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1.  Intrahepatic cholestasis of pregnancy 
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery. ICP is observed in 0.4–1% of pregnancies in most areas of Central and Western Europe and North America, while in Chile and Bolivia as well as Scandinavia and the Baltic states roughly 5–15% and 1–2%, respectively, of pregnancies are associated with ICP. Genetic and hormonal factors, but also environmental factors may contribute to the pathogenesis of ICP. Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19–60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22–41%), and fetal loss (0.4–4.1%), particularly when associated with fasting serum bile acid levels > 40 μmol/L. The hydrophilic bile acid ursodeoxycholic acid (10–20 mg/kg/d) is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Delivery has been recommended in the 38th week when lung maturity has been established.
doi:10.1186/1750-1172-2-26
PMCID: PMC1891276  PMID: 17535422
2.  Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems 
Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICP.
doi:10.3748/wjg.14.5781
PMCID: PMC2751886  PMID: 18855975
Cholestasis of pregnancy; Canalicular ABC transporters; Pruritus; Fetal outcome; Ursodeoxycholic acid
3.  The Reversed Feto-Maternal Bile Acid Gradient in Intrahepatic Cholestasis of Pregnancy Is Corrected by Ursodeoxycholic Acid 
PLoS ONE  2014;9(1):e83828.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder associated with an increased risk of adverse fetal outcomes. It is characterised by raised maternal serum bile acids, which are believed to cause the adverse outcomes. ICP is commonly treated with ursodeoxycholic acid (UDCA). This study aimed to determine the fetal and maternal bile acid profiles in normal and ICP pregnancies, and to examine the effect of UDCA treatment. Matched maternal and umbilical cord serum samples were collected from untreated ICP (n = 18), UDCA-treated ICP (n = 46) and uncomplicated pregnancy (n = 15) cases at the time of delivery. Nineteen individual bile acids were measured using HPLC-MS/MS. Maternal and fetal serum bile acids are significantly raised in ICP compared with normal pregnancy (p = <0.0001 and <0.05, respectively), predominantly due to increased levels of conjugated cholic and chenodeoxycholic acid. There are no differences between the umbilical cord artery and cord vein levels of the major bile acid species. The feto-maternal gradient of bile acids is reversed in ICP. Treatment with UDCA significantly reduces serum bile acids in the maternal compartment (p = <0.0001), thereby reducing the feto-maternal transplacental gradient. UDCA-treatment does not cause a clinically important increase in lithocholic acid (LCA) concentrations. ICP is associated with significant quantitative and qualitative changes in the maternal and fetal bile acid pools. Treatment with UDCA reduces the level of bile acids in both compartments and reverses the qualitative changes. We have not found evidence to support the suggestion that UDCA treatment increases fetal LCA concentrations to deleterious levels.
doi:10.1371/journal.pone.0083828
PMCID: PMC3885440  PMID: 24421907
4.  Impaired fetal adrenal function in intrahepatic cholestasis of pregnancy 
Summary
Background
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease of unknown etiology. The aim of this study was to investigate the change in maternal and fetal adrenal function in clinical and experimental ICP.
Material/Methods
The maternal and fetal serum levels of cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined in 14 women with ICP and in pregnant rats with estrogen-induced intrahepatic cholestasis.
Results
In women with ICP, the fetal serum cortisol and DHEAS levels were significantly higher than those in women with normal pregnancy, after correcting the impact of gestational age at delivery. The relationship between fetal cortisol and maternal cholic acid levels was bidirectional; the fetal cortisol tended to increase in mild ICP, while it decreased in severe ICP. In pregnant rats with estrogen-induced cholestasis, the fetal cortisol level was significantly lower in the group with oxytocin injection, compared with the group without oxytocin injection (191.92±18.86 vs. 272.71±31.83 ng/ml, P<0.05). In contrast, the fetal cortisol concentration was increased after oxytocin injection in normal control rats.
