Intrahepatic cholestasis of pregnancy: clinical guidelines

List of Abbreviations

Terms and Definitions

Alanine aminotransferase (ALT) is an enzyme from the transaminase group, which is mainly synthesized in liver and kidney cells, and partially in skeletal muscle, myocardium, lungs, and pancreas.

Aspartate aminotransferase (AST) is an enzyme present in all cells of the body, but predominantly in the myocardium and other muscle tissues, as well as in the liver, and to a lesser extent in the kidneys.

Gamma-glutamyl transferase (GGT) is an enzyme (a natural catalyst for chemical reactions) involved in amino acid metabolism. GGT is found in the cells of many organs characterized by the active release and uptake of various substances (absorption and secretion).

Bile acids are organic acids that are part of bile and represent the end products of cholesterol metabolism; they play an important role in fat digestion and absorption; they promote the growth and functioning of normal intestinal microflora.

Cholestatic hepatosis of pregnancy is a dystrophic liver lesion caused by increased sensitivity of hepatocytes to sex hormones and genetically determined enzymopathies, the functional manifestation of which is

— metabolic disorders of cholesterol and bile acids in hepatocytes, and as a consequence

— impairment of bile formation and bile outflow through the intralobular bile ducts.

Ursodeoxycholic acid (UDCA) is an epimer of chenodeoxycholic acid and is a hydrophilic, non-cytotoxic bile acid

Alkaline phosphatase (ALP) is a group of enzymes found in almost all tissues of the body, with predominant localization in the liver, bones, and placenta. Phosphatases in cells participate in reactions cleaving the phosphoric acid residue from its organic compounds.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Intrahepatic cholestasis of pregnancy (ICP) is a reversible, often hereditary, cholestatic liver disease specific to pregnancy, manifesting as pruritus, elevated liver transaminases, and blood total bile acid levels, manifesting at the end of the second or beginning of the third trimester of pregnancy and spontaneously resolving 2-3 weeks after delivery[1] ^[2] [1-8].

The clinical significance of ICP lies in the potential risk to the fetus (antenatal fetal death, spontaneous or iatrogenic premature birth, intrapartum asphyxia) [3,9-12].

[1] Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022

[2] Guidelines for Outpatient Care in Obstetrics and Gynecology, edited by V.N. Serov, G.T. Sukhikh, V.N. Prilepskaya, V.E. Radzinsky. 3rd revised and expanded edition. Moscow: GEOTAR-Media, 2016, 1135 p.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of this disease is multifactorial and not fully understood. Currently, three main groups of etiological mechanisms are distinguished: genetic, hormonal, environmental [11].

Genetic factors can explain familial and ethnic cases of ICP. Heterogeneous mutations in the ABCB4 gene encoding multidrug resistance protein 3 (MDR3) have been found in families in which women developed this condition during pregnancy [11]. The frequency of these mutations among European patients with ICP was 16% [13-16]. Mutations in other canalicular transporter genes in hepatocytes are also associated with the development of this disease.

A genetically determined increased sensitivity of hepatocytes and biliary canaliculi to sex hormones has been noted [17]. Congenital defects in the synthesis of enzymes responsible for transporting bile components from hepatocytes into the bile ducts are possible. Pregnant women with ICP are more frequently found to have gastrointestinal and endocrine system disorders [17].

Currently, polymorphisms of 6 canalicular transporter genes affecting the synthesis and transport of bile acids, transport of conjugated metabolites, drug resistance, etc., have been described. A recent microfluidic/microarray study in 12 women with ICP and 12 healthy controls showed that 20 genes potentially correlate with ICP. Among them, activation of the gamma-aminobutyric acid receptor (GABA-2) may indicate its role in the pathogenesis of pruritus in ICP [14].

It was noted that 93.8% of pregnant women with ICP used drugs with a potential hepatotoxic effect (systemic antibacterial drugs, systemic hormonal contraceptives) before or during pregnancy. According to some studies, a correlation has been found between the development of ICP and the intake of pregn-4-ene derivatives [11, 17].

