The Microbiome Composition in Women With Recurring Intrahepatic Cholestasis of Pregnancy (ICP)

Study Overview
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Brief Summary
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This is an exploratory non-therapeutic study to study the microbiome patterns during pregnancy in women with ICP in order to identify specific bacterial strains for further product development.

Detailed Description
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Intrahepatic Cholestasis in Pregnancy (ICP) is a disease that appears in the later stage of pregnancy with itching (pruritus) and increased risk of fetal complications. It is the most prevalent pregnancy-specific liver disease, affecting between 1 and 20 % of all pregnant women, depending on ethnicity and geographic location. The condition is associated with an increased risk of adverse fetal outcomes, including preterm labour and intrauterine death. Further, ICP is associated with an increased risk for pre-eclampsia, thyroid disease, diabetes and cancer. ICP is typically present during the third trimester, when the serum concentrations of progesterone and estrogens reach their peak, and also, the time when the gut barrier has an increased permeability. In ICP subjects, both altered progesterone and bile acid metabolism is observed. The underlying etiology for ICP is unknown, but there are indications that the gut microbiota may be involved. It has become increasingly clear that the gut microbiota is associated with metabolic diseases and has an important function in metabolizing endogenous and dietary metabolites. Bile acids are metabolized by the gut microbiota by deconjugation and production of secondary metabolites, ursodeoxycholic acid (UDCA) being one example of a secondary bile acid produced by the microbiota. Bile acids are produced from cholesterol by a series of hepatic enzymes generating cholic acid (CA) and chenodeoxycholic acid (CDCA) in humans that are conjugated to predominantly glycine. These primary bile acids are stored in the gall bladder from where they are released upon a meal. The majority of conjugated bile acids are reabsorbed from the ileum, but through the action of microbial bile salt hydrolase (BSH), the bile acids escape reabsorption and enter the colon where they can be further metabolized. Accordingly, bile acid deconjugation reduces enterohepatic recirculation of bile acids and thereby reduces the total bile acid pool. Reduction of bile acid levels are crucial to reduce pruritus and reduce fetal complication risks in ICP. The aim is to identify biomarkers in the microbiota associated with ICP and the onset of this disease, or state of the disease, during pregnancy. Bacterial species that have a capability for UDCA production and correlate with sulphated progesterone metabolites are of specific interest. Furthermore, bacteria with sulphating and desulphating capabilities are also of interest.

Official Title
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Exploratory, Prospective, Non-therapeutic, Paired- Matched Controlled Two-arm Study to Investigate the Microbiome Composition in Women With Recurring Intrahepatic Cholestasis of Pregnancy (ICP)

Conditions
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Intrahepatic Cholestasis of Pregnancy

Intervention / Treatment
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* Other: Exploratory


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Arm 1 Pregnant woman > 18 years Signed informed consent for participation At least one previously completed parturition with ICP Willingness and ability to comply with the study procedures, visit schedules and other instructions regarding the study Arm 2 Pregnant woman ≥ 18 years (±5 calendar years from the matched subject in arm 1) Signed informed consent for participation At least one previously completed parturition No previous ICP Willingness and ability to comply with the study procedures, visit schedules and other instructions regarding the study Exclusion Criteria: Multifetal pregnancy (twins, triplets etc.) Latin American ethnicity Use of any systemic antibiotics within 3 months prior to enrollment Medical history of liver disease (other than previous ICP for subjects in arm 1) Medically significant gastrointestinal disorder which, in the opinion of the investigator, may affect the results or the subject ́s ability to comply with the study History or concurrent status of any clinically significant disease or disorder which, in the opinion of the investigator, may influence the results or the subject ́s ability to participate in the study Participation in any other clinical study that included drug treatment within 3 months prior to enrollment Serious bacterial or chronic viral infection such as human immunodeficiency virus (HIV) or hepatitis virus at enrollment visit Any other condition which, in the Investigator ́s opinion, makes the subject unsuitable for study participation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Previous ICP, recurrence<br>Pregnant women with at least one previously completed parturition with ICP and ICP during the present study | Other: Exploratory<br>* Fecal microbiome<br>|
| Previous ICP, non-recurrence<br>Pregnant women with at least one previously completed parturition with ICP and no ICP during the present study | Other: Exploratory<br>* Fecal microbiome<br>|
| No previous ICP<br>Pregnant women with at least one previously completed parturition with no previous ICP and no ICP during the present study | Other: Exploratory<br>* Fecal microbiome<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gut microbiome composition | Change in gut microbiome composition | Pregnancy week 9+0 - 19+6 until 6 weeks post-partum (+ 2 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bile acids levels | Change in total and individual bile acids | Pregnancy week 9+0 - 19+6 until 6 weeks post-partum (+ 2 weeks) | 
| Liver function test AST | Change in AST | Pregnancy week 9+0 - 19+6 until 6 weeks post-partum (+ 2 weeks) | 
| Liver function test ALT | Change in ALT | Pregnancy week 9+0 - 19+6 until 6 weeks post-partum (+ 2 weeks) | 
| Liver function test GGT | Change in GGT | Pregnancy week 9+0 - 19+6 until 6 weeks post-partum (+ 2 weeks) | 
| Liver function test bilirubin | Change in bilirubin | Pregnancy week 9+0 - 19+6 until 6 weeks post-partum (+ 2 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Microbiome