Liver Disease and Pregnancy

During pregnancy, the liver undergoes physiological and anatomical changes Physical examination findings include telangiectasias, spider angiomas and palmar erythema can be seen during the late half of the pregnancy because of the elevated levels of oestrogen. serum alkaline phosphatase (ALP) increases up to four times in the third trimester as a result of the elevated levels of placental alkaline phosphatase. Other liver biochemical tests such as serum alanine transferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and total and free bilirubin typically remain within normal limits so any abnormal value should warrant further evaluation. As there is haemodilution, it is normal to have a mild decrease in serum albumin. Total cholesterol, triglyceride, fibrinogen and ceruloplasmin are augmented during pregnancy while prothrombin time (PT) and activated partial thromboplastin time (APTT) remain stable. Ultrasonography examination in pregnancy normally shows a normal biliary tree, increased fasting gallbladder volume and residual volume post contraction.

The prevalence of hepatitis B virus (HBV) is generally similar in the pregnant population as the general population and every pregnant woman should be screened for the HBV surface antigen (HBsAg). Women with chronic HBV (CHB) should have additional tests such as HBV viral load, hepatitis B e antigen, and alanine aminotransferase level to assess for disease activity.

Pregnancy can affect the natural history of HBV, placing pregnant women with CHB at an increased risk for HBV flares (6-14%), particularly in the postpartum period (10-50%). The majority of these flares are self-limiting and hepatic decompensation is rare.

The majority of infant HBV infection is due to exposure to vaginal blood and secretions during delivery and in women with a viral load >200,000IU/ml, maternal to child transmission (MTCT) occurs in up to 1025% despite receiving HBV immunoglobulin and vaccination. For these women, the use of antiviral therapy in the third trimester is recommended. Among the antivirals considered safe in pregnancy tenofovir is preferred as it has the most robust safety data in pregnancy and a high barrier to resistance. Ideally treatment should be initiated early in the third trimester to allow sufficient time for the viral load to decrease to below 200,000IU/ml, and in women using antivirals for the sole purpose of decreasing MTCT, treatment may be stopped shortly after delivery or continued if planning to breastfeed.

For the infant, an IM dose of 0.5mL Hepatitis B immunoglobulin and a HBV vaccine first dose be given within 12 hours of delivery is recommended, and has been shown to reduce rates of MTCT from 90% to 10%.

While most women with Hepatitis C infection have uneventful pregnancies, infection with the hepatitis C virus (HCV) has been associated with adverse pregnancy outcomes such as preterm birth, IUGR, congenital abnormalities, and increased risk for developing intrahepatic cholestasis of pregnancy (ICP). There is an approximate 5.8% risk of mother to child transmission (MTCT), which is the leading cause for HCV infection in children and can occur both in utero and in the peripartum period. This risk is elevated in women who inject drugs during pregnancy and nearly doubles in women that are coinfected with HIV.

There is currently no treatment for HCV that is approved for use during pregnancy, and as such the mainstay of care for these patient is to reduce the risk of MTCT as much as possible by avoiding prolonged rupture of membranes and invasive monitoring as much as is feasible and testing of infants born to infected mothers. Antiviral therapy has been used successfully in some cases with the aim of reducing the risk of MTCT, although more data is needed to support this approach across the board. Many people with HCV are asymptomatic, and screening in pregnant women is currently done on an at-risk basis, however there is evidence that routine screening for all pregnant women is cost effective.

NAFLD is increasingly common in the Western world with a prevalence of approximately 20-30% and is characterised by hepatic steatosis in the absence of excessive alcohol intake. NAFLD is also associated with metabolic syndrome, which may increases the risk of adverse pregnancy outcomes such as preterm delivery, post-partum haemorrhage, and hypertensive complications and as such women with this disease should receive preconceptual counselling on the increased risks. Given the prevalence, it is likely that most people with NAFLD are unaware of their diagnosis.

The infants born to these mothers are at an increased risk of early obesity and childhood NAFLD, most likely due to multiple factors not just NAFLD. Currently the only treatment options for NAFLD are diet and exercise, and ideally patients would have their weight and blood sugar optimised prior to conception. Advice is given on pregnancy weight gain, which depends on the booking BMI. Close monitoring and treatment of associated risks such as hyperglycaemia and hypertension is also imperative during pregnancy. Moderate exercise during pregnancy has been associated with improved maternal and fetal outcomes and could benefit these mothers and infants. Breastfeeding has also been shown to produce benefits in normalising glucose and triglycerides.

Autoimmune Liver Disease

Autoimmune hepatitis (AIH) is an immune-mediated liver disease characterised by chronic inflammation associated with increased gammaglobulins and the presence of specific serum autoantibodies. While the exact aetiological mechanism is still unknown, the disease is characterised by progressive destruction of the liver parenchyma which over time leads to liver cirrhosis.