Estrogens may play a role in the genesis of ICP, as evidenced by the development of this complication mainly in the third trimester when the concentration of these hormones in the blood reaches its peak, and a higher incidence is observed in women with multiple pregnancies. ICP may also be associated with changes in progesterone metabolism [11, 18].

The formation of a large amount of sulfated progesterone metabolites leads to the overload of hepatocyte transport systems in genetically predisposed women [18].

The manifestation of ICP occurs as a result of the combined action of genetically determined and congenital defects in the metabolism of bile components, exogenous and endogenous factors [11,17]. Risk factors for the development of ICP include GDM, preeclampsia [6,19], selenium and vitamin D deficiency [20], multiple pregnancy, maternal age over 35 years [17], as well as allergic/atopic reactions [21]. The probability of ICP recurrence in subsequent pregnancies is 60-70% [5,6].

An important risk factor is a hereditary predisposition to the development of this disease [6,9,17].

The main links in the pathogenesis of ICP are: excessive entry of bile elements into the blood, a decrease in the amount of secreted bile in the intestine, and the toxic effect of bile components on hepatocytes and biliary canaliculi [13,14,17,18,22].

1.3 Epidemiology of the Disease or Condition

The prevalence of ICP varies widely from 0.2 to 27% depending on race, ethnicity, and geographical location, being the second most common cause of jaundice in pregnant women (after viral hepatitis). This pathology is most frequently encountered in the Caucasus (up to 27.6%), Chile and Bolivia (15.1%), and Scandinavian countries (2.8%) ³ [10]. In European, Asian, North and South American, and Australian countries, the prevalence is less than 1% [22]. Seasonal fluctuations have been noted, with an increased incidence of ICP in Sweden, Finland, and Chile during the winter months [11]. This may indicate the contribution of environmental factors to the development of the disease [17].

1.4 Features of Coding the Disease or Condition

O26.6 - Liver disorders in pregnancy, childbirth and the puerperium

1.5 Classification of the disease or condition

• Mild degree. Pruritus is mild. Transaminase activity is elevated 2-3 times, alkaline phosphatase and gamma-glutamyl transferase levels are increased. Other clinical and laboratory signs of the disorder are absent. The risk of obstetric complications is minimal.

• Moderate degree. Pronounced skin pruritus. ALT and AST activity is increased 3-6 times, concentrations of cholesterol, ALP, and GGT are elevated, and hemostasis parameters are impaired. Ultrasound may reveal sludge in the gallbladder lumen. The most frequent form of the disease with potential fetal growth restriction.

• Severe degree. Pronounced skin pruritus. Significant increase in enzyme activity, laboratory signs of escalating coagulopathy, clinical presentation of gastroenterological disorders. Fetal distress. Continuation of pregnancy is hazardous for the mother and fetus.

Pruritus of pregnant women** and severity of ICP depending on bile acid levels [23]:

³ Obstetrics: National Guidelines / edited by G.M. Savelieva, G.T. Sukhikh, V.N. Serov, V.E. Radzinsky. - 2nd ed. - Moscow: GEOTAR-Media, 2018.

*The upper limit of normal bile acid concentration during pregnancy is 18 µmol/L [23].

** Pruritus of pregnant women is the main clinical symptom of ICP

1.6 Clinical presentation of the disease or condition

ICP typically debuts in the II-III trimesters, most frequently at 30-32 weeks of pregnancy [5,6,11,12].

The main symptom of ICP is skin pruritus (upon exclusion of other causes). Initially, it is localized predominantly on the soles and palms [5,6,11]. Subsequently, the skin pruritus becomes generalized [12]. In intensity, it can range from mild to agonizing and intolerable. It most often intensifies at night, leading to insomnia, fatigue, and emotional disorders [12].

Skin pruritus usually appears some time before abnormalities in laboratory parameters. Abdominal pain syndrome, nausea, and vomiting are not characteristic of ICP [11].

