Liver Disease and Pregnancy

Introduction

Up to 3% of pregnant women suffer from pregnancy-associated liver diseases, which are the most frequent cause of liver dysfunction in pregnancy. Due to significant morbidity and mortality for both mother and infant in severe cases, a rapid evaluation is essential to distinguish it from non-pregnancy-related liver dysfunction.

Besides, liver disease unrelated to pregnancy can present de novo in pregnancy, or pregnancy can occur in women with pre-existing liver pathology.

The risks of pregnancy in women with pre-existent liver pathology and recent advances in our understanding of specific risks and outcomes is discussed in the study by Westbrook, Rachel H. et al. published in the Journal of Hepatology (J Hepatol. 2016;64:933-45). This booklet aims to provide an overview on the liver diseases specific to the pregnancy and an update on their pathogenesis, treatment and outcomes.

Normal Physiological Changes in Pregnancy

During pregnancy, owing to the many physiological and hormonal changes, there is a rise in maternal heart rate, cardiac output by 40%, circulating plasma volume by 30% and a reduction in peripheral vascular resistance. This results in a hyper-dynamic circulation—a physiological state commonly observed in patients with decompensated chronic liver disease.

Pregnant women may show palmar erythema and the presence of multiple spider naevi in up to 70% cases. Blood flow to the liver remains constant during pregnancy and it remains impalpable as it is displaced upwards into the thoracic cavity due to the expanding uterus. Gallbladder motility decreases, resulting in an increased risk of developing gallstones.

Maternal alkaline phosphatase (ALP) increases in the third trimester when ALP is produced both from the placenta and as a result of fetal bone development. The alpha-fetoprotein (AFP) level increases in pregnancy as AFP is produced by the fetal liver. Other common biochemical and hematological tests, including urea, hemoglobin levels and the prothrombin time, remain unchanged or slightly reduced due to hemodilution. Elevations in transaminases, bilirubin or the prothrombin time are abnormal and indicate a pathological state that requires further assessment.

Pregnancy being a pro-coagulant state, clotting factors (I, II, V, VII, X, and XII) and fibrinogen are increased.

Due to compression of the inferior vena cava (IVC) by the enlarging uterus and a reduction in venous return, small clinically insignificant esophageal varices can occur in up to 50% of pregnant women in the late second and third trimester.

Liver biopsy is rarely indicated in pregnancy as liver histology is essentially normal in the pregnant women, although electron microscopy shows some increase in the endoplasmic reticulum.

The classification of liver disease in pregnancy is mentioned in the table below:

HELLP = hemolysis, elevated liver enzymes and low platelets

Pregnancy-Related Liver Diseases

The liver diseases specific to the pregnancy can be classified into those of early pregnancy (hyperemesis gravidarum [HG]) and those of late pregnancy (acute fatty liver of pregnancy [AFLP], pre-eclampsia with hepatic involvement, including HELLP syndrome, and liver rupture/infarction and intrahepatic cholestasis of pregnancy [ICP]).

Hyperemesis Gravidarum

HG is the most severe form of illness, a spectrum of nausea and vomiting of pregnancy seen in 0.3- 2% of pregnancies. Symptoms usually, but not exclusively, begin before 9 weeks’ gestation with intractable vomiting, resulting in dehydration, ketosis and weight loss of greater than 5%. The exact etiology, though, is unclear. Human chorionic gonadotropin (HCG) hormone, which peaks in the first trimester, has been shown to correlate with the severity of HG. Hence, it is more common in molar and twin pregnancies where HCG levels are significantly elevated. HCG can physiologically activate the thyroid-stimulating hormone (TSH) receptor, resulting in suppressed TSH and elevated T4.

Biochemical abnormalities seen include renal dysfunction secondary to dehydration, electrolyte abnormalities such as hypokalemia and hypomagnesemia secondary to vomiting, and reduced oral intake. Abnormalities in liver enzymes occur in approximately 50% of cases that require hospitalization.

