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Liver Disease in Pregnancy

Hepatic Complications in Preeclampsia


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Clinical Obstetrics and Gynecology: March 2020 - Volume 63 - Issue 1 - p 165-174
doi: 10.1097/GRF.0000000000000501
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Preeclampsia is a multiorgan hypertensive disease in pregnancy that affects 2% to 8% of pregnancies globally.1 In the United States, the rate of preeclampsia has increased dramatically in the last 2 to 3 decades.2 Worldwide, pregnancies affected by preeclampsia, and preeclampsia spectrum disorders, contribute to a significant portion of severe maternal morbidity and mortality.3

Preeclampsia comprises a large and varied disease spectrum. The diagnosis of preeclampsia and preeclampsia with severe features relies on hypertension with the addition of laboratory abnormalities that reveal evidence of end-organ damage due to the disease.4 Preeclampsia without severe blood pressures is diagnosed by blood pressure of ≥140/90 on 2 occasions >4 hours apart at >20 weeks of gestation with the additional finding of proteinuria (protein to creatinine ratio of ≥0.3 or 300 mg of protein per 24 h urine collection) or presence of severe features (yielding a diagnosis of preeclampsia with severe features).4 Severe features include: blood pressure ≥160/110 on 2 occasions >4 hours apart or with administration of antihypertensives, platelet count <100,000×109/L, serum creatinine >1.1 (or twice the patient’s baseline creatinine), impaired liver function with elevated serum transaminases to twice the upper limit of normal, new headaches unresponsive to treatment, visual disturbances, epigastric or right upper quadrant pain unresponsive to treatment, and pulmonary edema.4 Right upper quadrant pain, or epigastric pain in the epigastrium that may radiate to the right hypochondrium or back, is thought to originate from stretching of Glisson capsule as a result of hepatic swelling and bleeding,5 and is one of the cardinal symptoms of preeclampsia with severe features.4

The clinical presentation of hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome reflects a serious disease on the preeclampsia spectrum that generally exhibits severe laboratory abnormalities with or without hypertension or proteinuria.4 Per ACOG, the diagnosis of HELLP is made with the following laboratory findings: lactate dehydrogenase (LDH) elevated to >600 IU/L, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevated more than twice the upper limit of normal, and platelet count <100,000×109/L.4 Eclampsia describes the aforementioned diseases with the addition of tonic-clonic seizure activity that is otherwise unexplained. A very rare hepatic complication of this disease spectrum involves the development of a hepatic subcapsular hematoma with or without rupture, which is life-threatening. Liver involvement can be associated with all these preeclampsia spectrum diseases and has been described in 15% to 50% of preeclampsia and eclampsia related deaths.6

In the last several years, there has been significant attention and insight into the role of preeclampsia in future maternal cardiovascular health. In cases of preeclampsia with severe features and specifically HELLP syndrome, the hepatic complications also portend significant short-term and long-term maternal health implications. Hepatic findings can range from unaffected liver function to significant transaminitis, to hepatic subcapsular hematoma and rupture, and very rarely need for transplant. The liver is a unique organ in its ability to regenerate and generally improves rapidly after delivery. In this section, we will discuss the physiology of normal hepatic function in pregnancy, the pathophysiology of the abnormalities noted in hepatic function during the process of preeclampsia development, the management of preeclampsia, imitators of HELLP syndrome, the utility of various biomarkers in the diagnosis and prognosis of the preeclampsia disease spectrum, possible underlying genetic factors predisposing women to developing hepatic abnormalities with preeclampsia, and finally prognosis and management of a subcapsular hematoma.

Hepatic Function in Normal Pregnancy

Changes to hepatic function are not unique to preeclampsia. Importantly, physiologic changes in hepatic function and production occur in pregnancy; however, hepatic histology appears to be unchanged and intact. Elevated levels of estrogen and progesterone affect the metabolic, synthetic, and excretory functions of the liver (Table 1).7 AST, ALT, and bilirubin tend to decrease mildly in pregnancy. There is an increase in protein synthesis in the liver leading to elevation of coagulation factors and fibrinogen. In addition, increase in blood volume leads to a decrease in albumin in the first and second trimester via hemodilution. Finally, alkaline phosphate is increased in pregnancy, as it is not specific to the liver and is produced by the fetus and placenta.8

