetal death, placental abruption, maternal renal disease, cardiomyopathy, and postpartum hemorrhage.

There are conflicting data on the risk factors for EOV. Many earlier studies concluded that cesarean section, especially with a classic uterine incision, increased the risk of EOV. This concept has since been modified: cesarean section of any type has been found to be unrelated. Similarly, amniotomy was once thought to increase the risk of EOV, but is now thought to be unrelated. One population-based cohort study looked at 149 cases of EOV, 80 of which were fatal. They reported that spontaneous vaginal birth had a 12-fold higher risk of EOV than cesarean section, and instrumental vaginal birth had almost 3-fold the risk of cesarean section. They concluded that cesarean section was a protective factor in the case of fatal EOV. Amnioinfusion does correlate with a 3-fold increased risk of AEPO, possibly due to increased uterine distension.[ 8 ] Notably, 66% of patients with AEPO reported prior allergy, consistent with the secondary name of this condition “anaphylactoid syndrome of pregnancy,” exceeding the rate of atopy in the general population. Additionally, 8% of pregnancies affected by AEPO result from in vitro fertilization, exceeding the baseline rate of IVF.

Placental anomaly (PAS) is the condition most closely associated with PE, and carries a 10-fold increased risk.[ 9 ] The severity of PAS correlates with a higher incidence of PE. The introduction of amniotic fluid and fetal components into the maternal circulation causes intense pulmonary vasoconstriction and bronchoconstriction. These effects occur not only as a result of physical obstruction, but primarily as a result of the release of inflammatory cytokines that respond to the foreign material. These mediators activate coagulation and fibrinolytic pathways, leading to the development of DIC.

Pathogenesis

Amniotic fluid embolism is characterized by disruption of the placental-amniotic interface, resulting in the entry of amniotic fluid and fetal elements such as hair, meconium, skin cells, and intestinal mucin into the maternal circulation. It is important to note that the presence of flat cells in the pulmonary circulation is no longer the only diagnostic feature of EFE, as the clinical picture plays a decisive role. [ 10 ], [ 11 ], [ 12 ]

Accompanying the entry of amniotic and fetal substances are tissue factors with procoagulant properties. Activation of histamine, endothelin, and leukotrienes leads to physiological changes that result in cardiovascular collapse. [ 13 ] Potential portals of entry include the placental site, jugular veins, or uterine surgical incisions. Once in the pulmonary arterial tree, it triggers a pathological maternal anaphylactoid immune response, releasing inflammatory mediators.

The initial phase involves intense and transient pulmonary vasoconstriction, possibly associated with bronchospasm. This leads to acute pulmonary artery obstruction, right ventricular and right atrial dilation, and significant tricuspid regurgitation. Hypoxia and right ventricular failure subsequently occur. A less common type of EOV has been reported that presents with only a bleeding component and DIC without maternal hemodynamic instability.

Following right ventricular enlargement, left ventricular function is significantly depressed due to myocardial ischemia caused by hypoxia or coronary artery spasm. This ventricular enlargement results in protrusion of the intraventricular septum into the left ventricle, resulting in obstruction and systolic dysfunction. As a result, pulmonary artery pressure increases and cardiac output decreases. Associated arrhythmias such as ventricular fibrillation, asystole, and pulselessness have been reported. Thus, survivors of this critical condition may experience hypoxic brain injury or multisystem organ failure.[ 14 ]

Sudden cardiovascular collapse is induced by hypoxemia and hypotension. The introduction of amniotic fluid and fetal elements triggers the activity of inflammatory mediators, including platelet activating factor, tissue necrosis factor-alpha (TNF-alpha), interleukin 6, interleukin 1, phospholipase A2, endothelin, plasminogen activators, thromboplastins, and complement factors. This activation initiates the coagulation cascade and the fibrinolytic system, leading to the fibrinolytic form of DIC. Amniotic fluid in the maternal circulation activates platelet factor III, leading to platelet aggregation and activation of coagulation factor Xa. Amniotic fluid and fetal elements may penetrate the uterus, causing severe uterine atony and aggravating bleeding. Superimposed abnormal activation of coagulation and fibrinolytic pathways results in severe coagulopathy, observed in approximately 80% of patients with EOV. Decreased coagulation factors may occur either immediately at the time of cardiopulmonary collapse or in a delayed manner. Bleeding may be severe, persistent, and fatal.

