Amniotic Fluid Embolism

Amniotic fluid embolism (AFE) is a life-threatening obstetric emergency characterized by sudden cardiorespiratory collapse and disseminated intravascular coagulation.

AFE occurs in 2-8 per 100,000 deliveries and is responsible for between 7.5% and 10% of maternal mortality in the United States.[1]

Steiner and Luschbaugh first described AFE in 1941, after they found fetal debris in the pulmonary circulation of women who died during labor. Data from the National Amniotic Fluid Embolus Registry suggest that the process is more similar to anaphylaxis than to embolism, and the term anaphylactoid syndrome of pregnancy has been suggested because fetal tissue or amniotic fluid components are not universally found in women who present with signs and symptoms attributable to AFE.[2]

The diagnosis of AFE has traditionally been made at autopsy when fetal squamous cells are found in the maternal pulmonary circulation; however, fetal squamous cells are commonly found in the circulation of laboring patients who do not develop the syndrome. The diagnosis is essentially one of exclusion based on clinical presentation. Other causes of hemodynamic instability should not be neglected.

The pathophysiology of amniotic fluid embolism (AFE) is incompletely understood. It was originally believed that fetal cells and debris occluded the pulmonary vasculature.[3] Fetal material is not always found in the maternal circulation in patients with AFE, and material of fetal origin is often found in women who do not develop AFE.  A study performed to investigate whether fetal squamous cells from amniotic fluid could obstruct the maternal pulmonary vasculature causing cardiopulmonary collapse, found that the mean cell count in amniotic fluid was 695 +/- 600 squamous cells per mL of fluid.  The adult lung contains 480 million alveoli with 280 billion pulmonary capillaries. They concluded that even if the entire volume of amniotic fluid were transferred to the maternal circulation, the available squamous cells would only obstruct 1 in 1 million pulmonary capillary segments resulting in clinically undetectable obstruction.[4]

Clark has proposed that fetal antigens enter the maternal circulation triggering a response similar to systemic inflammatory response syndrome (SIRS) with activation of the coagulation cascade leading to DIC and inflammatory mediated suppression of myocardial function.[5]

Benson et al[6] tested 2 hypotheses concerning the pathophysiology of AFE: (1) Clinical symptoms result from mast cell degranulation with the release of histamine and tryptase, or (2) Clinical symptoms result from activation of the complement pathway. Nine women with AFE were compared with 22 women with normal labors. Serum from patients with AFE was collected within 14 hours of symptom onset and frozen. Urine was collected within 12-24 hours after symptom onset. Control patients had complement levels measured on admission, during labor, and the day after delivery.  Six of the 9 women with AFE died, and all 9 required blood transfusions for disseminated intravascular coagulation (DIC). Seven women had no evidence of mast cell degranulation (ie, either urinary histamine or serum tryptase). Compared with postpartum control patients, complement levels in the AFE group were severely depressed. C3 in the AFE group was 44 compared with 117.2 in the postpartum group. C4 was 10.7 in the AFE group versus 29.4 in the postpartum group. These differences were statistically significant. This suggests that complement activation may play an important role in the pathophysiology of AFE.

Farrar and Gherman[7] reported the case of a 40-year-old multipara in active labor with acute onset of facial erythema, seizures, hypoxia, cardiac arrest, DIC, and ultimately death. Fetal squames and fibrin thrombi were found in the pulmonary tree at autopsy. Blood drawn 2 hours after symptom onset had a serum tryptase level of 4.7 ng/mL (normal < 1 ng/mL). Mast cell degranulation is a central aspect of anaphylaxis which releases large quantities of tryptase. Kobayashi et al has proposed that serum tryptase levels may support the diagnosis of AFE.[8]

A case reported by Marcus et al,[9] in which AFE developed after a spontaneous rupture of membranes. No increase in mast cells or degranulation in lung tissue was shown by Giemsa staining. Serum tryptase levels were 11.4 ng/mL (normal < 11.4 ng/mL).

As these studies show, the initiating event and the complete pathophysiology are poorly understood.  Progression usually occurs in 2 phases. In phase I, pulmonary artery vasospasm with pulmonary hypertension and elevated right ventricular pressure cause hypoxia. Hypoxia causes myocardial capillary damage and pulmonary capillary damage, left heart failure, and acute respiratory distress syndrome. Women who survive these events may enter phase II. This is a hemorrhagic phase characterized by massive hemorrhage with uterine atony and DIC; however, fatal consumptive coagulopathy may be the initial presentation.