Hepatic Laboratory Reference Ranges in Pregnancy7

Hepatic Function and Histology in Preeclampsia

The exact pathophysiology in preeclampsia has not been completely elucidated, although significant advances have been made in understanding the disease. It is dogmatically thought that a triad of abnormal spiral artery remodeling, maternal endothelial dysfunction, and high circulating antiangiogenic proteins, such as soluble fms-like tyrosine kinase-1 (sFlt-1) likely each play a part in the pathogenesis of the disease.9

When assessing the overall health of the liver, γ-glutamyltransferase (GGT), ALT and AST are used. ALT is mainly distributed in the liver whereas AST is distributed in heart, liver, lung, bone, muscle, kidney, and pancreas.10 Myocytes have the highest levels of AST expression followed by hepatocytes. Expression of GGT also occurs in other tissue including pancreas, lung, and placenta. Elevated liver function tests (LFTs) in preeclampsia are thought to result from disruption of the endothelium resulting in decreased prostacyclin levels and increased thromboxane levels, which decreases the prostacyclin to thromboxane ratio and results in vasoconstriction of hepatic blood vessels. The subsequent effect of hepatic hypoxia leads to necrosis, degeneration of hepatocytes and elevated liver enzymes.8

In preeclampsia with severe features and HELLP, AST and ALT can be elevated in the range of 100 to 400u/l. However, it is unlikely for these enzymes to reach levels found in acute hepatitis. AST is typically increased to a greater degree than ALT, which may help distinguish it from other hepatic diseases.4 It is also common to see elevations in LDH from the combination of hepatic damage and hemolysis, especially in HELLP syndrome. Bilirubin may also be increased given significant hemolysis. Dysfunction can also be seen in the production of coagulation factors, but this is generally less clinically significant in the absence of thrombocytopenia or severe hepatic damage.

Therefore, it is unsurprising that a disease that can cause such significant hepatic dysfunction shows evidence of pathology on histologic evaluation of the liver. Microvesicular fat changes, ischemic lesions, and periportal and sinusoidal fibrin deposition with hemorrhagic necrosis in the surrounding parenchyma are classically found on histology in the livers of preeclamptic women.11,12 In addition, an imbalance of antiangiogenic factors and proangiogenic factors in preeclampsia could account for the observed liver damage.13

Management of Preeclampsia and HELLP Syndrome

The most important tenets of management of preeclampsia include controlling severe hypertension and administering magnesium sulfate for seizure prophylaxis to appropriate patients.

Preeclampsia without severe features can be managed with close blood pressure monitoring and laboratory observation to ensure no progression to preeclampsia with severe features or HELLP, until 37 weeks’ gestation at which time delivery is recommended.4 Fetal surveillance should also be performed during this time interval. The decision to manage preeclampsia without severe features as an inpatient or outpatient can be made by the provider, presuming the patient is reliable and will attend frequent visits. The patient’s medical comorbidities should also be considered in the decision to manage her as inpatient or outpatient. The decision to administer magnesium sulfate in this population can be made by the provider, as there is currently no consensus regarding the prophylactic use of magnesium sulfate for the prevention of seizures for women with preeclampsia without severe features.4 When preeclampsia with or without severe features or HELLP syndrome is diagnosed after 37 weeks’ gestation, delivery is recommended.

Patients diagnosed with preeclampsia with severe features or HELLP between 34 0/7 and 36 6/7 weeks’ gestation, should also be delivered. Late preterm steroids may be initiated, especially if pursuing induction of labor, but delivery should not be delayed for late preterm steroids at this gestational age.4 Patients with preeclampsia with severe features or HELLP syndrome at any gestational should receive seizure prophylaxis with magnesium sulfate.

For patients with preeclampsia with severe features at <34 weeks’ gestation, expectant management may be considered if the maternal status is stable. In this scenario, betamethasone should be initiated. There are both maternal and fetal conditions that preclude expectant management. Maternal conditions include uncontrolled severe hypertension, persistent headaches unresponsive to treatment, visual disturbances, epigastric or right upper quadrant pain unresponsive to treatment, stroke, myocardial infarction, worsening renal dysfunction, pulmonary edema, eclampsia, and suspected abruption.4 Fetal conditions include abnormal fetal monitoring, fetal death, fetus without expectation for survival (lethal anomaly or extreme prematurity), and persistent reversed end-diastolic umbilical artery flow.4 Expectant management is not appropriate for HELLP syndrome at any gestational age and delivery should be planned for all patients diagnosed with HELLP syndrome. Some providers consider delaying delivery 48 hours for betamethasone administration among stable patients diagnosed with HELLP syndrome at <34 weeks’ gestation, although this decision should be made in consultation with a maternal-fetal medicine specialist.

