Pregnancy-Related Liver Disease

General ConsiderationsTop

Liver disease can affect up to 3% individuals during pregnancy. Liver disease in pregnancy can be pregnancy specific or occur because of a preexisting liver condition (Table 1). During pregnancy, liver metabolism is increased; the upper limit of normal (ULN) for transaminases decreases slightly by the third trimester, while the alkaline phosphatase (ALP) concentration increases in pregnancy (ULN, 400 IU/L). Bilirubin, international normalized ratio (INR), and gamma-glutamyl transferase (GGT) levels remain unchanged (Table 2).

Timing (gestational age), associated symptoms, pattern of liver enzyme elevation, and other laboratory tests can help distinguish between pregnancy-related liver diseases (Table 3). Ultrasonography is the preferred imaging modality; however, magnetic resonance imaging (MRI) without gadolinium enhancement can also be used during pregnancy.

The liver diseases unique to pregnancy include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and acute fatty liver of pregnancy (AFLP). The prompt recognition of the underlying cause of liver enzyme elevation is imperative, as pregnancy-related liver disease can be associated with morbidity and mortality for both the mother and fetus.

Hyperemesis GravidarumTop

1. Clinical features and diagnosis: HG is defined as severe nausea and vomiting resulting in dehydration, electrolyte abnormalities, and weight loss. It occurs in the first trimester and usually resolves by 20 weeks of gestation. Although nausea and vomiting of pregnancy affects up to 90% of pregnancies, HG is less common (0.3%-2% of pregnancies) and should be considered a diagnosis of exclusion. Studies have shown that hypersensitivity to the growth differentiation factor 15 (GDF15, vomiting hormone) is associated with HG.

Initial investigations to evaluate for HG include complete blood count (CBC), electrolytes and extended electrolytes, creatinine, urea, liver enzymes, and a dipstick urinalysis (to assess for ketosis). If the clinical presentation is consistent with HG, thyroid-stimulating hormone (TSH) testing is recommended to assess for thyrotoxicosis. Pelvic ultrasonography should also be performed to confirm a viable intrauterine pregnancy and exclude multiple gestation and trophoblastic disease.

Liver enzyme levels are abnormal in up to 50% of cases. The pathogenesis of liver enzyme elevation is unclear. Liver injury in the setting of dehydration, malnutrition, and an increased cytokine level has been proposed. Transaminases can be elevated (in the range of 100s IU/L). Bilirubin can also be mildly increased. HG is not associated with jaundice. Liver enzymes normalize with the cessation of vomiting. If there are persistent abnormalities in liver enzyme levels, alternative diagnoses must be evaluated (Table 1).

2. Treatment of HG is supportive and may include IV fluids, electrolyte replacement, antiemetics (Table 4), and nutritional supplementation. Prenatal vitamins can be switched to multivitamins not containing iron. In this case, folic acid should be taken separately. Although Wernicke encephalopathy is a very rare complication of HG, thiamine supplementation should be given to patients admitted with vomiting or with severely reduced dietary intake, especially before receiving any dextrose-containing fluids. Common antiemetics used in pregnancy include diclectin, dimenhydrinate, metoclopramide, and ondansetron. Combinations of different medications may be required. If present, treatment of reflux and constipation is also recommended. The Hyperemesis Education & Research website provides a helpful stepwise approach. A trial of glucocorticoids can be considered in refractory cases where standard therapies by an experienced provider have failed.

The severity of HG can be monitored using the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE-24) scoring system (Table 5). Inpatient admission is advised if the PUQE-24 score is ≥13. During admission, thromboprophylaxis with low-molecular-weight heparin is recommended given the increased risk of thrombosis during pregnancy. Emotional support is essential when caring for patients with HG, as it is associated with significant psychiatric morbidity and impacts quality of life. Screening for both depression and anxiety is recommended with appropriate psychiatric referrals and treatment, if indicated.