Amniotic fluid embolism (AFE) is considered an unpredictable and unpreventable event with an unknown cause. In the national registry, 41% of patients had a history of allergies.

Reported risk factors for development of AFE include multiparity, advanced maternal age, male fetus, and trauma. In a retrospective review of a 12-year period encompassing 180 cases of AFE, of which 24 were fatal, medical induction of labor increased the risk of AFE.[10]  In the same study, AFE was positively associated with multiparity, cesarean section or operative vaginal delivery, abruption, placenta previa, and cervical laceration or uterine rupture.[11, 12, 13, 14]

Fong et al found that non-Hispanic blacks have more than twice the risk of developing AFE and also found a 25-fold higher risk of the condition in women with cerebrovascular disorders and a 70-fold greater risk in those with cardiac disease. In addition, the study, of 182 patients with AFE, found a strong association between AFE and renal disease, placenta previa, polyhydramnios, placental abruption, and eclampsia and with procedures such as amnioinfusion, classical cesarean delivery, and dilation and curettage. The risk of AFE was also found to rise with maternal age, with the greatest increase occurring after age 39.[1]

United States and international statistics

Incidence of amniotic fluid embolism (AFE) is estimated at 1 case per 8,000-30,000 pregnancies. The true incidence is unknown because of inaccurate diagnoses and inconsistent reporting of nonfatal cases.

In 2011, AFE was the leading cause of death during childbirth in Germany.[15]

In Australia, AFE is cited as the leading direct cause of maternal death. Estimates range from 1 in 8000 to 1 in 80000 deliveries.[16]

In the United Kingdom incidence is estimated at 1.9 per 100000 to 7.7 per 100000 deliveries.[17]

Race-, sex-, and age-related demographics

No racial or ethnic predilection has been thought to exist. However, a study by Fong et al suggested that non-Hispanic blacks have more than twice the risk of developing AFE.[1]

AFE only occurs in women.

Advanced maternal age may be a risk factor. No relationship to age has been found in the National Amniotic Fluid Embolus Registry; however, at least two studies have noted an increased incidence in women aged 30 years and older.[18, 19] One study by Fong et al indicated that the greatest risk increase occurs after age 39.[1]  Another study by Lisonkova et al on the associations between maternal age and severe maternal morbidity reported that woman 35 years of age and older had increased adjusted rates of amniotic fluid embolism (AOR = 8.0, 95% CI 2.7-23.7).[19]

Mortality/Morbidity

Note the following:

• Maternal mortality approaches 80%. However, it was 61% in the US national registry, which listed 46 cases.

• Amniotic fluid embolism (AFE) is the cause of 5-10% of maternal mortality in the United States.

• Of patients with AFE, 50% die within the first hour of onset of symptoms. Of survivors of the initial cardiorespiratory phase, 50% develop a coagulopathy.

• A population-based study using the California Office of Statewide Planning and Development database reviewed 1,094,248 deliveries over a 2-year period. Of 53 cases of AFE, 14 patients (26.4%) died and 35 patients (66%) developed DIC.[20]

• Maternal survival is uncommon, although the prognosis is improved with early recognition and prompt resuscitation. The United Kingdom AFE registry reported a mortality of 37%; of the women who survived AFE, 7% were neurologically impaired.[21]  

• Neonatal survival has been reported to be 79% in the US registry and 78% in the UK registry. The intact infant survival rate is 70%. Neurologic status of the infant is directly related to the time elapsed between maternal arrest and delivery.

• The risk of recurrence is unknown. Successful subsequent pregnancies have been reported. The recommendation for elective cesarean delivery during future pregnancies in an attempt to avoid labor is controversial.

Complications

Pulmonary edema is a common occurrence in survivors. Pay close attention to fluid input and output.

Left heart failure may occur. Some sources recommend inotropic support.

Treat DIC with blood components. Consider activated factor VIIa for severe hemorrhage. Bilateral uterine artery embolization has been successful in controlling blood loss in 2 reported cases.