Autopsies of women who died from EOV have revealed pulmonary edema, amniotic fluid embolism to the lungs, and alveolar hemorrhage. Additional findings may include myocardial infarction, acute renal failure due to acute tubular necrosis, and cerebral infarctions.

Histopathology

Prevalence of pulmonary edema

• Pulmonary edema is a common feature in 70% of postmortem examinations of people who died from EOV.
• This condition represents a major pathological feature that underlines its importance in cases of EOV.

Microscopic presence of amniotic fluid substances

• Although amniotic fluid substances are present in the lungs, their microscopic identification may be difficult due to their small size.
• Histological examinations may not always detect these tiny particles, potentially leading to underrecognition.[ 15 ]

Alveolar hemorrhage

• In association with pulmonary edema, alveolar hemorrhage is a common histologic finding in the lungs of individuals affected by AFE.
• The observation of alveolar hemorrhage adds another layer to the pathological changes associated with this condition.

These clinical pearls shed light on the complex pathological aspects of EOV, highlighting the importance of considering macroscopic and microscopic findings in the diagnosis and understanding of this challenging obstetric emergency.

Symptoms amniotic fluid embolism

The medical history or current health data of a patient experiencing EOV may reveal factors such as advanced maternal age, multiple gestations, placental problems (placenta accreta, placenta abruptio, placenta previa), preeclampsia, gestational diabetes, polyhydramnios, amniocentesis, use of amnioinfusion, amniotomy, cervical lacerations, or any surgery on the pregnant uterus. In the classic scenario, women in late labor suddenly develop acute dyspnea accompanied by hypotension. Other symptoms may be preceded by signs of agitation, anxiety, altered mental status, or a sense of impending doom. Seizures may occur, leading to cardiac arrest, followed by massive hemorrhage associated with DIC, ultimately causing death, often within an hour of onset. Statistics show that 53% of women with EOV appear during or just before labor, with the rest appearing an average of 19 minutes after labor.

Amniotic fluid embolism usually presents with cardiac arrest, but other manifestations include respiratory collapse and disseminated intravascular coagulation. Many patients lose consciousness, and some may have seizure activity (10% to 50%), probably due to cerebral hypoxia. Physical examination typically reveals the patient is in cardiovascular collapse characterized by severe hypoxemia, hypotension, and cyanosis. The classic triad of amniotic fluid embolism consists of hypoxia, hypotension, and coagulopathy with normal body temperature. Funduscopic examination may reveal minute bubbles in the retinal arteries. Tachypnea may be present, often accompanied by a characteristic holosystolic high-pitched murmur of tricuspid regurgitation. This murmur is loudest at the lower left sternal border, radiating to the right sternal border. Bleeding may range from massive to minimal, and uterine atony (83%) worsens the bleeding. Initial bleeding usually occurs from the vagina but may also occur at surgical incisions. Full-blown DIC occurs in approximately 83% of patients. Warning symptoms such as shortness of breath or agitation may precede cardiovascular collapse.[ 16 ]

Complications and consequences

Survivors of amniotic fluid embolism may experience a number of serious complications, including:

• Renal failure.
• Heart failure.
• Long-term respiratory failure leading to respiratory failure in adults.
• Myocardial infarction.
• Arrhythmias.
• Cardiomyopathy.
• Chronic heart failure.
• Left ventricular systolic dysfunction.
• Long-term coagulopathy.
• Respiratory failure (long-term).
• Prolonged bronchospasm.
• Liver failure.
• Cardiogenic pulmonary edema.
• Cramps.
• Anoxic encephalopathy.
• Various cognitive or neurological impairments.