Objective examination reveals excoriations, jaundice of the sclera and skin [6,7]. Encephalopathy or other stigmata of liver failure, as well as hepatosplenomegaly, are not characteristic of ICP and require additional evaluation to rule out other liver diseases [11,12,17].

Jaundice is considered an inconsistent symptom of intrahepatic cholestasis of pregnancy (ICP). It is observed in 10-15% of cases due to conjugated bilirubin. Pronounced jaundice requires the exclusion of viral hepatitis [11,17].

Pregnancy complications

The main complications include preterm birth, fetal hypoxia, and intrauterine fetal demise, as well as neonatal respiratory distress syndrome [5-9,14]. Placental insufficiency is not characteristic of this disease^[1]. ICP accounts for 1.2% of preterm birth causes^[2]. Pregnant women with ICP also have a higher risk of developing preeclampsia and gestational diabetes mellitus, which requires blood pressure monitoring, proteinuria assessment, and gestational diabetes testing in accordance with clinical guidelines for these profiles [24].

Elevated bile acid levels in the blood of a pregnant woman with ICP can stimulate prostaglandin release, increase myometrial sensitivity to oxytocin and its contractility, which causes preterm birth in 12–44% of cases [25].

Bile acids are the most sensitive indicator of ICP, specifically an increased cholic-to-chenodeoxycholic acid ratio. Serum bile acid levels have important prognostic value [25]. The risk of complications in ICP statistically increases with early onset (before 33 weeks) of the disease [25,26].

According to various studies, in the group of patients with total serum bile acids > 100 µmol/L, intrauterine fetal demise occurred in 10-15% of cases, most frequently after 37 weeks [26,27], while there is no correlation between transaminase levels and stillbirth [24,28].

ICP can have an adverse effect on the fetal condition, leading to hypoxia, low birth weight, liver pathology, and respiratory distress syndrome in 10–44% of cases [3,6,9].

An increase in bile acid levels can be observed in the amniotic fluid, blood, and meconium of the fetus and newborn [25]. Meconium staining of the amniotic fluid is characteristic of patients with ICP [28,29].

In ICP, the rate of perinatal loss averages 4.7% [25]. The risk of antenatal fetal death in recurrent cholestasis with bile acid levels above 100 µmol/L is 4 times higher than in a physiological pregnancy [25] [24,28]. ICP in twin pregnancies has a more severe course compared to singleton pregnancies [30] and is associated with an increased risk of stillbirth [24,28].

The incidence of postpartum hemorrhage in ICP does not exceed that in physiological pregnancy [7], but in severe ICP it reaches 20%, which is associated with vitamin K deficiency. An increase in purulent-septic complications, primarily kidney and urinary tract infections, has also been noted^[3].

The maternal prognosis is favorable. ICP, even with recurrences during subsequent pregnancies, leaves no residual changes in the mother's liver^[4] [5,6].

The most unfavorable prognosis for the course of ICP is observed with pronounced jaundice and cytolytic syndromes, and early (25-27 weeks) onset of the disease [31].

^[1] Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. Green-Top Guideline No 43.2011.

^[2] American Gastroenterological Association Institute guidelines on the medical management of gastrointestinal diseases during pregnancy. Clinical Gastroenterology and Hepatology. 2008; 6:426-31

^[3]  Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. Green-Top Guideline No 43.2011.

^[4] Tram T. Tran, et al. ACG Clinical Guideline: Liver Disease and Pregnancy. The American Journal of Gastroenterology.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

- pruritus (itching);

- elevated total blood bile acids >19 µmol/L [23];

- the diagnosis is considered confirmed if it meets the regulated criteria following antenatal treatment and normalization of liver function tests in the postpartum period.

Differential diagnosis

ICP can be diagnosed only in the absence of other causes that can cause liver damage [5,6,11,17]. First of all, it is necessary to exclude diseases in which the probability of extremely unfavorable maternal and fetal outcomes is high (see Appendix B) [11,17].