The risk of complications generally corresponds to the stage of AIH at which the pregnancy occurs, with cirrhosis conferring a higher risk if associated with impaired liver function. Ideally a patient with AIH should be optimised before becoming pregnant. The model for end-stage liver disease (MELD) is often used as a prognostic indicator in women with preexisting liver disease in planning a pregnancy. The score ranges from 6 to 40 and is used to assess how severe a patient’s liver disease is using serum creatinine (if patient has been dialyzed twice within last seven days then this value should be taken as 4.0), INR, and serum bilirubin (see above).

Women with liver cirrhosis and a MELD score >10) are considered at higher risk for pregnancy, although patients with compensated cirrhosis can have successful pregnancies. Medical treatment of AIH during pregnancy is generally includes glucocorticoids such as prednisolonewith azathioprine. The most serious complications of AIH cirrhosis during pregnancy related to increased portal hypertension and variceal bleeding, particularly during the third trimester and ideally all patients should have an upper endoscopy to identify and prophylactically ligate any highrisk varices.

Up to 20% of women with AIH may “flare” during or shortly after pregnancy, which can be managed with higher doses of prednisolone. The incidence of flares increases with the post-partum return of normal immunity, and LFTS should be monitored during this period.

Liver transplantation is associated with a survival benefit and increased life expectancy in patients with decompensated cirrhosis. Advanced liver disease causing decompensated cirrhosis often causes infertility in women due to a lack of ovulation, however many of women that receive a liver transplant regain their fertility following transplant. For women wanting to conceive after liver transplant, planning can begin one year post transplant when the patient has achieved stable liver function and a period without acute cellular rejection.

The predominant risks in pregnancy after liver transplantation are acute cell rejection, loss of graft function, bacterial and viral infections, gestational diabetes (GDM), and pre-eclampsia/eclampsia.

Immunosuppressive drugs such as tacrolimus, and cyclosporin can be used during pregnancy, but do carry a small increased risk of hypertension, pre-eclampsia, and eclampsia, though this may be also as a result of the conditions themselves. Cyclosporin blood levels should be monitored due to the increased hepatic clearance of cyclosporin during pregnancy. Both of these drugs also carry an increased risk of transient hyperkalaemia in the newborn. Prednisolone can also be used during pregnancy, but carries the risk of growth restriction, GDM, preterm birth, and higher incidences of cleft palate and adrenal insufficiency in the newborn. Women with a liver transplant may benefit from GDM screening in the first trimester, and again at 24-28 weeks. In contrast to the above drugs, mycophenolate- mofetil (MMF) is teratogenic and should be discontinued at least six-weeks prior to conception or ideally longer.

Intrahepatic cholestasis of pregnancy (IHCP) is the most common form of hepatic disease in pregnancy, it is a reversible cholestatic condition whose incidence is estimated at 0.51.8% in Europe. Risk factors include maternal age >35 years, multiparity, history of oral contraceptive use, fertility treatments and previous IHCP. Regarding pathogenesis, it is a multifactorial disease that arises in genetically predisposed women during the second or third trimester when their serum concentration of oestrogen reaches its peak and resolves spontaneously after birth when sex hormone levels fall. The diagnosis is suspected based on the symptom of pruritus that classically involve the palms and soles which worsens at night and is not associated with a rash, and abnormal elevated serum bile acids (>10μmol/L). IHCP is a diagnosis of exclusion once other causes of pruritis or abnormal LFTs have been ruled out.

Medical treatment includes oral ursodeoxycholic acid though other medications may be required if symptoms are refractory. Traditionally a diagnosis of IHCP, due to concerns regarding intrauterine death, has mandated early delivery (around 37 weeks’ gestation) though more recently guidelines have changed to provide more individualised care, depending on the clinical situation, wishes of the woman, and level of serum bile acid elevation.

Acute fatty liver

AFLP is a medical and obstetric emergency that affects 1 in 7,00020,000 and occurs in the late third trimester with microvesicular fatty infiltration of hepatocytes. Risk factors include multiple gestation and male fetus. The pathogenesis involves mitochondrial dysfunction due to 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) enzyme deficiency in the fetus which leads to accumulation of hepatotoxic fatty acid metabolites.

Diagnosis is made clinically with the aid of the Swansea criteria (Table 1, adapted from Mikolasevic, 2018, above), the presence of six or more features in the absence of other etiologies is suggestive of AFLP.Liver biopsy is considered the gold standard for diagnosing but is rarely done due to inherent risks in pregnancy.

The treatment is delivery of the fetus, which may be preterm and supportive care typically resulting in rapid recovery. However, management of complications may continue for days to weeks. This condition might recur in subsequent pregnancies. The international recommendation is that all women with AFLP and their children should have molecular testing for LCHAD.

