Severe Intrahepatic Cholestasis Of Pregnancy Research Articles

Effect of maternal ursodeoxycholic acid treatment on fetal atrioventricular conduction in patients with intrahepatic cholestasis of pregnancy.

The aim of this study was, firstly, to investigate the difference in fetal atrioventricular conduction in patients with and without intrahepatic cholestasis of pregnancy (ICP) by measuring the fetal PR interval; secondly, to evaluate the altering effect of ursodeoxycholic acid (UDCA) treatment on the fetal PR interval in ICP patients. The study consisted of 42 ICP patients and 48 healthy pregnant women. Fetal echocardiography was performed to measure the mechanical PR interval. The fetal PR interval and the clinical characteristics were compared between the two groups. The effect of UDCA treatment on the fetal PR interval in ICP patients was evaluated. In ICP patients, significantly longer fetal PR intervals were observed than in the control group (123.21±8.54 vs. 115.13±5.95 ms, p<0.001). In the ICP group, there was a positive correlation between the fetal PR interval and maternal fasting total bile acid levels (TBA) (r=0.514, p=0.001). After one week of treatment with UDCA in patients with ICP, the PR interval was shorter than before, although the reduction was not statistically significant (120.98±6.70 vs. 123.21±8.54 ms, p=0.095). In patients with severe ICP (TBA>40 mmol/L, n=10), a significant reduction in the fetal PR interval was observed after treatment with UDCA (127,5ms [IQR, 118,0-134,75] before vs. 122ms [IQR, 109,5-126,5] after, p=0,037). Fetal PR interval increased in ICP patients in correlation with maternal serum TBA concentration. Treatment with UDCA may have limited positive effects on the fetal AV conduction system. The beneficial effects of UDCA on the fetal PR interval may be more pronounced in patients with higher bile acid levels.

Evaluation of alanine aminotransferase/aspartate aminotransferase ratio and high-density lipoprotein for predicting neonatal adverse outcomes associated with intrahepatic cholestasis of pregnancy.

To determine the association between lipid metabolism and intrahepatic cholestasis of pregnancy (ICP), and explore the value of maternal alanine aminotransferase/aspartate aminotransferase (ALT/AST) and high-density lipoprotein (HDL) in predicting adverse neonatal outcomes in women with ICP. A total of 147 pregnant women with ICP admitted to The Fourth Hospital of Shijiazhuang and 120 normal pregnant women in the same period were selected in this study. The Mann-Whitney U test and Chi-square tests were used to compare the differences in clinical data. Multivariate logistic regression was used to analyze the relationship between ALT/AST and the occurrence of adverse pregnancy outcomes in patients with ICP. The combined predictive value of ALT/AST and HDL was determined by receiver operating characteristic (ROC) curve analysis. Among 147 women with ICP, 122 women had total bile acid (TBA) levels of 10-39.9 µmol/L, and 25 had TBA ≥ 40 µmol/L. There was significantly lower gestational age in patients with severe ICP than in those with mild and control groups (all p<0.05), and the weight of newborns in the maternal ICP group was significantly lower than in the control group (p<0.05). Increasing TBA levels was associated with higher AST, ALT, ALT/AST, and lower HDL level (all p<0.05). Meanwhile, higher levels of ALT/AST was positively associated with neonatal hyperbilirubinemia [adjusted odds ratio (AOR) = 4.019, 95% CI [1.757-9.194, p=0.001] and cardiac injury [AOR = 3.500, 95% CI [1.535-7.987], p=0.003]. HDL was a significant protective factor for neonatal hyperbilirubinemia and cardiac injury [AOR = 0.315, 95% CI [0.126-0.788], p=0.014; AOR = 0.134 (0.039-0.461), p=0.001]. The area under the ROC curve (AUC) for prediction of neonatal hyperbilirubinemia by ALT/AST combined with HDL was 0.668 [95% CI [56.3-77.3%], p = 0.002], and the sensitivity and specificity were 47.1% and 84.0%, respectively. To predict neonatal cardiac injury, the AUC value was 0.668 [95% CI [56.4-77.1%], p = 0.002], with sensitivity and specificity were 41.2% and 87.1%, respectively. The levels of higher ALT/AST and lower HDL were significantly associated with the risk of ICP-related adverse neonatal outcomes. Moreover, ALT/AST combined with HDL has moderate clinical value in predicting the adverse outcomes of neonatal hyperbilirubinemia and cardiac injury.

Intrahepatic Cholestasis of Pregnancy during COVID-19 Pandemic.

