Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05691036 |
| Other study ID # |
2022-2107 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
December 8, 2022 |
| Est. completion date |
July 2025 |
Study information
| Verified date |
January 2023 |
| Source |
Postgraduate Institute of Medical Education and Research |
| Contact |
Dr Madhumita Premkumar, DM |
| Phone |
7087003409 |
| Email |
drmadhumitap[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Intrahepatic cholestasis of pregnancy (ICP) is a disorder characterized by itching, elevated
fasting serum bile acids ≥10μmol/L (and elevated serum transaminases), with increased risks
of perinatal complications, including spontaneous preterm labor, fetal distress, infant
respiratory distress syndrome, meconium-stained liquor (MSL), and sudden intrauterine death
(IUD). The Incidence of ICP varies from 0.1 to 15.6% of all pregnancies, with the highest
cases in Chile, South Asia, America, and Scandinavia. The burden of ICP in India according to
various states is as follows Punjab (3.1%), Chandigarh (4.8%), Delhi (0.79%), West Bengal
(3.3%), and Lucknow (Uttar Pradesh) (2.8%).
Description:
Many physiological, anatomical, and hormonal changes occur in the body during pregnancy to
facilitate the best possible growth of the fetus. A functional liver and bile acids (BA)
milieu are critical for the development of the fetus, and adverse pregnancy outcomes are
possible in women who have primary liver disease. Some pre-existing hepatobiliary diseases
may be diagnosed incidentally during pregnancy, such as chronic viral hepatitis. Some common
pregnancy-related liver diseases are Intrahepatic Cholestasis of pregnancy (ICP), hemolysis
elevated liver enzymes and low platelets (HELLP) syndrome, and acute fatty liver of pregnancy
(AFLP). ICP is a cholestatic disorder characterized by (i) pruritus, with onset in the second
and third trimester of pregnancy, without any primary skin lesions, (ii) elevated fasting
serum bile acids ≥10μmol/L (and elevated serum transaminases), (iii) spontaneous relief of
signs and symptoms within two to three weeks after delivery, and (iv) absence of other
diseases that cause pruritus and jaundice. Many studies have attempted to associate maternal
serum bile acids/ total bile acids with adverse fetal outcomes. ICP is associated with
increased risks of perinatal complications, including spontaneous preterm labor, fetal
distress, infant respiratory distress syndrome, meconium-stained amniotic fluid, and sudden
intrauterine death (IUD). Recent data suggest that women with jaundice had higher rates of
prenatal abnormalities than women with just pruritus in ICP. Pruritus can appear as early as
seven weeks without causing a rash. Itching is usually noticed early on the palms of the
hands and the soles of the feet, although it can occur everywhere on the body. Other symptoms
of ICP include dark urine, increased clotting time, fatigue, nausea, loss of appetite,
jaundice, and discomfort in the upper right quadrant of the abdomen. It may be mild and
tolerable for some patients but may also be very severe and disabling. Women with ICP develop
mild jaundice and subclinical steatorrhea. Jaundice typically develops 1 to 4 weeks after the
onset of pruritus. Subclinical steatorrhea with fat malabsorption leads to vitamin K
deficiency resulting in prolonged prothrombin time and postpartum hemorrhage.
The incidence and prevalence of ICP vary with ethnicity and geography. Ethnic distribution of
ICP as Caucasian (53.6%), South Asian (22.6%), African (0.6%), Asian (8.4%), and Australian
(3.8%) were noted (8). Among the Asians, Asian of Indian origin 1.24%, Pakistan origin of
1.46%, and whites of 0.62% were found to show Indians and Pakistan origin of Asian have a
higher prevalence than whites. Concerning the geographic distribution of ICP, the Incidence
of ICP varies from 0.1 to 15.6% of all pregnancies, with the highest cases in Chile, South
Asia, America, and Scandinavia. In the case of individual countries such as Chile, 9%,
Canada, 0.07%, China, 0.32%, and North California, 1.9% incidence were reported. It is more
common in South America as compared to other northern European continents. The incidence of
ICP was reported as 0.5-1.5% of pregnancies in Finland. As this study will be done among the
Indian population, the burden of ICP in India is reported as Punjab at 3.1%, Chandigarh at
4.8%, Delhi at 0.79%, Nepal at 1.1.5%, West Bengal at 3.3%, Lucknow 2.8%, indicating an
urgent need to focus and find out cost-effective and early prognosis and diagnosis of ICP.