Given the risk of preterm delivery, thrombocytopenia, and hemolysis in patients with preeclampsia and HELLP syndrome, all patients admitted to the hospital should be seen and evaluated by an anesthesiologist to make a multidisciplinary plan for anesthesia. Patients with significant thrombocytopenia are likely not candidates for neuraxial anesthesia, although the platelet levels at which this is offered differ among institutions.

Hepatic Imitators of HELLP Syndrome

Differentiating disease processes that mimic the hepatic findings in preeclampsia with severe features and HELLP syndrome often requires an astute clinician. The imitators of HELLP syndrome described here are mentioned as they differ from HELLP in presenting symptoms and laboratory findings. This will include the key methods to differentiate between disease processes, however, is by no means a comprehensive review of these individual diseases.


TTP-HUS are 2 microangiopathic hemolytic syndromes which are very rare in pregnancy and the puerperium.12 Patients may present with abdominal pain, nausea, vomiting, epistaxis, petechiae, purpura, neurological dysfunction including headache, vision changes, confusion, or seizure.12 Some patients may also report fever. Laboratory findings are notable for severe hemolysis with marked thrombocytopenia and only mild elevation in transaminases.14,15 LDH is generally >1000 in these disorders, and von Willebrand multimers are present in at least 80% of cases, which is unique from HELLP.15 Schistocytes will be seen on peripheral smear. There are several unique laboratory findings that can help differentiate TTP from HUS. For example, patients with TTP may be found to have profound thrombocytopenia <20,000/mm3, and significant decrease ADAMTS13 activity, both of which are uncommon in HUS or HELLP. Renal dysfunction is more common in HUS than TTP, and may also serve to differentiate disease processes. Unless treated appropriately, TTP-HUS can progress to death in up to 90% of patients due to multiorgan failure.14


AFLP is most commonly diagnosed in the third trimester or postpartum period with days to weeks of malaise, anorexia, nausea, vomiting, epigastric pain, and jaundice.12 Laboratory evaluation is notable for severe and early coagulopathy or DIC and markedly depressed antithrombin III, both due to reduced production of factors by the liver.12 Although there is significant coagulopathy in AFLP, hemolysis is rare, which may help to differentiate it from HELLP. Both HELLP and AFLP will have transaminitis, although elevated bilirubin is more common in AFLP. Serum electrolytes may reveal metabolic acidosis which may lead to patients presenting with the chief complaint of decreased fetal movement. Metabolic acidosis in these patients may lead to nonreassuring fetal monitoring.12 Imaging with computed tomography (CT) or magnetic resonance imaging can assist in making the diagnosis, and these modalities are more sensitive than ultrasound.12 Liver biopsy is the gold standard for the diagnosis of AFLP but is rarely done.


Patients with SLE exacerbation may present with hypertension, proteinuria, and microscopic hematuria, making differentiating this disease process from preeclampsia or HELLP exceptionally difficult.12 The findings of extrarenal manifestations of SLE, such as rash and joint pain, can help to differentiate the disease from preeclampsia or HELLP. Hematologic findings in SLE can include pancytopenia, including thrombocytopenia, as well as hemolysis. SLE exacerbation with the presence of lupus nephritis will generally have findings of active urine sediment, decreased C3 and C4, elevated double-stranded DNA.14

Up to 30% to 40% of patients with SLE also have antiphospholipid antibody syndrome, and may also present with thrombocytopenia or hemolytic anemia, and are at high risk of developing clots throughout the body. Catastrophic antiphospholipid antibody syndrome is a rare complication that is characterized by acute thrombotic microangiopathy affecting small vessels at least 3 organs.12 Clots may occur in the liver, and the presence of clot in the hepatic veins is known as Budd-Chiari syndrome and results in liver necrosis and infarcts.12,14 Anticoagulation is a mainstay of treatment for this life-threatening condition, and therefore prompt diagnosis is imperative.