Conclusions
The data indicate that fetal stress-responsive system is stimulated in mild ICP, but it is suppressed in severe ICP, which might contribute to the occurrence of unpredictable sudden fetal death. Further studies are warranted to explore the role of impaired fetal adrenal function in the pathogenesis of ICP and the clinical implications.
doi:10.12659/MSM.881766
PMCID: PMC3539589  PMID: 21525808
cortisol; dehydroepiandrosterone sulfate; intrahepatic cholestasis of pregnancy; fetal death; cholic acid; human; rat
5.  Intrahepatic cholestasis of pregnancy 
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by maternal pruritus in the third trimester, raised serum bile acids and increased rates of adverse fetal outcomes. The etiology of ICP is complex and not fully understood, but it is likely to result from the cholestatic effects of reproductive hormones and their metabolites in genetically susceptible women. Equally unclear are the mechanisms by which the fetal complications occur. This article reviews the epidemiology, clinical features, diagnosis, etiology and management of ICP.
doi:10.3748/wjg.15.2049
PMCID: PMC2678574  PMID: 19418576
Cholestasis; Pregnancy; Pruritus; Bile acid
6.  ATP8B1 mutations in British cases with intrahepatic cholestasis of pregnancy 
Gut  2005;54(6):829-834.
Background: Intrahepatic cholestasis of pregnancy (ICP) affects approximately 0.7% of pregnancies in the UK and is associated with prematurity, fetal distress, and intrauterine death. Homozygous mutations in the ATP8B1 gene cause cholestasis with a normal serum gamma-glutamyl transpeptidase (γ-GT), and have been reported in two forms of cholestasis: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC).
Aims: To establish whether mutations in ATP8B1 are associated with ICP in British cases
Patients: Sixteen well phenotyped women with ICP without raised γ-GT were selected for sequence analysis. Subsequently, 182 patients and 120 controls were examined for the presence of the variants detected.
Methods: All coding exons were sequenced in 16 cases. Eight ICP cases, including two women carrying a mutation, were investigated using in vivo hepatic 31P magnetic resonance spectroscopy (MRS)
Results: Two heterozygous ATP8B1 transitions (208G>A and 2599C>T) that resulted in amino acid substitutions were identified; 208G>A was identified in three cases. MRS revealed an increased phosphodiester signal (Mann-Whitney U test, p = 0.03) and a decreased phosphomonoester/phosphodiester ratio (p = 0.04) in ICP cases compared with controls.
Conclusions: We were able to demonstrate ATP8B1 mutations in ICP. MRS studies suggest that susceptibility to ICP is associated with a relative rise in biliary phospholipid. These data also suggest that MRS may be used for non-invasive assessment of the liver and biliary constituents in cholestasis.
doi:10.1136/gut.2004.058115
PMCID: PMC1774530  PMID: 15888793
bile; liver; magnetic resonance spectroscopy; intrahepatic cholestasis of pregnancy
7.  Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene 
Gut  2006;56(2):265-270.
Background
Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut‐off level for serum bile acid (⩾40 μmol/l) was determined for increased risk of fetal complications.
Objectives
To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP‐binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy.
Methods
For genetic analysis, 52 women with bile acid levels ⩾40 μmol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing.
Results
In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at‐risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012).
Conclusion
Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.
doi:10.1136/gut.2006.092742
PMCID: PMC1856745  PMID: 16891356
8.  Intrahepatic Cholestasis of Pregnancy Levels of Sulfated Progesterone Metabolites Inhibit Farnesoid X Receptor Resulting in a Cholestatic Phenotype 
Hepatology (Baltimore, Md.)  2013;57(2):716-726.
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here we report that the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, coadministration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR, resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (Hepatology 2013;)
doi:10.1002/hep.26055
PMCID: PMC3592994  PMID: 22961653
9.  Bile acid patterns in meconium are influenced by cholestasis of pregnancy and not altered by ursodeoxycholic acid treatment 
Gut  1999;45(3):446-452.