Prompt treatment with intravenous rehydration, correction of hyponatremia and hypokalemia, thromboprophylaxis, thiamine supplementation, and antiemetic treatment to enable slow reintroduction of oral fluids and diet is essential. Treatment of nausea and vomiting of pregnancy with vitamin B₆ or vitamin B₆ plus doxylamine is safe and effective and should be considered as first-line pharmacotherapy. Second-line therapies, including dopamine antagonists (metoclopramide), phenothiazines (chlorpromazine, prochlorperazine) and anticholinergics (dicycloverine), have reasonable safety data. Refractory cases may respond to ondansetron or glucocorticoids. HG is a reversible condition with no permanent hepatic damage, but often re-occurs in subsequent pregnancies.

Infarction and Intrahepatic Cholestasis of Pregnancy

ICP, the commonest pregnancy-specific liver disease, is a reversible form of cholestasis characterized by pruritus in pregnancy and elevated fasting or post-prandial serum bile acids with spontaneous relief of signs and symptoms within 6 weeks of delivery. ICP has a high recurrence rate in subsequent pregnancies with a variable incidence, ranging from 3 to 5% of pregnant women in Chile to 0.7% in the UK; it is rarely reported in African countries. It typically presents in the third trimester but it can present as early as 7 weeks of gestation; more commonly in multiple pregnancy and in women that have received fertility treatment. Postulated hypotheses include elevated estrogen and progesterone metabolites in pregnancy, which unmask the disease in genetically susceptible women.

The presenting symptom of ICP is usually pruritus, typically worse on the palms and soles, but this may be generalized or affect any part of the body. The only associated rash is secondary to excoriations from scratching. Some women also complain of dark urine and pale feces.

The diagnosis of ICP is based on a combination of pruritus and elevated serum bile acid concentrations above the normal reference range both reversible within 4–6 weeks after pregnancy and after exclusion of other potential etiologies. Approximately 15% of cases have genetic variation in one of the hepatocanalicular transport proteins.

The first-line treatment for ICP is ursodeoxycholic acid (UDCA), which results in improved maternal symptoms and biochemistry in approximately 75% of cases by enhancing biliary transport of bile acids, is anti-apoptotic, and is likely to improve excretion of pruritogens.

Combined use of UDCA and rifampicin, a potent pregnane X-receptor agonist, has been postulated to have synergistic beneficial effects in non-obstructive cholestasis. In approximately one-third of women with ICP that do not respond to UDCA alone, combining rifampicin with UDCA improves the symptoms and biochemical derangements. S-adenosyl methionine enhances phospholipid excretion and has been reported to improve pruritus and biochemical abnormalities in some studies. Dexamethasone has no impact on the symptoms or biochemical markers in ICP and should only be used if advised by obstetricians to promote fetal lung maturity. It is often helpful to use aqueous cream with 1–2% menthol, as this may reduce the pruritus sufficiently to enable women to fall asleep. Vitamin K supplementation may reduce the risk of postpartum hemorrhage or neonatal hemorrhage. Small studies have demonstrated improved serum bile acid levels with activated charcoal and reduced pruritus with guar gum and cholestyramine. A high prevalence of hepatitis C infection in women with ICP has been reported. Whether this reflects an enhanced susceptibility to hepatitis C infection in women with ICP or vice versa remains unclear. If women have ongoing symptoms or biochemical hepatic impairment for more than 3 months’ postpartum, an alternative/additional diagnosis should be sought.

Pre-Eclampsia, Eclampsia and HELLP Syndrome

Pre-eclampsia is a multisystem disorder defined as de novo hypertension after the 20th week of pregnancy (blood pressure [BP] 140/90) combined with proteinuria (>300 mg/day), other maternal organ dysfunction, such as renal insufficiency, liver involvement, neurological or hematological complications, uteroplacental dysfunction, or fetal growth restriction. Pre-eclampsia affects between 3 and 5% of all pregnancies and can present from 20 weeks’ gestation to as late as 1 month postpartum. The presence of seizures differentiates pre-eclampsia from eclampsia. HELLP syndrome is considered as a severe form of pre-eclampsia. Risk factors for pre-eclampsia are previous pre-eclampsia or hypertension in pregnancy, chronic kidney disease, hypertension, diabetes, and autoimmune disorders.

It is postulated that abnormal placentation leads to placental hypoperfusion, which, in some patients, progresses to endothelial dysfunction, leading to the multi-systemic involvement characteristic of pre-eclampsia.

