Amniotic Fluid Embolism


Background
Amniotic fluid embolism (AFE) is a rare obstetric emergency in which it is postulated that amniotic fluid, fetal cells, hair, or other debris enter the maternal circulation, causing cardiorespiratory collapse.
In 1941, Steiner and Luschbaugh described AFE for the first time after they found fetal debris in the pulmonary circulation of women who died during labor.
Current 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.1
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. In a patient who is critically ill, a sample obtained by aspiration of the distal port of a pulmonary artery catheter that contains fetal squamous cells is considered suggestive of but not diagnostic of AFE syndrome.2 The diagnosis is essentially one of exclusion based on clinical presentation. Other causes of hemodynamic instability should not be neglected.
Pathophysiology
The pathophysiology of AFE is poorly understood. Based on the original description, it was theorized that amniotic fluid and fetal cells enter the maternal circulation, possibly triggering an anaphylactic reaction to fetal antigens. However, 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.
Benson et al3 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 Gherman4 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).
A case reported by Marcus et al5, in which AFE developed after a spontaneous rupture of membranes, demonstrated no increase in mast cells or degranulation in lung tissue as shown by Giemsa staining. Serum tryptase levels were 11.4 ng/mL (normal <11.4 ng/mL).
The initiating event is poorly understood. However, usually during labor or other procedure, amniotic fluid and debris, or some as yet unidentified substance, enters the maternal circulation; this may trigger a massive anaphylactic reaction, activation of the complement cascade, or both. 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.
Frequency
United States
Incidence of 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.
International
Incidence is similar to that of the United States.
Mortality/Morbidity
Maternal mortality approaches 80%. Mortality was 61% in the US national registry, which listed 46 cases. Five to 10% of maternal mortality in the United States is due to AFE. 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.

The United Kingdom AFE registry reports a mortality of 37%. Of those who survived AFE, 7% were neurologically impaired.6

Survival is uncommon, although the prognosis is improved with early recognition and prompt resuscitation. Most women who survive have permanent neurologic impairment. Neonatal survival was 79% in the US registry and 78% in the UK registry.
Race
No racial or ethnic predilection exists.
Sex
AFE only occurs in women.
Age
Previously, advanced maternal age was believed to be a risk factor. No relationship to age has been found in the National Amniotic Fluid Embolus Registry.




History
Amniotic fluid embolism (AFE) usually occurs during labor but has occurred during abortion, after abdominal trauma, and during amnioinfusion.
A woman in the late stages of labor becomes acutely dyspneic with hypotension; she may experience seizures quickly followed by cardiac arrest. Massive DIC-associated hemorrhage follows and then death. Most patients die within an hour of onset.

Currently no definitive diagnostic test exists. The United States and United Kingdom AFE registries recommend the following 4 criteria, all of which must be present to make the diagnosis of AFE.6, 1, 7
1. Acute hypotension or cardiac arrest
2. Acute hypoxia
3. Coagulopathy or severe hemorrhage in the absence of other explanations
4. All of these occurring during labor, cesarean delivery, dilation and evacuation, or within 30 minutes postpartum with no other explanation of findings
Physical
In case reports, patients are described as developing acute shortness of breath, sometimes with a cough, followed by severe hypotension. 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.)7
• Altered mental status/confusion/agitation
Causes
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.8 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.

DIFFERENTIALS

Anaphylaxis
Aortic Dissection
Cholesterol Embolism
Myocardial Infarction
Pulmonary Embolism
Septic Shock
Other Problems to be Considered
Placental abruption
Aspiration