BACKGROUND—Data on meconium bile acid composition in newborn babies of patients with intrahepatic cholestasis of pregnancy (ICP) are relatively scant, and changes that occur on ursodeoxycholic acid (UDCA) administration have not been evaluated.
AIMS—To investigate bile acid profiles in meconium of neonates from untreated and UDCA treated patients with ICP. Maternal serum bile acid composition was also analysed both at diagnosis and delivery to determine whether this influences the concentration and proportion of bile acids in the meconium.
PATIENTS/METHODS—The population included eight healthy pregnant women and 16 patients with ICP, nine of which received UDCA (12.5-15.0 mg/kg body weight/day) for 15±4 days until parturition. Bile acids were assessed in the meconium by gas chromatography-mass spectrometry and in maternal serum by high performance liquid chromatography.
RESULTS—Total bile acid and cholic acid concentrations in the meconium were increased (p<0.01) in newborns from patients with ICP (13.5 (5.1) and 8.4 (4.1) µmol/g respectively; mean (SEM)) as compared with controls (2.0 (0.5) and 0.8 (0.3) µmol/g respectively), reflecting the total bile acid and cholic acid levels in the maternal serum (r = 0.85 and r = 0.84, p<0.01). After UDCA administration, total bile acid concentrations decreased in the mother (~3-fold, p<0.05) but not in the meconium. UDCA concentration in the meconium showed only a 2-fold increase after treatment, despite the much greater increase in the maternal serum (p<0.01). Lithocholic acid concentration in the meconium was not increased by UDCA treatment.
CONCLUSIONS—UDCA administration does not influence the concentration and proportion of bile acids in the meconium, which in turn are altered by ICP. Moreover, this beneficial treatment for the mother does not increase meconium levels of potentially toxic metabolites of UDCA such as lithocholic acid.


Keywords: bile acids; cholestasis; pregnancy; cholic acid; meconium; ursodeoxycholic acid therapy
PMCID: PMC1727639  PMID: 10446117
10.  Role of ABCC2 common variants in intrahepatic cholestasis of pregnancy 
The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.
doi:10.3748/wjg.14.2126
PMCID: PMC2701541  PMID: 18395921
Intrahepatic cholestasis of pregnancy; ABCC2; MRP2; Gene variants
11.  Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy 
Gut  2003;52(7):1025-1029.
Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease.
Patients and methods: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3.
Results: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families.
Conclusions: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.
PMCID: PMC1773695  PMID: 12801961
intrahepatic cholestasis of pregnancy; obstetric cholestasis; linkage analysis
12.  Prevalence of liver disease in pregnancy and its outcome with emphasis on obstetric cholestasis: An Indian scenario 
Objective
To determine the prevalence of liver disease in pregnant Indian women and the risk of adverse pregnancy outcomes resulting from intrahepatic cholestasis.
Methods
We analyzed 5947 pregnant women, A total of 79(1.32%) patients had abnormal liver tests. 47 (0.79%) women who gave birth at Sant Parmanand Hospital from January 1997 to August 2008 had pregnancy complicated by cholestasis. Fisher’s exact 2-Tail p-value analysis was used to compare pregnancy characterstics of this group with those of the general obstetric population (n = 5300).
Results
Obstetric cholestasis started at a mean ± SD of 31 ± 4 weeks’ gestation, with pruritus as the leading symptom.. Affected pregnant women had meconium stained liquor significantly more often (40.4%) than the general obstetric population (18.86%). Intrahepatic cholestasis increased the low basic risk of preterm delivery, thereby increasing the need for neonatal care in the general population. Increased incidence of postpartum hemorrhage was also significant(29.78%) p<0.0004.
Conclusion
Intrahepatic cholestasis of pregnancy has an adverse effect on maternal and fetal prognosis, and affected pregnancies merit closer surveillance.
doi:10.1007/s13224-010-0068-2
PMCID: PMC3394613
13.  Dermatoses of Pregnancy - Clues to Diagnosis, Fetal Risk and Therapy 
Annals of Dermatology  2011;23(3):265-275.