Clinical features of pre-eclampsia may be absent with the diagnosis made during routine antenatal care; if present, they include right upper quadrant pain, headache, visual changes, nausea and vomiting. Many women are hyper-reflexic and edema is common. Elevated serum transaminases occur in 30% of cases.

The management of pre-eclampsia is supportive. The only cure is delivery of the placenta and the fetus should be delivered as soon as possible by the safest route, especially if the fetus is beyond 34 weeks’ gestation, fetal distress is evident, or there is evidence of maternal deterioration. Hypertension should be treated with intravenous labetalol, intravenous hydralazine and oral nifedipine as first-line agents for acute lowering of BP in pregnant women. If gestation is less than 34 weeks, glucocorticoids should be given to promote fetal lung maturity. Patients may require coagulation support. Magnesium sulfate should be given to women with HELLP syndrome and other forms of severe pre-eclampsia.

HELLP syndrome occurs in approximately 10–20% of women with pre-eclampsia. The diagnosis of HELLP syndrome is based mainly on clinical features with presenting symptoms that include right upper quadrant or epigastric pain in approximately 65% of cases, nausea and vomiting (35% of cases), headache (30% of cases) and rarer complaints, including bleeding and jaundice. Imaging of the abdomen should be considered in all women with HELLP syndrome and is imperative in those with abdominal pain, shoulder tip pain or hypotension in order to investigate for the life-threatening complications of hepatic hemorrhage, rupture and infarction, which have been reported to occur in up to 45% of women with HELLP syndrome. The management is as for pre-eclampsia.

The typical pattern of abnormal liver function tests (LFTs) in specific gestational liver diseases are given in Table 2.

ALT, alanine transaminase; tBA, total serum bile acids; tBil, total bilirubin; U&E,; LDH,  lactate dehydrogenase; WBC,white blood cells; USS,ultrasound scanning.

*During a 15-month study period, out of a total of 4,377 deliveries, 142 women (3%) with 206 diagnoses were found to have abnormal liver function tests. Of these, 138 diagnoses were pregnancy-specific liver disease. One additional woman had hepatic infarct/hematoma.

^†Symptoms of thyrotoxicosis are rarely seen. TSH is normally suppressed during the first trimester but it is detectable in uncomplicated pregnancy.

Hepatic Rupture, Infarction and Hematoma

Hepatic hemorrhage and rupture is associated with 50% mortality and can complicate pre-eclampsia, eclampsia, HELLP syndrome and patients with AFLP. Patients can present with abdominal pain, pyrexia and, if severe, hypovolemic shock and cardiovascular collapse. Laboratory investigations show raised liver enzymes in several thousands, leukocytosis and anemia. Imaging in the form of computed tomography or magnetic resonance is the investigation of choice.

Contained hematomas can be managed conservatively with aggressive coagulation support, prophylactic antibiotics and transfusion as required and in case of hemodynamic instability, urgent angiography with hepatic artery embolization and/or surgical intervention (packing of the liver, hepatic artery ligation and resection) is warranted.

Acute Fatty Liver of Pregnancy

AFLP, a rare complication of pregnancy, usually occurs in the third trimester and is a medical and obstetric emergency as it can be fatal for both the mother and baby.

It affects approximately 1 in 20,000 pregnancies, but the true incidence is likely, however, to be higher. Risk factors include nulliparity, male infants, and twin pregnancies.

The onset is usually between the 30^th and 38^th gestational week although up to 20% of patients present postnatally. Presenting features range from non-specific symptoms such as nausea, vomiting and abdominal pain to those of acute liver failure like hypoglycemia, coagulopathy, jaundice and encephalopathy. Pre-eclampsia is common but not invariable. Biochemical changes such as hyperbilirubinemia and a variable elevation of serum transaminases, elevated serum ammonia, lactic acid and amino acid levels are seen reflecting mitochondrial failure. Renal dysfunction, leukocytosis and thrombocytopenia are also common. Disseminated intravascular coagulation is seen in approximately 10% of patients. Potential complications include ascites, pleural effusions, acute pancreatitis, respiratory and renal failure.

Early recognition with rapid delivery of the fetus followed by maternal supportive care vastly improves prognosis for both the mother and the baby. Maternal mortality rates have dropped to less than 10% (2008) versus 92% prior to 1970.

