A Longitudinal Study of Alterations in Metabolic Markers and Gut Hormones in Pregnant and Non-pregnant Patients With Intrahepatic Cholestasis of Pregnancy, Gestational Diabetes Mellitus and Normal Pregnant and Non-pregnant Controls
Conditions: Intrahepatic Cholestasis of Pregnancy, Gestational Diabetes Mellitus
Sponsor: Imperial College London

 
 
 
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CLINICAL STUDY PROTOCOL 
 
Full Title:          
 
 
 
 
 
 
                    Short Title:       
 
 
Chief Investigator: Professor Catherine Williamson 
 
Rec Ref: 11/LO/0396  
 
IRAS 68898 
 
Funder: The Wellcome Trust:  WT092993MA 
 
Version 4 - 22 February 2018   
 
Date of Protocol: 22/02/18   
Table of contents 
A longitudinal study of alterations 
in metabolic markers and gut 
hormones in pregnant and non-
pregnant patients with 
intrahepatic cholestasis of 
pregnancy, gestational diabetes 
mellitus and normal pregnant 
and non-pregnant controls 
The Metabolic Profile in intrahepatic 
cholestasis of pregnancy and 
gestational diabetes mellitus 

 
 
 
2
Title Page 
1 
Table of Contents 
2 
CI and Study Contacts 
3-4 
Study summary and abbreviations 
5 
Background 
6-8 
Hypothesis 
9 
Study Objectives and Outcomes  
9 
Study design 
9-12 
Eligibility 
12-13 
Adverse Events 
13-14 
Statistics 
14 
Procedures 
14-15 
Regulatory issues 
15-17 
References 
17-19 
                                                                                                                  
 
 
 
 
 
 
 
 
 
Chief Investigator 
Professor Catherine Williamson 
Honorary Consultant Professor in Obstetric Medicine 

 
 
 
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MBChB, MD, FRCP 
Imperial College London 
Ground Floor, IRDB Building 
Du Cane Road 
London W12 0NN 
0209 584 2191 
07971 193686 
catherine.williamson@imperial.a.c.uk 
Fax 0209 594 2154 
________________________________________________________________ 
Study Team 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                
                                                          
                                                                                
 
 
 
 
 
 
 
 
 
Sponsor  
Imperial College London 
 
Miss Bryony Jones  
Consultant Obstetrician & Fetal and 
Maternal Medicine Specialist              
Queen Charlotte & Chelsea Hospital  
Centre for Fetal Care 
Du Cane Road  
London W12 0NN 
Email: Bryony.Jones@imperial.nhs.uk            
Ms Jenny Chambers                        
Clinical Trials Coordinator 
Imperial College London 
Ground Floor IRDB Building,                         
Du Cane Road  
London W12 0NN 
T: 0208 383 3990/07843 660349   Fax: 
020 8383 5284                                              
E: jenny.chambers@imperial.ac.uk 
Dr Peter Dixon                                              
Post Doctoral Scientist  BSc PhD                     
Imperial College London                                
Ground Floor IRDB Building 
Du Cane Road                                                  
London W12 0NN 
Tel: 0207 594 2172                                          
Email:  

 
 
 
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Miss B Ward 
Research Governance Manager 
Joint Research Compliance Office  
Imperial College London and Imperial College Healthcare NHS Trust 
Room 5L10A, 5th Floor,  
Lab Block, Charing Cross Hospital 
Fulham Palace Road 
London, W6 8RF 
Tel: 0203 312 2242 
Fax: 0203 312 2244 
Email: becky.ward@imperial.ac.uk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Summary 
Title 
A longitudinal study of alterations in metabolic markers and 
gut hormones in pregnant and non-pregnant patients with 
obstetric cholestasis and normal pregnant and non-pregnant 
controls. 
Short Title 
The Metabolic Profile in intrahepatic cholestasis of 
pregnancy and diabetes mellitus 
Methodology 
A prospective case control study  

 
 
 
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Study Duration 
 Until 30/04/2020 
Objectives 
To establish whether women affected by intrahepatic 
cholestasis of pregnancy (ICP)) and gestational diabetes 
mellitus (GDM) are predisposed towards developing 
metabolic disease in pregnancy and in later life. We will do 
this by measuring metabolic markers and assessing glucose 
homeostasis. 
Population 
Pregnant and non pregnant parous women 
Eligibility 
Pregnant and non pregnant women who have been affected 
by  ICP and GDM together with matched controls 
 
 
GLOSSARY OF ABBREVIATIONS 
OC 
Obstetric Cholestasis 
ICP 
Intrahepatic Cholestasis of Pregnancy 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
GCP 
Good Clinical Practice 
CI 
Chief Investigator 
GDM 
Gestational Diabetes Mellitus 
 
 
1. Background 
 
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). 
 