The specific dermatoses of pregnancy represent a heterogeneous group of pruritic skin diseases that have been recently reclassified and include pemphigoid (herpes) gestationis, polymorphic eruption of pregnancy (syn. pruritic urticarial papules and plaques of pregnancy), intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. They are associated with severe pruritus that should never be neglected in pregnancy but always lead to an exact work-up of the patient. Clinical characteristics, in particular timing of onset, morphology and localization of skin lesions are crucial for diagnosis which, in case of pemphigoid gestationis and intrahepatic cholestasis of pregnancy, will be confirmed by specific immunofluorescence and laboratory findings. While polymorphic and atopic eruptions of pregnancy are distressing only to the mother because of pruritus, pemphigoid gestationis may be associated with prematurity and small-for-date babies and intrahepatic cholestasis of pregnancy poses an increased risk for fetal distress, prematurity, and stillbirth. Corticosteroids and antihistamines control pemphigoid gestationis, polymorphic and atopic eruptions of pregnancy; intrahepatic cholestasis of pregnancy, in contrast, should be treated with ursodeoxycholic acid. This review will focus on the new classification of pregnancy dermatoses, discuss them in detail, and present a practical algorithm to facilitate the management of the pregnant patient with skin lesions.
doi:10.5021/ad.2011.23.3.265
PMCID: PMC3162253  PMID: 21909194
Atopic eruption of pregnancy; Dermatoses of pregnancy; Intrahepatic cholestasis of pregnancy; Pemphigoid gestationis; Polymorphic eruption of pregnancy; Pruritus
14.  Prenatal sensitization of a postnatal trigger for metabolic disease 
The Journal of Clinical Investigation  2013;123(7):2786-2788.
Intrahepatic cholestasis of pregnancy (ICP), marked by elevated maternal serum bile acid levels, occurs in late pregnancy and is often associated with poor perinatal outcomes. In this issue of the JCI, Papacleovoulou et al. analyze the long-term consequences of ICP and find that teens born to mothers with ICP exhibit enhanced characteristics of metabolic syndrome relative to controls. The authors also used a new ICP mouse model to support and extend these findings, demonstrating that in utero exposure to bile acids induces persistent epigenetic alterations and abnormal placental lipogenesis, setting the stage for later metabolic dysfunction.
doi:10.1172/JCI69399
PMCID: PMC3696571  PMID: 23926602
15.  Intrahepatic cholestasis of pregnancy: When should you look further? 
Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy (ICP), a condition associated with significant fetal complications. Although the etiology of ICP is unclear in many cases, certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver disease. We report a kindred of Anglo-Celtic descent, among whom many members present with ICP, gallstones or cholestasis related to use of oral contraception. Genetic studies revealed a novel mutation in the ABCB4 gene, which codes for a phospholipid transport protein. The clinical significance of this mutation and the importance of identifying such patients are discussed.
doi:10.3748/wjg.15.1126
PMCID: PMC2655184  PMID: 19266607
ABCB4 gene; ABCB4 transporter; Phospholipids; Cholestasis of pregnancy; Gallstones
16.  Maternal cholestasis during pregnancy programs metabolic disease in offspring 
The Journal of Clinical Investigation  2013;123(7):3172-3181.
The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%–2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985–1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
doi:10.1172/JCI68927
PMCID: PMC3696570  PMID: 23934127
17.  In Search of an Accurate Evaluation of Intrahepatic Cholestasis of Pregnancy 
Scientifica  2012;2012:496489.