The use of plasma exchange following delivery results in improved clinical outcomes including reduced maternal mortality in non-randomized clinical trials. Successful liver transplantation has been sporadically reported. Recent studies show that an elevated lactate and the presence of hepatic encephalopathy were the only admission parameters predictive of death or need for LT.

Pre-Existing Liver Diseases and Pregnancy

Cirrhosis and Portal Hypertension

Due to reduced fertility in women with cirrhosis and metabolic /endocrine dysfunction, pregnancy is rare. Disruption of the hypothalamic-pituitary axis with disturbed estrogen metabolism leads to anovulation, amenorrhea and infertility. Increased rate of spontaneous pregnancy loss, preterm labor and perinatal death has been observed in those who conceive. There is a risk of maternal worsening of liver synthetic function and hepatic decompensation, including the development of ascites, variceal hemorrhage and encephalopathy.

Variceal bleeding secondary to portal hypertension is the leading cause of maternal mortality in pregnant patients with underlying cirrhosis

Portal hypertension worsens with pregnancy and peaks in the second trimester due to increased circulating blood volume and a direct pressure of the gravid uterus on the IVC, impairing venous return. A patient with pre-existent varices will have up to a 25% risk of developing an episode of variceal hemorrhage during pregnancy. In non-cirrhotic portal hypertension (NCPH), synthetic liver function in usually preserved and the reproductive system is rarely affected.

The optimal management of portal hypertension during pregnancy remains challenging with the absolute need for variceal screening during the second trimester, primary prophylaxis against variceal hemorrhage, and the management of a variceal hemorrhage during pregnancy largely undefined.

Prophylactic endoscopic band ligation of varices is advised preconception in a patient with ‘‘at risk” varices; for varices that lack ‘‘high-risk stigmata”, beta-blockers should be commenced as the benefit is thought to outweigh any potential risk. The American Association for the Study of Liver Diseases recommends that once pregnant, women with cirrhosis should have a screening endoscopy in the second trimester. Upper gastrointestinal endoscopy is safe during pregnancy, with fetal hypoxia due to sedation or positioning being the main concern.

There are no recommendations as to the preferred mode of delivery (vaginal versus caesarean section) in patients with portal hypertension. It is preferable to avoid excessive straining during labor in women with documented varices, and a shortened second stage of labor is recommended, with forceps or ventouse-assisted delivery if needed. Caesarean section should be performed according to obstetric indications.

The treatment of an acute variceal bleed in pregnancy, like in the non-pregnant patient, is to ensure resuscitation and stabilization of the mother, antibiotic prophylaxis, and safe and timely endoscopic therapy. Vasopressin or synthetic analogs are avoided because of their vasoconstrictive effects and associated uterine ischemia.

Chronic Hepatitis B Virus Infection and Pregnancy

Pregnant women should be screened for hepatitis B surface antigen (HBsAg) in early pregnancy. Pregnancy does not have a major effect on the liver disease in mothers with chronic hepatitis B, except in the context of cirrhosis.

All hepatitis B-positive women should be monitored closely during pregnancy and in the postpartum period for exacerbations of disease. The risk of ALT flares is somewhat raised during pregnancy and postpartum but mortality is rare. Infection of infants born to HBsAg-positive mothers or of children early in life confers a high risk of chronic infection. All infants born to HBsAg-positive mothers should receive hepatitis B vaccine and hepatitis B immunoglobulin as soon as possible after birth, preferably within 24 hours.

Women should have their HBV DNA level checked at the start of the third trimester as vaccine prophylaxis may fail in infants born to mothers with high HBV DNA >10⁷ IU/ml. HBV transmission can be prevented in this group by concurrent nucleoside analog therapy during the third trimester and subsequent discontinuation of therapy at 1–3 months postpartum for those women who do not need continued therapy. Tenofovir has been suggested as the first-line nucleoside analog in pregnancy by the Society for Maternal-Fetal Medicine. Delivery mode should be decided by obstetric indications and caesarean section is not recommended for the sole indication of reduction of vertical HBV transmission. Breastfeeding should be encouraged, provided immunoprophylaxis is given at birth.

Hepatitis C

No universal consensus exists regarding screening of pregnant women for hepatitis C virus (HCV) infection though risk-based approaches have been adopted in many centers.

