Intrahepatic cholestasis of pregnancy
P.V. Kozlov1, I.V. Samsonova2
1Pirogov Russian National Research Medical University, Moscow, Russian Federation
2City Clinical Hospital No. 52, Moscow, Russian Federation
Intrahepatic cholestasis of pregnancy (ICP) is a reversible form of cholestasis which occurs in pregnant women and manifests with itchy skin, elevated serum bile acids and/or liver enzymes, and postnatal spontaneous resolution (within 2 to 6 weeks) without any other causes. The paper addresses recent data on the etiology, pathogenesis, and diagnostic markers of ICP. Pregnancy management algorithms (including fetal functional monitoring) to minimize the risks of prenatal morbidity and mortality are described. Diagnostic criteria for intrahepatic cholestasis of pregnancy, the importance of the changes in liver enzyme activity, and differential diagnostic aspects of pregnancy complications associated with higher risks of maternal death (i.e., preeclampsia, acute fatty liver of pregnancy, HELLP syndrome etc.) are highlighted. Pharmacotherapy for ICP as well as obstetric management approaches including terms and methods of delivery are discussed considering recent domestic and fore ign published data and guidelines provided by professional healthcare societies.
Keywords: pregnancy, cholestasis of pregnancy, intrahepatic cholestasis, liver enzymes, treatment.
For citation: Kozlov P.V., Samsonova I.V. Intrahepatic cholestasis of pregnancy. Russian Journal of Woman and Child Health. 2019;2(4):274–279.
Intrahepatic cholestasis of pregnancy (ICP) is a reversible form of cholestasis which occurs in pregnant women and manifests with itchy skin, elevated serum bile acids and/or liver enzymes, and postnatal spontaneous resolution (within 2 to 6 weeks) without any other causes. In multi-ethnic population, 0.7% of pregnancies are complicated by ICP . ICP pathogenesis is mediated by genetic, hormonal, and environmental factors. Thus, ICP complicates 1.2% to 1.5% of pregnancies in Indo-Asian and Pakistan-Asian regions, 2.4% in Chile, and 2.8% in Scandinavian countries. The highest rate of ICP is reported in Araucanian Indians. In European countries, ICP prevalence is less than 1% .
Risk factors for ICP are genetics, chronic liver diseases (including hepatitis C and cholelithiasis), medications, multiple pregnancy, and in vitro fertilization . The most important risk factors are genetic predisposition and anamnestic ICP. In these cases, ICP will recur in 45% to 90% of future pregnancies .
The diagnosis of ICP involves evaluation of clinical presentations as well as laboratory and instrumental tests . Diagnostic criteria are itchy skin (that cannot be accounted for by other causes) and elevated serum liver enzymes and bile acids. In ICP, itchy skin generally occurs after 24 weeks of pregnancy in 23% of pregnant women and often remains the only symptom for a long time. Palms, foots, and abdomen are typical localizations of itch and scratches. Itching is more severe at night since bile production is an ongoing process and at nights, almost all bile acid pool (~ 4 g) remains in the gallbladder. As a result, the quality of life of pregnant women reduces. Itching can occur several days before the elevation of liver markers . Mild jaundice due to conjugated bilirubin is reported in 10% of cases. Pale stool (steatorrhea) and dark urine are very rare symptoms of cholestasis. However, ICP is not the leading cause of jaundice and itching, therefore, additional tests are required to exclude other causes .
Early laboratory (biochemical) markers and diagnostic criteria for ICP in asymptomatic disease are elevated serum bile acids and/or liver enzymes and, later, conjugated bilirubin. In most pregnant women, 1 or 2 liver enzymes are elevated . The level of bile acids is the most sensitive ICP marker which can increase before other liver enzymes. During pregnancy, serum levels of bile acids are within reference ranges seen in non-pregnant women but can slightly elevate in the third trimester due to the changes in bile acid metabolism resulting from high levels of circulating estrogens thus indicating the risk of cholestasis in healthy pregnancy. Isolated increase in serum bile acids and bilirubin occurs rarely, however, their normal levels do not exclude ICP. The levels of bile acids and liver enzymes should be evaluated considering fasting reference ranges for pregnant women since plasma levels of bile acids significantly increase after a meal. The upper limit of normal (ULN) of liver enzymes in pregnant women is 20% less than in non-pregnant women. Bile acid concentration of < 14 μmole and alanine aminotransferase (ALT) concentration of < 32 IU/l should be considered as normal ones [4, 5].
