1. Understand the different reference ranges for liver function tests and enzymes during pregnancy
2. Identify the key points for individual pregnancy-related conditions
3. Be aware of differentiating factors between various liver conditions of pregnancy
Pregnancy directly affects the physiology of the liver (figure 1) and hepatic disorders can influence pregnancy outcomes. The relationship between both is evident but not well defined.
Physiological Changes During Pregnancy
Adaptations of physiology during pregnancy optimise maternofoetal gas exchange. Blood volume increases throughout pregnancy and plateaus in the late third trimester. Progesterone and oestrogen levels rise and influence hepatic metabolism, synthesis, and excretory functions. Hyperoestrogenaemia results in spider naevi and palmar erythema in 60% of normal pregnancies,1 showing similarities to patients with chronic liver disease. Blood parameters also change during pregnancy (Figure 2). Most normalise within 2 weeks of delivery but can take up to 12 weeks.
Pregnancy-Specific Liver Disorders
Liver disease in pregnancy is uncommon but is an important cause of maternofoetal morbidity and mortality. Acute liver failure (ALF) is rare.
- Defined as hypertension (blood pressure ≥140/90 mm Hg) that occurs after 20 weeks’ gestation with new-onset proteinuria (≥300 mg/dL/day), with or without multisystem involvement2
- Clinical features: nausea, vomiting, or epigastric pain
- The previously high associated high maternal mortality has fallen to roughly 1% in developed countries and continues to reduce.
- Haemolysis, Elevated Liver Enzymes and Low Platelet (HELLP) Syndrome
A severe form of pre-eclampsia seen in 4–20% of cases
- Characterised by haemolysis, thrombocytopenia, and elevated liver enzymes
- ELLP syndrome without haemolysis is a variant
- Complications are disseminated intravascular coagulation and acute renal failure
- Rare complications are hepatic haematoma or hepatic rupture, which are associated with high mortality (16–60%); there is a low threshold to image these patients if symptomatic
Acute Fatty Liver of Pregnancy (AFLP)
- This is a rare condition that presents in the third trimester
- Hypertension and proteinuria are seen in 50% of patients
- The risks of maternal and perinatal mortality are high
- Presentation involves a non-specific prodrome, nausea/vomiting, malaise, and jaundice
- Diabetes insipidus can result from impaired hepatic metabolism of placental vasopressin, leading to excessive clearance of anti-diuretic hormone with symptomatic polydipsia or polyuria; desmopressin is a helpful treatment for these symptoms
- ALF can ensue, characterised by hepatic encephalopathy, coagulopathy, and hypoglycaemia
- The Swansea criteria can aid diagnosis (Table 1)
Differentiating between pre-eclampsia, HELLP, and AFLP can be difficult (Table 2). Patients judged to be at risk of developing pregnancy-related hypertensive disorders should be initiated on daily aspirin (before 16 weeks’ gestation) to reduce the risk of pre-term (<37 weeks’ gestation) pre-eclampsia.3 Management of these conditions involves treatment of underlying hypertension and stabilisation before delivery, for instance by correction of coagulopathy. Some centres recommend empirical antimicrobials if ALF is developing, in an attempt to prevent and treat bacterial/fungal infections which can complicate the course of ALF. Studies report variable efficacy.4,5 No data support the use of N-acetylcysteine to treat AFLP, but benefits have been demonstrated in other causes of non-paracetamol induced ALF.6 ALF can occasionally lead to the need for emergency liver transplantation.
Other pregnancy-specific conditions
Intrahepatic Cholestasis of Pregnancy
- Affects up to 2% of pregnancies7.
- Arises secondary to impaired excretion of bile acids
- Pruritis typically occurs from 25 weeks’ gestation
- Earlier presentation or a severe phenotype might indicate underlying mutations in genes that cause familial cholestasis (e.g. ABCB4)8.
- Cholestatic liver enzymes and aminotransferases are substantially raised (reaching up to 20 times the upper limit of normal)
- Bile acids have a vasoconstrictive effect leading to chronic placental insufficiency, which can result in foetal anoxia, prematurity, distress, and stillbirth (risk is greatest if bile acid concentrations are >100 µmol/L)9
- Management involves vitamin K, ursodeoxycholic acid, rifampicin, and colestyramine7
Pregnancy in Patients with Liver Disease
- The most common cause of hepatic dysfunction in pregnancy worldwide (Table 3)
- Compared to the non-pregnant population, pregnant women are more likely to develop acute hepatitis, hepatic encephalopathy, hepatorenal syndrome, and ALF (particularly those infected with hepatitis E virus or herpes simplex virus)
Autoimmune hepatitis and cholestatic disorders
- Autoimmune hepatitis generally improves during pregnancy, but 20% of patients will experience flares
- Immunosuppression should continue during pregnancy, except for mycophenolate mofetil, which should be stopped 12 weeks prior to conception
- Poor disease control (e.g. non-compliance) and recurrent autoimmune hepatitis flares in the year before conception are associated with inferior outcomes
- Pregnancies in patients with primary biliary or primary sclerosing cholangitis have an increased risk of pre-term delivery and intrahepatic cholestasis of pregnancy
- Ursodeoxycholic acid may require up-titration during pregnancy
- In the absence of cirrhosis, maternofoetal outcomes are favourable
Cirrhosis and portal hypertension
- Women with cirrhosis rarely become pregnant due to high rates of infertility
- Pregnancy in these women is associated with high mortality (roughly 10%)
- Portal hypertension worsens during pregnancy, which increases the risk of variceal haemorrhage
- Variceal screening should be performed during the second trimester
- Concerns over variceal rupture during labour often makes Caesarean section the preferred mode of delivery (although this is controversial)
- Prognosis can be predicted by pre-pregnancy MELD scores12
- Women should be advised to wait 1 year after transplantation before becoming pregnant
- Provided that graft and kidney function are good, pregnancy may be managed as normal but with additional foetal-growth scans
- Immunosuppression should continue throughout pregnancy (except mycophenolate mofetil)
- Organ rejection during pregnancy is rare
- The livebirth rate is 70%, but with increased risk of pre-term delivery, low birthweight, pre-eclampsia, and gestational diabetes13
- This is a rare condition characterised by hepatic venous outflow obstruction, leading to ascites, hepatomegaly, and right upper quadrant pain
- Risk is increased due to pro-thrombotic status during pregnancy
- The prevalence of gallstones is increased in pregnancy due to enhanced bile lithogenicity and stasis secondary to impaired gallbladder contractility
- If required, laparoscopic cholecystectomy and therapeutic endoscopy can take place from the second trimester onwards
Management of Liver Disease During Pregnancy
Pregnant women with severe hepatic disease require an individualised care plan with multidisciplinary input. Decisions regarding timing and mode of delivery require careful evaluation of maternal and foetal risks. Early communication with a transplant unit could be warranted, as the development of ALF may necessitate urgent transfer. The best predictors for deterioration (death or liver transplantation) are lactate concentration >2.8 mg/dL in combination with hepatic encephalopathy.14 While the value of N-acetylcysteine in pregnancy is unproven, there is no evidence that it causes harm.