Until now, biochemical parameter for diagnosis of intrahepatic cholestasis of pregnancy (ICP) mostly used is the rise of total serum bile acids (TSBA) above the upper normal limit of 11 μM. However, differential diagnosis is very difficult since overlapped values calculated on bile acids determinations, are observed in different conditions of pregnancy including the benign condition of pruritus gravidarum. The aim of this work was to determine the better markers in ICP for a precise diagnosis together with parameters associated with severity of symptoms and treatment evaluation. Serum bile acid profiles were evaluated using capillary electrophoresis in 38 healthy pregnant women and 32 ICP patients and it was calculated the sensitivity, specificity, accuracy, predictive values and the relationships of certain individual bile acids in pregnant women in order to replace TSBA determinations. The evaluation of the results shows that LCA and UDCA/LCA ratio provided information for a more complete and accurate diagnosis and evaluation of ICP than calculation of solely TSBA levels in pregnant women.
doi:10.6064/2012/496489
PMCID: PMC3820586  PMID: 24278705
18.  Roles of PPARγ/NF-κB Signaling Pathway in the Pathogenesis of Intrahepatic Cholestasis of Pregnancy 
PLoS ONE  2014;9(1):e87343.
Background
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood.
Aim
To assess the expression of peroxisome proliferator-activated receptorγ (PPARγ) and nuclear factor kappa B (NF-κB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARγ/NF-κB signaling pathway in the possible mechanism of ICP.
Methods
Clinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARγ and NF-κB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARγ/NF-κB signaling pathway and ICP.
Results
The serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-α in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARγ and NF-κB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARγ and NF-κB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05).
Conclusions
The higher expressions of PPARγ and NF-κB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP.
doi:10.1371/journal.pone.0087343
PMCID: PMC3906154  PMID: 24489901
19.  Comparative Proteomics Analysis of Placenta from Pregnant Women with Intrahepatic Cholestasis of Pregnancy 
PLoS ONE  2013;8(12):e83281.
Introduction
Intrahepatic cholestasis of pregnancy (ICP) usually occurs in the third trimester and associated with increased risks in fetal complications. Currently, the exact cause of this disease is unknown. In this study we aim to investigate the potential proteins in placenta, which may participate in the molecular mechanisms of ICP-related fetal complications using iTRAQ-based proteomics approach.
Methods
The iTRAQ analysis combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to separate differentially expressed placental proteins from 4 pregnant women with ICP and 4 healthy pregnant women. Bioinformatics analysis was used to find the relative processes that these differentially expressed proteins were involved in. Three apoptosis related proteins ERp29, PRDX6 and MPO that resulted from iTRAQ-based proteomics were further verified in placenta by Western blotting and immunohistochemistry. Placental apoptosis was also detected by TUNEL assay.
Results
Proteomics results showed there were 38 differentially expressed proteins from pregnant women with ICP and healthy pregnant women, 29 were upregulated and 9 were downregulated in placenta from pregnant women with ICP. Bioinformatics analysis showed most of the identified proteins was functionally related to specific cell processes, including apoptosis, oxidative stress, lipid metabolism. The expression levels of ERp29, PRDX6 and MPO were consistent with the proteomics data. The apoptosis index in placenta from ICP patients was significantly increased.
Conclusion
This preliminary work provides a better understanding of the proteomic alterations of placenta from pregnant women with ICP and may provide us some new insights into the pathophysiology and potential novel treatment targets for ICP.
doi:10.1371/journal.pone.0083281
PMCID: PMC3877025  PMID: 24391750
20.  Intra-hepatic Cholestasis of Pregnancy: A Comprehensive Review 
Intra-hepatic cholestasis of pregnancy is a cholestatic disorder characterized by i) pruritus, with onset in the third trimester of pregnancy, without any primary skin lesions, ii) elevated fasting serum bile acids > 10 μmol/L (and elevated serum transaminases), iii) spontaneous relief of signs and symptoms within two to three weeks after delivery, and iv) absence of other disease that cause pruritus and jaundice. It is believed to be a multi-factorial disease with interplay between genetic, environmental and hormonal factors. Incidence is between 0.02% to 2.4% of all pregnancies; with wide geographical variations. Maternal prognosis is usually good but can result in adverse fetal outcomes like meconium staining of amniotic fluid, fetal bradycardia and even fetal loss. Response to anti-histaminic is poor. Of all the medical therapies that have been described for the treatment for IHCP, ursodeoxycholic acid has the best response in relieving pruritus in mother, and probably has a role in preventing even the perinatal complications. Timely diagnosis and treatment is urged in order to prevent fetal complications and an early delivery between 37 to 38 weeks should be contemplated in severe cases, especially once fetal lung maturity is attained.