Intrahepatic Cholestasis of PregnancyTop

1. Clinical features and diagnosis: ICP is the most common pregnancy-related liver disorder. It is characterized by generalized pruritus, especially of the palms and soles, and raised serum bile acid concentration (among others, cholic acid and chenodeoxycholic acid). The pruritus tends to be more prominent at night. Importantly, there is no associated skin rash. Transaminases are often elevated but are usually <1000 IU/L (alanine aminotransferase [ALT] > aspartate aminotransferase [AST]). Bilirubin is elevated in up to 10% of cases. In women with steatorrhea, the INR may be abnormal due to malabsorption of fat-soluble vitamins, specifically vitamin K. ICP tends to occur in the second half of pregnancy, but it can present as early as in the first trimester. Both pruritus and liver enzyme elevation may precede bile acid elevation.

The incidence of ICP varies with ethnicity, geographic location, and season. It is most common in South America and northern Europe. Other risk factors include multiple gestation, assisted reproduction, and preexisting cholestatic liver disease. Furthermore, several genes involved in bile acid transport have been linked to the development ICP.

Additional investigations including hepatitis C serology, liver autoantibodies (anti–smooth muscle antibody, antimitochondrial antibody), cytomegalovirus (CMV) infection, Epstein-Barr virus (EBV) infection, and liver ultrasonography to exclude cholelithiasis can be considered if aminotransferases are elevated, although the diagnostic yield of these investigations is very low. The 2022 Royal College of Obstetricians and Gynaecologists (RCOG) guideline on ICP recommends pursuing additional investigations in the setting of atypical clinical symptoms, early-onset or severe ICP, or delayed resolution of abnormal liver function post partum.

Adverse outcomes include fetal distress, meconium-stained amniotic fluid, preterm delivery, neonatal intensive care unit (NICU) admission, and stillbirth. It has been shown that the risk of stillbirth is higher than the background risk when the peak bile acid level is >100 micromol/L.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational data and increased due to the strength of association. 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 Mar 2;393(10174):899-909. doi: 10.1016/S0140-6736(18)31877-4. Epub 2019 Feb 14. Erratum in: Lancet. 2019 Mar 16;393(10176):1100. PMID: 30773280; PMCID: PMC6396441.

It is hypothesized that bile acids may cause arrhythmias and vasoconstriction of placental vessels. There is no method of fetal monitoring that can help predict or reduce the risk of adverse outcomes. Pregnant individuals are advised to monitor fetal movements and to present for assessment if they have any concerns.

2. Treatment: The frequency of monitoring depends on the degree of bile acid elevation and gestational age. The RCOG recommends more frequent testing in the third trimester to help inform the timing of delivery. Counseling on the use of cool compresses, topical creams, and antihistamines is recommended; however, the effectiveness of these treatments is uncertain. The mainstay of treatment has historically been ursodeoxycholic acid (starting from 10-15 mg/kg daily in divided doses). Recent studies have shown that it does not reduce adverse perinatal outcomes, thus questioning its widespread use for ICP. However, given the lack of other treatment options and the safety profile of ursodeoxycholic acid, it is our local practice to prescribe it for the treatment of ICP, especially in women with bile acid levels >40 micromol/L in whom there is a suggestion of a reduction in spontaneous late preterm birth.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Ovadia C, Sajous J, Seed PT, et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis. Lancet Gastroenterol Hepatol. 2021 Jul;6(7):547-558. doi: 10.1016/S2468-1253(21)00074-1. Epub 2021 Apr 27. PMID: 33915090; PMCID: PMC8192305. Chappell LC, Bell JL, Smith A, et al; PITCHES study group. Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial. Lancet. 2019 Sep 7;394(10201):849-860. doi: 10.1016/S0140-6736(19)31270-X. Epub 2019 Aug 1. PMID: 31378395; PMCID: PMC6739598. Fleminger J, Seed PT, Smith A, et al. Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a secondary analysis of the PITCHES trial. BJOG. 2021 May;128(6):1066-1075. doi: 10.1111/1471-0528.16567. Epub 2020 Nov 8. PMID: 33063439; PMCID: PMC8246759. Rifampin has been proposed as a potential add-on therapy to ursodeoxycholic acid if bile acid levels remain elevated or the patient has refractory pruritus, but there are no randomized controlled trials to support its routine use in ICP. Although uncommon, rifampin has been associated with drug-induced hepatoxicity, therefore referral to a specialist in ICP and close monitoring of liver enzymes is advised.