Infants born in emergencies during maternal AFE are at increased risk of developing hypoxic ischemic encephalopathy (HIE). This often results in significant cognitive impairment in the child, potentially manifesting as chronic epilepsy, movement disorders, and developmental delays.[ 17 ]

Diagnostics amniotic fluid embolism

The diagnosis of amniotic fluid embolism is based on exclusion criteria after the occurrence of a clinical scenario that matches its characteristics.[ 18 ] It is essentially a clinical diagnosis as there is no reliable and definitive test for AFE. AFE is suspected when sudden dyspnea, dysphoria, hypotension, cardiovascular collapse and coagulopathy occur following postpartum events such as active labor, rupture of membranes, vaginal delivery or cesarean section. AFE has also been observed during or after elective termination of pregnancy, both induced and surgical. Initial evaluation is usually performed during aggressive cardiopulmonary resuscitation with an emphasis on the two major systemic failures: hemodynamic and hematologic.

Transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) plays a crucial role in diagnosis, if available. TEE is preferred if the patient is stable. Significant echocardiographic findings in TTE include right ventricular dilation, hypokinesis, strain, tricuspid regurgitation, and right atrial enlargement. Early cardiac thrombi may be seen in the enlarged right ventricle or right atrium. A characteristic feature associated with TTE is intraventricular septal deviation into the left ventricle, resulting in left ventricular obstruction and systolic dysfunction resembling a “D” shape.

Immediate blood collection is required for urgent typing and cross-matching, complete blood count, comprehensive metabolic panel, and full coagulation panel including platelets, prothrombin time, partial thromboplastin time, bleeding time, fibrinogen, d-dimer, and fibrin degradation products (FDPs). The International Society on Thrombosis and Haemostasis (ISTH) provides a formal scoring system to determine the presence of DIC in pregnancy based on platelet count, international neutralization ratio (INR), and fibrinogen level. Scores >3 indicate the presence of DIC in pregnancy. [ 19 ]

Establishing precise criteria for diagnosing AFE has been challenging due to the lack of a single definitive test. Various international standards have been established to define AFE: The American Society for Maternal-Fetal Medicine (SMFM) established objective criteria following a consensus symposium with the Amniotic Fluid Embolism Foundation in 2016. The criteria include the presence of the following conditions:

1. Sudden cardiopulmonary collapse or hypotension (systolic blood pressure <90 mmHg) with hypoxia (SpO2 <90%).
2. Severe bleeding or DIC as defined by ISTH.
3. Symptoms occur either during labor or after delivery of the placenta (or up to 30 minutes later).
4. Absence of fever or other explanation for the observed findings.[ 20 ]

The SMFM acknowledges that there may be cases that fall outside these parameters, for example during pregnancy termination. They explain that their primary aim is to establish standardised criteria for reporting studies. While recognising that their standards may cover many exceptional cases, they hope to minimise such cases. Critical clinical findings associated with EOV include coagulopathy, pulmonary hypertension and neurological symptoms. Some authors have suggested a modified version of the above definition that would include warning signs such as seizures, agitation, anxiety, sense of impending death, confusion and syncope. It has been recommended that the diagnostic criteria proposed by the SMFM be further validated in future large prospective cohort studies.

Differential diagnosis

The differential diagnosis of EOV includes obstetric, non-obstetric and anesthetic etiologies.

• Anaphylaxis.
• Aortic dissection.
• Cholesterol embolism.
• Myocardial infarction.
• Pulmonary embolism.
• Septic shock.
• Air embolism.
• Eclamptic convulsions and coma.
• Convulsions due to toxic reaction to local anesthetics.
• Aspiration of gastric contents.
• Hemorrhagic shock in an obstetric patient.