2.1 Complaints and Anamnesis

The main symptom of ICP is pruritus (when other causes are excluded). Initially, it is localized predominantly on the soles and palms^[1]. Then the itching becomes generalized. In intensity, it can range from mild to "excruciating" or "unbearable." It often intensifies at night, leading to insomnia, fatigue, and emotional disorders [5,6,11,17]. Pruritus usually appears some time before laboratory abnormalities. Jaundice is an inconsistent symptom. It is observed in 10-15% of cases due to conjugated bilirubin [11,17].

• Pregnant women with suspected ICP (or established ICP) are recommended a thorough medication history review to rule out drug-induced liver injury [6,11,17].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

^[1] Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. Green-Top Guideline No 43.2011.

2.2 Physical Examination

Comment: Self-monitoring of fetal movements is an accessible, cost-effective, and important method for the patient to monitor fetal condition, which in some cases prevents antenatal fetal death. This method is recommended for all pregnant women, but given the higher risk of antenatal fetal death in patients with ICP, special attention should be paid to it.

^[1] Tram T. Tran, et al. ACG Clinical Guideline: Liver Disease and Pregnancy. The American Journal of Gastroenterology.

2.3 Laboratory Diagnostics

Comments: patients with mild ICP and blood bile acid levels within 19-39 µmol/L should undergo weekly testing as they approach 38 weeks. When blood bile acid levels are within 40-99 µmol/L and upon reaching 35 weeks of gestation, weekly determination is necessary. An increase in bile acid levels above 100 µmol/L requires hospitalization and resolution of the issue regarding extracorporeal correction methods and/or delivery [42].

Comments: An elevation of total bile acids >19 µmol/L is a diagnostic criterion for ICP [17,25,26]. A high-risk factor for antenatal fetal death is considered to be total bile acid levels exceeding 100 mmol/L [12,25,26]. Transaminases (AST, ALT) are elevated in 80% of cases. Serum transaminases can reach values exceeding 1000 U/L [45]. Their elevation correlates with the severity of ICP [46]. Elevated total and conjugated bilirubin levels, which occur in 10-20% of pregnant women, may indicate severe forms of the disease [6,17]. GGT levels remain within normal limits or are slightly elevated. GGT levels may be elevated in ABCB4 gene mutations [13,14].

Comments: Elevated ALP levels are uninformative during pregnancy, ^{[1] [2]} as they are caused by numerous placental isoforms^[3] [21].

Comments: Prothrombin time generally remains within normal limits. Its prolongation may occur in vitamin K deficiency. Hyperglycemia may develop [17].

Comment: An increase in transaminase levels may occur on days 1–2 after delivery due to enhanced cytolysis. Postpartum cytolysis against the background of vitamin K deficiency can lead to the development or manifestation of coagulopathy, manifested by prolonged prothrombin time and aPTT [7]. Pruritus resolves and laboratory parameters normalize within 7–10 days postpartum [11]. Several authors suggest performing a follow-up laboratory test 6–8 weeks after delivery to rule out pathological liver changes [45].

¹⁰   Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. Green-Top Guideline No 43.2011.

¹¹ Obstetrics: National Guidelines I ed. by G.M. Savelieva, G.T. Sukhikh, V.N. Serov, V.E. Radzinsky. 2nd ed. Moscow: GEOTAR-Media, 2018.

^[3] Tram T. Tran, et al. ACG Clinical Guideline: Liver Disease and Pregnancy. The American Journal of Gastroenterology.

2.4 Instrumental Diagnostics

Comment: Cholelithiasis is the most common finding [22]. In the absence of prior pathology, changes in the liver parenchyma or dilation of the bile ducts are not characteristic of ICP [5, 6, 17].

Comment: Abdominal MRI without contrast enhancement can be performed in the second and third trimesters of pregnancy. Abdominal CT has teratogenic effects and is associated with the development of childhood hematological malignancies, but it can be performed using a minimal radiation protocol (2–5 rad).