Background and Objectives: Intrahepatic cholestasis of pregnancy (ICP) stands as one of the most prevalent concerns in maternal-fetal medicine, presenting a significant risk to fetal health and often associated with liver dysfunction. Concurrently, the coronavirus-19 (COVID-19) infection can lead to hepatic cell injury through both direct and indirect pathways. Hypothetically, these two conditions may coincide, influencing each other. This study aimed to comparatively assess the incidence and severity of ICP before and during the COVID-19 pandemic. Methods: A retrospective cohort study was conducted, comparing the incidence and severity of ICP between January 2018 and February 2020 (pre-COVID-19 period) and March 2020 to March 2022 (COVID-19 period) across two hospitals, encompassing 7799 deliveries. The diagnosis of ICP was established using the ICD-10 code and defined as total bile acids (BA) levels ≥ 10 μmol/L. Statistical analysis included descriptive statistics, Chi-square and Mann-Whitney U tests, as well as multiple or logistic regression analysis. Results: A total of 226 cases of ICP were identified. The incidence of mild cholestasis (BA < 40 μmol/L) was lower during the pandemic compared to before (3% before versus 2%, p < 0.05), while the incidence of moderate and severe ICP remained unchanged (0.6% before vs. 0.4%, p = 0.2). Overall, the total incidence of ICP was lower during the pandemic (3.6% before versus 2.4%, p = 0.01). No significant differences were observed in severity (as defined by BA and liver function test levels), rates of caesarean section, or neonatal birth weights. Conclusions: During the COVID-19 pandemic, the total incidence of ICP appeared to be lower. However, this reduction was primarily observed in cases of mild ICP, potentially indicating challenges in detection or reduced access to medical services during this period. The incidence of moderate and severe ICP remained unchanged, suggesting that these forms of the condition were unaffected by the pandemic's circumstances.

Gestational diabetes mellitus aggravates adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy

PurposeTo evaluate the effect of intrahepatic cholestasis of pregnancy (ICP) with gestational diabetes mellitus (GDM) on perinatal outcomes and establish a prediction model of adverse perinatal outcomes in women with ICP.MethodsThis multicenter retrospective cohort study included the clinical data of 2,178 pregnant women with ICP, including 1,788 women with ICP and 390 co-occurrence ICP and GDM. The data of all subjects were collected from hospital electronic medical records. Univariate and multivariate logistic regression analysis were used to compare the incidence of perinatal outcomes between ICP with GDM group and ICP alone group.ResultsBaseline characteristics of the population revealed that maternal age (p < 0.001), pregestational weight (p = 0.01), pre-pregnancy BMI (p < 0.001), gestational weight gain (p < 0.001), assisted reproductive technology (ART) (p < 0.001), and total bile acid concentration (p = 0.024) may be risk factors for ICP with GDM. Furthermore, ICP with GDM demonstrated a higher association with both polyhydramnios (OR 2.66) and preterm labor (OR 1.67) compared to ICP alone. Further subgroup analysis based on the severity of ICP showed that elevated total bile acid concentrations were closely associated with an increased risk of preterm labour, meconium-stained amniotic fluid, and low birth weight in both ICP alone and ICP with GDM groups. ICP with GDM further worsened these outcomes, especially in women with severe ICP. The nomogram prediction model effectively predicted the occurrence of preterm labour in the ICP population.ConclusionsICP with GDM may result in more adverse pregnancy outcomes, which are associated with bile acid concentrations.

Role of Systemic Immune Inflammatory Index to Predict Intrahepatic Cholestasis of Pregnancy.

The goal was to investigate the change of systemic immune inflammation index (SII) in high-risk pregnant women diagnosed with intrahepatic cholestasis of pregnancy (ICP). Between May 2018 and April 2020, we retrospectively enrolled 218 pregnant women who were followed in our hospital from the first trimester to delivery. We looked at the sociodemographics, laboratory data, SII values, Apgar ratings, and newborn birth weights of pregnant women with ICP. We also compared SII values in the first (SII 1), second (SII 2), and third trimesters (SII 3) between ICP and the control group. In the ICP group, the neutrophil level increased in the second trimester and decreased in the third trimester. The SII 2 was significantly higher in the severe ICP group, and when the SII values of the subgroups were examined, the SII 2 was significantly higher in the severe ICP group. The SII 2 showed a significant cutoff value for ICP with 92% sensitivity and 96% specificity. Again, a positive but weak correlation was found between SII 2 and SII 3 and FBA. When the neonatal outcomes were evaluated between the groups, gestational age at birth, birth weight and Apgar scores at 1 and 5 minutes were significantly lower in the ICP group. The relationship between SII and ICP was investigated for the first time in the literature and a significant cutoff value was found with the SII of the 2nd day. This showed that inflammation occupies an important place in the pathophysiology of cholestasis.