Differential diagnostics of amniotic fluid embolism and thromboembolism of small branches of the pulmonary artery

Symptoms	Amniotic fluid embolism	PE of small branches
Tachycardia	Short term	Long lasting
Decreased saturation	Short term	Long lasting
Dyspnea	Short term	Long lasting
Increased airway pressure	Short term	Long lasting
Clotting time	Extended	Shortened
Electrocardiographic signs of right heart overload	Short-term	Long lasting
Increased central venous pressure	Short term	Long lasting

Treatment amniotic fluid embolism

To prevent EOV, uterine trauma should be avoided during procedures such as catheter insertion under pressure or rupture of membranes. Placental incision during cesarean section should also be avoided if possible. Since one of the most common predisposing factors is considered to be violent labor, which can occur naturally, excessively strong and frequent uterine contractions should be stopped by intravenous β-adrenergic drugs or magnesium sulfate. In addition, oxytocidal drugs that can provoke excessive tetanic contractions of the uterus should be used correctly and judiciously.

The key factors in the management of EOV are early recognition, immediate resuscitation and delivery of the fetus. Early recognition of EOV is critical to a successful outcome. Management is primarily supportive and resuscitative.

General [ 21 ]

• Maintenance of vital signs. The initial goal is rapid correction of maternal hemodynamic instability, which includes correction of hypoxia and hypotension, to prevent additional hypoxia and subsequent end-organ failure.
• Oxygenation and airway control with tracheal intubation and administration of 100% O ₂ with positive pressure ventilation should be achieved as soon as possible.
• Fluid therapy is necessary to counteract hypotension and hemodynamic instability. Treatment of hypotension involves optimizing preload with rapid volume infusion of isotonic crystalloids and colloids. Although both agents can restore blood volume during ongoing bleeding, red blood cell transfusion is necessary to restore oxygen-carrying capacity.
• Transthoracic or transesophageal echocardiography may help guide fluid therapy with assessment of left ventricular filling. An arterial line and pulmonary catheter may also help guide therapy. Vasopressor therapy is indicated for refractory hypotension.
• Correction of coagulopathy. Blood and blood products, including fresh frozen plasma (FFP), platelets, and cryoprecipitate, should be available and administered early in the resuscitation phase of AFE. If platelets <20,000/μL or if bleeding occurs and platelets are 20,000–50,000/μL, transfuse platelets at 1–3 U/10 kg/day.
• FFP administration to normalize PT.
• If fibrinogen level is <100 mg/dL, administer cryoprecipitate. Each unit of cryoprecipitate increases fibrinogen level by 10 mg/dL.
• Arterial catheterization for accurate blood pressure monitoring and frequent blood sampling should also be considered.

Pharmacological [ 22 ], [ 23 ]

Vasopressors and inotropic support are usually needed to varying degrees in EOV. Central venous access should be established for vasopressor infusion and monitoring. The choice of vasopressor depends on the clinical scenario.

• Epinephrine may be a first-line drug of choice because it is used for other anaphylactoid reactions in addition to its alpha-adrenergic vasoconstrictor effect.
• Phenylephrine, a pure α-1 agonist, is often an excellent choice in the early stages of AFE treatment, since systemic vasodilation is the most prominent circulatory impairment at this point.
• Inotropic support such as dopamine or norepinephrine may be ideal because of additional β-adrenergic effects that improve cardiac function.
• Vasopressin can be used as primary therapy or as an adjunct to other inotropic therapies, and has the advantage of sparing the pulmonary vasculature from vasoconstriction, particularly at low doses. In right ventricular failure, milrinone or other phosphodiesterase inhibitors should be considered.[ 24 ]
• Digoxin: acts directly on the heart muscle and conduction system. Digoxin causes an increase in the force and velocity of systolic contraction, a slowing of the heart rate, and a decrease in the conduction velocity through the AV node.
• Hydrocortisone: Since EOS is more similar to an anaphylactic reaction, immune response mediating steroids are recommended.
• Oxytocin: The most commonly used uterotonic. Reduces inflammation by inhibiting polymorphonuclear leukocyte migration and reversing increased capillary permeability.
• Methylergonovine (Methergine): acts directly on the smooth muscle of the uterus, causing a sustained tetanic uterotonic effect that reduces uterine bleeding.
• Carboprost tromethamine: a prostaglandin similar to F2-alpha (dinoprost) but has a longer duration of action and causes myometrial contractions that cause hemostasis at the placental site, which reduces postpartum hemorrhage.
• Successful use of recombinant factor VIIa (rfVIIa) has been reported,[ 25 ] although this has also been associated with massive intravascular thrombosis.
• Aprotinin is also effective in reducing bleeding in EOV.
• Other antifibrinolytic drugs such as aminocaproic acid and tranexamic acid have been described for the treatment of obstetric hemorrhage and menorrhagia and may also be considered during EOV.