 
 
 
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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 
are also known to cause increased colonic motility in rabbits (Snape et al., 1980) and 
cardiac dysrhythmias in rats (Williamson et al., 2001), which could explain meconium 
staining of the amniotic fluid and sudden fetal death respectively. While it is known that 
bile acids can be transported by proteins in the placenta, the precise role of the placenta 
in bile, lipid and glucose metabolism is not known. Our group has demonstrated that 
cholestasis alters lipid pathways in mouse placentas (unpublished data) but this has not 
been studied in humans. 
 
BILE ACID HOMEOSTASIS: 
Bile acids are the end product of hepatic cholesterol metabolism and act as the 
main route of excretion for cholesterol. In the adult human two primary bile acids are 
produced by the liver, i.e. cholic acid and chenodeoxycholic acid. There is some 
evidence that maternal bile acids gradually rise with advancing gestation, but they 
usually remain within normal limits (< 14 uMol /L) (Fulton et al., 1983; Pascual et al., 
2002). This is in contrast to an ICP  pregnancy, where maternal bile acids may be raised 
to 100 times the upper limit of normal (Walker et al.,2002). In OC, elevated levels of bile 
acids are also found in the fetal circulation (Laatikainen, 1975). 
 
THE ROLE OF BILE ACIDS IN LIPID AND GLUCOSE METABOLISM: 

 
 
 
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There is accumulating evidence that FXR, the nuclear hormone receptor 
responsible for regulation of bile acid homeostasis, also plays a role in the regulation of 
lipid and glucose metabolism. FXR null mice have been shown to have abnormal blood 
lipid profiles including elevated plasma cholesterol, low density lipoprotein, high density 
lipoprotein and triglyceride levels (Ma, 2006). They also exhibit glucose intolerance and 
reduced insulin sensitivity (Zhang, 2006). Furthermore, ICP patients have raised levels 
of cholesterol and other lipid parameters (Dann et al. 2006). Specifically, the serum 
concentrations of low-density lipoprotein (LDL), apolipoprotein B-100, cholesterol and 
total cholesterol were markedly increased in women with ICP. They have also been 
shown to have impaired glucose tolerance (Wójcicka-Jagodzińska et al. 1989). Recent 
data from our group (Martineau et al. 2014, 2015) and others (Marschall et al. 2014) 
have shown that women with ICP have increased rates of GDM, and implicate raised 
serum bile acids in susceptibility to diabetes mellitus. Therefore this study will also 
include women with ICP and superimposed GDM in addition to women with GDM in the 
absence of ICP. This will enable us to evaluate the impact of cholestasis on the onset of 
diabetes mellitus in pregnant women. 
 
In cholestasis bile acids accumulate in the liver, and this results in the induction 
of pathways that enhance bile acid excretion. This may also cause abnormal cholesterol 
and triglyceride levels.  Bile acids also signal via FXR in the gut. Bile acids are stored in 
the gallbladder in the fasting state and released following ingestion of a meal. Once bile 
acids are in the intestine they are transported into enterocytes (gut cells) where they 
activate FXR which causes production and release of the hormone FGF19. FGF19 binds 
the FGF4 receptor on hepatocytes, and signals (via the jnk kinase pathway) to suppress 
cholesterol 7 alpha-hydroxylase (CYP7A1), a critical rate-limiting enzyme in synthesis of 
bile acids from cholesterol. There have been no studies of the gut-liver axis in 
pregnancy, but we hypothesise that abnormal bile acid signalling causes raised 
cholesterol in addition to increased serum bile acids. 
 
Bile acids also bind the G-protein-coupled receptor (TGR5). In the gut this results 
in release of glucagon-like peptide-1 (GLP-1)(Thomas et al. 2009). GLP-1 is an anti-
diabetic hormone that increases glucose-dependent insulin production and decreases 
glucagon production by the pancreas. To date, there have been no studies of the 
relationship between cholestasis and GDM and the levels of other fasting gut hormones 
that may influence glucose and lipid metabolism in pregnancy.   