WORKUP


Lab Studies
• Arterial blood gas (ABG) levels: Expect changes consistent with hypoxia/hypoxemia.
•
o Decreased pH levels (reference range = 7.40-7.45)
o Decreased PO2 levels (reference range = 104-108 mm Hg)
o Increased PCO2 levels (reference range = 27-32 mm Hg)
o Base excess increased
• CBC with platelets
•
o Hemoglobin and hematocrit levels should be within reference ranges.
o Thrombocytopenia is rare. If platelets are less than 20,000/΅L, or if bleeding occurs and platelets are 20,000-50,000/΅L, transfuse platelets at 1-3 U/10 kg/d.
• Prothrombin time and activated partial thromboplastin time
•
o 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.
o Activated partial thromboplastin time (aPTT) may be within reference ranges or shortened.
• If fibrinogen level is less than 100 mg/dL, administer cryoprecipitate. Each unit of cryoprecipitate raises the fibrinogen level 10 mg/dL.
• Blood type and screen in anticipation of the requirement for a transfusion.
Imaging Studies
• Chest radiograph posteroanterior and lateral findings are usually nonspecific, but evidence of pulmonary edema may be observed.
Other Tests
• A 12-lead ECG may show tachycardia, ST segment and T-wave changes, and findings consistent with right ventricle strain.
Procedures
• Arterial line to accurately measure blood pressure and to obtain ABG readings
• Pulmonary artery catheter to monitor wedge pressure, cardiac output, oxygenation, and systemic pressures
Histologic Findings
On autopsy, blood vessels in the lungs may show evidence of fetal debris (eg, squamous cells, vernix, mucin).
Aguilera et al9 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.
Marcus et al5 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 colleagues10 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 al11 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.

TREATMENT


Medical Care
Treatment is supportive.
• 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.
• Consider pulmonary artery catheterization in patients who are hemodynamically unstable.
• Continuously monitor the fetus.
• 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/΅L.
• Lim and colleagues12 reported a case of AFE in which the coagulopathy was treated with activated recombinant factor VIIa. The range of doses to treat serious bleeding is from 20-120 mcg/kg.
• Hemodialysis with plasmapheresis13 and extracorporeal membrane oxygenation with intra-aortic balloon counterpulsation14 have been described in case reports with successful outcomes in treating AFE patients with cardiovascular collapse.
Surgical Care
Perform emergent cesarean delivery in arrested mothers who are unresponsive to resuscitation.
Goldszmidt and Davies15 reported 2 cases of 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.
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.
• Consult the intensive care service in anticipation of transfer to that unit.
• Consult neurologists as needed if a patient shows signs of neurologic deficits.