• Liver biopsy (percutaneous liver biopsy or ultrasound-guided liver biopsy) is recommended in extreme cases when other methods fail to provide conclusive data. This is the least safe method, as it requires intracavitary intervention, but it is the most accurate [5, 6, 11, 17, 45, 53].

LOE CLOE 5Level of recommendation strength C (level of evidence - 5).

Comment: ICP poses the greatest danger to the fetus, primarily associated with an increased rate of stillbirth. However, Doppler ultrasound of uteroplacental blood flow and antenatal cardiotocography are not reliable diagnostic methods for preventing fetal death in ICP and cannot be considered specific for predicting stillbirth [27, 54]. At the same time, these tests reflect the overall fetal condition and serve as a provisional "safeguard" for the physician and a monitoring tool in the absence of other reliable tests [3, 4, 9, 55]. Bile acid values in the range of 19–99 µmol/L in the absence of other risk factors carry general population risks of stillbirth. The pathophysiology of stillbirth is not fully understood; presumably, bile acids cause acute fetal hypoxia as a consequence of arrhythmia or acute vasospasm of the placental vessels [24].

2.5 Other Procedures

• All patients with suspected ICP are recommended to undergo an evaluation (examination, consultation) by a dermatologist to rule out skin diseases that may manifest as pruritus [17, 32].

GCR BLEL 3Recommendation Grade B (Level of Evidence — 3).

Comment: If ICP symptoms persist 6–8 weeks postpartum, other chronic liver diseases should be considered, such as primary biliary cholangitis, primary sclerosing cholangitis, ABCB4 deficiency, or chronic hepatitis C, in which pruritus may appear in the final weeks of pregnancy ^[1]. Indications for further workup and differential diagnosis include: elevated aminotransferase activities (ALT, AST), blood concentrations of total and conjugated bilirubin more than 2–3 times the upper limit of normal, suspected diabetes mellitus, presence of dermatitis, scabies, eczema, and other dermatological conditions [11, 17].

^[1] American Gastroenterological Association Institute Guidelines on the Medical Management of Gastrointestinal Diseases during Pregnancy. Clinical Gastroenterology and Hepatology. 2008; 6:426–31.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Medical treatment

Comment: #UDCA** belongs to bile acid preparations and is prescribed at a daily dose of 10–15 mg/kg [62–64]. The daily dose can be taken twice a day (preferably in the second half of the day) or once at bedtime. Therapy is prescribed for 2 weeks, with follow-up determination of blood AST and ALT activity and blood bile acid levels; if laboratory parameters normalize, the issue of discontinuing therapy is decided, and if laboratory signs of cholestasis persist, therapy is continued until delivery. The use of #UDCA** leads to a reduction in pruritus and an improvement in maternal laboratory parameters within several days in 67–80% of cases [59]. It is hypothesized that the mechanism of action of this group of drugs is related to the replacement of the hydrophobic bile acid pool in bile [57, 59, 60]. This may reduce toxic damage to hepatocyte membranes and enhance the transport of bile acids from the fetus across the placenta. A meta-analysis including 12 RCTs involving 662 pregnant women demonstrated the efficacy and safety of #UDCA** and a reduction in adverse effects on the maternal and fetal organisms [58]. Another meta-analysis based on pooled data revealed total disappearance of pruritus under the influence of #UDCA** (OR = 0.23; 95% CI 0.13–0.55), reduction of pruritus (OR = 0.27; 95% CI 0.10–0.50), as well as a reduction in ALT, AST, and total bile acid levels compared to controls (placebo groups, patients receiving bile acid sequestrants, #dexamethasone**, ademetionine**, or untreated pregnant women) [65]. If the effect is insufficient, the dose of #UDCA** can be increased to 25 mg/kg/day [64]. #UDCA** does not improve pregnancy outcomes, but serves as a method for relieving pruritus and has limited utility [27, 66].

Comment: Combined administration regimen: ademetionine** 500 mg twice a day, #UDCA** 250 mg 3 times a day until delivery [82].

