Clinical Trial: The Metabolic Profile in Intrahepatic Cholestasis of Pregnancy and Diabetes Mellitus

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: A Longitudinal Study of Alterations in Metabolic Markers and Gut Hormones in Pregnant and Non-pregnant Patients With Intrahepatic Cholestasis of Pregnancy, Gestational Dia

Brief Summary:

ICP is known to cause abnormal bile acid homeostasis and to be associated with an increased risk of diseases of the biliary system in later life. There have been small studies (Dann et al. 2006; Wójcicka-Jagodzińska et al. 1989) suggesting that it causes dyslipidaemia (raised lipids) and impaired glucose tolerance in pregnancy. However the underlying mechanisms of these abnormalities is not known. Similarly the influence of cholestasis on fetal metabolism is not known, and nor is the role of the placenta. It is also not known whether women with ICP have a predisposition to abnormal lipid and glucose homeostasis when they are not pregnant.

GDM is characterized by raised plasma glucose levels in pregnant women (in the absence of pre-pregnancy diabetes mellitus). This condition is associated with large-for-gestational age babies and obstructed labour. Women with GDM have increased risk of subsequent type 2 diabetes mellitus, and if they have this condition in a subsequent pregnancy there is an increased risk of stillbirth. This work is important to understand the causes of the metabolic abnormalities associated with ICP and GDM. If we demonstrate abnormal lipid and glucose profiles, these may be of relevance to the fetal complications of both disorders. It will also be of relevance to the future health of affected women and their children.

Detailed Summary:

CLINICAL FEATURES OF INTRAHEPATIC CHOLESTASIS OF PREGNANCY:

Intrahepatic cholestasis of pregnancy (ICP), is a pregnancy−specific liver disorder which typically presents with maternal pruritus (itching) in late pregnancy and affects about 0.7% of women in the UK. Biochemically, it is characterised by liver dysfunction with raised serum bile acids, and clinically by a significantly increased incidence of fetal complications, including spontaneous preterm labour, fetal distress, meconium staining of the amniotic fluid and sudden fetal death (Geenes and Williamson 2009).

The cause of ICP is complex and not fully understood. In addition the pathological mechanisms behind the adverse fetal outcomes have not been elucidated. The maternal disease is likely to be caused by interaction between sex hormone metabolites and bile acids in genetically susceptible women (Abu-Hayyeh et al. 2010). To date, we and others have identified genetic variation in several biliary transporters e.g. ABCB4, ATP8B1, ABCB11 and the main bile acid receptor, FXR, that predispose women to the disease (Dixon et al., 2000; Mullenbach et al., 2005; Pauli−Magnus et al., 2004; Van Mil et al, 2007; Dixon et al. 2009). Due to their inherent toxicity, bile acids are also likely to be responsible for the fetal component of the disease. Consistent with this the incidence of fetal complications has been shown to be increased in pregnancies where the levels exceed 40 uMol /L (Glantz et al., 2004). There are currently several theories about how bile acids may affect fetal wellbeing; with regard to the increased incidence of spontaneous prematurity, they have been shown to cause premature delivery in sheep (Campos et al., 1986), and increased myometrial contractility in response to oxytocin (Germain et al., 2003; Israel et al., 1986). Furthermore, bile acids
Sponsor: Imperial College London

Current Primary Outcome: To establish whether raised serum bile acids are associated with abnormalities in cholesterol and triglycerides in the mother and fetus mother and fetus. [ Time Frame: 5 years ]

Original Primary Outcome: That raised serum bile acids are associated with abnormalities in cholesterol and triglycerides in the mother and fetus. [ Time Frame: Five years ]

Current Secondary Outcome: To establish the relationship between raised serum bile acids in the mother and fetus and abnormalities in: Glucose homeostasis, gut liver signaling hormones related to FGF 19 and C4 levels, Gut hormone secretion [ Time Frame: 5 years ]

Original Secondary Outcome:

• The relationship between raised serum bile acids in the mother and fetus and abnormalities in glucose homeostasis. [ Time Frame: Five years ]
  To establish the relationship between elevated bile acids in pregnancy (as seen in Obstetric Cholestasis) and the incidence of impaired fasting glycemia and impaired glucose tolerance. To do this the serum bile acid level will be measured, and if raised >14umol/L we will investigate whether the raised serum bile acids are associated with raised plasma glucose levels in the mother or in the fetal umbilical cord blood at delivery.
• The relationship between raised serum bile acids in the mother and fetus and abnormalities in gut liver signalling hormones related to FGF 19 and C4 levels [ Time Frame: 5 years ]
  To assess the effect of elevated maternal serum bile acids (in Obstetric cholestasis acids) on serum concentrations of intestinal FGF 19, hepatic C4 and the fetus. To do this the serum bile acid level will be measured, and if raised >14umol/L we will investigate whether the raised serum bile acids are associated with reduced plasma FGF19 or raised C4 levels in the mother or in the fetal umbilical cord blood at delivery.
• The relationship between raised serum bile acids in the mother and fetus and abnormalities in gut hormone secretion [ Time Frame: 5 years ]
  To assess for alterations in plasma gut hormone concentrations (Glucagon-like peptide-1) and elevated bile acids, as seen in pregnancies complicated by Obstetric Cholestasis. To do this the serum bile acid level will be measured, and if raised >14umol/L we will investigate whether the raised serum bile acids are associated with raised plasma GLP-1 levels in the mother.

Dates:
Date Received: September 26, 2011
Date Started: November 2011
Date Completion: April 2018
Last Updated: January 9, 2017
Last Verified: December 2016