Diagnosis

The most commonly used definition of HG is severe or protracted nausea and vomiting leading to dehydration, electrolyte abnormalities and loss of at least 5% of prepregnancy body weight.6 7 HG develops in the first trimester and is a clinical diagnosis after excluding other causes of nausea and vomiting.7

Abnormal LFTs develop in approximately 50% of patients from mild elevation in serum aminotransferases to 20 times the upper limit of normal (ULN) (table 2).1 8 Jaundice and hepatic synthetic dysfunction are rare. Hypokalaemia, hypomagnesaemia, hypophosphataemia, raised serum urea and creatinine are common. Biochemical and liver function abnormalities should normalise on resolution of symptoms and persistently deranged LFTs warrant consideration of an alternative diagnosis, such as viral hepatitis.9

Management

Treatment of HG is supportive with intravenous rehydration, electrolyte replacement and antiemetics.1 7 9 There is varying guidance on antiemetic therapy and a Cochrane meta-analysis has found that no single antiemetic is superior to others.10 Specific medications for first-line to fourth-line therapy recommended for use are demonstrated in table 3. The American College of Obstetricians and Gynecologists (ACOG) and the European Association for the Study of the Liver (EASL) recommend pyridoxine alone or in combination with doxylamine as first-line therapy.1 11 The Royal College of Obstetricians and Gynaecologists (RCOG) does not recommend use of pyridoxine based on a lack of evidence on efficacy.7 Corticosteroids should only be used after standard treatment has failed and are recommend by ACOG, RCOG, EASL and the American Association for the Study of Liver Diseases (AASLD), although the evidence for their effectiveness is conflicting.1 7 9–12 Thiamine supplementation is required to prevent Wernicke’s encephalopathy, which is recommended by AASLD, RCOG, ACOG and EASL.1 7 9 11

Ongoing vomiting, despite medical therapies, should prompt consideration of enteral or parenteral nutrition.7 11 There are no established criteria for enteral or parenteral feeding. Enteral feeding with nasogastric, nasoduodenal or nasojejunal tubes is safer, leaving total parenteral nutrition as a last resort.7 13

Serum urea and electrolytes should be checked daily and maternal body weight should be monitored.7 The Pregnancy-Unique Quantification of Emesis score is a validated system based on three parameters including (1) duration of nausea, (2) number of vomiting episodes and (3) number of dry heaves (in the preceding 12 hours) which can be used to monitor progress.14

Prognosis

Poor weight gain in HG is associated with fetal growth restriction, preterm birth, small for gestational age babies and low Apgar scores.15–17 Maternal complications are uncommon and include Wernicke’s encephalopathy, which presents with confusion and nystagmus. HG typically resolves by 20 weeks gestation but may in rare cases persist throughout the pregnancy.18 There are no long-term consequences on liver function.1 Recurrence of HG in subsequent pregnancies is common.15 19

Diagnosis

There is no international consensus on diagnostic criteria for IHCP, but generally the diagnosis is based on unexplained pruritus in pregnancy with raised bile acids or abnormal LFTs.24 The predominant symptom is pruritus, especially of the palms and soles and is usually worst at night.20 It typically develops in the third trimester, however, presentations as early as week 7 of gestation have been documented.1 There may be excoriation marks, but any other rash should lead to consideration of alternative skin conditions, such as eczema and pruritic eruption of pregnancy.25 The pruritus is followed by generalised symptoms, such as fatigue, nausea and jaundice in <25% of IHCP.26 Alternative diagnoses should be sought if jaundice is the presenting symptom.26 There may be other features of cholestasis such as steatorrhoea and dark urine.27

The onset of pruritus typically precedes biochemical abnormalities.28 LFTs should be checked in pregnant woman with pruritus and repeated if normal.21 29 Elevated fasting serum bile acids are the most sensitive indicator of IHCP.21 Abnormalities in LFTs are common, with aminotransferases elevated up to 10 times the ULN, and can be as high as 1000 IU/L. When jaundice does occur, it is often mild with bilirubin <100 µmol/L. Raised GGT is rare. Prothrombin time (PT) is normal unless there is vitamin K malabsorption. Liver biopsy is generally not indicated.21