Ademetionine** belongs to the ATC group "other drugs for the treatment of gastrointestinal diseases and metabolic disorders". According to the product information, SAMe** breaks down fats and promotes their elimination from the liver, participates in the synthesis of biologically active substances and phospholipids, and exhibits regenerative and detoxifying properties. By the end of the 1st week of use, it also exhibits a pronounced antidepressant effect [11]. The bioavailability of oral SAMe** is low, therefore its parenteral administration in the form of intravenous infusions is recommended [11, 31, 67, 68]. The duration of therapy is determined individually by an obstetrician-gynecologist and a gastroenterologist under dynamic clinical and laboratory monitoring.

• The administration of vitamin K group preparations (ATC B02BA) is recommended only in the presence of signs of impaired fat absorption (steatorrhea) and prolonged prothrombin time [28, 70].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

3.2 Other Treatment

• Efferent therapy methods (extracorporeal detoxification - plasmapheresis) for intrahepatic cholestasis of pregnancy (ICP) are recommended for pregnant women with ICP in the following situations: pronounced clinical presentation of ICP, lack of a sustained clinical response to traditional medical therapies; significant elevation of liver enzymes: ALT, AST, ALP; bile acids, cholesterol, total and conjugated bilirubin; and hemostatic disorders manifested by the activation of intravascular coagulation [71, 72].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: There are no high-level evidence studies regarding efferent therapy methods for ICP.

• In cases of early-onset ICP, it is recommended to perform fetal respiratory distress syndrome (RDS) prophylaxis at 24–34 weeks of gestation [6, 59, 78, 79].

GPP ALE 1Grade of Recommendation A (Level of Evidence 1)

For the prevention of fetal RDS, #betamethasone** is recommended intramuscularly at a dose of 12 mg twice with a 24-hour interval, or #dexamethasone** intramuscularly at a dose of 6 mg 4 times with a 12-hour interval (total dose of 24 mg) over 48 hours [80, 81].

GPP CLE 4Grade of Recommendation C (Level of Evidence 4)

Comments: Shorter dosage intervals than those described above, often referred to as an «accelerated course», even when delivery appears imminent, have not demonstrated potential benefits. #Dexamethasone** and #betamethasone** are off-label drugs in the context of fetal RDS prevention, and written informed consent from the patient must be obtained prior to their use.

— in mild ICP (total serum bile acid level of 19–39 µmol/L), the risk of stillbirth remains low, but prolongation of pregnancy beyond 40 weeks of gestation is not recommended [9, 28, 73];

— delivery at 38–39 weeks for pregnant women with moderate ICP (total serum bile acid level of 40–99 µmol/L) and no other risk factors [9, 28, 73, 74].;

— delivery at 35–36 weeks for pregnant women with severe ICP (total serum bile acid level of 100 µmol/L or higher) and no other risk factors [9, 28].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• Pre-induction and induction of labor (using antigestagens and prostaglandins) are not contraindicated and are recommended to be carried out in accordance with established protocols [69].

LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)

• ICP is not a factor that determines the mode of delivery. The decision regarding the choice of delivery mode is recommended to be determined by obstetric practice algorithms [75].

GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)

• Continuous intrapartum monitoring using fetal cardiotocography is recommended during labor for dynamic fetal condition assessment [28, 60].

GPP CLE 5Grade of Recommendation C (Level of Evidence 5)

[1] Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022

[2] Serov V.N., Sukhikh G.T., eds. Rational pharmacotherapy in obstetrics, gynecology and neonatology. A guide for practitioners, vol. 1. Obstetrics, neonatology. 2nd ed. Moscow: Litterra; 2010 (in Russ.)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

• Patients with a history of ICP are recommended to minimize the intake of the following medications: systemic hormonal contraceptives (ATC group G03A), sex hormones, and modulators of the genital organ function (primarily estrogens and progestogens) to reduce the drug load, considering their predominant metabolic pathway through the hepatic barrier [76].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

6. Organization of Medical Care

It is necessary to timely resolve the issue of hospitalization of the pregnant woman in an inpatient facility for treatment, as well as determination of the timing and method of delivery at the outpatient stage [11, 59]. Hospitalization should be carried out in Level 3 hospitals in cases of early-onset ICP (before 34 weeks); at later stages, hospitalization in Level 2 hospitals is possible.