The recurrence risk of AFE is unknown. Case reports exist of successful uneventful pregnancies after a pregnancy complicated by AFE.[22]

In a study of 33 cases of AFE in Australia and New Zealand, the most common initial symptoms were a feeling of agitation or of impending doom (27%), hypotension (21%), dyspnea (15%) and evidence of fetal compromise (15%). Coagulopathy was the initial symptom in only 3% of patients but 73% ultimately developed a coagulopathy and 85% required transfusion of blood products. Six percent of patients presented with either cardiac arrest or an arrhythmia.[23]

The classic history is that a woman in the late stages of labor becomes acutely dyspneic with hypotension.  There may be a preceding period of agitation or a sense of impending doom.  Altered mentation may or may not be present. She may experience seizures quickly followed by cardiac arrest. If undelivered, the fetus will demonstrate loss of heart rate variability followed by decelerations and ultimately a terminal bradycardia. Massive DIC-associated hemorrhage follows and then death. Most patients die within an hour of onset.

Data from the United Kingdom Obstetric Surveillance System (UKOSS) from 2005-2011 showed that 53% of women given a diagnosis of AFE presented at or before delivery. The remaining patients presented an average of 19 minutes after delivery.[17]

In the United States AFE registry 70% of patients presented during labor, 19% presented during cesarean delivery and 11% presented after delivery.

There are case reports of AFE occurring during abortion, after abdominal trauma, amniocentesis and during amnioinfusion.

A uniform diagnostic criteria for amniotic fluid embolism has been suggested in order to ensure that researchers use the same definition when reporting events. All of the following must be present for a diagnosis of AFE[5] :

1. Sudden onset of cardiorespiratory arrest or both hypotension (systolic BP < 90mm HG) and respiratory compromise (dyspnea, oxygen saturation < 90%)

2. Documentation of overt DIC following the events in item 1. Coagulopathy must be detected prior to the loss of enough blood to itself be the cause of a dilutional or consumptive coagulopathy.

DIC during pregnancy is assessed using the scoring system of the International Society of Thrombosis and Hemostasis.  A score ≥ 3 is consistent with overt DIC in pregnancy.

Scoring system for DIC during pregnancy (Open Table in a new window)

            

3. Clinical onset during labor or within 30 minutes of the delivery of the placenta

4. No fever (≥38.0 C) during labor

The authors stress that the above criteria are for research only and that in clinical practice patients may have atypical AFE in which all the required elements are not met. The Amniotic Fluid Embolism foundation is interested in plasma and serum obtained during the admission from patients experiencing AFE. Instructions for samples and records can be found on the Amniotic Fluid Embolism Foundation website.

The United Kingdom Obstetric Surveillance System (UKOSS) and the Australasian Maternity Outcomes Surveillance System (AMOSS) defines AFE for the purpose of case reporting as[16, 24] :

EITHER a clinical diagnosis based on acute hypotension or cardiac arrest, acute hypoxia or coagulopathy in the absence of any other potential explanation for the symptoms and signs observed

OR a pathological/postmortem diagnosis based on the presence of fetal squames or hair in the lungs.

 

 

 

The classic triad of AFE is hypoxia, hypotension and coagulopathy. The following signs and symptoms are indicative of possible AFE:

• Hypotension: Blood pressure may drop significantly with loss of diastolic measurement.

• Dyspnea: Labored breathing and tachypnea may occur.

• Seizure: Tonic clonic seizures are seen in 50% of patients.

• Cough: This is usually a manifestation of dyspnea.

• Cyanosis: As hypoxia/hypoxemia progresses, circumoral and peripheral cyanosis and changes in mucous membranes may manifest.

• Fetal bradycardia: In response to the hypoxic insult, fetal heart rate may drop to less than 110 beats per minute (bpm). If this drop lasts for 10 minutes or more, it is a bradycardia. A rate of 60 bpm or less over 3-5 minutes may indicate a terminal bradycardia.

• Pulmonary edema: This is usually identified on chest radiograph.

• Cardiac arrest

• Uterine atony: Uterine atony usually results in excessive bleeding after delivery. Failure of the uterus to become firm with bimanual massage is diagnostic.

• Coagulopathy or severe hemorrhage in absence of other explanation (DIC occurs in 83% of patients.)[25]

• Altered mental status/confusion/agitation

On chest radiographs, posteroanterior and lateral findings are usually nonspecific, but evidence of pulmonary edema may be observed.