The American College of Gastroenterology (ACG) advises that liver ultrasonography should be performed in all cases to rule out cholelithiasis, whereas AASLD and RCOG recommend only in select cases.9 26 29 RCOG advises screening for viral hepatitis and autoimmune liver disease according to individual risk factors.29 AASLD advise that all women should be tested for hepatitis C, if not done previously, given the higher prevalence of hepatitis C in IHCP.9 23 30 Pre-eclampsia and AFLP should be considered in atypical cases.21

Management

Ursodeoxycholic acid (UDCA) is the first-line treatment recommended for IHCP by ACG, ACOG, AASLD and EASL.9 21 26 31 ACG and AASLD advise UDCA at a dose of 10–15 mg/kg of maternal body weight per day.9 26 ACOG advises starting at 10–15 mg/kg/day in 2–3 daily doses, which can be uptitrated to a maximum of 21 mg/kg/day.31 EASL advises 10–20 mg/kg/day, which can be uptitrated to 25 mg/kg/day.21 Despite the largest trial of UDCA identifying no benefit in maternal symptoms,32 a recent systematic review and meta-analysis has detected a reduction in stillbirth and preterm birth with UDCA.33

Second-line therapies include S-adenosyl-methionine (recommended by AASLD, RCOG, ACOG and EASL), rifampicin (recommended by AASLD, ACOG and EASL) cholestyramine (recommended by AASLD and ACOG) and dexamethasone (recommended by RCOG).9 21 29 31 All of these therapies lack robust evidence for improvement in pruritus.9 29 EASL do not advise dexamethasone on the basis that it is an inadequate treatment for IHCP.21 Antihistamines (diphenhydramine and hydroxyzine suggested by ACOG, chlorphenamine suggested by RCOG) can be used for sedation at night but do not improve pruritus.9 29 31 Topical emollients are also safe for use.21 29 31 Vitamin K supplementation at 5–10 mg daily is recommended if the PT is prolonged, with more frequent monitoring of PT in women taking cholestyramine.9 29

Delivery at 37 weeks prevents stillbirth after this point. RCOG advises that a discussion regarding the induction of labour after 37 weeks should be made with the patient.29 ACOG advises delivery at 36 weeks if bile acids are ≥100 µmol/L or between 36 and 39 weeks if bile acids are <100 µmol/L.31 Monitoring of the disease as advised by the RCOG includes weekly measurements of LFTs.29 ACOG advises repeated bile acid measurements to guide timing of delivery, but does not recommend weekly testing.31

Prognosis

Biochemical tests and antenatal fetal monitoring are poor predictors of adverse fetal outcome including fetal death.29 However, high bile acid concentrations >40 µmol/L show some correlation with adverse fetal outcomes which include fetal distress, preterm birth and meconium-stained amniotic fluid.34 35 A small additional risk of stillbirth is associated with serum bile acids >100 µmol/L.36

Symptoms and LFTs generally resolve within 4–6 weeks after delivery.21 LFTs and serum bile acid concentrations should be checked at 6 weeks after delivery.29 If there are persistent symptoms or deranged LFTs post-delivery, other liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis should be excluded.9 21 26 29 For severe disease with persistence post-delivery, genetic analysis should be considered for mutations associated with paediatric familial cholestatic disorders such as ABCB4 (encoding the multidrug resistance protein 3), ABCB11 (ATP binding cassette subfamily B encoding the Bile Salt Export Pump), ATP8B1 (ATPase class 8B member 1 encoding a phosphatidyl serine flippase), ABCC2 (the multidrug resistance-associated protein 2), and TJP2 (encoding tight junctional proteins).37

IHCP has a high rate of recurrence of up to 90% of subsequent pregnancies.24 It is also associated with an increased risk of cholestasis with the use of the combined OCP,24 higher rates of cholelithiasis23 and a slightly increased risk of developing hepatobiliary cancer.38

Prevention

High-risk factors for developing pre-eclampsia include40:

• Hypertensive disease during a previous pregnancy.