 
 
 
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IMPORTANCE: 
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. 
 
 
 
2. Hypothesis 
There is a relationship between cholestasis and abnormalities of lipid and glucose 
homeostasis in the mother and baby  
 
That there are abnormalities in bile acid, lipid and glucose homeostasis in women who 
have previously had ICP compared to controls.  
  
That the placenta may play a role in bile, lipid and glucose homeostasis in ICP cases 
and controls 
 
Some of the hormonal signals that cause ICP-associated GDM may also cause GDM in 
non-cholestatic women. 
 

 
 
 
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3. Study Objectives and outcomes 
Objectives: 
• 
To evaluate the relationship between bile acid, lipid and glucose metabolites in 
the mother and fetus in ICP, GDM and uncomplicated pregnancies. 
 
Outcomes: 
Primary Outcome 
• 
To establish whether raised serum bile acids are associated with abnormalities in 
cholesterol and triglycerides in the mother and fetus 
Secondary Outcome 
• 
To establish the relationship between raised serum bile acids in the mother and 
fetus and abnormalities in: 
1. Glucose homeostasis 
2. Gut liver signaling hormones related to FGF 19 and C4 levels 
3. Gut hormone secretion 
 
4. Study design 
In the non pregnant group we aim to recruit 40 women and 40 matched controls. 
In the pregnant women with and without ICP or GDM we aim to recruit 40 in each group 
together with matched controls. 
Written consent will be obtained from all participants.  
 
Potential participants (both cases and controls) will be identified from the antenatal, 
obstetric medical and day assessment clinics at Queen Charlotte's and Chelsea 
Hospital, St Mary's Hospital and other participating units. Midwives and clinicians will be 
able to refer women who have previously had the conditions after asking them if they 
would be interested in speaking to someone from the research team regarding the study. 
Posters will be used in clinical areas and in the cafe area by the antenatal clinic to 
highlight the research. Women will also be approached directly in these clinics by 
researchers.  
 
Non-pregnant females may be identified through organisations such as ICP Support and 
from posters in gynaecology clinics and hospital areas such as the entrance lobby to the 
main hospital where the shop and cash machine is situated. Clinicians and nurses will 

 
 
 
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also be able to refer women to the research team after asking the patient if they would 
be interested in speaking to someone from the research team. 
 
The study will be a case-control study. The pregnancy cohort will be recruited 
prospectively and will undergo longitudinal study. The non-pregnant participants will also 
be recruited prospectively but this will be a cross-sectional study. 
 
The study will comprise of the following groups of women.  In the groups that comprise 
pregnant women, maternal blood will be collected at delivery together with placental 
samples and cord blood (once delivery has taken place and the cord has been clamped 
and cut).  The collection of these types of samples will allow the researchers to fully 
investigate the metabolites, bile acids and hormones implicated in the disorder together 
with the potential impact they may have on both mother and baby. 
 
Group 1 are non-pregnant women who have either had normal pregnancies in the past 
or who have had at least one pregnancy affected by intrahepatic cholestasis of 
pregnancy (ICP)  and/or gestational diabetes mellitus (GDM). This group should only 
have to attend the study for one day. 
 
Group 2 are women who are identified in early pregnancy. They are either expected to 
go on to have normal pregnancies or are women with a previous history of ICP and/or 
GDM. These women may be asked to participate up to three times. This will mean they 
will need to attend for three separate days. However, this will be linked to their regular 
visits to the hospital.  
 
Group 3 are women who have been diagnosed during their current pregnancy with ICP 
and/or GDM. These women may be asked to participate twice. This will mean they need 
to attend for two separate days. However, this will be linked to their regular visits to the 
hospital which is likely to be at least once a week. 
 
All participants will be given a standard meal (designed by a dietician) to eat the evening 
before the study day. Vegetarian and allergy needs will have been taken into account. 
They will then come to Queen Charlotte's & Chelsea Hospital (or other participating 
centres) at 8 am the following morning.  Each participant will be given a choice regarding 
the collection of the blood samples. They can have an intravenous cannula inserted or 

 
 
 
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they can be bled separately each time or have a mixture of both procedures.  For 
example, the first few samples could be taken separately and then a cannula could be 
inserted for the remaining samples that need to be collected and which are close in 
timing to each other. The first sample that is collected as soon as they arrive is a fasting 
sample.  
 