Systemic Inflammation Response Index as a diagnostic and prognostic predictor of intrahepatic cholestasis of pregnancy: A case-control study from a tertiary center.

To investigate the diagnostic and prognostic value of the Systemic Inflammation Response Index (SIRI) in intrahepatic cholestasis of pregnancy (ICP). The present case-control study comprised 386 participants, including 192 women with ICP and 194 gestational age-matched pregnant women. Increased fasting biliary acid (FBA) levels (≥10 μmol/L) were accepted as ICP criteria. SIRI values were calculated for the first trimester (SIRI 1), time of diagnosis (SIRI 2), and time of delivery (SIRI 3). The ICP and control groups were compared based on SIRI values, and on obstetrical and neonatal outcomes. The ICP subgroups based on FBA levels (severe ICP [FBA ≥40 μmol/L] and mild ICP [FBA <40 μmol/L]) were also compared for SIRI and pregnancy outcomes. Adverse outcomes were significantly higher in the ICP group (P < 0.001). SIRI 2 and SIRI 3 showed negative significant differences between the ICP and control groups, with P values of 0.001 and 0.009, respectively. A significant difference in ICP severity subgroups (P = 0.046) was observed for SIRI 3. In receiver operating characteristics curve analyses, optimal cut-off values for the prediction of ICP were found to be 2.01 and 2.08 for SIRI 2 and SIRI 3, respectively. A cut-off value 1.74 was determined to predict the disease severity for SIRI 3. SIRI has clinical significance in accordance with the inflammatory etiology of ICP. SIRI might be used with other clinical and laboratory findings for ICP diagnosis and prediction.

Profiles and integration of the gut microbiome and fecal metabolites in severe intrahepatic cholestasis of pregnancy

BackgroundThe pathogenesis of intrahepatic cholestasis of pregnancy (ICP) remains unknown. The gut microbiome and its metabolites play important roles in bile acid metabolism, and previous studies have indicated the association of the gut microbiome with ICP.MethodsWe recruited a cohort of 5100 participants, and 20 participants were enrolled in the severe ICP group, matched with 20 participants in the mild ICP group and 20 controls. 16S rRNA sequencing and nontargeting metabolomics were adapted to explore the gut microbiome and fecal metabolites.ResultsAn increase in richness and a dramatic deviation in composition were found in the gut microbiome in ICP. Decreased Firmicutes and Bacteroidetes abundances and increased Proteobacteria abundances were found in women with severe but not mild ICP compared to healthy pregnant women. Escherichia-Shigella and Lachnoclostridium abundances increased, whereas Ruminococcaceae abundance decreased in ICP group, especially in severe ICP group. The fecal metabolite composition and diversity presented typical variation in severe ICP. A significant increase in bile acid, formate and succinate levels and a decrease in butyrate and hypoxanthine levels were found in women with severe ICP. The MIMOSA model indicated that genera Ruminococcus gnavus group, Lachnospiraceae FCS020 group, and Lachnospiraceae NK4A136 group contributed significantly to the metabolism of hypoxanthine, which was significantly depleted in subjects with severe ICP. Genus Acinetobacter contributed significantly to formate metabolism, which was significantly enriched in subjects with severe ICP.ConclusionsWomen with severe but not mild ICP harbored a unique gut microbiome and fecal metabolites compared to healthy controls. Based on these profiles, we hypothesized that the gut microbiome was involved in bile acid metabolism through metabolites, affecting ICP pathogenesis and development, especially severe ICP.

Evaluation of maternal serum vascular endothelial growth factor C and D levels in intrahepatic cholestasis of pregnancy.

This study aimed to investigate maternal serum vascular endothelial growth factor (VEGF) C and D levels in patients with intrahepatic cholestasis of pregnancy (ICP). A total of 83 patients, including 41 patients with ICP and 42 healthy pregnant women, were included in the study. We first compared the maternal serum VEGF-C and VEGF-D levels between the ICP and control groups and then examined the correlation between the serum VEGF-C level and the bile acid level in patients with severe ICP. We observed statistically significantly higher serum VEGF-C levels and lower VEGF-D levels in the ICP group compared with the healthy controls (P < 0.001 and P = 0.015, respectively). According to receiver operating characteristic analysis, the optimal cutoff value for ICP was 147 ng/mL in the determination of the VEGF-C level (specificity and sensitivity: 76%). In patients with severe ICP, the serum VEGF-C statistically significantly correlated with the bile acid level (P = 0.019). This study showed that the maternal serum VEGF-C level was higher and the VEGF-D level was lower in patients with ICP compared with healthy pregnant women. We also found that the VEGF-C level was correlated with the serum bile acid level in patients with severe ICP. Serum VEGF-C level can be used in the diagnosis and follow-up of intrahepatic pregnancy cholestasis.