Differential diagnosis of ICP
Differential diagnosis of ICP includes skin diseases (i.e., eczema, atopic dermatitis, pyoderma, folliculitis etc.), pregnancy complications (i.e., preeclampsia, HELLP syndrome characterized by Hemolysis, Elevated Liver enzymes, and a Low Platelet count, acute fatty liver of pregnancy), cholelithiasis, hepatitis A, B, and C, infectious mononucleosis (Epstein-Barr virus) and cytomegalovirus infection, primary biliary cirrhosis (antimitochondrial antibodies, anti-smooth muscle antibodies) (see Table 1) .
Drug-induced cholestasis affecting 1/10,000 to 1/100,000 individuals who receive medications at therapeutic doses is of particular importance (see Fig. 1) [5, 6].
Drug-induced liver injury (DILI) is accounted for by downregulation or dysfunction of hepatobiliary transporters (resulting in impaired bile secretion at hepatocellular level) or induction of idiosyncrasy- or hypersensitivity-like inflammation at cholangiocellular level. Individual susceptibility to cholestasis induced by various medications can be mediated by genetically determined expression of hepatobiliary transporters and enzymes involved in biotransformation. DILI is classified into three categories (based on the elevation of major liver enzymes), i.e., hepatocellular, cholestatic, and mixed. Hepatocellular DILI is characterized by ALT more than 5 times ULN and ALT/alkaline phosphatase (ALP) ratio more than 5 times ULN. Cholestatic DILI is characterized by ALP more than 2 times ULN and ALT/ALP ratio less than 2 times the lower limit of normal (LLN). Cholestatic liver disease accounts for 30% of drug-induced hepatomegaly. In general, cholestatic DILIs are less severe but resolved significantly slower than hepatocellular DILIs. Mixed DILIs are characterized by both ALT and ALP more than 2 times ULN and ALT/ALP ratio 2 to 5 times ULN .
Offending drug discontinuation and careful monitoring of clinical manifestations and biochemical parameters are recommended in verified DILI (III/C2). Ursodeoxycholic acid (UDCA) and corticosteroids are often effective for DILIs, but there are no well-controlled studies supporting their use (III/С2) .
In ICP, concentrations of liver enzymes and/or bile acids should be measured at least once a week before the delivery. In persistent itchy skin and normal biochemical parameters, liver enzymes and bile acids should be measured at least once a week until their levels increase or the itching resolves . Improvement of liver enzymes most likely indicates incorrect diagnosis of ICP.
Clinical relevance and perinatal risks in ICP-complicated pregnancy
ICP is associated with potential risks of preterm labor (4-12%), in particular, iatrogenic one (7-25%), increased caesarian section rate (from 10% to 36%), meconium passage (from 7.6-12.0% to 25.0-44.3% in full-term pregnancy and from 3% to 18% in preterm birth), and postpartum bleeding (from 2% to 22%) [7, 8]. The risk of perinatal complications including preterm labor, meconium passage, and fetal asphyxia is significantly higher in early (before 34 weeks of pregnancy) itching onset and bile acid concentration > 40 μmole/l . Thus, the rate of meconium passage linearly increases by 19.7% for every 10 μmole/l of bile acids and is 10-44% at the concentration of bile acids > 40 μmole/l. The risk of stillbirth in ICP is 0-11%; more than 70% of stillbirths occur before 37 weeks of pregnancy [7-10]. Reliable biochemical criteria as well as specific methods of antenatal fetal surveillance to predict stillbirth are missing. Fetal death is generally sudden and not associated with the criteria of placental insufficiency (including intrauterine growth restriction, oligohydramnios, and pathological Doppler signs).