Sometimes it can be difficult to determine the exact cause of liver dysfunction during pregnancy. Consideration of multiple diagnoses is appropriate. Escalation to tertiary care is suitable in the context of severe disease.
Figure 1: Physiological Changes to the Liver During Pregnancy
Figure 2: Normal Biochemical Changes During Pregnancy
Table 1: The Swansea Criteria
Table 2: Potential Differentiating Factors Between HELLP and AFLP
+ = can be present
++ = likely to be present
+++ = very likely to be present
– = unlikely to be present
Abbreviation: LCHAD, long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency.
Table 3: Causes of Viral Hepatitis During Pregnancy
1 Angel G. Effect of pregnancy on pre-existing liver disease physiological changes during pregnancy. Ann Hepatol 2006;5:184-186.
2 American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122-1131.
3 Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;77:613-622.
4 Rolando N, Gimson A, Wade J, et al. Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology 1993;17:196-201.
5 Karvellas CJ, Cavazos, J, Battenhouse H, et al. Effects of Antimicrobial Prophylaxis and Blood Stream Infections inPatients With Acute Liver Failure: A Retrospective Cohort Study. Clin Gastroenterol Hepatol 2014;12:1942-9.e1.
6 Lee WM, Hynan LS, Rossaro L, et al. Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137:856-864.
7 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol 2009;51:237-267.
8 Dixon PH, Sambrotta M, Chambers J, et al. An expanded role for heterozygous mutations of ABCB4, ABCB11, ATP8B1, ABCC2 and TJP2 in intrahepatic cholestasis of pregnancy. Sci Rep 2017;7:11823.
9 Ovadia C, Seed PT, Sklavounos A, et al. Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses. Lancet 2019;393:899-909.
10 Marschall HU, Wikström Shemer E, Ludvigsson JF, et al. Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: a population-based cohort study. Hepatology 2013;58:1385-1391.
11 Pérez-Gracia MT, Suay-García B, Mateos-Lindemann ML. Hepatitis E and pregnancy: current state. Rev Med Virol 2017;27:e1929.
12 Gonsalkorala ES, Cannon MD, Lim TY, et al. Non-invasive markers (ALBI and APRI) predict pregnancy outcomes in women with chronic liver disease. Am J Gastroenterol 2019;114:267-275.
13 Rahim MN, Long L, Penna L, et al. Pregnancy in liver transplantation. Liver Transpl 2020;26:564-581.
14 Westbrook RH, Yeoman AD, Joshi D, et al. Outcomes of severe pregnancy-related liver disease: refining the role of transplantation. Am J Transplant 2010;10:2520-2526.
Mussarat N Rahim
Dr Mussarat Rahim is currently a Clinical Research Fellow at King’s College Hospital. She graduated from Imperial College in 2009 and completed her training in Gastroenterology & Hepatology in the KSS deanery in September 2018. Post-CCT, Dr Rahim is undertaking research, as part of an MD, in pregnancy-related liver disease. Her other research interests include autoimmune liver disease. In June 2019, she was elected as a trainee representative for the BSG liver section.
Michael A Heneghan
Professor Heneghan is a Consultant Hepatologist at King’s College Hospital with specialist interests in pregnancy-related liver disease, autoimmune conditions and liver transplantation. He has published over 150 peer-reviewed papers in these fields. He trained at the University College of Dublin and qualified in 1992. After his Residency in Galway, he trained in Gastroenterology and Hepatology between 1995-2001 in Ireland, London and the USA. Professor Heneghan worked at Duke University Medical Centre in North Carolina before starting at King’s College Hospital as Senior Lecturer and Consultant Hepatologist. He was previously the Clinical Lead for Hepatology Services at King’s College Hospital. In addition, he runs a combined multi-disciplinary Obstetric Hepatology Service at King’s College Hospital with one of the lead Obstetricians and a Professor in Obstetric Medicine. He has several roles within different societies, including the BSG and BASL. He is also the recipient of the EASL Pregnancy Registry grant since 2017.