Risk-stratified management strategies for intrahepatic cholestasis of pregnancy: A tertiary center population review over nearly 5 years.

Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse perinatal outcomes, resulting in a higher risk of perinatal morbidity and mortality. The authors conducted a retrospective study of 2385 singletons with ICP who underwent risk-stratified management strategies. To explore the risks of perinatal outcomes of ICP, subgroup analyses were performed using different total bile acid (TBA) levels. In this study, there was only one stillbirth and one neonatal death. Among the study cohort, 2299 patients had ICP with a TBA level ≥10 μmol/L and 86 had ICP with a TBA level <10 μmol/L. The 2299 patients with ICP (TBA level ≥ 10 μmol/L) were divided into three groups: mild ICP (n = 1803), severe ICP (n = 400), and extremely severe ICP (n = 96). Increased TBA concentration was associated with an increased incidence of preterm birth, newborn asphyxia, neonatal intensive care unit hospitalization, meconium-stained amniotic fluid, and low birth weight in the three groups (P < 0.05). Furthermore, severe and extremely severe ICP with hypotonic absonant uterine contraction had a significant effect on neonatal asphyxia (odds ratio, 5.06 [95% confidence interval, 1.09-23.37]; P < 0.05) and meconium-stained amniotic fluid (odds ratio, 2.37 [95% confidence interval, 1.43-3.93]; P < 0.05). Hypotonic absonant uterine contractions could be high-risk stressors for severe and extremely severe ICP; hence, proper prenatal care is recommended. Risk-stratified management strategies for ICP are critical to obtaining better maternal-fetal outcomes.

Antenatal thiopurine exposure in women with IBD is associated with intrahepatic cholestasis of pregnancy

ABSTRACT Background Pregnant women with inflammatory bowel disease (IBD) continue thiopurines to maintain remission. Other studies have reported intrahepatic cholestasis of pregnancy (ICP) in IBD pregnancies exposed to thiopurines. We aimed to investigate whether thiopurines are associated with an increased risk of ICP. Research design and methods Single-center retrospective cohort study comparing incidence of ICP in thiopurine-exposed versus non-exposed patients with IBD compared with age-matched pregnant controls. Results The IBD cohort consisted of 386 pregnancies in 243 patients with IBD, with 386 age-matched controls. In patients with IBD, ICP was significantly more common among thiopurine-exposed pregnancies (9.0% vs 1.8%; odds ratio [95% confidence interval] = 5.34 [1.78–16.02]; p = 0.021). IBD patients with thiopurine exposure were significantly more likely to experience ICP compared to non-IBD controls (9.0% vs 1.3%; p < 0.001). Patients with IBD not exposed to thiopurines had a comparable ICP incidence with controls (1.8% vs 1.3%; p = 0.75). Severe ICP occurred in 80% of thiopurine-exposed ICP cases versus 40% in non-exposed (p = 0.25), versus 20% in controls (p = 0.09). Conclusion Thiopurine exposure was associated with a significantly increased risk of ICP among patients with IBD compared to non-exposed IBD patients and age-matched general population controls. The course of ICP was not significantly different in thiopurine-exposed cases.

Risk factors associated with cesarean section and adverse fetal outcomes in intrahepatic cholestasis of pregnancy.

To determine the risk factors for cesarean section (CS) and adverse fetal outcomes (AFOs) in patients with intrahepatic cholestasis of pregnancy (ICP) based on the severity of maternal hypercholanemia. A hospital-based retrospective cohort study was performed between January 1, 2015, and December 31, 2019. A total of 227 nulliparous women with a singleton fetus complicated by ICP were included. The patients were divided into two groups according to the levels of total bile acids, that is, mild (10 μmol/L < total bile acids < 40 μmol/L) and severe (≥40 μmol/L). The patients' clinical characteristics and fetal outcomes were assessed. Among the 227 eligible women, 177 (78.0%) were allocated to the mild group and 50 (22.0%) were in the severe group. Women with severe ICP also had a significantly higher incidence of planned and unplanned CS compared with mild ICP subjects (52.0% vs. 23.7% and 22.0% vs. 6.8%, respectively; p < 0.001). The indications for CS showed that fetal intolerance (65.4% vs. 14.3%) was higher in severe ICP compared with mild ICP (p < 0.001). Severe ICP was associated with an increased risk of preterm delivery (p < 0.001), low birthweight (p = 0.001), and neonatal intensive care unit (NICU) admission (p < 0.001). Women with severe ICP (OR 6.397, 95%CI 3.041-13.455, p < 0.001) or preeclampsia (OR 12.434, 95%CI 5.166-29.928, p < 0.001) had increased risks of AFOs compared to controls. Severe ICP and preeclampsia are associated with a higher incidence of AFOs.