Neonatal transmission occurs in 3–5% of HCV RNA=positive mothers in the absence of HIV co-infection. HIV co-infection has been associated with increased risk of HCV transmission. A meta-analysis suggested that maternal HCV infection is significantly associated with a higher risk of preterm births. No evidence exists to suggest that mode of delivery influences the risk of vertical transmission, and breastfeeding is not contraindicated in women with HCV infection.

Autoimmune Hepatitis and Pregnancy

The most common maternal complication is a flare in autoimmune disease activity either during the gestational (7–21% incidence) period or, more commonly, in the postpartum period (11–81% incidence). In the majority of patients, a flare can be controlled by a step-up of immunosuppressive therapy but, rarely, can lead to hepatic decompensation with the potential need for liver transplant or death of the patient and/or fetus. Azathioprine has good safety data for its use in pregnancy and lactation. Women need stable immunosuppression throughout pregnancy and that azathioprine therapy should be continued at the same dose used to maintain maternal disease control throughout the gestational period.

Liver Transplantation and Pregnancy

Acute cellular rejection (ACR) complicates between 10 and 17% of patients in the gestational period and 3 and 12% of patients in the postpartum period. The incidence of ACR can be significantly reduced by delaying pregnancy for 1 year following LT.

Immunosuppression should be continued throughout pregnancy with common agents, including azathioprine, tacrolimus, cyclosporine and steroid therapy, as it is generally safe and any small risk to the fetus is much outweighed by the risk of rejection and graft failure by discontinuation.

Mycophenolate is associated with congenital abnormalities—external ear and other facial malformations such as cleft lip and palate—and, ideally, should be discontinued within at least 6 months before conception.

Liver Disease Coincidentally Arising with Pregnancy

Acute Viral Infections and Pregnancy

Acute viral hepatitis is the commonest cause of jaundice occurring in pregnancy worldwide. Although hepatitis A virus (HAV) infection in pregnancy is not a major cause of maternal or neonatal morbidity, in utero infection has been associated with fetal meconium peritonitis, neonatal cholestasis and preterm labor; hence, high-risk women need to be vaccinated. HAV infection in pregnancy has a clinical course similar to the non-pregnant population, and fulminant hepatitis is rare.

There is a well described but unexplained increased mortality of acute hepatitis E (genotypes 1 and 2) infection in pregnant women. Mortality from fulminant hepatic failure secondary to hepatitis E virus (HEV) can be up to 50%. Women with HEV infection during pregnancy also have a higher risk of obstetric complications like antepartum hemorrhage, intrauterine fetal death, and worse fetal outcomes including prematurity and stillbirth. Management is supportive, and ribavirin use is contraindicated because of the teratogenic effects.

Herpes simplex viral hepatitis (types 1 and 2) is rare, normally affecting immunosuppressed patients, and pregnant women are more at risk than the general population. The clinical picture is an acute elevation of liver enzymes with coagulopathy usually in the absence of jaundice; muco-cutaneous lesions are evident in 50%. Histology is characteristic, and CT shows multiple sub 1 cm hypovascular infarcted areas. Treatment with acyclovir should not be delayed if herpes simplex infection is suspected.

Pregnancy and Thrombosis

Pregnancy is recognized as a pro-coagulant state with an increase in clotting factors (I, II, V, VII, X, and XII) and fibrinogen levels alongside a physiological reduction in protein C concentrations. Budd-Chiari syndrome (BCS) can present de novo in pregnancy or pregnancy can result in thrombus extension with an acute to chronic presentation. In the past, reports of BCS presenting in pregnancy were associated with poor outcomes for the fetus and mother, with death from hepatic failure or portal hypertension being common. The treatment for BCS has evolved over several decades and 5-year survival rates have improved from 50% to 90%.

Conclusion

Though liver disease in pregnancy and pregnancy in women with liver disease is rare, it represents a clinically important group of patients due to the increased morbidity and mortality for both the mother and baby.

It is important to ensure that women of childbearing age have contraceptive advice that takes their liver disease into consideration, and to give them informed pre-pregnancy counseling. In women with a liver disease who are pregnant, rapid referral to specialist physicians with experience of managing hepatic disorders in pregnancy is essential.

All the same, maternal and fetal outcomes are improving due to ongoing research, improved guidelines and our better understanding of disease mechanisms and therapeutic options.

Reference

BMJ 2013, Oct 25:34.