Intrahepatic Cholestasis Of Pregnancy Group Research Articles

Expression and clinical significance of short-chain fatty acids in patients with intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver condition that typically arises in the middle and late stages of pregnancy. Short-chain fatty acids (SCFAs), prominent metabolites of the gut microbiota, have significant connections with various pregnancy complications, and some SCFAs hold potential for treating such complications. However, the metabolic profile of SCFAs in patients with ICP remains unclear. To investigate the metabolic profiles and differences in SCFAs present in the maternal and cord blood of patients with ICP and determine the clinical significance of these findings. Maternal serum and cord blood samples were collected from both patients with ICP (ICP group) and normal pregnant women (NP group). Targeted metabolomics was used to assess the SCFA levels in these samples. Significant differences in maternal SCFAs were observed between the ICP and NP groups. Most SCFAs exhibited a consistent declining trend in cord blood samples from the ICP group, mirroring the pattern seen in maternal serum. Correlation analysis revealed a positive correlation between maternal serum SCFAs and cord blood SCFAs [r (Pearson) = 0.88, P = 7.93e-95]. In both maternal serum and cord blood, acetic and caproic acids were identified as key metabolites contributing to the differences in SCFAs between the two groups (variable importance for the projection > 1). Receiver operating characteristic analysis demonstrated that multiple SCFAs in maternal blood have excellent diagnostic capabilities for ICP, with caproic acid exhibiting the highest diagnostic efficacy (area under the curve = 0.97). Compared with the NP group, significant alterations were observed in the SCFAs of maternal serum and cord blood in the ICP group, although they displayed distinct patterns of change. Furthermore, the SCFA levels in maternal serum and cord blood were significantly positively correlated. Notably, certain maternal serum SCFAs, specifically caproic and acetic acids, demonstrated excellent diagnostic efficiency for ICP.

Characteristics and diagnostic value of serum bile acids profile in pregnant women with intrahepatic cholestasis of pregnancy and asymptomatic hypercholanemia of pregnancy

Objective: To analyze serum bile acid profiles in pregnant women with normal pregnancy, intrahepatic cholestasis of pregnancy (ICP) and asymptomatic hypercholanemia of pregnancy (AHP), and to evaluate the application value of serum bile acid profiles in the diagnosis of ICP and AHP. Methods: The clinical data of 122 pregnant women who underwent prenatal examination in Xuzhou Maternal and Child Health Care Hospital from June 2022 to May 2023 were collected, including 54 cases of normal pregnancy group, 28 cases of ICP group and 40 cases of AHP group. Ultraperformance liquid chromatography-tandem mass spectrometry was used to measure the levels of 15 serum bile acids in each group, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA), glycolcholic acid (GCA), glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), glycolithocholic acid (GLCA), glycoursodeoxycholic acid (GUDCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), taurodeoxycholic acid (TDCA), taurolithocholic acid (TLCA) and tauroursodeoxycholic acid (TUDCA). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to screen differential bile acids. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficacy of differential bile acids and combined indicators between groups. Results: (1) Compared with normal pregnancy group, the serum levels of LCA, GCA, GCDCA, GDCA, GLCA, UDCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in ICP group were significantly different (all P<0.05), while the levels of LCA, DCA, GCA, GCDCA, GDCA, GLCA, TCA, TCDCA, TDCA, TLCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). Compared with ICP group, the serum levels of CDCA, DCA, UDCA, TDCA, GUDCA and TUDCA in AHP group were significantly different (all P<0.05). (2) In the OPLS-DA model, the differential bile acids between ICP group and AHP group were TUDCA, TCA, UDCA, GUDCA and GCA, and their variable importance in projection (VIP) were 1.489, 1.345, 1.344, 1.184 and 1.111, respectively. TCA, GCDCA, GCA, TDCA, GDCA and TCDCA were the differentially expressed bile acids between AHP group and normal pregnancy group, and their VIP values were 1.236, 1.229, 1.197, 1.145, 1.139 and 1.138, respectively. (3) ROC analysis showed that the area under the curve (AUC) of TUDCA, TCA, UDCA, GUDCA and GCA in the differential diagnosis of ICP and AHP was 0.860, and the sensitivity and specificity were 67.9% and 95.0%, respectively. The AUC of TCA, GCDCA, GCA, TDCA, GDCA and TCDCA in the diagnosis of AHP was 0.964, and the sensitivity and specificity were 95.0% and 93.1%, respectively. Conclusions: There are differences in serum bile acid profiles among normal pregnant women, ICP and AHP. The serum bile acid profiles of pregnant women have potential application value in the differential diagnosis of ICP and AHP and the diagnosis of AHP.