Biomarkers and Prediction of Preeclampsia and HELLP Syndrome


Studies have evaluated the efficacy of utilizing LFTs as predictors for preeclampsia development and prognosis. A population-based cohort study from Korea10 evaluating N=192,571 women of whom n=3973 developed preeclampsia suggested that women with higher ALT levels before pregnancy had higher risk for developing preeclampsia compared with women with normal ALT levels [1.21, 95% confidence interval (CI): 1.07-1.31]. Interestingly this association was not appreciated for abnormal AST (1.01, 95% CI: 0.87-1.17) or GGT (1.05, 95% CI: 0.93-1.19) levels.

A recent systematic review by Thangaratinam et al16 evaluating 13 primary articles including N=3497 women suggested that LFTs performed better in predicting adverse maternal versus fetal or neonatal outcomes. The sensitivity of LFTs to predict any maternal complication ranged from 0.04 (95% CI: 0-0.34) to 0.95 (95% CI: 0.63-1.0), and the specificity ranged from 0.17 (95% CI: 0.14-0.20) to 0.97 (0.93-0.99). The area under the curve (AUC) for the prediction of any adverse maternal outcome was 0.79 (95% CI: 0.51-0.93). The largest positive and negative likelihood ratios (LRs) were observed for maternal development of eclampsia (LR+=9.1, 95% CI: 3.3-25.5; LR=0.12, 95% CI: 0.92-0.99). In contrast, the sensitivity and specificity for fetal/neonatal outcomes were 0.11 (95% CI: 0-0.67) to 0.86 (95% CI: 0.23-1) and 0.66 (95% CI: 0.59-0.73) to 0.88 (95% CI: 0.83-0.92), respectively. It is not surprising from these studies that elevated LFTs appear to contribute to both the prediction and prognosis of the disease process; however, in isolation, they do not appear to be the most effective biomarkers based on test characteristics.


Next, we will focus on lipid biomarkers that have been evaluated in the development of preeclampsia. Hypertriglyceridemia is a hallmark for endothelial dysfunction in preeclampsia, and lipid levels appear significantly increased around 12 weeks before disease onset.8 Interestingly, the liver and placenta are important organs for free fatty acid beta-oxidation and cross-talk exists between the 2 entities. Increases in free fatty acid to albumin ratio is increased in early gestation before preeclampsia disease development.8 Furthermore, a study by Spracklen et al17 suggested a significant elevation in the weighted mean difference (WMD) of the total cholesterol level (WMD=20.20 mg/dL, 95% CI: 8.7-31.70) and non–high-density lipoprotein cholesterol levels (WMD=11.57 mg/dL, 95% CI: 3.47-19.67) as early as the first and second trimesters in women who developed preeclampsia compared with those who did not. High-density lipoprotein cholesterol levels were only significantly decreased in the third trimester among women with preeclampsia compared with normotensive women (WMD=−8.86 mg/dL, 95% CI: 11.5-6.21) and low-density lipoprotein cholesterol levels were not significantly different in second (WMD=3.89, 95% CI: −0.19 to 7.97) and third trimesters (WMD=10.92 mg/dL, 95% CI: −0.59 to 22.42). These data suggest that while the exact mechanism is unknown, maternal lipid metabolism possibly through production on endothelial dysfunction is modified with hepatic involvement as a compensatory process to increase energy supply to fetus, but utility of high-density and low-density cholesterol levels as biomarkers for prediction of disease appears limited.


HELLP syndrome, as discussed above, is a severe phenotype in the disease spectrum of preeclampsia which may occur with or without hypertension. Studies have demonstrated potential biomarkers beyond LFTs in the first trimester to predict preeclampsia, however, fewer studies have focused specifically on the development of HELLP syndrome, which has direct hepatic implications. A recent study by Oliveira et al18 evaluated N=2969 pregnancies with n=147 that developed preeclampsia without HELLP syndrome and n=12 that developed preeclampsia with HELLP syndrome. Maternal clinical and demographic characteristics were evaluated as potential predictors. A prediction model including maternal race, nulliparity, and prior history of HELLP syndrome or preeclampsia gave an AUC for the development of HELLP syndrome of 0.80 (95% CI: 0.7-0.91). In contrast, the AUC for preeclampsia development was 0.67 (95% CI: 0.54-0.79).