Stress regulation of WFS1 and PERK-p-eIF2α-ATF4 signaling pathway in placental tissue cells of intrahepatic cholestasis of pregnancy

IntroductionThe placental tissue stress of intrahepatic cholestasis of pregnancy (ICP) is activated by ERS under hypoxia condition. PERK signaling pathway is the key pathway for UPR regulation, and is first to activated during ERS. WFS1, as an important regulatory gene of UPR pathway, participates in ERS regulation. The purpose of our study is to explore the expression level and mutual regulation mechanisms of WFS1 and PERK-mediated UPR pathway in ICP placental tissue cell under stress. MethodsBlood and placenta samples were obtained from the ICP patients and ethinylestradiol (EE)-induced intrahepatic cholestasis pregnant rats. IHC and WB were used to detect the expression of WFS1, key factors of PERK pathway (GRP78, PERK, eIF2a, P-eIF2α, ATF4) and placental stress peptides (CRH, UCN). Furthermore, qPCR was carried out to detect mRNA expression of above indicators. ResultsThe expression levels of WFS1 and key factors of PERK pathway were significantly increased in severe ICP placental tissues. Moreover, qPCR and WB showed that relative mRNA and protein expression levels of WFS1 and key factors of PERK pathways in placenta tissues of severe ICP and EE-induced intrahepatic cholestasis pregnant rats were higher than those in control group to varying degrees, while CRH and UCN were descended. Meanwhile, after WFS1-siRNA targeted silencing of the WFS1 gene, the protein expression levels of PERK, P-eIF2α, ATF4 were significantly increased, while CRH and UCN protein were significantly decreased. DiscussionOur study revealed that the activation of WFS1 and PERK-p-eIF2α-ATF4 signaling pathway may contribute to stress regulation in placental tissue cells of intrahepatic cholestasis of pregnancy, thereby avoiding adverse pregnancy outcomes.

The spatial expression of mTORC2-AKT-IP3R signal pathway in mitochondrial combination of endoplasmic reticulum of maternal fetal interface trophoblast in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is complicated by adverse fetal outcomes and even fetal death, the mechanism remains unclear. This study aims at evaluating the differential expression of mTORC2-AKT-IP3R signaling pathway, which accurately regulate Ca2+ transfer across mitochondria-associated membranes (MAMs) and determine the stress intensity experienced by endoplasmic reticulum (ER) and mitochondria, in patients diagnosed withICP. We combined western blot analysis and placental immunofluorescence co-localization detection to assess the expression and co-localization of the mTORC2-AKT-IP3R signaling pathway in severe (maternal total bile acid (TBA) levels≥40 μmol/L) and mild (maternal TBA 10-40 μmol/L) ICP. Compared with the control and mild ICP groups, phosphorylated protein kinase B (p-AKT) levels were significantly upregulated in the severe ICP group. Placental Rictor levels were lower in the mild ICP group than in the control group and were further downregulated in the severe ICP group. IP3R3 and p-IP3R3 levels were lower in placentas in the severe ICP group than in those in the mild ICP and control groups. Moreover, the co-localization of IP3R3 and p-AKT in patients in the mild and severe ICP groups was significantly elevated compared with that in patients in the control group. In patients with severe ICP, limited expression of Rictor and elevated p-AKT levels would suppress IP3R3/p-IP3R3 levels in MAMs. This inhibition might influence the transportation of Ca2+ from the ER to the mitochondria, thus weaken the stress adaptation associated with MAMs. Our results reveal the possible pathophysiological mechanism of adverse fetal outcomes in ICP.

P496 Antenatal thiopurine exposure in women with IBD is associated with intrahepatic cholestasis of pregnancy