Intrahepatic cholestasis of pregnancy and its association with preeclampsia and gestational diabetes: a retrospective analysis.

To evaluate maternal and neonatal outcomes in patients with intrahepatic cholestasis of pregnancy (ICP). Patients who gave birth in our hospital between January 2018 and March 2022 were retrospectively reviewed from the hospital database and patient file records. The study comprised 1686 patients, 54 in the ICP group and 1632 controls. Patients who had ICP after 20weeks of gestation and were monitored and delivered at our facility were enrolled. Maternal demographic and obstetric characteristics data were examined. Perinatal outcomes were also assessed. Logistic regression analysis was used to determine adverse maternal outcomes. The mean age was 29years. ART, GDM, and preeclampsia were significantly higher in the ICP group. The mean serum bile acid level was 19.3 ± 3μmol/L in the ICP group. There was a higher risk of GDM and pre-eclampsia in women with ICP compared with those without and a significant association between ICP and adverse perinatal outcomes. There was a statistically significant relation between the presence of ICP and spontaneous preterm delivery, iatrogenic preterm delivery, 5th-minute Apgar scores < 7, and NICU requirement. No significant relationship was found between the presence of ICP and SGA and meconium. There was a significant relationship between the presence of ICP, mode of delivery, and PPH (p < 0.05). Those with ICP had a lower gestational week and birth weight, and higher rates of cesarean delivery and PPH. ICP should prompt close monitoring and management to mitigate the potential exacerbation of adverse outcomes, including preeclampsia, GDM, and preterm birth.

The correlation between serum total bile acid and adverse perinatal outcomes in pregnant women with intrahepatic cholestasis of pregnancy (ICP) and non-ICP hypercholanemia of pregnancy.

The association between excessive serum total bile acid (TBA) and adverse perinatal outcomes in individuals with non-intrahepatic cholestasis of pregnancy (non-ICP) hypercholanemia has not been determined, and it is unclear if this link is similar to that observed in patients with ICP. To examine the adverse perinatal outcomes in two specific subcategories: those with ICP and those with non-ICP, including individuals with liver disease and asymptomatic hypercholanemia of pregnancy (AHP), at different levels of TBA. Investigate the correlation between TBA levels and adverse perinatal outcomes of ICP, liver disease, and AHP. From 2013 to 2021, pregnant women with excessive TBA levels were taken from the electronic medical record database of our hospital and categorized into three groups: ICP (n = 160), liver disease (n = 164), and AHP (n = 650). This was done as part of a retrospective cohort research project. Multivariable regression and subgroup analyses were performed to examine the association between TBA levels and adverse perinatal outcomes in each group. The study found no significant differences in adverse perinatal outcomes between the ICP and liver disease groups at different TBA levels. However, at moderate TBA levels, both groups had a higher risk of adverse perinatal outcomes than the AHP group (p < 0.017). Among liver disease cases with TBA ≥ 100µmol/L, three cases of perinatal deaths (6.67%) associated with moderate-to-severe acute hepatitis occurred between 27 and 33 weeks of gestation. A 59% higher chance of perinatal death was found for every 10 µmol/L rise in TBA, even after significant variables and confounders were taken into account (adjusted odds ratio (aOR) = 1.59; 95% confidence interval (CI): 1.06-2.40; p = 0.03). If a pregnant woman has moderate-to-severe liver disease and TBA ≥ 100µmol/L, preterm termination of pregnancy (before 34 weeks) may be considered.