Fetal surveillance involves subjective assessment of fetal movements, ultrasound echography, cardiotocography, and amnioscopy (after 36-37 weeks of pregnancy in verified ICP). Prognostic value of ultrasound echography and cardiotocography for fetal surveillance and the assessment of perinatal outcome is weak .
In ICP, prenatal (at 36 weeks of pregnancy) hospital admission is recommended to address childbirth method and terms (including labor induction). Evidence base for immediate (preterm) delivery in ICP is limited, however, inducing labor in severe cholestasis with significantly elevated liver enzymes and bile acid concentration > 40 μmole/l is a fairly common practice [5, 7]. When discussing delivery, parents should be warned that perinatal complications cannot be exactly predicted in ICP; preterm delivery is therefore useful to reduce the risk of stillbirth. In addition, neonatal intensive care may be required. Thus, after induction of labor, the rates of admission to neonatal intensive care units for infants born at 37, 38, and 39 weeks are 7-11%, 6%, and 1.5%, respectively. Decision about delivery should be based both on laboratory tests and other risk factors as no strong correlation between liver enzyme levels and fetal outcomes was revealed. Final decision about childbirth method and terms should be made after providing detailed information on fetal risks associated with induction of labor and potential fetal deterioration in prolonged pregnancy .
When itching or liver enzyme elevation occur, pharmacotherapy should be discontinued as soon as possible. In particular, medications commonly reported to induce cholestasis (e.g., erythromycin, amoxicillin plus clavulanic acid etc.) should be stopped.
Water-soluble creams and gels containing menthol temporally reduce itch intensity and are considered safe during pregnancy. However, evidences of their efficacy are still missing. Temporary effect is possible.
UDCA reduces itch intensity and improves liver functions. UDCA replaces more hydrophobic endogenous bile acids in bile and prevents hepatocyte membrane injury. UDCA is characterized by pleiotropic, cytoprotective, antioxidant, and antifibrogenic effects, reduces hepatocyte susceptibility to pro-inflammatory agents, and improves lipid spectrum. Combination of UDCA and vitamin E provides cytoprotective and metabolic effects, decreases apoptosis rate and serum transaminase activity, and improves circulating adiponectin level . In cholesterol-associated diseases of biliary tract (i.e., biliary sludge, cholecystolithiasis, gallbladder cholesterolosis etc.), replacement ursotherapy significantly reduces cholesterol level and resolves biliary sludge. In pregnant women, UDCA is prescribed for clinically manifest cholestatic liver diseases in the second and third trimesters of pregnancy (I/В1). In ICP, UDCA decreases itch intensity and liver enzyme concentrations (I/В1) [6, 13, 14]. However, no reliable decline in perinatal mortality was reported . Recommended dosage of UDCA is 10 mg/kg of body weight daily. Initial dose may be 1 g a day (250 mg 4 times a day) and may be increased to 1.5 g a day. UDCA is best taken with or after food. No adverse reactions either in the mothers or the children were reported .
Antihistamines (H1 blockers) can produce beneficial sedative effect when taking at bedtime but have no significant impact on itch intensity .