Drugs are used in 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.
Drug Category: Sympathomimetic/vasopressor agents
Used in AFE to maintain blood pressure.
Drug Name Dopamine (Intropin)
Description 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.
Adult Dose 2-5 mcg/kg/min IV; titrate to BP and cardiac output
Pediatric Dose Not established
Contraindications Documented hypersensitivity; pheochromocytoma; ventricular fibrillation, hypovolemia
Interactions Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of dopamine
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Monitor urine flow, cardiac output, pulmonary wedge pressure, and BP during infusion; prior to infusion, correct hypovolemia with either whole blood or plasma, as indicated; monitoring central venous pressure or left ventricular filling pressure may be helpful
Drug Category: Inotropes/inotropic agents
Used to improve myocardial contractility in patients with amniotic-fluid embolism.
Drug Name Digoxin (Lanoxin, Lanoxicaps)
Description 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.
Adult Dose 0.5 mg IV push, then 0.25 mg IV q4h for 2 doses, followed by 0.25 mg PO qd
Pediatric Dose Not established
Contraindications Documented hypersensitivity; ventricular fibrillation; beriberi heart disease; idiopathic hypertropic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome
Interactions Medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, oral amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil; medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, oral colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (eg, carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Calcium may produce arrhythmias in digitalized patients; hypercalcemia predisposes patient to digitalis toxicity; hypocalcemia can make digoxin ineffective until serum calcium levels are normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients with incomplete AV block may progress to complete block when treated with digoxin; exercise caution in patients with hypothyroidism, hypoxia, and acute myocarditis
Drug Category: Corticosteroids
Some authorities suggest steroid use may be helpful in AFE because the process may be immune mediated.
Drug Name Hydrocortisone (Hydrocortone, Hydrocort, Cortef)
Description Because AFE is more similar to an anaphylactic reaction, steroids that mediate the immune responses are recommended.
Adult Dose 500 mg IV q6h
Pediatric Dose Not established
Contraindications Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Drug-induced adrenocortical insufficiency; drug-induced psychosis; caution in hyperthyroidism, osteoporosis, peptic ulcer disease, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis
Drug Category: Uterotonics
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.
Drug Name Oxytocin (Pitocin, Syntocinon)
Description Most commonly used uterotonic. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Adult Dose 10 U IM or 10-40 U IV at 250 mL/h in 1000 mL NS
Pediatric Dose Not established
Contraindications Documented hypersensitivity; pregnant patients with severe toxemia, unfavorable fetal positions, and a contracting uterus with hypertonic or hyperactive patterns; labor in which vaginal delivery should be avoided such as invasive cervical carcinoma, cord presentation or prolapse, active herpes genitalis, total placenta previa, and vasa previa
Interactions Pressor effect of sympathomimetics may increase when used concomitantly with oxytocic drugs, causing postpartum hypertension
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions A uterus that is overstimulated can be hazardous to both mother and fetus; hypertonic contractions can occur in a patient whose uterus is hypersensitive to oxytocin, regardless of whether it was appropriately administered; oxytocin has intrinsic antidiuretic effect that when administered by continuous infusion and patient is receiving fluids by mouth, can cause water intoxication
Drug Name Methylergonovine (Methergine)
Description Acts directly on uterine smooth muscle, causing a sustained tetanic uterotonic effect that reduces uterine bleeding.
Adult Dose 0.2 mg IM; may repeat q10-15min for 3 doses
Pediatric Dose Not established
Contraindications Documented hypersensitivity; glaucoma, Tourette syndrome; anxiety
Interactions Concurrent administration of methylergonovine with vasoconstrictors or other ergot alkaloids may produce additive effect
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions Caution in sepsis, obliterative vascular disease, or hepatic or renal insufficiency
Drug Name Carboprost tromethamine (Hemabate)
Description Prostaglandin similar to F2-alpha (dinoprost), but has longer duration and produces myometrial contractions that induce hemostasis at placentation site, which reduces postpartum bleeding.
Adult Dose 0.25 mg IM q10-15min; not to exceed 3 doses
Pediatric Dose Not established
Contraindications Documented hypersensitivity; pelvic inflammatory disease
Interactions Increases toxicity of oxytocic agents
Pregnancy X - Contraindicated; benefit does not outweigh risk
Precautions Caution in cardiovascular disease, asthma, hypotension or hypertension, adrenal disease, diabetes, renal or hepatic disease, a compromised uteri, and jaundice; do not inject IV (may induce hypertension and bronchospasm)

FOLLOW-UP


Further Inpatient Care
Admit the patient into the ICU.
Transfer
Transfer to a level 3 hospital may be required once the patient is stable.
Deterrence/Prevention
AFE is an unpredictable event.
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.
Prognosis
• Maternal mortality is 61%.
• Most survivors have neurologic deficits.
• The intact infant survival rate is 70%. Neurologic status of the infant is directly related to the time elapsed between maternal arrest and delivery.
• 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.

MISCELLANEOUS


Medical/Legal Pitfalls
• Failure to respond emergently is a pitfall. AFE is a clinical diagnosis. Steps must be taken to stabilize the patient as soon as symptoms manifest.
• Failure to perform perimortem cesarean delivery in a timely fashion is a pitfall. After 5 minutes of unsuccessful CPR, abdominal delivery is recommended.
• Failure to consider the diagnosis during legal abortion is a pitfall. A review of the literature indicates that most case reports of AFE have occurred during late second-trimester abortions.