Metabolomic profiling of serum and tongue coating of pregnant women with intrahepatic cholestasis in pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of cesarean section and adverse fetal outcomes. Currently, ICP diagnosis depends largely on serum levels of bile acids and lacks sensitivity and specificity for accurate diagnosis. Tongue diagnosis is an important diagnostic tool in traditional Chinese medicine (TCM) and is used in our clinic as complementary treatment and personalized medicine for ICP. However, the molecular basis of the manifestation of greasy white tongue coatings in ICP remains unknown. In this study, we performed untargeted metabolomic profiling of the serum, tongue coating, and saliva of 66 pregnant women, including 22 with ICP. The metabolomic profiles of the serum and tongue coatings showed marked differences between the two clinical groups. Forty-six differentially abundant metabolites were identified, and their relative concentrations correlated with total bile acid levels. These differential metabolites included bile acids, lipids, microbiota- and diet-related metabolites, and exposomes. Conventional biochemical markers, including serum aminotransferases and bilirubin, were not significantly increased in the ICP group, whereas the total cholesterol and triglyceride levels were significantly increased as early as the first trimester. Our data provide insights into the pathophysiology of ICP and implicate the gut-liver axis and environmental exposure. Tongue coating has the potential to be a non-invasive diagnostic approach. Further studies are required to validate the clinical utility of these findings.

Proteomic Biomarkers of Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, which can lead to adverse fetal outcomes, including preterm labor and intrauterine death. The pathogenesis of ICP is still unclear. We hypothesized that pathological index leads to abnormal placenta changes in ICP. Investigation of these differences in protein expression in parallel profiling is essential to understand the comprehensive pathophysiological mechanism underlying ICP. The present study screened differentially expressed proteins (DEPs) as novel diagnostic markers for ICP. Proteomic profiles of placental tissues from 32 ICP patients and 24 healthy volunteers (controls) were analyzed. Our founding was valid by following western blotting and immunohistochemistry staining, respectively. The association of the key protein expression with clinicopathological features of ICP was further analyzed. A total of 178 DEPs were identified between the ICP and control groups. Functional enrichment analysis showed these proteins were significantly enriched in the PPAR singling pathway by KEGG and PPARα/RXRα activation by IPA. Apolipoprotein A2 (APOA2) was the only upregulated protein, which uniquely identified in ICP groups and related to both pathways. Validation of western blotting and immunohistochemical staining analysis showed significantly higher APOA2 expression in the ICP group than in the control group. Furthermore, the expression of APOA2 is associated with clinicopathological features in ICP groups. Receiver operating characteristic (ROC) curve analyses showed that the AUC of APOA2 was 0.8984 (95% confidence interval (CI): 0.772-1.000). This study has identified up-regulated APOA2 associated with PPAR singling pathway and PPARα/RXRα activation in ICP. Thus, APOA2 may be involved in ICP pathogenesis, serving as a novel biomarker for its diagnosis.

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.

İlk Trimesterde Monosit Sayısı ve Monosit Bazlı Kan Hücre İndekslerinin Gebeliğin İntrahepatik Kolestazı Gelişimi, Şiddeti ve Prognozunu Öngörmedeki Rolü

Abstract&#x0D; Aim: To evaluate the effect of monocyte count and monocyte-based whole blood cell indices in the prediction of intrahepatic cholestasis of pregnancy (ICP) in the first trimester.&#x0D; Materials and Method: The clinical data of patients who presented to the Perinatology Clinic of the Turkish Ministry of Health ----xxxxxxx--- ICP between January 1, 2021, and October 1, 2022, were evaluated retrospectively. Maternal demographic parameters, gestational age at birth, fetal birth weight, first-trimester white blood cell, neutrophil, platelet, monocyte, lymphocyte, and basophil counts, lymphocyte-to-monocyte ratio (LMR), platelet-to-monocyte ratio (PMR), neutrophil-to-monocyte ratio (NMR), and basophil-to-monocyte ratio (BMR) were recorded. These parameters were compared between the ICP and control groups. The relationship between monocyte count, monocyte-based blood cell indices, and fasting bile acid levels was evaluated in the ICP group. The cut-off values of the first-trimester monocyte count and monocyte-based blood cell indices for the prediction of ICP were determined.&#x0D; Results: Gestational week at birth and fetal birth weight were significantly lower, and the neonatal intensive care requirement was significantly higher in the ICP group (p

COVID-stasis of Pregnancy: An Increased Prevalence of COVID-19 in Patients with Cholestasis.