Left uterine displacement is critical in resuscitation efforts if the fetus remains in utero. It has been reported that immediate cesarean section will improve neonatal neurological recovery and overall maternal outcome if performed within 5 minutes of maternal cardiovascular arrest. Maternal resuscitation efforts are also enhanced by relieving aortocaval compression during labor.

Recently, successful results have been reported with other novel approaches to treat AFE, including exchange transfusion, extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass, right ventricular assist device, uterine artery embolization, intra-aortic balloon pump therapy with ECMO. Continuous hemofiltration, cell salvage combined with blood filtration, and serum protease inhibitors are few other recommended treatments in the literature.[ 26 ]

Hysterectomy may be required in patients with persistent uterine bleeding to control blood loss. rfVII has also been described as a treatment for bleeding that occurs in EOV, but should be used with caution as a recent review of case reports showed worse outcomes. Both aerosolized prostacyclin and inhaled nitric oxide (NO) act as direct pulmonary vasodilators and have been used successfully to treat acute pulmonary vasoconstriction in EOV.

Few physicians have tried heparin for the treatment of EOV, but its use remains controversial. This controversy arises because both DIC and embolism have been reported in patients with EOV. [ 27 ] In addition to heparin, aspirin has been tried in several animal studies. Heparin prophylaxis maintained platelet counts, whereas aspirin prophylaxis did not. They concluded that aspirin is not an effective prophylactic agent. [ 28 ]

Forecast

Survival after EOV has improved significantly due to early recognition of the syndrome and immediate and early resuscitative measures. It has been previously documented that 50% of patients die within the first hour and about two-thirds within 5 hours of the event, with a high incidence of severe and irreversible neurological damage among survivors. Although mortality has decreased, morbidity remains high with severe sequelae. In addition to neurological impairment, acute oliguric or nonoliguric renal failure, heart failure with left ventricular dysfunction, cardiogenic pulmonary edema, arrhythmias, myocardial ischemia or infarction have been reported. Other reported sequelae include respiratory failure with noncardiogenic pulmonary edema and refractory bronchospasm: [ 29 ], [ 30 ]

• The prognosis after EOV is very poor, and most women do not survive.
• If the patient survives the embolism, most survivors experience neurological deficits.
• The infant survival rate is 70%. The child's neurological status is directly related to the time elapsed between the termination of pregnancy and birth.
• The risk of recurrence is unknown. Successful subsequent pregnancies have been reported.

Despite our lack of understanding of the pathophysiological processes of AFE, it is clear that early and aggressive management (including immediate cesarean section) of patients with clinically suspected AFE improves both fetal and maternal resuscitation and increases survival. It is important to always consider AFE in the differential diagnosis of sudden cardiopulmonary instability in the mother and to remember that the absence of DIC and hemorrhage does not exclude the diagnosis of AFE. Further studies of serum diagnostic tests such as zinc coproporphyrin, STN antigen, and complement C3 and C4 are needed. Selective pulmonary vasodilators such as NO for the treatment of severe pulmonary hypertension during the acute phase of AFE and rfVIIa for the treatment of severe DIC refractory to conventional treatments show promise.[ 31 ]

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