A study by Lind Malte et al19 evaluated the vasoactive peptides atrial natriuretic peptide, endothelin, arginine vasopressin, and adrenomedullin that regulate vascular tone and renal fluid excretion in addition to sFlt-1:placental growth factor ratio in the prediction of HELLP and preeclampsia with severe features. The study included N=215 participants, and AUCs were calculated to evaluate the prediction. The combination of C-terminal proendothelin 1, sFlt-1, and systolic blood pressure performed the best with a 1-week AUC of 0.94 and a 2-week AUC of 0.83. AUCs of the individual biomarkers including the sFlt-1:placental growth factor ratio was 0.81 for 1 week and 0.77 for 2 weeks. This study suggests that evaluating other biomarkers directly associated with vascular regulation and thus dysregulation may be promising for prediction of HELLP syndrome. However, significantly larger cohort studies are needed before utilizing these tests in the clinical setting.

Liver Stiffness (LS) and Preeclampsia

LS, measured by transient elastography (TE) is the preferred modality to noninvasively assess liver fibrosis. Interestingly, Ammon et al20 screened LS in N=537 women during pregnancy, of whom n=22 developed preeclampsia. The study noted LS increased exclusively in the third trimester in normal pregnancies (LS=6.0±2.3 kPa) compared with the first (4.3±1.0 kPa) and second (4.5±1.2 kPa) trimesters (P<0.001). In preeclamptic pregnancies, the mean third trimester LS was significantly higher than controls (17.9±20.7 vs. 6.0±2.3 kPa, P<0.001). LS predicted preeclampsia with an AUC of 0.815 (0.722-0.907). Postpartum, LS decreased in both women without preeclampsia and with preeclampsia; however, the women without disease had significantly lower LS (4.2±1.0 kPa) compared with those with hepatic disease (5.6±1.3 kPa, P<0.0001). This data suggests in women without liver disease, LS increase as a result of mechanical factors such as elevated intra-abdominal pressures and its hemodynamic consequences thus quickly declining postpartum. LS could be an interesting noninvasive tool to evaluate women as further studies are performed understanding the pathophysiology of hepatic involvement in preeclampsia.20

Another study by Frank Wolf et al5 evaluated LS by TE postpartum in n=32 women with preeclampsia and n=16 normotensive women. Interestingly, whereas there was no difference in hepatic steatosis measured by this modality between the 2 groups (226.3 vs. 224.9 kPa, P=0.442), there was again a notable difference in the fibrosis between the 2 groups (4.57 vs. 3.66 kPa, P=0.01). Similar to the data developed from serum biomarkers, further understanding of the magnitude, duration, and reversibility of LS or hepatic fibrosis appears necessary to contribute to our knowledge of the preeclampsia disease process before using it in a clinical setting. Furthermore, as TE is a noninvasive modality that appears safe and effective in pregnancy and postpartum, it suggests itself as a reasonable tool to utilize in the research setting to elucidate the physiology of hepatic impairment during preeclampsia.

HELLP Syndrome and Genetic Predisposition

Many studies have evaluated the possibility of having a genetic predisposition for developing preeclampsia. However, fewer studies have focused specifically on HELLP syndrome with liver dysfunction. Given the role that abnormal placentation in early pregnancy resulting from increased apoptosis of villous trophoblasts could play in the development or preeclampsia with severe features or HELLP, Raguema et al21 evaluated genetic polymorphism in the Fas receptor-ligand system. The Fas receptor and ligand play an important role in apoptosis and promote apoptosis of maternal lymphocytes to prevent these cells from recognizing and destroying cytotrophoblasts, allowing for normal trophoblast invasion and placental growth. Raguema and colleagues genotyped Fas-670A/G and the FasIVS2nt124A/G gene polymorphism using polymerase-chain reaction among women with preeclampsia compared with women without disease. The frequency of the Fas-670G gene variant was significantly increased among women with preeclampsia compared with those without (42% vs. 30%, P<0.001). Furthermore, the Fas-670G was specifically associated with increased liver enzymes and HELLP, suggesting genetic predisposition to this phenotype of disease compared with all preeclampsia.