Place an arterial line to accurately measure blood pressure and to obtain arterial blood gas (ABG) readings. Place a pulmonary artery catheter to monitor wedge pressure, cardiac output, oxygenation, and systemic pressures.

There are no laboratory tests to either confirm or refute the diagnosis of AFE.[26] Laboratory values are useful in providing supportive measures for the patient.

Arterial blood gas (ABG levels

Expect changes consistent with hypoxia/hypoxemia, such as the following:

• Decreased pH levels (reference range = 7.40-7.45)

• Decreased PO2 levels (reference range = 104-108 mm Hg)

• Increased PCO2 levels (reference range = 27-32 mm Hg)

• Base excess increased

CBC with platelets

Hemoglobin and hematocrit levels should be within reference ranges.

Thrombocytopenia is rare. If platelets are less than 20,000/µL, or if bleeding occurs and platelets are 20,000-50,000/µL, transfuse platelets at 1-3 U/10 kg/d.

Coagulation studies

Prothrombin time (PT) is prolonged because clotting factors are used up. Values are institution specific, but intervention is indicated when the PT is 1.5 times the control value. Administer fresh frozen plasma (FFP) to normalize the PT.

Activated partial thromboplastin time (aPTT) may be within reference ranges or shortened.

Rotational thromboelastometry (ROTEM) has been used as a point of care test to guide management of the coagulopathy.[27]  

Fibrinogen level

If fibrinogen level is less than 100 mg/dL, administer cryoprecipitate. Each unit of cryoprecipitate raises the fibrinogen level 10 mg/dL.

Type and screen

Blood type and screen in anticipation of the requirement for a transfusion.

Electrocardiography

A 12-lead ECG may show tachycardia, ST segment and T-wave changes, and findings consistent with right ventricle strain.

On autopsy, blood vessels in the lungs may show evidence of fetal debris (eg, squamous cells, vernix, mucin).

Aguilera et al[28] reported fetal epithelial squamous cells obstructing 80% of pulmonary capillaries and fetal epithelial squamous cells in the alveoli on autopsy. A blood sample from a central venous catheter also showed fetal squames. Another study by Koike et al reported that serum squamous cell carcinoma antigen levels were significantly higher in women with AFE than those in healthy controls.[29]

Marcus et al[9] found focal interstitial hemorrhages in the kidneys, the left ventricle, and the interventricular septum. Alcian blue periodic acid-Schiff (PAS) stain was positive for mucin in the vasculature and oil red O stain for lipid was positive in the lungs.

Hankins and colleagues[30] reported on goats injected with fresh amniotic fluid (n=8), filtered amniotic fluid (n=14), and meconium-stained fluid with solid debris (n=7). The animals were euthanized 3 hours after the procedure and samples of the lungs were taken. Amniotic fluid debris was found in 7 out of 7 of the meconium-stained group, 2 out of 8 of the fresh fluid group, and 1 out of 14 of the filtered group. Hankins et al concluded that, in this model, histopathologic confirmation of AFE was unreliable except in cases involving meconium-stained fluid.

Kobayashi et al[31] used antibody TKH-2, which reacts with meconium and the mucin derived from amniotic fluid (glycoprotein) to stain the lung tissue of women with AFE. TKH-2 immunostaining appears to be a sensitive method of detecting mucin in the lungs of women suspected of having an amniotic fluid embolus.

Admit the patient with amniotic fluid embolism (AFE) into the intensive care unit (ICU).

Treatment is supportive and includes the following:

• Administer oxygen to maintain normal saturation. Intubate if necessary.

• Initiate cardiopulmonary resuscitation (CPR) if the patient arrests. If she does not respond to resuscitation, perform a perimortem cesarean delivery.

• Treat hypotension with crystalloid and blood products. Use pressors as necessary.

• Avoid excessive fluid administration. During the initial phase, right ventricular function is suboptimal.  Excess fluid may overdistend the Right ventricle which could increase the risk of a right sided myocardial infarction.

• Consider pulmonary artery catheterization in patients who are hemodynamically unstable.