Participants in group 1, 2 and 3 will be involved for most of the day, arriving at 8am in 
the morning and leaving around 4pm in the afternoon.   Following the collection of the 
fasted sample outlined above participants will be provided with a breakfast. At one and 
two hours after breakfast blood samples will be taken. Finally, participants will have a 
standardised lunch with venous blood samples taken 15 minutes before consumption 
and further blood samples taken at the time of consumption and 20, 60, 120, and 180 
minutes post consumption. 
 
In total we will take 9 samples of blood from women in groups 1, 2 and 3. This will 
constitute a total of no more than 120 mls (approximately 9 tablespoons) of blood being 
taken on the day of the study.  
The protocol will be performed only once for women in group 1. It will be performed twice 
for women in group 2 (at 11-13 weeks and 28-40 weeks). Women in group 2 who go on 
to develop ICP and/or GDM again in the current pregnancy will be transferred to group 3 
at the time of diagnosis. Hence, it is possible that the protocol may be performed four 
times (11-13 weeks, third trimester, at the time of diagnosis, and 1-4 weeks after starting 
treatment with ursodeoxycholic acid). In reality this is unlikely to happen and hasn’t so 
far in the study but we would like to retain this option should a participant meet the 
criteria and be happy to take part four times. For women in group 3 the protocol will be 
performed twice (at diagnosis and 1-4 weeks after starting treatment with 
ursodeoxycholic acid). We will record if women are also taking metformin. All of this will 
be discussed carefully with the participants and all participants will be advised that 
participating just once will still give us valuable data.  
 
5. Eligibility 
Inclusion Criteria 
Inclusion criteria: 
Cases 

 
 
 
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• 
Women with intrahepatic cholestasis of pregnancy, defined as pruritus in 
pregnancy in association with raised serum bile acids and in the absence of an 
alternative cause. 
• 
Women with gestational diabetes mellitus (GDM) according to the diagnostic 
criteria used at the referring centre 
• 
Non-pregnant parous females with previous ICP or GDM. 
• 
Women who are able to give consent. 
• 
Women >16 and <70 years of age.  
 
Controls 
• 
Pregnant women not affected by ICP or GDM . 
• 
Non-pregnant parous females with previous uncomplicated pregnancy. 
• 
Women who are able to give consent. 
• 
Women >16 and <70 years of age. 
Exclusion Criteria 
Exclusion Criteria: 
 
• 
Males. 
• 
Non-pregnant females with other medical disorders that can cause liver 
impairment, abnormal lipid or glucose metabolism in pregnancy, e.g. pre-
eclampsia, acute fatty liver of pregnancy, pre-existing diabetes mellitus 
• 
Pregnant females with a history of other medical disorders that can cause liver 
impairment, abnormal lipid or glucose metabolism in pregnancy, e.g. pre-
eclampsia, acute fatty liver of pregnancy, pre-existing diabetes mellitus 
• 
Women who are not able to give consent. 
• 
Women <16 and >70 years of age. 
 
 
6. Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a participant during the 
study participation days. An existing medical condition (unless it worsens on the study 
participation days) is not classed as an AE.  
 
All AEs will be recorded in the notes of the participant and on an AE form 
 

 
 
 
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A serious advent event (SAE) is any untoward and unexpected medical occurrence or 
effect that: 
• 
Results in death 
• 
Is life threatening to mother and/or baby 
• 
Requires hospitalization 
• 
Results in persistent or significant disorder incapacity ability  
 
 
All SAEs and action taken as a result will be recorded in the notes of the participant and 
on an SAE form. An SAE form should be completed and faxed to the Chief Investigator 
within 24 hours. All SAEs should be reported to the appropriate research ethics 
committee where in the opinion of the Chief Investigator, the event was: 
• 
‘related’ i.e. resulted for the administration of any research procedures; and 
• 
‘unexpected’, i.e. an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the 
Chief Investigator becoming aware of the event using the NRES SAE form for non-IMP 
studies. 
Contact details for reporting SAEs 
Professor Catherine Williamson – 0207 594 2197/07971 193686 
Fax: 0207 594 2154 Attention: URGENT - Professor Catherine Williamson 
Please send SAE forms to Professor Catherine Williamson, Dept of Surgery & Cancer, 
IRDB Building, Du Cane Road, London, W12 ONN 
 
It is not anticipated that there will be any increased risk of adverse events or serious 
adverse events in this study.  However, it could be that a participant may have an 
unexpected reaction to the food they eat i.e. an allergic reaction and appropriate action 
will need to be taken in the event of this happening.  
 
