A postpartum perfect storm
Authors: Adanma Ayanambakkam, Kerry C. Owens, Jennifer J. McIntosh, Carla M. Nester, James N. George
Journal: American Journal of Hematology (2017)

A 32-year-old healthy African-American woman had an uncomplicated third pregnancy with a healthy baby boy delivered by cesarean section at 39 weeks. Her first pregnancy ended with fetal death at 22 weeks, attributed to placental abruption; her second pregnancy was uncomplicated. On postpartum Day 1, her blood pressure was 129/67, hematocrit 25%, platelet count 276,000/µL. She was discharged on Day 2. On Day 5, she saw her obstetrician because of a severe headache. She had no visual symptoms. Her blood pressure was 123/63, platelet count was 309,000/µL, and serum AST/ALT were 29/13 U/L. Her obstetrician was not alarmed by the headaches. Although the course of this pregnancy and delivery were normal, and the clinical and laboratory evaluation on Day 5 were also normal, the placental abruption during her first pregnancy increases her risk in subsequent pregnancies. Although headache is a common initial symptom of preeclampsia, her obstetrician was reassured by the normal blood pressure, platelet count and liver function tests. The following day, Day 6, she had a generalized tonic-clonic seizure, fell down the stairs, and was unresponsive and incontinent. At the emergency room of her local hospital in a small city, her initial blood pressure was 138/86. Physical examination was normal except for the neurologic abnormalities. Laboratory data included hematocrit, 37%; platelet count, 75,000/µL; serum creatinine, 2.1 mg/dL; serum AST/ALT, 52/13 U/L. No previous serum creatinine values were available. Later that evening she developed severe hypertension (193/117). Neuroimaging demonstrated diffuse cerebral edema with symmetrical white matter attenuation in the parietal and occipital lobes, consistent with posterior reversible encephalopathy syndrome (PRES) (Figure 1). Neuroimaging also demonstrated tiny punctate hemorrhages in the cerebral cortex bilaterally and a very small left subarachnoid hemorrhage. Eclampsia was diagnosed. She was treated with intravenous magnesium, mannitol, and multiple anti-hypertensive medicines. Magnetic resonance imaging (MRI) of the patient's brain on postpartum Day 6. The left image is a coronal view demonstrating increased signal uptake (white) in the parietal lobes bilaterally. The center and right images are axial views. The center image is more cephalic (higher) and demonstrates increased signal uptake in the parietal lobes. The right image is more caudal (lower) and demonstrates increased signal uptake in the occipital lobes bilaterally. The increased signal uptake is caused by cerebral edema and illustrates the typical pattern of posterior reversible encephalopathy syndrome (PRES). The small, bilateral intracranial hemorrhages associated with her preeclampsia and the small subarachnoid hemorrhage, probably caused by the trauma of falling downstairs, are not visible on these MRI images The diagnosis of eclampsia is established in this patient by the occurrence of postpartum seizures and hypertension. Normal liver function tests and absence of liver tenderness excluded HELLP (hemolysis, elevated liver function tests, low platelets) syndrome. Although eclampsia typically occurs during pregnancy, preceded by preeclampsia, it can occur up to six weeks postpartum and without preceding preeclampsia. Eclampsia can also occur without hypertension at the time of initial presentation. Severe headache and visual changes are common symptoms preceding eclampsia. The occurrence of PRES is consistent with eclampsia; the tiny bilateral punctate cortical hemorrhages may be the result of her severe hypertension; the subarachnoid hemorrhage may be the result of falling down the stairs. Moderate thrombocytopenia is consistent with eclampsia. Mild abnormalities of kidney function can occur with eclampsia, but acute kidney injury (AKI) suggested by the initial serum creatinine of 2.1 mg/dL is unexpected. On Day 7 she was afebrile, awake but confused. Her blood pressure was controlled. However her anemia and thrombocytopenia became more severe, requiring red cell and platelet transfusions. Her serum creatinine continued to increase. On Day 9 she was transferred to a tertiary medical center in the closest large city. On Day 10 her hematocrit was 22% and platelet count 19,000/µL despite multiple transfusions. Serum creatinine was 6.6 mg/dL; lactate dehydrogenase (LDH) was 2591 U/L. Coagulation tests including, fibrinogen concentration, were normal. The peripheral blood smear demonstrated many schistocytes. The direct antiglobulin test was negative. Thrombotic thrombocytopenic purpura (TTP) was considered because of the severe microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Complement-mediated thrombotic microangiopathy (C-TMA, also described as atypical hemolytic-uremic syndrome [aHUS]) was thought to be more likely because of the severity of the AKI. Eculizumab was given; plasma exchange (PEX) was not begun. Eclampsia can be associated with MAHA and thrombocytopenia, but severe MAHA and thrombocytopenia requiring multiple transfusions does not typically occur. Therefore consideration of a thrombotic microangiopathy (TMA) syndrome was appropriate. TTP may be the most familiar TMA syndrome and its frequency is increased during pregnancy or postpartum. TTP commonly causes mildly increased serum creatinine, but severe AKI requiring dialysis is rare. Therefore C-TMA was an appropriate diagnosis, prevention of end-stage kidney disease was the primary objective, and eculizumab was appropriate treatment. The frequency of C-TMA is also increased during pregnancy or postpartum. On Day 11, the patient was intermittently alert but remained very weak. Dialysis was begun. Severe anemia and thrombocytopenia persisted. Her platelet count had increased to 132,000/µL on Day 12 following platelet transfusions but then decreased to 18,000/µL on Day 13. Blood cultures were negative. Tests for antinuclear, anticardiolipin, and antiphospholipid antibodies were negative. The aPTT was normal; testing for lupus anticoagulant was not done. At this time, the severity of thrombocytopenia has become a greater concern. It may be too soon to expect benefit of eculizumab, but it is appropriate to consider diagnoses other than C-TMA, which is not expected to cause severe thrombocytopenia. Sepsis, systemic lupus erythematosus, and antiphospholipid syndrome were excluded. The severity of thrombocytopenia is typical of TTP. On Day 13, PEX for TTP was begun. Later that day, ADAMTS13 activity (drawn, Day 9) was reported as <3% with a functional inhibitor (1.6 Bethesda units). No additional eculizumab was given. Corticosteroids as adjunctive treatment for TTP were not given because they may worsen PRES. The patient has now met diagnostic criteria for both eclampsia and acquired, autoimmune TTP. To postulate a third diagnosis, C-TMA, seems inappropriate. However continuation of eculizumab should be considered because of the persistent severe AKI and the potential for end-stage renal disease. A rationale for not continuing eculizumab could be a hypothesis that the combination of eclampsia plus TTP may cause severe AKI, even though either disorder alone is rarely associated with severe AKI. Another consideration is that eculizumab would be required daily, following each PEX. The expense of daily eculizumab would be extreme. On Day 14, after one PEX, the patient improved dramatically. She was alert and, although she had no recollection of the days preceding her seizures, her memory was increasingly clear for the days following her hospitalization. Corticosteroids were begun. Clinical improvement supported the diagnosis of TTP. Immunosuppressive treatment, in addition to PEX, is important to achieve a durable remission. Corticosteroids are routine. Some hematologists also use rituximab as routine initial treatment for TTP. On Day 21, the patient's platelet count had increased to 201,000/µL (with no platelet transfusions for four days) and her LDH had decreased from 3703 U/L to 657 U/L. Her mental status and strength were normal. She continued to require regular dialysis and her hypertension required three medications. Day 21 was her last PEX. It appeared that she would soon go home, although with continuing dialysis. The response to PEX and corticosteroids further supports the diagnosis of TTP. The persistent kidney failure and hypertension may be attributed to the resolving eclampsia, complicated by TTP. That night, Days 21–22, the patient had sudden severe chest pain, extreme dyspnea, and hypoxemia requiring intubation. Chest X-ray demonstrated bilateral pulmonary edema. A ventilation-perfusion lung scan had low probability for pulmonary embolism. Transthoracic echocardiogram demonstrated severe systolic dysfunction with diffuse hypokinesis; the left ventricle ejection fraction was 25%. Myocardial infarction was excluded by electrocardiogram and cardiac enzymes. The diagnosis was peripartum cardiomyopathy. Intravenous diuretics and dialysis ultra-filtration with a goal of net-negative fluid balance were begun. The postpartum onset of acute heart failure, in the absence of other identifiable causes, is consistent with peripartum cardiomyopathy. Although its occurrence is rare, its frequency is greatly increased in women with eclampsia. Since TTP causes systemic microvascular thrombi and organ ischemia, the presence of TTP may also have increased her risk for the occurrence of cardiomyopathy. On Day 27 she was extubated but still required oxygen for respiratory distress. On Day 29 a kidney biopsy demonstrated the characteristic features of acute, severe TMA with thrombosis, endothelial injury, and subendothelial edematous expansion involving arterioles and glomerular capillaries. There was no interstitial fibrosis. TMA is consistent with the diagnosis of TTP. The kidney pathology would be identical in patients with C-TMA and similar, but less severe, in women with eclampsia. The absence