• Continuously monitor the fetus. Deliver immediately following cardiac arrest if gestational age is ≥ 23 weeks.[26]

•  Early evaluation of clotting status and early initiation of massive transfusion protocols is recommended.[26]

• Treat coagulopathy with FFP for a prolonged aPTT, cryoprecipitate for a fibrinogen level less than 100 mg/dL, and transfuse platelets for platelet counts less than 20,000/µL.

• Lim and colleagues[32] reported a case of AFE in which the coagulopathy was treated with activated recombinant factor VIIa (rVIIa). The range of doses to treat serious bleeding is from 20-120 μg/kg. In a systematic review of case reports, 16 patients received rVIIa and 28 patients did not. The patients who received rVIIa had statistically worse outcomes, including death and multiple organ failure. The authors suggest that rVIIa only be used when hemorrhage cannot be stopped by other means.[33]

• Hemodialysis with plasmapheresis[34] and extracorporeal membrane oxygenation (ECMO) with intra-aortic balloon counterpulsation[35] have been described in case reports with successful outcomes in treating AFE patients with cardiovascular collapse. The use of anticoagulation during ECMO may worsen bleeding in patients with AFE.  Use of ECMO is not routinely recommended.[26]

Consultations

Women who survive AFE will probably require ICU admission. Left heart failure is a common late occurrence. Additionally, survivors will probably have neurologic sequelae.

Therefore, consult the intensive care service in anticipation of transfer to that unit, and consult neurologists as needed if a patient shows signs of neurologic deficits.

Management should be by a multidisciplinary team including anesthesia, critical care, respiratory therapy, and maternal-fetal medicine.[26]

Transfer

Transfer to a level 3 hospital may be required once the patient is stable.

Perform emergent cesarean delivery in arrested mothers who are unresponsive to resuscitation.

Goldszmidt and Davies[36] reported 2 cases of amniotic fluid embolism (AFE) in which the hemorrhage was controlled with bilateral uterine artery embolization. In both cases, bleeding was arrested with the procedure and both patients survived.

Drugs are used in amniotic fluid embolism (AFE) to stabilize the patient. Pressors are used to maintain blood pressure, and inotropes are used to improve contractility. Use of steroids has been suggested because the process may be immune mediated. Uterotonics may be used to limit postpartum bleeding.

Epinephrine (Adrenalin, Auvi-Q, EpiPen)

 

Epinephrine has a larger ionotropic effect than norepinephrine and also produces a small amount of bronchodilation.  It is considered first line for anaphylactic shock.  Side effects include tachycardia and transient lactic acidosis.

Norepinephrine (Levarterenol, Levophed)

Considered safer than epinephrine or dopamine. First-line for cardiogenic shock. Arterial effects may increase coronary blood flow and venous effects may increase preload.

Class Summary

Used in AFE to maintain blood pressure.

Dopamine (Intropin)

One of several drugs that can be used to maintain perfusion. Dopamine increases myocardial contractility and systolic BP with little increase in diastolic BP. Also dilates the renal vasculature, increasing renal blood flow and GFR.  Dopamine has falled out of favor due to an increase in adverse events.  It is now only used in cases of shock refractory to other medications.

Class Summary

Used to improve myocardial contractility in patients with amniotic-fluid embolism.

Digoxin (Lanoxin, Lanoxicaps)

Cardiac glycoside that acts directly on the cardiac muscle and conduction system. Digoxin causes an increase in force and velocity of systolic contraction, a slowing of the heart rate, and decreased conduction velocity through the AV node.

Class Summary

Some authorities suggest steroid use may be helpful in AFE because the process may be immune mediated.

Hydrocortisone (Hydrocortone, Hydrocort, Cortef)

Because AFE is more similar to an anaphylactic reaction, steroids that mediate the immune responses are recommended.

Class Summary

Cause the uterus to contract. Uterine atony (failure of the uterus to contract and involute, thus closing off the bleeding spiral arteries after delivery of the placenta) may be a source of significant postpartum bleeding.

Oxytocin (Pitocin, Syntocinon)

Most commonly used uterotonic. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Methylergonovine (Methergine)

Acts directly on uterine smooth muscle, causing a sustained tetanic uterotonic effect that reduces uterine bleeding.

Carboprost tromethamine (Hemabate)

Prostaglandin similar to F2-alpha (dinoprost), but has longer duration and produces myometrial contractions that induce hemostasis at placentation site, which reduces postpartum bleeding.