Abstract Background Pregnant women with Inflammatory Bowel Disease (IBD) continue thiopurines to maintain remission. Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy, often causing distressing maternal symptoms and with potential implications for pregnancy outcome. Case studies have reported treatment-resistant intrahepatic cholestasis of pregnancy in thiopurine-exposed IBD pregnancies. We aimed to investigate whether thiopurines are associated with an increased risk of ICP and the course of ICP in the setting of thiopurine therapy. Methods Single-centre retrospective cohort study comparing incidence and course of ICP in thiopurine exposed vs non-exposed patients with IBD and compared with age-matched pregnant controls. Results The IBD cohort consisted of 386 pregnancies in 243 patients with IBD, with 386 age-matched controls without IBD. In patients with IBD, ICP was more common amongst thiopurine exposed pregnancies (n=10 9.0% vs n=5 1.8%; OR 5.34 [1.78-16.02]; p=0.021). Only thiopurine exposure was associated with the development of ICP. Age, disease activity, IBD phenotype, previous surgery, mesalazine, biologic, and steroid exposure were not associated. All thiopurine exposed ICP cases (of which 4 received ursodeoxycholic acid) improved symptomatically without thiopurine discontinuation. The incidence of ICP was significantly lower in women without IBD compared with women with IBD (n=5 1.3% vs n=15 4.1%; p=0.039). Thiopurine-exposed IBD patients had higher odds of experiencing ICP compared to non-IBD controls (n= 10 9.0% vs n=5 1.3%; OR 7.55 [2.52-22.57]; p&amp;lt;0.001). IBD patients not exposed to thiopurines had a comparable ICP incidence to controls (n-=5 1.8% vs n=5 1.3%; p=0.75). Severe ICP (total serum bile acids ≥40 µmol/l) occurred in 80% of thiopurine exposed patients, vs 40% in non-exposed (p=0.25), vs 20% in controls (p=0.09). We found no evidence of an unfavourable course of ICP in thiopurine exposed IBD cases. Median week of delivery was not significantly different among ICP cases in all three groups (p=0.39). Conclusion Thiopurine exposure was associated with a significantly increased risk of ICP amongst patients with IBD compared to non-exposed IBD patients and age-matched general population controls. The course of ICP was not significantly different in thiopurine exposed cases. Clinicians involved in the management of patients with IBD should be aware of the potential risk for ICP and assess bile acids when symptoms occur. Prospective studies are required to understand the potential relationship between thiopurine metabolites and ICP.

Elevated GABRP expression is correlated to the excessive autophagy in intrahepatic cholestasis of pregnancy

In intrahepatic cholestasis of pregnancy (ICP) patients, high concentrations of bile acids altered the normal maternal-fetal-unit physiological condition and could bring negative influence on placenta functionality. GABRP is the pi subunit of the gamma-aminobutyric acid type A receptor (GABAA) and plays pivotal role in regulating GABAA receptor's physiological function. Here we presented evidence that increased expression of GABRP in parallel with autophagic biomarkers, LC3 and ATG14, in patients with ICP. Methods: A total of 27 participants, including 18 ICP patients and 9 healthy pregnancies were recruited according to strict inclusion criteria. Placentas of ICP patients and controls were collected immediately after cesarean section before labor onset. GABRP and autophagic markers expression in placenta were investigated by immunohistochemistry (IHC), RT-qPCR, and Western blot. Results: The neonatal birthweight and gestational weeks were significantly lower in severe ICP group, while the hepatic enzymes were elevated in ICP group. Semiquantitative analysis of IHC revealed the AOD of GABRP in severe ICP patients was higher than that in mild ICP patients and control pregnancies. Western blot and RT-qPCR analysis both indicated that the expression of GABRP and ATG14 were significantly elevated in severe ICP patients. Moreover, GABRP was correlated with TBA (r = 0.64, p < 0.05), ATG14 (r = 0.87, p < 0.05), direct bilirubin (r = 0.54, p < 0.05), ALT (r = 0.72, p < 0.05), and AST (r = 0.67, p < 0.05). Conclusion: There were elevated expression of GABRP, ATG14 and LC3 in ICP placentas compared with uncomplicated pregnancies. The expression of GABRP was associated with autophagy and was correlated with the TBA levels.

Feto-Maternal Effects of Adding Rifampicin to Ursodeoxycholic Acid in the Treatment of Intrahepatic Cholestasis of Pregnancy.