Indications for hospitalization:

1) Early onset of the disease (less than 26 weeks).

2) Inefficacy of conservative therapy for 7 days.

3) For the purpose of performing efferent therapy methods.

4) Occurrence of pregnancy complications.

5) Persistent symptoms of cholestasis or its relapse after treatment at 36 weeks or later for delivery.

Discharge criteria:

- Satisfactory condition of the pregnant/postpartum woman

- Normalization or steady downward trend in liver transaminases (ALT and AST)

- Normalization or steady downward trend in total bile acids

- Satisfactory fetal condition according to ultrasound Dopplerometry and cardiotocography in the pregnant woman

7. Additional Information

Not applicable.

Criteria for Evaluating the Quality of Medical Care

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Authors

1) Khodjaeva Zulfiya Sagdullaevna - Dr. of Sci. (Med.), Professor, Deputy Director for Scientific Work of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

2) Klimenchenko Natalya Ivanovna - Cand. of Sci. (Med.), Associate Professor, Senior Researcher at the 1st Obstetric Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

3) Shmakov Roman Georgievich - Dr. of Sci. (Med.), Professor, Director of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

4) Artymuk Natalia Vladimirovna - MD, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova, Kemerovo State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Siberian Federal District (Kemerovo).

No conflict of interest.

5) Belokrinitskaya Tatyana Evgenyevna - MD, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Advanced Training and Professional Retraining, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Far Eastern Federal District (Chita).

No conflict of interest No conflict of interest

6) Protopopova Natalia Vladimirovna - MD, Professor, Honored Doctor of the RF, Head of the Department of Obstetrics and Gynecology, Irkutsk State Medical Academy of Postgraduate Education - Branch of the Russian Medical Academy of Continuous Professional Education (Irkutsk)

No conflict of interest.

7) Nikolaeva Anastasia Vladimirovna - PhD, Chief Physician, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

8) Gorina Ksenia Alekseevna - Junior Researcher, 1st Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

9) Baranov Igor Ivanovich - MD, Professor, Head of the Department of Scientific and Educational Programs, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

10) Pavlovich Stanislav Vladislavovich - PhD, Associate Professor, Academic Secretary, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

11) Khlanovskaya Marina Gennadyevna - Clinical Resident, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

12) Dolgushina Natalia Vitalievna - MD, Professor, Deputy Director - Head of the Department of Scientific Activity Organization, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).

No conflict of interest.

13) Filippov Oleg Semenovich - MD, Professor, Professor of the Department of Obstetrics and Gynecology, Faculty of Advanced Training for Physicians, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Deputy Director of the Department of Medical Care for Children and Obstetrics Services of the Russian Ministry of Health (Moscow)

No conflict of interest.

14) Adamyan Leila Vagovna - MD, Professor, Academician of the Russian Academy of Sciences, Deputy Director for Science, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health (Moscow).

No conflict of interest.

15) Tskхай Vitaly Borisovich - MD, Professor, Head of the Department of Perinatology, Obstetrics and Gynecology, Krasnoyarsk State Medical University named after Professor V.F. Voyno-Yasenetsky (Krasnoyarsk).

No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

1. obstetricians-gynecologists

2. students; residents, postgraduate students in obstetrics and gynecology

3. educators, researchers

Table 1. Scale for evaluating levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for evaluating levels of evidence (LE) for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnosis, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Related documents.

• Federal Law No. 323-FZ dated November 21, 2011 "On the Fundamentals of Health Protection of Citizens in the Russian Federation".

• Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On Approval of Criteria for Assessing the Quality of Medical Care".