Symptoms of ICP resolve soon after delivery, but liver enzymes may normalize after a few weeks. Rechecking liver enzymes in the postpartum period is recommended to ensure normalization. If liver enzymes remain elevated 4 to 6 weeks post partum, additional investigations should be undertaken to evaluate for an alternative liver pathology. The risk of ICP recurrence in future pregnancies is high (90%).

Preeclampsia and EclampsiaTop

See Pregnancy-Related Hypertension, see Preeclampsia, see Eclampsia.

HELLP SyndromeTop

1. Clinical features and diagnosis: HELLP syndrome often presents as part of preeclampsia, but it can also occur without hypertension in 10% to 15% of cases. It typically develops in the second or third trimester or post partum. Development before 20 weeks of gestation should prompt a search for an alternative etiology. Clinical manifestations include right upper quadrant or epigastric pain, nausea, vomiting, edema, headache, hypertension, and other features of preeclampsia (see Preeclampsia). Transaminases can be elevated up to low 1000s IU/L. Hemolysis may be absent, but if present, both unconjugated bilirubin and lactate dehydrogenase (LDH) levels are increased and haptoglobin concentration is reduced. Peripheral blood smear should be performed to assess for schistocytes. Complications include renal failure, pulmonary edema, severe hypertension, placental abruption, subcapsular hematoma, and hepatic rupture. Fetal and neonatal implications include fetal growth restriction, preterm delivery, NICU admission, and intrauterine fetal demise (IUFD).

2. Treatment: Preeclampsia with superimposed HELLP syndrome is an indication for delivery. Like other pregnancy-related liver diseases, HELLP syndrome resolves with the delivery of the placenta. Given its association with hypertensive disorders of pregnancy, close blood pressure monitoring and initiation of antihypertensive therapy, if indicated, is key. Additional information on treatment: see Pregnancy-Related Hypertension, see Preeclampsia, see Eclampsia. HELLP syndrome increases the risk of preeclampsia, preterm delivery, and fetal growth restriction in subsequent pregnancies.

Acute Fatty Liver of PregnancyTop

1. Clinical features and diagnosis: AFLP is a rare but life-threatening condition, necessitating early detection. Impaired fatty acid oxidation in the fetus due to enzyme deficiencies results in the accumulation of metabolites in the maternal blood, leading to hepatotoxicity. The most studied cause is long-chain 3-hydroxyacyl-coenzyme A-dehydrogenase (LCHAD) deficiency. Fetal and neonatal implications include intrauterine growth restriction and IUFD. Maternal and perinatal mortality is estimated to be ~2% and 11%, respectively.

Symptoms of AFLP are often vague, making the diagnosis challenging. Furthermore, superimposed preeclampsia/HELLP syndrome can occur. AFLP presents after 30 weeks of gestation and can be characterized by general malaise, vomiting, abdominal pain, jaundice, or polyuria/polydipsia (due to transient vasopressin disorders [diabetes insipidus]). Hepatic failure and associated encephalopathy may also occur. Transaminases are increased but often <500 IU/L, whereas the unconjugated bilirubin concentration is markedly elevated. The Swansea criteria can be used to help diagnose AFLP when ≥6 features are present: vomiting; abdominal pain; polydipsia/polyuria; encephalopathy; elevated bilirubin level; hypoglycemia; elevated urea level; leukocytosis; ascites or a "bright" liver echopattern on ultrasonography; elevated transaminase (AST or ALT) levels; elevated ammonia level; elevated creatinine level; coagulopathy; microvesicular steatosis on liver biopsy. Additional laboratory findings may include acute kidney injury, leukocytosis, lactic acidosis, hyperuricemia, elevated ammonia levels, coagulopathy, and hypoglycemia. Ultrasonography is often normal, as the fatty infiltration is microvesicular. Therefore, MRI may be more sensitive. Liver biopsy is the gold standard for diagnosis but is usually not necessary.

2. Treatment: Multidisciplinary care is critical if AFLP is suspected or diagnosed. Early liaison with intensive care and hepatology specialists is recommended. Management consists of expedited delivery and supportive care. Liver transplant may be considered if liver function does not improve following delivery. The rate of recurrence in subsequent pregnancies is low unless a disorder of fatty acid oxidation is uncovered (eg, LCHAD deficiency).

TablesTop