doi:10.4103/0019-5154.113971
PMCID: PMC3726904  PMID: 23919027
Intra-hepatic cholestasis; pregnancy dermatosis; pruritus gravidarum
21.  Causes of Trauma in Pregnant Women Referred to Shabih-Khani Maternity Hospital in Kashan 
Archives of Trauma Research  2012;1(1):23-26.
Background
Trauma occurs in 7% of pregnancies and is a major cause of morbidity and mortality in the mother and fetus.
Objectives
The present study was conducted in Kashan in 2009–2010 to evaluate the causes of trauma in pregnancy.
Patients and Methods
This descriptive study analyzed data from 32 pregnant women with trauma who were referred to the maternity hospital from 2009 to 2010. Data included age, gestational age, mother’s occupation, cause of trauma, maternal-fetal complications, gravidity, and parity. The diagnosis of maternal and fetal complications was based on clinical examinations by a gynecologist and results of blood tests, urine analysis tests, and sonography. Data were analyzed as frequency distributions.
Results
the causes of trauma included falling (9 cases (28.1%)), abdominal trauma (8 cases ( 25%)), spousal feud (3 cases (9.4%)), motorcycle accident (2 cases (6.25%)), car accident (2 cases (6.25%)), falling from a motorcycle (2 cases (6.25%)), falling or fainting resulting in head trauma (1 case (3.1%)), pain from crossing over a bump in the car (1 cases (3.1%)), and unspecified causes (4 cases (12.55%)). The causes of traumas occurred between 5 and 40 weeks of gestation. In 17.2% of the cases, trauma occurred prior to 20 weeks of gestation. However, there was no significant relationship between the cause of trauma and maternal age or gestational age. Vaginal bleeding and retroplacental clots were reported in 2 (6.25%) cases and 1 (3.1%) case, respectively.
Conclusions
Nearly half of the women presenting with trauma had experienced spousal feud or domestic violence; therefore, it is necessary to recognize spousal abuse and provide adequate support to traumatized pregnant women.
doi:10.5812/atr.5291
PMCID: PMC3955936
Domestic Violence; Pregnant Women; Wounds and Injuries
22.  Fetal mortality associated with cholestasis of pregnancy and the potential benefit of therapy with ursodeoxycholic acid. 
Gut  1995;37(4):580-584.
Cholestasis of pregnancy is associated with increased fetal morbidity and mortality and should be treated actively. The significance attached to pruritus in pregnancy is often minimal, but it is a cardinal symptom of cholestasis of pregnancy, which may have no other clinical features. Eight women with previous cholestasis of pregnancy were referred to The Liver Unit within a 12 month period for advice concerning future pregnancies. Thirteen pregnancies had been affected by cholestasis of pregnancy and 12 had been treated expectantly with resultant perinatal morbidity or mortality in 11 (one normal delivery), including; eight stillbirths, two premature deliveries with fetal distress (one died in perinatal period), and an emergency caesarean section for fetal distress. The other pregnancy was treated actively and delivery was uncomplicated. Subsequently, three of these cases with recurrent cholestasis of pregnancy were referred while pregnant. In each, cholestasis developed with severe pruritus, gross increase of serum bile acids, and deranged liver tests. Each was treated with the choleretic agent ursodeoxycholic acid, with rapid clinical improvement and resolution of deranged biochemistry. In conclusion, cholestasis of pregnancy continues to be treated expectantly despite its association with increased morbidity and mortality and evidence suggesting improved prognosis with active treatment and the potential of reducing the associated perinatal mortality. In an uncontrolled series of three patients with cholestasis of pregnancy, ursodeoxycholic acid seemed to provide safe and effective therapy.