• Chronic kidney disease.

• Autoimmune disease such as systemic lupus erythematosus (SLE), antiphospholipid syndrome or autoimmune liver diseases.

• Type 1 or 2 diabetes.

• Chronic hypertension.

Factors denoting moderate risk:

• First pregnancy.

• Age 40 years or older.

• Pregnancy interval of more than 10 years.

• Body mass index of 35 kg/m² or more at first visit.

• Family history of pre-eclampsia.

• Multifetal pregnancy.

A large randomised controlled trial has shown low-dose aspirin to reduce the incidence of preterm pre-eclampsia in women with high risk factors.44 Women with one high risk factor or more than one moderate risk factor should be advised to take low-dose aspirin (75–150 mg daily) from 12 weeks of pregnancy until delivery.40 45

Diagnosis

Symptoms of liver involvement are non-specific and include right upper quadrant or epigastric pain (due to stretching of Glisson’s capsule from hepatic swelling), nausea, vomiting and headaches.26 Elevations of AST and ALT can be up to 10 times the ULN (table 2). AST is typically increased to a greater extent than ALT which can be helpful in differentiating pre-eclampsia from other liver diseases.45 Bilirubin and albumin usually remain within the normal range.

Management

There is no specific medical treatment for liver involvement in pre-eclampsia. Abnormal LFTs with abdominal pain meets the criteria for severe pre-eclampsia and immediate delivery is required if beyond 34 weeks gestation, and considered at earlier gestations.40 45 Prior to delivery, tight control of maternal blood pressure should be achieved with labetalol, nifedipine or hydralazine.40 45 Intravenous magnesium sulphate should be administered for seizure prophylaxis if delivery is planned within 24 hours.45 Monitoring of LFTs should be performed until results return to the normal range.40

Prognosis

Liver-related maternal complications include liver infarction, rupture and haemorrhage. Other maternal complications include pulmonary oedema, renal dysfunction and cerebral haemorrhage. The severity of LFT derangement can help to predict adverse maternal but not fetal outcomes.46 Fetal complications include preterm delivery, intrauterine growth restriction and intrauterine death.40

Post-delivery, LFTs usually normalise within 2 weeks. There is significant evidence to suggest that women who have had pre-eclampsia have a higher long-term risk of developing cardiovascular disease, type 2 diabetes and renal disease in later life.47–49

Diagnosis

HELLP syndrome usually presents between 28 and 36 weeks of gestation but may develop in the first week post partum. Patients may be asymptomatic or have non-specific symptoms including right upper quadrant or epigastric pain, nausea, vomiting, headache, and malaise.52 Hypertension and proteinuria are present in up to 85% of cases.26

Diagnostic criteria for HELLP syndrome, such as the Tennessee and Mississippi criteria (table 4), include the triad of haemolysis, thrombocytopaenia and deranged LFTs.55–57 When the triad is not fulfilled, it is termed incomplete HELLP or ELLP syndrome.56 58 There is typically a moderate increase in aminotransferases and a mild elevation in unconjugated bilirubin (table 2). Other features include an elevated lactate dehydrogenase (LDH), schistocytosis on peripheral smear and an elevated uric acid.56 PT can be raised in severe liver injury or disseminated intravascular coagulation (DIC). The elevation of aminotransferases is much greater in HELLP syndrome than in pre-eclampsia. Elevation of aminotransferases, rising LDH and uric acid in severe pre-eclampsia might indicate progression to HELLP syndrome which is important to recognise because of the potentially life-threatening nature of this syndrome. Liver biopsy is not indicated for diagnosis of HELLP syndrome and would be hazardous because of the risk of bleeding.1 9

Other differential diagnoses to consider include haemolytic uraemic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP) and AFLP.59