HUS as briefly described above has a disease process similar phenotypically to HELLP. The pathogenesis of HUS involves activation of the alternative pathway of complement (APC). Heterozygous germline mutations in genes that function in APC are found in 50% of HUS patients. Vaught et al22 hypothesize that a similar mechanism could be involved in the development of HELLP syndrome. They evaluated n=13 participants with HELLP compared with n=19 healthy controls and n=18 with HUS. When compared with controls, HELLP subjects were more likely to have a rare germline variant in an APC gene (46% vs. 8%, P=0.01). Interestingly, there was no difference between the HELLP and HUS cohorts for the presence of a genetic variant (46% vs. 56%, P=0.12). Researching the genetic predisposition to developing preeclampsia with hepatic involvement appears promising. Future studies expounding the role of the gene-environment interaction could shed significant light on the phenotypic variation appreciated with preeclampsia.

Subcapsular Hematoma


Development of a subcapsular hematoma is a rare but life-threatening complication of preeclampsia affecting 1:40,000 to 1:250,000 pregnancies. Mainly associated with hepatic dysfunction, it is thought to complicate 0.9% to 1.6% of HELLP syndrome cases.23 Rupture of the hematoma is one of the most catastrophic complications of HELLP syndrome and often involved the right lobe of the liver preceded by parenchymal hemorrhage. Maternal mortality rates with a hematoma range from 17% to 59%.23 Unfortunately, the symptoms can be nonspecific including right upper quadrant or epigastric pain, nausea, vomiting, hypotension or shock. These symptoms could be mistaken for pulmonary embolism, acute cholecystitis or pancreatitis.


There is no clear consensus on the imaging modality for diagnosing a subcapsular hematoma. Given the high mortality rate and the need for rapid imaging, portable ultrasound is a reasonable screening imaging technique to establish the diagnosis at bedside.23 CT scan is the more definitive imaging modality.

Conservative management with close hemodynamic monitoring, transfusion of blood products, monitoring of respiratory and renal status, and repeat imaging (CT or ultrasound) is necessary. Surgery is generally reserved for those with increasing size of the hematoma, hemodynamic instability or rupture. A mainstay of operative therapy involves packing to control bleeding. Other options could consider synthetic absorbable mesh to compress liver, deep mattress sutures of liver parenchyma, use of hemostatic products, or hepatic artery interruption by surgical ligation or transcatheter embolization. The need to consider transplant is necessary when hepatic necrosis is noted with hematoma rupture. Interestingly, the data appears mixed on results after liver transplantation.24 Data on recurrence rates of subcapsular hematoma are unclear. Management in a subsequent pregnancy should involve close monitoring for early signs of preeclampsia or HELLP, and low-dose aspirin therapy for women with early-onset preeclampsia/HELLP syndrome.


Shames and colleagues evaluated results from 8 liver transplants in women with HELLP syndrome in the United States between 1987 and 2003 from the Organ Procurement and Transplantation Network data. Six of the 8 subjects survived in 2005 with both deaths occurring within 30 days of transplantation.24 Interestingly, a study by Qian et al25 in China used a 1:10 propensity score-matched approach evaluating the long-term survival of women who received a liver transplant for liver failure status post-HELLP compared with those who did not. The 10-year intent to treat survival was 63.6% for nontransplanted HELLP patients compared with 61.8% for matched patients (P=0.369). Overall survival was also similar between HELLP subjects and matched subjects with 10-year survival at 64.2% versus 61.8% (P=0.985). Interestingly, the death censored graft survival for HELLP patients at 10 years was lower than matched patients transplanted for other indications (63.4% vs. 75.4%, P=0.04). A similar intent to treat for both groups suggests that because of the systemic effects of HELLP, physiologic factors other than liver dysfunction could adversely add to the recovery course leading to higher rate of early graft loss in this cohort.25 The data regarding liver transplantation posthepatic dysfunction or HELLP appears mixed in terms of graft survival as this outcome and treatment are low in prevalence. Further studies with broader population mix are necessary.


In closing, there is much that is known about the diagnosis and treatment of the hepatic complications of preeclampsia and HELLP syndrome. Yet, there is still work to be done to identify patients at risk for developing these pregnancy complications that contribute significantly to severe maternal morbidity and mortality.


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preeclampsia; liver disease; HELLP

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