To evaluate the relationship between intrahepatic cholestasis of pregnancy (ICP) and coronavirus disease 2019 (COVID-19). We performed a retrospective cohort study of pregnant women undergoing induction of labor (IOL) at a single institution between May 2020 to January 2021. Primary exposure was diagnosis of intrahepatic cholestasis of pregnancy (ICP). The primary outcome was the prevalence of COVID-19 as determined by reverse-transcriptase polymerase chain reaction testing on nasopharyngeal swabs for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) on routine admission testing. Secondary outcomes were abnormal laboratory values and adverse fetal outcomes. Logistic regression with log link analysis was performed comparing patients undergoing IOL for ICP compared with IOL for all other indications. The moderating effect of ethnicity was assessed by the interaction between ethnicity and ICP in a logistic regression model. The Wilcoxon rank-sum test and Fisher's exact test were performed for the secondary outcome analyses. Over the course of the study, 596 patients underwent IOL: 24 for ICP and 572 for other indications. The overall prevalence of COVID-19 positivity in the cohort was 5.5% (33 of 596). Those with ICP were more likely to test positive for COVID-19 compared with those with other IOL indications (29.2 vs. 4.5%, RR = 6.4, 95% CI: 2.8-12.5, p < 0.001). All patients with ICP who tested positive for COVID-19 were Hispanic. To analyze the moderating effect of ethnicity, the results of the logistic model found the interaction between ethnicity and ICP to not be significant (p = 0.991). In patients with ICP, the median AST (aspartate aminotransferase) was higher than those with COVID-19 (p = 0.0182). There were no adverse fetal outcomes in the ICP group. In this single-site retrospective cohort study, we demonstrated an increased prevalence of COVID-19 in those with ICP in general and among Hispanic patients specifically. Despite this difference, there was no increased risk of adverse fetal outcomes. · There is an increased prevalence of COVID-19 among Hispanic patients with ICP.. · The median AST of COVID-19-positive patients was significantly higher than COVID-19-negative patients.. · There was no increased risk of adverse fetal outcomes in with COVID-19 and ICP..

A chemical derivatization-based pseudotargeted liquid chromatography-tandem mass spectrometry method for sensitive and high coverage determination of bile acids in human serum

Global profiling of bile acids (BAs) is imperative for understand their function and disease pathogenesis. But it is still a challenging task, as the collision-induced dissociation (CID) fragment ions of unconjugated BAs showed low ion intensities to insufficient analysis. Herein, we developed a highly sensitive method for pseudotargeted profiling of BAs by chemical derivatization. In the developed method, a labeling reagent, 2-dimethylaminoethylamine (DMED), was adopted to label the carboxyl group of BAs. The results demonstrated that the detection sensitivities of unconjugated BAs were increased by 4–200 folds after DMED-labeling. Moreover, to profile other potential BAs not included in the 91 known targets, diverse survey experiments were performed on Qtrap-MS to search BAs for both precursor and fragment ion species, and retention index (RI) strategy was adopted to facilitate the identification of isomers. Finally, MRM-based LC-MS/MS method was validated for the pseudotargeted profiling of the BAs submetabolome with good linearity (r2 ≥ 0.990 for 89 known BAs) and high sensitivity (0.05–0.5 ng/mL for unconjugated BAs), covering unconjugated, glycine, taurine, sulfuric acid, glucuronic acid, and as well as those doubly-conjugated with above types. With this method, a total of 107 BAs, covering 54 BAs identified by authentic standards and 53 BAs candidates, were successfully determined in human serum of women with intrahepatic cholestasis of pregnancy (ICP). Multivariate analysis revealed deferentially expressed BAs. ICP disease altered the BAs profile with a reduced proportion of unconjugated, sulfate- and doubly-conjugated BAs and an increased proportion of glycine and taurine conjugates. Altered proportion and profile of BAs in ICP groups were gradually recovered during the ursodeoxycholic acid (UDCA) therapy. Overall, the strategy of DMED-labeling technique combined with diverse survey experiments is sufficiently sensitive and robust to comprehensively analysis of metabolic profiling of BAs in human serum.

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.

Role of aspartate aminotransferase to platelet ratio in the prediction and prognosis of intrahepatic cholestasis of pregnancy: A case-control study from a tertiary center.

To evaluate the aspartate aminotransferase to platelet ratio (APRI) score as a predictive and prognostic test in intrahepatic cholestasis of pregnancy (ICP). This study was conducted in 198 patients diagnosed with ICP and 204 healthy pregnant women who presented to a tertiary center between 2019 and 2022. APRI scores; laboratory findings in the first, second, and third trimesters; and perinatal outcomes were compared between the two groups. The ICP group was evaluated for correlation between APRI scores and composite adverse outcomes. Two different receiver operating characteristic analyses were performed to determine optimal cutoff values of predictive APRI score of ICP and composite adverse outcomes in patients with ICP. