Objective
Our aim was to provide a description of clinical and laboratory finding: pregnancy outcomes in women with acute fatty liver of pregnancy (AFLP). We also characterize the duration of recovery of multiorgan system dysfunction that begins after delivery.
Study Design
All women who were admitted to Parkland Hospital with AFLP were identified; their clinical and laboratory findings, pregnancy outcomes, and postpartum resolution of AFLP were reviewed.
Results
Between 1975 and 2012, there were 51 women who were identified to have AFLP. The most common complaints were persistent nausea and vomiting (57%), hypertension (57%), and abdominal pain (53%). More than 90% of these women had at least 1 of these findings or combinations thereof. A combination of hepatic and renal dysfunction was nearly universal, but with variable severity. Procoagulant synthesis was impaired in more than three-fourths of the women, which served to intensify obstetric hemorrhage for which 50% of the 51 women received blood and component transfusions. The stillbirth rate was 120 of 1000 pregnancies, and there were 2 maternal deaths. Composite recovery times of various markers of hepatic and renal function indicated normalization of most laboratory values within 7-10 days after delivery.
Conclusion
The clinical features and laboratory findings of women with AFLP derive from the central pathologic process: liver failure. After delivery, clinical recovery typically is seen within 3-4 days; however, laboratory abnormalities can persist for much longer.
Maternal deaths from acute liver failure caused by microvesicular fatty infiltration were first described >150 years ago. In 1903, Williams briefly cited this rare occurrence, and only sporadic cases were reported during the ensuing 4 decades. In 1940, Sheehan published detailed histopathologic findings from autopsies of pregnant women with acute fatty liver failure; most of these deaths were from hepatotoxicity (related to chloroform), which was a commonly used anesthetic. He termed the idiopathic cases as obstetric acute yellow atrophy . Thereafter, removal of chloroform and tetracycline antibiotic use in obstetrics obviated most cases. Burroughs et al later provided a meticulous pathologic description of these women as having widespread microvesicular fatty infiltration of swollen hepatocytes with minimal necrosis and cholestasis. These women had moderate-to-severe renal insufficiency, and many of them also had profound coagulopathic changes.
Over the past 20 years, maternal deaths from acute fatty liver of pregnancy (AFLP) has declined to approximately 10% along with a concomitant decrease in perinatal deaths. This is despite major morbidity that is consequential to liver failure that includes kidney injury and coagulopathy-intensifying obstetric hemorrhage. Because most investigators assume that earlier recognition of AFLP has the best maternal and fetal outcomes, recent criteria were developed that might facilitate an earlier diagnosis or that could be used to confirm it retrospectively. One such set was the Swansea Criteria proposed by Ch’ng et al and subsequently verified by the United Kingdom Obstetrical Surveillance System. Although it is generally agreed that recovery begins at or around the time of delivery, these reports provide only scant details concerning recovery of hepatic and renal function. The purpose of our study was to provide the clinician with a reasonable expectation of the duration of recovery of multiorgan system abnormalities that are associated with AFLP.
Materials and Methods
From 1975-2012, ≥1 of the investigators were involved in the care of women who were admitted to Parkland Hospital with a diagnosis of AFLP. These names were entered into a registry, and with approval from the Institutional Review Boards at the University of Texas Southwestern Medical Center and Parkland Hospital, data were extracted from these medical records. For the entire study period, the criteria for diagnosis included evidence of acute liver failure with characteristic clinical findings accompanied by laboratory evidence that confirmed hepatic dysfunction along with collateral multiorgan system aberrations. We also applied both the “Swansea criteria” proposed by Ch’ng et al and the “AFLP-triad” of Vigil-de Gracia and Montufar-Rueda to confirm the diagnoses. Women were excluded if they were found to have viral hepatitis or hepatotoxicity that was caused by chemical agents and drugs. Patients with hemolysis, elevated liver enzymes, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count syndrome) without evidence of hepatic insufficiency were not considered to have AFLP.
Parkland Hospital is a tax-supported institution that serves the medically indigent women of Dallas County, Texas. In conjunction with the University of Texas Southwestern Medical Center at Dallas, obstetric care is coordinated and provided throughout pregnancy, delivery, and the puerperium period by members of the divisions of obstetrics and maternal-fetal medicine. Throughout the years of this report, women who were diagnosed with AFLP were treated in relatively uniform fashion by residents who were supervised by obstetrics faculty and fellows. In brief, for evaluation of maternal and fetal status, women were admitted to the labor and delivery suite, obstetric intermediate care unit, or the medical or surgical intensive care unit. The obstetric intermediate care unit is a high-dependency unit as defined by the Society of Critical Care Medicine and previously described by Zeeman et al. Anesthesia residents and faculty are available on-site, and 24/7 consultation is available from medical and surgical specialty services. After evaluation and stabilization, obstetrics management, especially expediting delivery, are the mainstays of care.
For this study, patient information was de-identified and stored in a computerized database. Maternal demographics, clinical findings and laboratory results, management, delivery and pregnancy outcomes, and postpartum recovery were reviewed. Laboratory findings were those that were determined by methods contemporaneously in use for various biochemical, hematologic, and coagulation tests. The severity and duration of hepatic necrosis were assessed by serial measurements of serum aspartate aminotransferase (AST) concentrations. The extent of liver dysfunction and recovery were assessed with serial measurements of serum cholesterol and albumin, bilirubin conjugation and clearance, and procoagulant proteins and anticoagulant activity. Acute kidney injury was determined by serial measurement of serum creatinine concentration. Additional hematologic and coagulation studies were performed as available by medical technologists in the Obstetrical Hematology Research Laboratory. Imaging studies were performed dependent on contemporaneous availability to include ultrasonography, computed tomography, and magnetic-resonance imaging. Hepatic tissue to confirm microvesicular fatty infiltration was obtained by liver biopsy in 9 women and at autopsy in another 2 women.
Results
From 1975-2012, there were 51 women with AFLP. Of these, 48 women were from the Parkland Hospital obstetrics population, and the 3 women were transferred from area hospitals. During this 38-year period, approximately 492,000 women were delivered at our hospital; thus, the frequency of AFLP was 1 per 10,000 births. With the exception of a propensity for twin gestations of 14%, their demographic characteristics were similar to women from our general obstetrics population. Their mean maternal age was 27.4 ± 7.3 years (range, 15–42 years), and 41% of them were nulliparous.
The clinical presentation of these women was variable and largely dependent on the severity of liver dysfunction. The 5 most common symptoms and their frequency are shown in Table 1 . Persistent nausea and vomiting, hypertension, or abdominal pain was seen in >50% of these women, and >90% of the women had at least 1 of these symptoms or a combination thereof. As shown in Table 1 , all 51 women had laboratory evidence for varying degrees of hepatocellular necrosis that was indicated by elevated serum transaminase levels. Hepatic dysfunction was also universal. Specifically, in the 28 women in whom cholesterol levels were determined, all of the levels were abnormally decreased when compared with reference ranges for normal pregnancy; all of the women had hyperbilirubinemia, and 16% of the women had encephalopathy. Of special clinical concern, seriously diminished procoagulant factor levels were common, and one-half of all women had a plasma fibrinogen level of <150 mg/dL. Leukocytosis was nearly universal (98%); however, hypoglycemia (<60 mg/dL) was documented in only 18% of the women. Acute kidney injury was nearly universal, and 76% of these women had a serum creatinine level of ≥1.5 mg/dL.
| Factor | Percentage |
|---|---|
| Symptoms | |
| Nausea and vomiting | 57 |
| Hypertension | 57 |
| Abdominal pain | 53 |
| Jaundice | 33 |
| Encephalopathy | 16 |
| Laboratory | |
| Hepatic transaminase elevation (mean: 453 ± 334 U/L a ) | 100 |
| Creatinine level b | |
| >1.0 mg/dL | 96 |
| ≥1.5 mg/dL | 76 |
| Thrombocytopenia level | |
| <150,000/μL | 69 |
| <100,000/μL | 20 |
| <50,000/μL | 10 |
| Leukocytosis level: >13,000/μL | 98 |
| Hyperbilirubinemia: >1.1 mg/dL (mean: 3.7 ± 2.0 mg/dL a ) | 100 |
| Cholesterol level c : <220 mg/dL (mean: 129 ± 47 mg/dL) | 100 |
| International normalized ratio: >1.5 | 60 |
| Prothrombin time: >15 sec | 48 |
| Hypofibrinogenemia d | |
| <150 mg/dL | 49 |
| <100 mg/dL | 29 |
| Hypoglycemia e | 18 |
| Lipase f (mean: 293 ± 681 U/L a ) | 24 |
| Ultrasonography: bright liver | 27 |
b Normal serum creatinine values during pregnancy = 0.4-0.9 mg/dL
c Normal serum cholesterol values during pregnancy = 220-350 mg/dL
d Normal plasma fibrinogen levels during pregnancy = 300-700 mg/dL
e Hypoglycemia defined as <60 mg/dL
Selected demographics and pregnancy outcomes are shown in Table 2 . Gestational age at delivery ranged from 31.7–40.9 weeks, and 20% of the women were delivered <34 weeks’ gestation. Hemorrhage from coagulopathy that was associated with liver failure was the most common complication. This was particularly problematic because of the cesarean delivery rate of nearly 50%. More than 50% of these 51 women required transfusions; of these, one-third of the women received >10 units of blood and components, and one-fourth of the women required platelet transfusions for persistent surgical oozing. Pancreatitis developed after delivery in 8 of the 51 women from 2-10 days after delivery. In none of the women was this severe, and the condition of each affected woman responded to conservative measures within 3-5 days. Peak amylase values with pancreatitis ranged from 55–1538 U/L, and peak lipase values ranged from 50–3330 U/L. There were 8 women with hepatic encephalopathy; 3 of these women underwent tracheal intubation for ventilator support or airway protection. Related to this, 1 maternal death was in a transferred woman with encephalopathy who vomited and aspirated before intubation could be performed; she died of acute respiratory distress syndrome. Shown in Figure 1 is a cross section of her liver at the time of autopsy. A second maternal death was due to fulminant liver failure with unsustainable hypotension. In both, microvesicular steatosis was confirmed histologically.
| Variable | Measure |
|---|---|
| Pregnancy outcomes | |
| Gestational age, wk a | 37.0 ± 2.6 (31.7–40.9) |
| Twin gestation, n (%) | 7 (14) |
| Vaginal delivery, n (%) | 26 (51) |
| Cesarean delivery-overall, n (%) | 25 (49) |
| Live fetus, n (%) | 25 (57) |
| Fetal compromise, n (%) | 10 (40) |
| Preterm delivery, n (%) | 20 (40) |
| <34 wk | 10 (20) |
| 34-37 wk | 10 (20) |
| Maternal complications, n (%) | |
| Blood and components transfusion | 28 (55) |
| Pulmonary edema | 7 (14) |
| Platelet-transfusions | 7 (14) |
| Encephalopathy | 8 (16) |
| Pancreatitis | 8 (16) |
| Tracheal intubation b | 3 (6) |
| Medical/surgical intensive care unit | 7 (14) |
| Dialysis | 1 (2) |
| Death | 2 (4) |
| Perinatal outcomes | |
| Birthweight, g a | 2545 ± 710 (1255–4090) |
| Birthweight <2000 g , n (%) | 10 (20) |
| Stillborn, n (%) | 7 (12) |
| Live born, n (%) | |
| Umbilical artery pH <7.0 | 4 (8) |
| Neonatal intensive care unit | 17 (33) |
| Neonatal death | 0 |
a Data are given as mean ± SD (range)
Selected perinatal outcomes are also shown in Table 2 . There were 7 twin pregnancies (14%). For all infants, the birthweight range of 1255–4090 g reflected gestational ages. From the total of 58 fetuses, 12% were dead at the time of admission; however, there were no further perinatal deaths. Two-thirds of these infants were male. The overall cesarean delivery rate for these 51 women was 49%. In 10 of these 25 women, cesarean delivery was done for evidence of fetal compromise on biophysical testing. One-third of all infants were admitted to the neonatal intensive care unit for acidosis or preterm birth. Long chain L-3-hydroxyacyl-CoA dehydrogenase (LCHAD) mutation testing was performed in some women through analysis of fragmented DNA that was obtained from microdissected formalin-fixed material. As previously reported, the common LCHAD mutation (G1528C [E474Q]) was not identified in 10 of these women. LCHAD testing had also been completed in some, but not all, of the neonates with limited value.
To depict recovery of the multiple organ system dysfunctions that was caused by liver failure with AFLP, we plotted selected analytes for epochs of time after delivery. As shown in Figure 2 , in general, arrest of hepatocellular necrosis was apparent within 1-2 days after delivery, as evidenced by decreasing AST levels. These levels usually peaked at or around the time of delivery, after which they dissipated rapidly to <100 U/L by the second or third postpartum day. After this, most of the levels were slightly elevated at the time of discharge; in a few women, they remained slightly elevated for up to several weeks. Recovery of hepatic function lagged behind the recovery of necrosis, as evidenced by serial serum cholesterol levels that continued to decline after delivery to reach a nadir at 3-4 days after which they began to increase ( Figure 2 ). In like manner, serum bilirubin levels either remained static or increased. In addition to diminished bilirubin conjugation and clearance, these levels were also influenced by ongoing brisk hemolysis as seen on peripheral blood smear analysis and scanning electron microscopy.
Resolution of renal dysfunction is shown in Figure 3 . Importantly, note that, in all but a few of these women, a baseline serum creatinine value was verified at the time of routine prenatal laboratory testing (0.54 ± 0.16 mg/dL) to be within the normal reference range. There were 2 types of renal dysfunction. The prerenal component was manifest by the rapid decline in serum creatinine values after delivery, which had decreased to <1 mg/dL by 7-10 days. There was also evidence for an acute kidney injury component, because at least 15% of these women had abnormally elevated creatinine values compared with those values that were reported by this time after a normal pregnancy.