Management

Women with HELLP syndrome generally require care in a high-dependency setting because of the risk of complications of bleeding, DIC, hepatic encephalopathy, hepatic rupture and acute renal dysfunction.40 Tight blood pressure control is crucial.40 45 Magnesium sulphate infusion is advised by ACOG, whereas the National Institute of Health and Care Excellence (NICE) advise consideration of magnesium sulphate.40 45 Platelet transfusion is advised by ACG and ACOG to maintain platelet counts above 40 000–50 000 cell/µL if bleeding or when invasive procedures, such as Caesarean section, are planned.26 60 It has been thought that corticosteroids would treat the proinflammatory component of HELLP syndrome. However, a Cochrane review found that despite improved platelet counts, dexamethasone did not improve maternal morbidity and mortality or perinatal death,61 and so is not recommended by NICE.40 ACOG also note that there is insufficient evidence for usage of steroids.45 Delivery is the only curative therapy and should take place as soon as the maternal condition has been stabilised.45

Laboratory results should be performed every 12 to 24 hours postpartum.45 AASLD advise that HELLP syndrome resulting in hepatic rupture or acute liver failure (ALF) should warrant transfer to a liver transplant centre for assessment.9 Indications for liver transplantation include persistent bleeding from a hepatic haematoma, hepatic rupture or ALF.62 63

Prognosis

Maternal mortality rate ranges between 1% and 3%.64 Liver-related complications include hepatic haematoma, rupture or infarction. Other maternal complications include stroke, acute kidney injury (AKI), DIC, placental abruption and pulmonary oedema.52 Fetal prognosis is related to gestational age at delivery, birth weight and neonatal condition at birth. Perinatal mortality is estimated to be between 8% and 34%.58

LFTs should start to resolve within 48 hours postpartum.52 Recurrence rate of HELLP syndrome in future pregnancies is probably in the region of 2%–6%.65 However, at least 20% of those with HELLP syndrome will develop some form of pre-eclampsia in a subsequent pregnancy.65

Diagnosis

Subcapsular liver haematomas usually develop in the late second or third trimester. Patients can present with epigastric or right upper quadrant pain radiating to the right shoulder, nausea, vomiting and hypotension.65 When hepatic rupture occurs, patients develop abdominal distension from haemoperitoneum and hypovolaemic shock.67 Bloods typically show a severe thrombocytopaenia and moderate elevations of aminotransferase concentrations, but elevations to 4000–5000 IU/L have been reported.65 Imaging should be performed in any patient with HELLP syndrome or pre-eclampsia with right upper quadrant pain, shoulder pain or shock, regardless of the LFTs as they do not correlate with findings on imaging.68 CT or MRI of the liver confirm the diagnosis. CT is the imaging of choice, as it is faster and safer for the unstable patient.66

Hepatic infarction is less common than hepatic haematoma but can also complicate pre-eclampsia and HELLP syndrome.69 Infarction can present with right upper quadrant pain and fever, associated with severe elevations in aminotransferases (1000–2000 IU/L or higher) and leukocytosis.65 The diagnosis is also confirmed with liver imaging, where infarction is typically seen in a peripheral location of the right liver.70

Management

Contained subcapsular haematomas with haemodynamic stability should be managed conservatively with close observations and repeat imaging to monitor the size of the haematoma.1 71 Blood transfusions and coagulation support should be used as required and prophylactic antibiotics considered.1 9 Patients with hepatic rupture should be transferred to a transplant centre.9

Haemodynamic instability suggests active bleeding and urgent hepatic angiography should be performed.9 Haemostasis can be achieved by embolisation of the hepatic artery or surgical methods, such as packing of the liver, hepatic artery ligation or resection of the affected liver.71 72 Transplant should be considered in cases of refractory haemorrhage or rapidly progressing ALF and has been successful in case reports.62 63

Prognosis

Consequences can be severe and the maternal mortality rate is thought to be 17%–59% for a haematoma, depending on whether it ruptures, when it is diagnosed and availability of therapy.66 Complications in the acute period include hypovolaemic shock, AKI and acute respiratory distress syndrome (ARDS). For conservatively managed haematomas, complete resolution can take up to several months.66 Infarctions also typically resolve on imaging after delivery.69

Diagnosis

AFLP may present with non-specific symptoms such as nausea, vomiting, headache, anorexia and abdominal pain. Some women will rapidly progress to liver failure with hepatic encephalopathy, jaundice, hypoglycaemia and coagulopathy. Symptoms almost always develop in the third trimester; however, cases have been reported in the late second trimester or postpartum period.73 There is also an association with pre-eclampsia but the reason for this is not well understood.