of interstitial fibrosis is evidence against any preceding chronic kidney disease and is encouraging for recovery of kidney function. On Day 34 the patient developed severe abdominal pain. Imaging demonstrated acute hemorrhagic pancreatitis with extreme pancreas enlargement (Figure 2). Multiple pseudocysts, as large as 12.2 × 4.8 × 5.9 cm, were present in the peri-pancreatic soft tissue as well as in the pancreas. Many pseudocysts contained blood. On Day 35, a repeat echocardiogram demonstrated decreased systolic function with a left ventricle ejection fraction of 17%. Dialysis was continued. Magnetic resonance imaging (MRI) of the abdomen on postpartum Day 34, with T1 and T2 weighted images using the magnetic resonance cholangiopancreatography (MRCP) protocol to assess the pancreas. The left image is from a normal subject to illustrate normal anatomy. (P) indicates the head of the pancreas with the body and tail extending to the right, in front of the aorta (A), to the right kidney (K). The spleen (S), liver (L), inferior vena cava (I) (with a branching vein), and stomach with gastric contents (G) are also labeled. Gastric contents cause a bright white signal. The center and right illustrations are MRI images are from the patient. The center image demonstrates the extreme swelling of the pancreas with extensive cystic changes and irregular peripheral margins merging with peri-pancreatic tissues (A). The brighter white irregular tissue at the posterior edge of the pancreas is caused by blood products, indicating hemorrhage within the pancreas. A clearly demarcated cyst is apparent in the tail of the pancreas, and the increased (white) signal at right margin of this cyst indicates hemorrhage. The right image demonstrates a large pseudocyst filled with blood products in the pancreatic tail (B). These images document severe hemorrhagic pancreatitis. The bright white oblong image anterior to the pancreas in the center and right images is caused by gastric contents The occurrence of severe pancreatitis and the deterioration of the patient's cardiac function is a critical change in her course. This patient has many risk factors for pancreatitis. The frequency of pancreatitis is increased with pregnancy, and further increased with preeclampsia/eclampsia. TMA syndromes cause systemic microvascular thrombosis with organ ischemia and increase risk for pancreatitis. Low perfusion due to the decreased cardiac output, corticosteroids and diuretics also increase risk for pancreatitis. The further deterioration of the patient's cardiac function is alarming. Between Days 35 and 50, the patient deteriorated rapidly. She became cachectic; her weight decreased from 155 to 92 pounds. Multiple abdominal drains were required for abscesses caused by the necrotic pancreas. She had bilateral pulmonary consolidations, presumed to be infectious pneumonia. Following Day 50, she had multiple episodes of bacteremia and fungemia. She remained ventilator dependent, requiring a tracheostomy on Day 61. She became unresponsive on Day 74 and died on Day 76. After the patient's death, complement-related gene analysis was performed. No mutations associated with C-TMA were identified. The accumulation of multiple critical disorders with their complications was overwhelming. The absence of complement-related mutations does not exclude the diagnosis of C-TMA. Following an uncomplicated pregnancy and delivery, this patient had a sequence of severe disorders that eventually caused her death. Each of the disorders is rare; to have them all together seems unbelievable. However, the occurrence of each of these disorders may in turn increase risk for the others. Her story may be described as cascade of accumulating critical complications—a perfect storm. Four of her disorders were diagnosed by established clinical, laboratory, and imaging data: eclampsia, TTP, peripartum cardiomyopathy, and pancreatitis. A possible fifth disorder, C-TMA, has no precise diagnostic criteria.1 It was initially suspected and treated, but was subsequently considered to be unlikely and treatment was stopped. However, with retrospective analysis we have considered that C-TMA may also have been present and contributed to her severe kidney injury, her critical course, and her death. Table 1 describes the frequency, clinical features, and mortality for each of these five disorders. Eclampsia was her initial disorder. Its frequency in the US is rare, 0.56 cases/10,000 deliveries.2 A review of eclampsia reported that 21% occurred postpartum and 25% of women were normotensive at the time of their initial seizure,10 consistent with this patient's presentation. Even with severe hypertension and encephalopathy, recovery is expected. Mortality from eclampsia in the US is 0.5%.2 Microangiopathic hemolysis, thrombocytopenia, and abnormal kidney function can all occur in women with eclampsia,11 but, in this patient, the warning that eclampsia was not her only disorder was the severity of these abnormalities. Postpartum day 10 was a turning point. It