It is also possible that a participant may experience a vasovagul (fainting) episode during 
venepuncture and appropriate care of the participant will implemented should this 
happen. 
 
 
7. Statistics 
 

 
 
 
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• 
Data analysis will take place at the Institute of Reproductive and Developmental 
Biology, Imperial College, London. It will be undertaken by the research scientists 
with statistical advice from the divisional statistician. 
• 
We will use conventional statistical analysis including tests of normal distribution and 
either Students T-test or the Mann-Whitney U test as appropriate. 
 
8. Procedure for entry to the study, schedule for sample analysis and data 
recording 
• 
The study will obtain ethics approval from NHS Research and Ethics Committee and 
Trust R&D prior to starting recruitment. 
• 
Patient information sheets will be provided and informed consent obtained.  
• 
Participants will be asked to give consent to have their medical records examined by 
members of the research group. This will be undertaken in order to check any 
previous data that maybe of relevance to the study e.g. previous history of ICP or 
GDM   
• 
The personal addresses telephone numbers and possibly e−mail addresses of 
participants are kept on file by the research group for future reference. This 
information is stored in a locked filing cabinet in a room within the research centre 
that is locked when not in use. Access is only granted to members of the research 
group. 
• 
The personal data of the participants is also stored on a university computer. The 
computer is non net−worked and it is password protected. Access is only available to 
members of the research group 
• 
Samples are linked-anonymised when they come into the laboratory for processing. 
The codes are kept in the PI's room (Professor Williamson) and only members of the 
research team have access to the coding book.  
• 
Samples may be made available to collaborators, but these will be linked-
anonymised and written consent from the participant will be obtained. If participants 
do not want their samples to be made available to collaborators they will have the 
option to opt out of this. 
• 
Personal data is stored in a locked filing cabinet in a different building within a locked 
filing cabinet in the research centre. Any data relating to results are also coded and 
retained on a non net worked computer. 

 
 
 
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• 
Only members of Professor Williamson's research team who are involved with the 
study will have access to the personal information included in the questionnaire. 
They will also have access to the medical records of the participants but only with the 
signed consent of the participants.  
• 
Relevant data such as blood results may also be made available to collaborators, but 
this will be in a linked anonymised format, and written consent from the participant 
will be obtained. 
 
9. Regulatory Issues  
 
9.1. Ethical Approval  
Prior to starting the study, we will seek ethical approval from NHS Research Ethics 
Committee (NHS REC). Amendments to the protocol will be made with the approval of 
the chief / principal investigator(s) and will be subject to review by the REC. The study 
will be carried out in accordance with the Declaration of Helsinki. 
 
9.2. Consent  
For participants recruited at Queen Charlotte's and Chelsea Hospital and St Mary's 
Hospital a member of the research team will meet with the participant to explain the 
study to them and to answer any questions that they may have. They will have as much 
time as they need to think about the study and will be given an information sheet to take 
home to look at, together with a letter explaining what happens next should they wish to 
take part, a medical questionnaire (which they will need to complete to check eligibility) 
and a pre-paid envelope. Following this, the participant will be given an appointment to 
come in to hospital to be formally recruited to the study and sign a consent form  
 
Participants recruited via the patient organisation will be sent an information sheet about 
the study via email/post. This gives them time to consider whether they are interested in 
taking part. If they are, they will be sent a letter acknowledging their interest and giving 
them the opportunity to ask any questions about the research. The letter will also include 
a consent form and a medical questionnaire. If they need to discuss the study they will 
be contacted at a time to suit them. Following this they will be asked to sign the consent 
form and return it to us in the post together with the completed questionnaire. 
 

 
 
 
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In addition to a written information sheet, all women will be provided with contact details 
for members of the research group and will be encouraged to make contact should they 
have any questions or concerns about the study. It will be made explicit to the 
participants that they can change their mind about taking part at any stage of the 
recruitment process and during the research period itself. 
 
9.3. Confidentiality  
The Chief Investigator will preserve the confidentiality of participants taking part 
in the study and is registered under the date Protection Act 
 
9.4. Indemnity  
Imperial College holds negligent harm and non-negligent harm insurance policies which 
apply to this study.  
 