Biochemical tests often show a raised AST, ALT, bilirubin, creatinine, ammonia, lactate and serum uric acid (table 2).78 Aminotransferases are usually in the range of 300–500 IU/L. Haematological tests typically demonstrate a leukocytosis, low to normal platelets and a normocytic normochromic anaemia. The coagulopathy is usually severe, with a prolonged PT, hypofibrinogenaemia and elevated D-dimer.76 79 Coagulopathy or DIC occur in approximately 70% of cases.78 The role of liver ultrasound is unclear, as a prospective study showed that only 25% of women had the classic echogenic findings.73 CT scan is more sensitive, however, only 50% of cases show typical features on CT scan.80 Liver biopsy is not required to confirm the diagnosis but can be useful in indeterminate cases to guide the need for an early delivery.9 81

AFLP can be challenging to distinguish from HELLP syndrome, as they share many clinical and laboratory features. Women with AFLP are more likely to have synthetic liver dysfunction with coagulopathy, hypofibrinogenaemia, lower cholesterol levels, higher bilirubin levels, hypoglycaemia, hepatic encephalopathy, hyperammonaemia, DIC and more severe AKI.82 83 Other differentials include HUS, TTP, paracetamol toxicity, exacerbation of SLE and overlap with pre-eclampsia and HELLP syndrome.59

The Swansea criterion (box 1) is a validated system to help diagnose AFLP but only in the absence of other liver diseases, such as HELLP syndrome, thus limiting its application.84 85 One recent study found that the Swansea criteria were fulfilled in women presenting with any cause of ALF.86

Management

Delivery is the only curative treatment as liver failure will continue until the fetus has been delivered.9 26 76 Before delivery, maternal stabilisation should be achieved with correction of hypoglycaemia, coagulopathy and hypertension.76 87 Maternal intensive supportive care in a multidisciplinary team is required following the delivery. Six-hourly LFTs, renal function and haematological parameters should be performed within the first 24–48 hours after delivery.76 78 In non-randomised trials, plasma exchange has been associated with hastening hepatic improvement and decreasing intensive care stay, but not with improved maternal mortality.88 89

Patients with ongoing deterioration in liver function after emergency delivery or patients who develop hepatic rupture should be transferred to a liver transplant centre for assessment.9 Transplantation should be considered in cases of ALF or hepatic rupture.9 Elevated lactate with hepatic encephalopathy appeared to be best predictors of maternal death or need of liver transplantation in one retrospective study.90

Prognosis

Maternal mortality has improved to <10% in recent years from as high as 80%–90% in the 1980s.73 78 This improvement is likely secondary to advances in obstetric care and earlier diagnosis. However, life-threatening complications remain including ALF, DIC, postpartum haemorrhage, acute renal failure and gastrointestinal bleeding.91 92 Cases of hepatic rupture and hepatic infarction in AFLP have also been documented in the literature.93

Fetal mortality rates are estimated to be up to 20%.78 All children of mothers with AFLP should be longitudinally monitored for symptoms of LCHAD deficiency.26 AASLD and ACG recommend that all children of mothers with AFLP should be screened at birth for LCHAD deficiency.9 26 The long-term outcomes in LCHAD deficiency are variable as most symptoms resolve with sufficient energy supply while some studies have reported the development of retinopathy, cardiomyopathy, metabolic crises, hypotonia and muscle pains.26 94 95

LFTs typically begin to fall within 1–2 days after delivery.96 Cholesterol and bilirubin levels lag by 3–4 days.97 Transaminases continue to decline to <100 IU/L, where they may plateau for up to 4 weeks.96 Complete normalisation of LFTs is expected in the majority of women, with no signs of chronic liver disease or major adverse events at 54 months postdelivery.98 In those who required liver transplantation, survival is comparable to liver transplantation for other causes of ALF.99 Recurrence of AFLP occurs in a minority of women in future pregnancies and may take a milder course.100