Background Various pharmacological agents are used to manage intrahepatic cholestasis of pregnancy (ICP) for maternal pruritus and to lower serum bile acids in fear of adverse fetal outcomes. Ursodeoxycholic acid (UDCA) is the most widely used drug, but some patients do not respond to it. Neither UDCA nor any other drug being used for ICP is based on a high level of evidence. Methods A total of 108 pregnant women with ICP who were receiving UDCA with or without rifampicin were included in a prospective observational study from December 2018 to November 2020. Seventy-eight patients receiving UDCA onlywere labeled as group A, and 30 patients receiving UDCA with rifampicin were labeled as group B. Results The study subjects were comparable in both groups with respect to demographic factors. Pruritus, being the major symptom of ICP, has a mean (standard deviation (SD)) onset at 30.02 (2.93) weeks and 26.70 (4.56) weeks of gestation in groups A and B, respectively. Group B patients had earlier onset of symptoms and earlier mean (SD) gestational age atdiagnosis at 28.89 (4.29) weekscompared to 32.47 (2.93) weeks in group A. Therefore, the mean (SD) gestational age to start UDCA was early in group B (29.32 (4.24) weeks). Relief in itch from UDCA was seen in 93.59% (73) in group A and 10% (3) in group B (partial relief). The mean (SD) duration for receiving only UDCA was 3.84 (2.07) weeks and 2.86 (1.58) weeks, respectively, for groups A and B. The mean (SD) gestational age at starting rifampicin was 32.11 (3.4) weeks for group B (n = 30).UDCA plus rifampicin was given for a mean (SD) duration of 3.48 (1.42) weeks. The mean (SD) dosage of UDCA given per day was 911.54 (229.05) mg in group A and 880(260.50) mg in group B (p value = 0.563). The mean (SD) dosage of rifampicin used in group B was 700(363.89) mg/day. The mean (SD) of baseline bile acids (pretreatment) was 36.94 (13) umol/L and 42.50 (15.23) umol/L in groups A and B, respectively (p value = 0.274). At the two-weekfollow-up, the mean (SD) value of serum bile acids was 22.92 (10.67) umol/L and 14.88 (10.27) umol/L in groups A and B, respectively (p value = 0.039). Group B having an earlier onset of ICP also had early gestational age at delivery at 35.70 (2.57) weeks versus 37.011 (1.18) weeks in group A. Of the babies in groups A and B,63%and 50% were born full term, respectively. There was no significant difference in the mode of delivery for both study groups. The mean (SD) birth weight of babies was 2,706.85 (206.19) grams for group A and 2,522.67 (342.20) grams in group B. Adverse neonatal outcomes for both groups were comparable (68.5% in group A and 70% in group B) (p value = 0.881). Of the patients,9%and 6.7% had antepartum stillbirth in groups A and B, respectively. Of the babies in groups A and B,10.3% and 6.7% were born with dark-colored meconium or placental membranes and cord stained with meconium, respectively. In groups A and B, 9% and 6.7% of the babies were born with thin/light green meconium-stained liquor,respectively. Conclusion Rifampicin, if added to UDCA for the management of ICP, does not cause any adverse fetal outcome. It is auseful adjunct to UDCA for severe and/or resistant ICP, and it helps improve pruritus and serum bile acids.

Diagnosis and Management of Intrahepatic Cholestasis of Pregnancy- A Retrospective Clinical Audit

Introduction: Pregnant women presenting with pruritus, serum bile acid (SBA) ≥10 µmol/L and/or alanine transaminase (ALT) &gt;30 U/l is diagnostic of intrahepatic cholestasis of pregnancy (ICP). A retrospective audit was performed to look at the diagnosis, management and outcomes of ICP patients in University Malaya Medical Center (UMMC). Methods: SBA requests from Obstetrics and Gynaecology Department from 1st January 2016 to 31st December 2020 were extracted from Laboratory Information System (LIS). The medical records (preexisting medical conditions, maternal and perinatal outcomes) of ICP were obtained. Mild and severe ICP were defined based on SBA 10-40µmol/L and SBA &gt;40 µmol/L, respectively. Results: SBA was requested for 202 pregnant women. The prevalence of ICP in our cohort was 0.18% (47 out of 26,697 deliveries). The average gestation at diagnosis was 35 weeks. Both SBA and liver enzymes were elevated in 25 (53.2%) whereas only SBA was elevated in 20 (42.6%) women. In two women, the diagnosis was made based on clinical symptoms and elevated liver enzyme alone. All with ICP had a livebirth and 31.9% were preterm. Severe ICP was noted in eight (17%) and all had cesarean section, whereas, in mild ICP, only 17 (44%) had a caesarean section. In those with normal SBA (n=149) at initial presentation, a repeat SBA was performed only in 12 (8.1%). Postpartum follow-up of ICP patients was observed in only 10 (21.2%). Conclusion: Despite being an uncommon diagnosis in our population, early diagnosis and timely delivery is important to reduce the major perinatal adverse outcomes. In women with persistent pruritus but without the biochemical evidence of ICP at the time of presentation should have repeat SBA and LFT done.

Severe Intrahepatic Cholestasis Pregnancy Is Associated With Maternal Endothelial Dysfunction: A Case-Control Study.