• Order of the Russian Ministry of Health No. 1130n dated October 20, 2020 "On Approval of the Procedure for Providing Medical Care in the Field of 'Obstetrics and Gynecology'" (Registered with the Russian Ministry of Justice on November 12, 2020, No. 60869)

• Obstetrics: National Guidelines / ed. by G.M. Savelieva, G.T. Sukhikh, V.N. Serov, V.E. Radzinsky. - 2nd ed. - M.: GEOTAR-Media, 2018.

• Guide to Outpatient and Polyclinic Care in Obstetrics and Gynecology, edited by V.N. Serov, G.T. Sukhikh, V.N. Prilepskaya, V.E. Radzinsky. 3rd revised and expanded edition. M.: GEOTAR-Media, 2016

• Serov V.N., Sukhikh G.T., eds. Rational Pharmacotherapy in Obstetrics, Gynecology and Neonatology. A Guide for Practitioners, vol. 1. Obstetrics, Neonatology. 2nd ed. M.: Litterra; 2010

• American Gastroenterological Association Institute Guidelines on the Medical Management of Gastrointestinal Diseases in Pregnant Women. Clinical Gastroenterology and Hepatology. 2008; 6:426-31

• Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. Green-Top Guideline No 43.2011.

• Tram T. Tran, et al. ACG Clinical Guideline: Liver Disease and Pregnancy. The American Journal of GASTROENTEROLOGY

• American College of Obstetricians and Gynecologists. ACOG committee opinion no. 764: Medically indicated Late-Preterm and EarlyTerm Deliveries. Obstet Gynecol 2019.

Appendix B. Physician Action Algorithms

Differential diagnosis of intrahepatic cholestasis of pregnancy [12]

* Summary table on the management of patients with ICP

Appendix C. Patient Information

Intrahepatic cholestasis of pregnancy is a complication of the second half of pregnancy associated with impaired liver function. In this condition, an excessive amount of bile acids enters the bloodstream.

The main symptom of this condition is pruritus (itching). If it appears, you should consult a doctor as soon as possible, who will prescribe a biochemical blood test with liver function panels and mandatory determination of bile acid levels. An elevated bile acid level in the pregnant woman's blood is the main diagnostic criterion for this condition. Other laboratory abnormalities may also occur, which require differential diagnosis with other diseases and complications of pregnancy.

Intrahepatic cholestasis of pregnancy is in some cases accompanied by quite severe pruritus, and with high bile acid levels, it can lead to deterioration of the fetus's condition, up to intrauterine demise if appropriate treatment and dynamic monitoring are absent. Therefore, one must remember the need to strictly follow the doctor's recommendations. You should monitor the frequency and character of fetal movements and regularly undergo cardiotocography and Doppler studies (ultrasound Doppler flowmetry of uteroplacental blood flow).

Upon establishing the definitive diagnosis, the doctor prescribes treatment with ursodeoxycholic acid preparations. Therapy is carried out under careful regular monitoring of the condition of the pregnant woman and the fetus. In some cases, hospitalization in a maternity hospital for examination, treatment, and monitoring is indicated. Ademetionine may be prescribed as an additional drug. Both of these medications are approved for use in pregnant women and do not exert adverse effects on the fetus.

In the absence of a sufficient effect from drug therapy, extracorporeal detoxification methods can be used—plasmapheresis, which is also not contraindicated in pregnant women. Its efficacy has been proven by a number of studies.

In intrahepatic cholestasis of pregnancy, delivery is carried out according to obstetrical indications, meaning spontaneous labor is not contraindicated. However, the timing and mode of delivery for each specific woman are determined individually, since in most cases labor should be induced earlier than 40 weeks (37–38 weeks) due to the increased risk of intrauterine fetal demise as gestational age increases. Depending on the condition of the birth canal, the doctor may propose a method for cervical ripening and labor induction.

Due to the increased risk of hemorrhagic and hypoxic complications, newborns with intrahepatic cholestasis require careful monitoring, timely examination, and treatment as indicated.

In the postpartum period, treatment is not required, as rapid normalization of laboratory parameters occurs. However, one should keep in mind the higher risk of developing intrahepatic cholestasis in subsequent pregnancies.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

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