PMCID: PMC1382915  PMID: 7489950
23.  Good pregnancy outcome despite intrahepatic cholestasis 
Objective
Pregnant women complaining of itching are screened for intrahepatic cholestasis (ICP) by laboratory tests in primary healthcare. Cases of ICP are referred to specialist care. In Finland, ICP occurs in 1% of pregnancies. The aim was to study the outcome of deliveries.
Design
Retrospective study of ICP pregnancies. Data were collected from the hospital discharge register, patient records, and the labour register.
Setting
The region of Tampere University Hospital in Finland.
Subjects
Altogether 687 ICP cases from 1969 to 1988 and two controls for each.
Main outcome measures
ICP patients were compared with controls in terms of mother's age, pregnancy multiplicity, weeks of gestation at delivery, frequency of induction and Caesarean section, length of ward period, child's weight, Apgar scores, and stillbirth.
Results
For ICP patients, the risk for hospital stay of 10 days or more was eightfold (OR 8.41), for gestational weeks less than 37 at delivery sevenfold (OR 7.02), for induction threefold (OR 3.26), for baby's low weight at birth almost twofold (OR 1.86), and for Caesarean section one and a half fold (OR 1.47). The possibility of the incidence of multiple pregnancy was two and a half fold (OR 2.49, 95%). ICP was not associated with mother's age, the baby's risk of stillbirth, or low Apgar scores.
Conclusion
ICP mothers are found and taken care of appropriately, and thus ICP is only a minor risk for mothers and their children.
doi:10.3109/02813431003784001
PMCID: PMC3442314  PMID: 20429741
Caesarean section; intrahepatic cholestasis; length of stay; pregnancy outcome; primary healthcare
24.  Maternal age and fetal loss: population based register linkage study 
BMJ : British Medical Journal  2000;320(7251):1708-1712.
Objective
To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman's reproductive history.
Design
Prospective register linkage study.
Subjects
All women with a reproductive outcome (live birth, stillbirth, spontaneous abortion leading to admission to hospital, induced abortion, ectopic pregnancy, or hydatidiform mole) in Denmark from 1978 to 1992; a total of 634 272 women and 1 221 546 pregnancy outcomes.
Main outcome measures
Age related risk of fetal loss, ectopic pregnancy, and stillbirth, and age related risk of spontaneous abortion stratified according to parity and previous spontaneous abortions.
Results
Overall, 13.5% of the pregnancies intended to be carried to term ended with fetal loss. At age 42 years, more than half of such pregnancies resulted in fetal loss. The risk of a spontaneous abortion was 8.9% in women aged 20-24 years and 74.7% in those aged 45 years or more. High maternal age was a significant risk factor for spontaneous abortion irrespective of the number of previous miscarriages, parity, or calendar period. The risk of an ectopic pregnancy and stillbirth also increased with increasing maternal age.
Conclusions
Fetal loss is high in women in their late 30s or older, irrespective of reproductive history. This should be taken into consideration in pregnancy planning and counselling.
PMCID: PMC27416  PMID: 10864550
25.  Pruritus in pregnancy 
Canadian Family Physician  2013;59(12):1290-1294.
Abstract
Question
Some of my pregnant patients complain about pruritus. Are there conditions in pregnancy that present with pruritus that might put the mother or fetus at risk?
Answer
Although most cases of pruritus can be attributed to itchy dry skin, there are conditions unique to pregnancy that involve pruritus as a leading symptom. These include pemphigoid gestationis, pruritic urticarial papules and plaques of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. These conditions are associated with severe pruritus and some might be associated with adverse fetal outcomes. Clinical history and physical examination are the most important diagnostic clues when evaluating pruritus in pregnancy.
PMCID: PMC3860924  PMID: 24336540

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