ICP is a multifactorial disease interplay between genetic, environmental, and hormonal
factors. Common risk factors are the history of oral contraceptive pill (OCP) use, twins,
selenium deficiency, genetic transporters defects, and recurrence in the subsequent
pregnancy. Patients are usually diagnosed in the second and third trimesters, with increased
incidence in winter. Genetic factors contribute as risk factors for ICP including mutation in
ATP binding cassette family as ATP binding cassette subfamily B member 4(ABCB4), ATP-binding
cassette, sub-family B member 11(ABCB11), ATPase Phospholipid Transporting 8B1(ATP8B1), ATP
Binding Cassette Subfamily C Member 2(ABCC2), and tight junction protein 2(TJP2) genes. Bile
mainly consists of bile salt, organic anions, electrolytes, phosphatidylcholine, and
cholesterol. These components are transported by active process against the concentration
gradient by specific transporters such as bile salt export pump (BSEP), Sodium taurocholate
co-transporting polypeptide (NTCP), major transporter for the secretion of bile acids from
hepatocytes into bile in humans. A study on deoxyribonucleic acid (DNA) of the Italian
population with the help of polymerase chain reaction (PCR) and automated sequencing. They
found five novel variants of mutation in ABCB4 and ABCB11 and confirmed the statistically
significant susceptibility to ICP. Environmental factors associated with ICP include seasonal
variation, selenium deficiency, and vitamin D deficiency. Hormonal factors such as estrogen
level, sulfated progesterone, intake of oral contraceptive pills, and second-trimester
hormonal changes in pregnant women can be attributed as risk factors for ICP. In the urine of
pregnant women with ICP, sulfated progesterone correlates with the severity of ICP. Apart
from these, other risk factors are responsible for ICP, and they found a statically
significant association between pregestational diabetes, tobacco use, history of
cholecystectomy, history of ICP in a previous pregnancy, and pregnancy-induced hypertension
(PIH).
Placental expression of genes due to placental hypoxia and proteins related to apoptosis,
oxidative stress, lipid metabolism, cell proliferation, and immunological response are
associated with ICP. Increased total serum BAs and changes in BAs profile reverse the
transplacental BA(bile acids) gradient, and increased inflammatory cytokines like interleukin
4(IL4), interleukin 6(IL6), interleukin 12 (IL12), and tumor necrosis factor(TNF) cause
respiratory distress in infants and preterm delivery. Immune response, vascular endothelial
growth factor(VGEF)signaling pathway, and G-protein-coupled receptor signaling were the most
common regulatory genes responsible for inflammatory response, vasculogenesis, and
angiogenesis, all essential in ICP pathogenesis. Autotaxin (ATX) is lysophosphatidic acid
(LPA) essential for angiogenesis and neuronal development during embryogenesis, cellular
motility, proliferation, and lymphocyte homing. ATX levels are reported to be increased
during pregnancy and correlate positively with gestational age. LPA and ATX levels were
significantly higher in ICP. A large prospective study in Sweden revealed severe perinatal
outcomes of ICP as spontaneous preterm labor, asphyxia events, meconium staining of amniotic
fluid, and placental and membrane changes did not occur until the level of serum bile acid
reached>40umol/L. ICP is a pregnancy-related disorder that is expected to resolve after
delivery. However, population-based cohort studies revealed that ICP acts as a risk factor
for hepatobiliary disease even after the completion of pregnancy. A significant association
between hepatitis C virus (HCV), non-alcoholic liver disease, gallstone, and cholelithiasis,
with increased risk of non-alcoholic pancreatitis in women, was observed in women with ICP. A
population-based cohort study, with an of 0.32%-0.58% of ICP in Sweden, gives a significant
risk association of ICP with gestational diabetes, pre-eclampsia, and a nonsignificant
association with postpartum hemorrhage. Total serum bile acids >40mmol/l as severe ICP and
associated with increased risk of gestational diabetes mellitus(GDM), pregnancy-induced
hypertension(PIH) was reported and managed with ursodeoxycholic acid (UDCA).
Some therapeutic agents such as ursodeoxycholic acid(UDCA), rifampicin, antihistaminic drugs,
vitamin K and some topical emollients have been used to alleviate nocturnal pruritus/
pruritus in ICP. Some trials related to reducing the adverse perinatal outcome of ICP were
done with the administration of UDCA, dexamethasone, cholestyramine, S-adenosyl
methionine(SAMe), plasmapheresis, and fish supplements. UDCA is currently the most effective
therapeutic agent used in clinical practice to manage ICP. Several meta-analyses with
observational studies or randomized trials have been done on the effectiveness of UDCA, but
the results are equivocal. Dexamethasone, rifampicin, SAMe, and cholestyramine also have some
roles in the management of ICP. However, reducing pruritus and other adverse perinatal
outcomes in pregnancy is unclear. UDCA was effective in improving clinical presentation,
normalization of serum profile, and a significant reduction in meconium staining, spontaneous
birth, or fetal distress compared to the control/ placebo group. Maternal total serum BAs are
significantly associated with reduced infant size and are small for gestational age. Since
ICP is the most typical pregnancy-related liver disorder, has multifactorial risk factors,
has unclear etiopathogenesis, and results in adverse perinatal outcomes. Pruritus may
considerably impair the patient's quality of life as a pregnant woman, causing sleep
deprivation and psychological suffering. Only a few studies have been done in India
concerning ICP, most of which are related to the reference range of total BAs and the
prevalence of ICP. There is no Indian data on how ICP affects the quality of life of a
pregnant woman or prospective assessment of genetic risk and bile acid metabolism. So, the
aim is to determine the bile acid profile and related metabolites in serum, identify
prognostic markers of ICP and assess related risk factors, including the effect of medication
and the quality of life of patients with ICP. This research will prospectively evaluate
perinatal outcomes and genetic risk factors, which have a bearing on neonatal health. Keeping
in mind the symptoms and severity of pruritus, the factors affecting the disease course of
pregnant women suffering from ICP will also be evaluated.