9.5. Sponsor Imperial College London will act as the main sponsor for this study. 
Delegated responsibilities will be assigned to the NHS trusts taking part in this study.  
 
9.6 Trust R&D Any amendments should also be approved by the sponsor and Trust 
R&D department. 
 
9.7. Funding 
The study has been funded by The Wellcome Trust and is also supported through 
internal funding.  
Participants will be awarded (in vouchers) £20 for every study day they take part in, up 
to a potential maximum of £60. 
 
9.8. Audits and Inspections  
The study is subject to inspection and audit by Imperial College London under their remit 
as sponsor and other regulatory bodies to ensure adherence to GCP and the UK Policy 
framework for health and social care. 
 
10.  References 
Abu-Hayyeh, S., P. Martinez-Becerra, et al. "Inhibition of Na+-taurocholate Co-transporting polypeptide-
mediated bile acid transport by cholestatic sulfated progesterone metabolites." J Biol Chem 285(22): 16504-
12. 

 
 
 
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Campos GA, Guerra FA, Israel EJ. Effects of cholic acid infusion in fetal lambs. Acta Obstet Gynecol Scand 
1986; 65: 23–26 
 
Dann AT, Kenyon AP, Wierzbicki AS, Seed PT, Shennan AH, Tribe RM. Plasma lipid profiles of women with 
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de Swiet M, Warnes G, Elias E, Higgins CF, Johnston DG, McCarthy MI, Williamson C. Heterozygous 
MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in 
protein trafficking. Hum Mol Genet 2000; 9: 1209–1217 
 
Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, 
Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C. Contribution of variant alleles 
of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut 2009; 58: 537–544 
 
Fulton IC, Douglas JG, Hutchon DJ, Beckett GJ. Is normal pregnancy cholestatic? Clin Chim Acta 1983; 
130: 171–176 
 
Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15(17): 2049–
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Germain AM, Kato S, Carvajal JA, Valenzuela GJ, Valdes GL, Glasinovic JC. Bile acids increase response 
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Israel EJ, Guzman ML, Campos GA. Maximal response to oxytocin of the isolated myometrium from 
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Laatikainen TJ. Fetal bile acid levels in pregnancies complicated by maternal intrahepatic cholestasis. Am J 
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Ma, K., P. K. Saha, et al. (2006). "Farnesoid X receptor is essential for normal glucose homeostasis." J Clin 
Invest 116(4): 1102-9. 
 
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Hepatology. 2013 Oct;58(4):1385-91. doi: 10.1002/hep.26444. Epub 2013 Aug 6. 
 
 
Martineau M, Raker C, Powrie R, Williamson C. Intrahepatic cholestasis of pregnancy is associated with 
an increased risk of gestational diabetes. Eur J Obstet Gynecol Reprod Biol. 2014 May;176:80-5. doi: 
10.1016/j.ejogrb.2013.12.037. Epub 2014 Jan 7. 
 
Martineau MG, Raker C, Dixon PH, Chambers J, Machirori M, King NM, Hooks ML, Manoharan R, Chen K, 
Powrie R, Williamson C. The metabolic profile of intrahepatic cholestasis of pregnancy is associated with 
impaired glucose tolerance, dyslipidemia, and increased fetal growth. 
Diabetes Care. 2015 Feb;38(2):243-8. doi: 10.2337/dc14-2143. Epub 2014 Dec 12. 
 
Müllenbach R, Bennett A, Tetlow N, Patel N, Hamilton G, Cheng F, Chambers J, Howard R, Taylor-
Robinson SD, Williamson C. ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy. 
Gut 2005; 54: 829–834 
Papacleovoulou, G., S. Abu-Hayyeh, et al. "Nuclear receptor-driven alterations in bile acid and lipid 
metabolic pathways during gestation." Biochim Biophys Acta. 
 
Pascual MJ , Serrano MA, El-Mir MY, Macias RI , Jiménez F, Marin JJ. Relationship between asymptomatic 
hypercholanaemia of pregnancy and progesterone metabolism. Clin Sci (Lond) 2002; 102: 587–593 
 
Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C, Zimmermann R, Kenngott S, 
Beuers U, Reichel C, Kerb R, Penger A, Meier PJ, Kullak-Ublick GA. Sequence analysis of bile salt export 

 
 
 
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