The aim of the present study was to evaluate maternal serum endocan levels, which are markers of vascular pathologies andstrongly associated with vascular inflammationand endothelial dysfunction, in pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP). The study comprised 30 pregnant women with mild ICP, 30 pregnantwomen with severe ICP, and 30 healthy pregnant women as a control group. The inclusion criteria were women with ICP, which was diagnosed based upon the presence of pruritus associated with elevated total bile acid (TBA) levels (> 10 μm/L), elevated aminotransferases, or both, and the absence of diseases that may produce similar laboratory findings and symptoms. Severe ICP was defined as TBA > 40 μmol/L. After diagnosis for ICP, blood samples were obtained before medication during hospitalization to analyze maternal serum endocan levels. Gestational age at delivery, delivery induction rates, birth weight, and newborn intensive care unit (NICU) admission rates were significantly higher in the severe ICP group than in the control group and mild ICP group. Gestational age for all groups when blood was sampled was similar. Maternal serum TBAsand aminotransferase levels were significantly higher in the severe ICP group than in the control group and mild ICP group. The mean serum endocan levels were 10.9 ± 2.6 ng/mL in the control group, 12.5 ± 2.8 ng/mL in the mild ICP group, and 24.3 ± 4.8 ng/mL in the severe ICP group (p < 0.001). Our results indicated that maternal serum endocan levels were increased in the presence of severe ICP and it can be speculated that increased bile acid levels were associated with maternal endothelial dysfunction.

Severe intrahepatic cholestasis of pregnancy due to a Sertoli-Leydig cell tumour in a woman with polycystic ovary syndrome: a case report

BackgroundIntrahepatic cholestasis of pregnancy (ICP) is a common gestational complication characterized by pruritus and elevated bile acids, usually occurring in the third trimester when the serum estrogen and progesterone levels are highest. Hyperandrogenism during pregnancy is a pathological state that is mostly induced by polycystic ovary syndrome (PCOS) but rarely by concomitant androgen-secreting ovarian tumours. To date, no correlation has been drawn between ICP and hyperandrogenism.Case presentationHere, we present a rare case of early-onset severe ICP in a PCOS patient conceived via in vitro fertilization-embryo transfer, with worsening hirsutism and acne due to high levels of testosterone and dehydroepiandrosterone sulphate, both of which were produced by a fast-growing ovarian Sertoli–Leydig cell tumour. Her serum estradiol was also very high, which was speculated to be converted from the circulating androgens by the placenta. She had preterm premature rupture of membranes and delivered at 30 weeks, followed by a rapid remission of ICP as her serum estradiol dropped. However, the excessive androgens did not retreat until the large ovarian tumour was surgically removed.ConclusionThis unusual case highlights the concurrence of original hyperandrogenism and subsequent hyperestrogenism during pregnancy and the resultant confounding manifestations. Obstetricians should be aware of the potential association between androgen excess and ICP via placental aromatization.

A Systematic Review On Complications of Intrahepatic Cholestasis of Pregnancy

A potentially dangerous liver condition called intrahepatic cholestasis of pregnancy (ICP) can appear during pregnancy. Primarily manifesting in the third trimester, characteristic symptoms include pruritus (itching) of the soles and palms, elevated blood bile acid levels, and impaired liver function. Several medications have been demonstrated to significantly improve biochemical indicators and gestational age of birth in patients with ICP, and they also alleviate the pruritus experienced by the mother. The use of these drugs during pregnancy may have serious consequences. This systematic review aims to describe maternal and foetal outcomes related to ICP and identify major biochemical and clinical predictors of foetal problems in women diagnosed with ICP. To provide context for the current investigation, Google Scholar and PubMed were searched for articles published between 2012 and 2022. References and bibliographies were employed in manual searches in addition to internet resources. Critical Appraisal Skills Program (CASP) evaluated all selected research papers. Findings were presented using descriptive summary table besides critical analysis. Risks of adverse perinatal outcomes, such as stillbirth and early delivery, were associated with twin pregnancies with ICP. But, premature delivery and neonatal hypoxia are more common in IVF-created twin pregnancies than in naturally conceived twin births. Severe ICP effects are linked with higher risks of stillbirth, admission to a neonatal intensive care unit, and preterm delivery. Some perinatal issues are associated with a mother's serum bile acid levels rising during pregnancy. Congenital disabilities, premature birth, and postpartum bleeding are all associated with ICP. Extreme instances of ICP frequently result in the abrupt and unexpected death of the fetus inside the uterus. ICP and stillbirth develop early in twin pregnancies. Therefore, delivering at 37 weeks may not be desirable. Enhancing fetal prognosis, particularly in twin pregnancies generated through IVF, requires early and correct diagnosis and proper medical intervention. To reduce the likelihood of an indicated preterm delivery, the decision to terminate a pregnancy in pregnancies created through IVF should be made carefully. Despite the fact that there was a clear link between ICP and preeclampsia and GDM, ICP did not raise the risk of stillbirth. Bile acid levels between the mother and fetus correlate, suggesting a causative link between BA levels, prenatal problems, and bad outcomes. Keywords: Intrahepatic cholestasis of pregnancy; pregnancy outcomes; gynecology; women health