HELLP – Haemolysis, elevated liver enzymes and low platelets

HELLP syndrome is a rare and severe variant of preeclampsia which happens in 0.2%-0.9% of pregnancies. This condition occurs in the late second or third trimester or in the early postpartum period. Risk factors include family history of HELLP syndrome and antecedents of HELLP or preeclampsia in previous pregnancies.

The pathophysiology of this condition involves abnormal development of placental vasculature, maternal endothelial dysfunction that cause poor perfusion and platelet aggregation which results in clot formation, platelet consumption, microangiopathic haemolytic anaemia and fibrin deposition in hepatic sinusoids leading to ischemic injury.

Signs and symptoms include hypertension, proteinuria, right upper quadrant abdominal pain, nausea and vomiting. Laboratory tests show elevated transaminases because of hepatocellular necrosis, lactate dehydrogenase, elevated unconjugated bilirubin and decreased haptoglobin due to haemolysis.

Complications of HELLP syndrome are disseminated intravascular coagulation (DIC), acute renal failure, pulmonary oedema, intracranial haemorrhage, placental abruption, hepatic infarction, haemorrhage or rupture; meanwhile fetal concerns include prematurity or intrauterine growth restriction, or tragically intrauterine death. While traditionally maternal mortality rate is reported as 5% with a fetal mortality rate of 40%, in the last thirty years increased recognition of the early symptoms and signs of HELLP has significantly reduced complications.

Treatment usually includes delivery and supportive care. Similar to pre-eclampsia, iatrogenic birth, supportive care, blood pressure management, seizure prophylaxis with magnesium sulphate are all part of management. If the gestational age is less than 34 weeks’ gestation maternal steroid (dexamethasone or betamethasone) can be administered to reduce neonatal complications including respiratory distress syndrome, intracranial haemorrhage or necrotising enterocolitis.

A crucially important consideration for both pre-eclampsia and HELLP is the misleading statement that “delivery is curative” – there are multiple case reports of worsening disease in the postnatal period. For example, it is common for blood pressure to increase in the few days after birth as fluid sequestered in the interstitial space returns to the vascular tree. Liver function tests can worsen before normalising. There is a risk of venous thromboembolism (VTE), and careful consideration should be given to balancing the risks of bleeding to that of VTE. As a result, senior input from multiple specialities may be required to provide appropriate care. Occasionally intensive care admission is appropriate and recommended.

Role of the MDT

As with any other medical condition in pregnancy, pre-existing or pregnancy associated liver diseases require multidisciplinary care. At the centre of this is the concept of patient centred care, where the person themselves are the expert on their experience of a condition and the healthcare professionals experts on the medical condition. Individualisation of care to provide support is invaluable, while still providing care that is evidence based and appropriate.

For women or pregnant people with no pre-existing disease, antenatal care can be provided to normal risk women in a supported care pathway provided by midwives. Women or pregnant people with pre-existing disease can, depending on their condition, have care provided by an assisted or specialist care pathway with both midwifery and obstetricians involved. The role of a hepatologist is crucial for pre-existing disease, whereas conditions such as IHCP are within the practice of obstetricians and midwives unless the disease is resistant to standard medications. Providing care using different “lenses” allows for more holistic care and it is incredibly useful to have joint clinics where patients can be seen by all relevant healthcare professionals with clear communication at all levels. Other healthcare professionals, including anaesthesiology, pharmacy, mental health support, neonatology, genetics, theatre staff, intensive care, medical scientists and pathology may also play a significant role in care of people with liver disease in pregnancy. Other factors to consider Pregnancy is obviously not a disease or a condition, and it would not be holistic to reduce it to the care of a disease. At the heart of this are two people – a mother and baby- and the wish for both to come through pregnancy, labour and birth safely. For some people pregnancy may be contraindicated and difficult decisions may be required for the family. Some people will choose to continue in the pregnancies having been informed and reflected on possible complications; others may choose not to continue. Other pregnancy care issues such as support, parent education, assessment of the growing fetus, nutrition, medication review, planning for birth and the postnatal period are all important. Not all women with liver disease, even transplantation, will require a caesarean birth, and vaginal birth may be appropriate for many.

Liver disease can affect pregnancies in many ways. For most, a diagnosis of cholestasis may be the most significant, with increased monitoring and perhaps earlier birth than planned. For a few, a complication such as AFLP, HELLP or liver haematoma due to PET may result in a long hospital stay and prolonged recovery. The role of the multidisciplinary team is crucial, and the person – women, pregnant person or transgender man with a uterus – remains in the centre of care.

Written by: Samantha Vega Figueroa, Escuela de Medicina y Ciencias de la Salud Tesalud, Tecnológico de Monterrey Campus Ciudad de México, Cassandra Herron, UCD School of Medicine, University College Dublin, Mary Higgins, UCD Perinatal Research Centre, National Maternity Hospital, Omar Elsherif, Hepatology, St Vincents University Hospital Dublin