Amniotic Fluid Embolism

Background: Amniotic fluid embolism (AFE) is a rare obstetric emergency in which 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.

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. Other causes of hemodynamic instability should not be neglected.

Pathophysiology: The pathophysiology of AFE is poorly understood. Amniotic fluid and fetal cells enter the maternal circulation, possibly triggering an anaphylactic reaction to fetal antigens.

Benson et al 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 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>

A case reported by Marcus et al, 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>

Amniotic fluid and debris enter 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:

• In the US: Incidence of AFE is estimated at 1 case per 8,000-30,000 pregnancies.

• Internationally: Incidence is similar to that of the United States.

Mortality/Morbidity: Maternal mortality approaches 80%. Mortality was 61% in the 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.

Survival is uncommon. Most women who survive have permanent neurologic impairment. Neonatal survival is 70%. No evidence indicates that survivors are at risk for AFE during future pregnancies.

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.

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/mL.
• Lim and colleagues 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.

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

Goldszmidt and Davies 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.

Medication
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) -- 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 - Safety for use during pregnancy has not been established.
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) -- 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 - Safety for use during pregnancy has not been established.
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) -- 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 - Safety for use during pregnancy has not been established.
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) -- 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 - Usually safe but benefits must outweigh the risks.
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) -- 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 - Unsafe in pregnancy
Precautions	Caution in sepsis, obliterative vascular disease, or hepatic or renal insufficiency

Drug Name	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.
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 in pregnancy
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)