Ademetionine is a metabolite of methionine that is produced in the course of ATP-dependent reaction catalyzed by methionine adenosyltransferase. This metabolite is involved in transmethylation, transsulfuration, transamination, and decarboxylation. Methylation is required to synthesize endogenous phosphatidylcholine in hepatocytes. Ademetionine is the precursor of cysteine, taurine, and glutathione in transsulfuration pathway. Ademetionine reduces the toxicity of bile acids in the hepatocyte by their conjugation and sulfation. Conjugation with taurine improves solubility of bile acids and their elimination from the hepatocyte. Taurine-conjugated bile acids are more soluble and readily removed from the hepatocyte. Sulfation of bile acids promotes their urinary elimination as well as their passage through the hepatocytic membrane and biliary excretion. Sulfated bile acids protect liver cell membranes from the toxic effect of non-sulfated bile acids (their high levels are found in hepatocytes in intrahepatic cholestasis). Ademetionine is the methyl-group donor in the synthesis of membrane phospholipids, neurotransmitters, nucleic acids, and proteins in transmethylation reactions (85% of these reactions occur in the liver). In ICP, ademetionine reduces itch intensity and liver enzyme concentration and provides choleretic and hepatoprotective effects continuing up to 3 months after stopping the treatment. The recommended dosage regimen for ademetionine is 400-800 mg daily (1 or 2 bottles) administered intravenously for 2 weeks. The maintenance daily dosage is 800-1600 mg per oral for 2-4 weeks [5, 16]. This agent is contraindicated in the first and second trimesters of pregnancy.
Corticosteroids are not considered a first-line treatment for cholestasis. Randomized studies on the efficacy of these agents are limited. Some authors recommend 10 mg of peroral dexamethasone for 7 days with a 3-day interval [5, 16]. Prednisolone is safe during the second and third trimesters of pregnancy and breastfeeding, however, its use in the first trimester of pregnancy increases the risk of cleft palate .
Vitamin K. ICP results from malabsorption of edible fat due to inadequate secretion of bile acids in gastrointestinal tract. Increased fat excretion in ICP can be subclinical (but with excess fat in feces) or clinical (steatorrhea) thus affecting vitamin K absorption that is required for the synthesis of coagulation factors II, VII, IX, and X. Women with fat malabsorption (in particular, as a result of biliary obstruction or liver diseases) may develop vitamin K deficiency. Water-soluble vitamin K (menadione sodium bisulfite) can be prescribed for ICP and prolonged prothrombin time in doses 5-10 mg daily after 34 weeks of pregnancy till childbirth to reduce the risk of postpartum bleeding by more than 3 times (III/С2). The risks and benefits to the mother and to the child should be weighed [5, 6]. In cholestasis, steatorrhea, or established low levels of fat-soluble vitamins, intake of A, E, and K vitamin complex is recommended (III/С2) .
Improvement of liver enzyme levels after childbirth confirms a diagnosis of ICP. Puerperant women with ICP require blood biochemistry within 7-10 days after childbirth to confirm the diagnosis. This test should be repeated in 6 and 8 weeks after childbirth to assess dynamic changes in the levels of liver enzymes and/or bile acids [5, 16]. If symptoms do not improve (or even progress) after childbirth, other chronic liver diseases (i.e., primary biliary cirrhosis, primary sclerosing cholangitis, chronic hepatitis C etc.) accompanied by itchy skin in the last few weeks of pregnancy should be considered.
Puerperant women with ICP should avoid estrogen containing contraceptives which provoke itching in 10% of women.
In view of a progressive increase in the maternal age at childbirth and extragenital comorbidities, early diagnosis of hepatic and biliary disorders as well as rational obstetric management are important and require differential approach. Some pregnancy complications, i.e., preeclampsia or HELLP syndrome, present with non-specific symptoms of liver dysfunction. Therefore, knowledge of differential diagnostic algorithms and obstetric management significantly reduces the risks of maternal and perinatal morbidity and mortality (see Fig. 2).
About the authors:
1Pavel V. Kozlov — MD, PhD, professor of the Department of Obstetrics and Gynecology, ORCID iD 0000-0002-9916-6128;
2Inna V. Samsonova — MD, PhD, Deputy Head Doctor for Medical Work, ORCID iD 0000-0002-1228-1765.
1Pirogov Russian National Research Medical University. 1, Ostrovityanov str., Moscow, 117437, Russian Federation.
2City Clinical Hospital No. 52. 3, Pekhotnaya str., Moscow, 123182, Russian Federation.
Contact information: Pavel V. Kozlov, e-mail: firstname.lastname@example.org. Financial Disclosure: no authors have a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 21.08.2019.
This work is licensed under a Creative Commons «Attribution» 4.0 License.