seemed that an additional diagnosis must be considered. TTP was the initial consideration because of its familiarity, its recognized association with pregnancy,12 and its typical severity of the hemolysis and thrombocytopenia. Among Oklahoma TTP Registry patients, the median hematocrit was 20% and platelet count 10,000/µL at the time of diagnosis.5 However the severity of her AKI with imminent need for dialysis appeared to be inconsistent with either eclampsia or TTP (Table 1). Two algorithms developed to assist the diagnosis of TTP included criteria for kidney function, that serum creatinine concentration is typically <200 µmol/L (<2.26 mg/dL)13 or <2.0mg/dL.14 in patients with TTP. Therefore C-TMA was considered. Although hemolysis and thrombocytopenia may be less severe in patients with C-TMA, kidney injury is severe and end-stage renal disease is common.4 At this time the kidney injury appeared to present the greatest danger and therefore eculizumab was given for the prevention of end-stage renal disease.1 Postpartum day 13 was another turning point. Thrombocytopenia and anemia remained severe. On this day it was decided that waiting for benefit from eculizumab was not appropriate. The risks of untreated TTP, which has a mortality of 90% without PEX treatment,15 appeared to present the greatest danger. Therefore plasma exchange was begun. The subsequent report that ADAMTS13 activity was <3% with a documented functional inhibitor confirmed the diagnosis of TTP.5 Eculizumab was not continued for two reasons. First, it seemed improbable that she would have three diagnoses; two diagnoses (eclampsia, TTP) already seemed extremely unusual. Second, continuation of eculizumab would have required daily administration, following each plasma exchange procedure; the cost would be extreme.16 The decision not to continue eculizumab was supported by her subsequent improvement with PEX and corticosteroids. Her platelet count recovered to normal; PEX was stopped. She remained dependent on dialysis. Postpartum day 22 was yet another turning point. She had sudden, severe pulmonary edema; peripartum cardiomyopathy was diagnosed. Although peripartum cardiomyopathy is a rare pregnancy-associated complication, its frequency is increased 54-fold in women with eclampsia, compared to women without eclampsia (348 vs. 6.5 cases/10,000 deliveries).2 Although 61% of white women with peripartum cardiomyopathy have complete recovery of left ventricular function (to ejection fraction >50%), the frequency of recovery is significantly less in African-American women (40%).17 This patient's ejection fraction continued to decrease until her death. Postpartum day 34 was the final turning point, when she developed severe hemorrhagic pancreatitis. The occurrence of pancreatitis was unexpected, but she had many risk factors for pancreatitis: eclampsia,18 TTP,19 C-TMA, cardiomyopathy, corticosteroids, diuretics. Multiple infected abdominal cysts led to repeated episodes of sepsis, and finally to her death. Following her death, we reconsidered the diagnosis of C-TMA and the issue of continuing eculizumab. Even though genetic testing did not identify mutations associated C-TMA, this does not exclude the diagnosis.1, 4 This patient fulfilled the diagnostic criteria for C-TMA1, 4 with one important exception. Severe ADAMTS13 deficiency (indicating TTP) is considered evidence against the diagnosis of C-TMA.1 Having experienced this patient's tragic cascade of critical complications, what would we do differently for a patient who presents with eclampsia and severe microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury? Our experience suggests that maximum treatment for all possible disorders is appropriate for women with eclampsia, whose risk for additional complications is great. We would not hesitate to consider both TTP and C-TMA. We would use maximum treatment for TTP, with rituximab20 in addition to PEX and corticosteroids. We would continue treatment with eculizumab for possible C-TMA, to provide maximum protection for her kidneys. Our experience is consistent with the recognized associations of all these disorders with pregnancy and with each other (Figure 3). Using intensive immunosuppression with corticosteroids, rituximab and eculizumab may increase risk for infection, and infections were the final cause of our patient's death. However, the potential for a cascade of critical complications associated with pregnancy requires a reevaluation of the risks and benefits of combining all potential effective treatments. A diagram of the interactions among the five disorders that were diagnosed or considered in this patient. Pregnancy increases risk for C-TMA, TTP, and cardiomyopathy. The occurrence of eclampsia further increases the risk for cardiomyopathy. C-TMA and TTP, causing systemic microvascular thrombi and organ ischemia, may also increase risk for cardiomyopathy. Eclampsia (and also pregnancy without preeclampsia or eclampsia), TTP, C-TMA, and cardiomyopathy all increase risk for pancreatitis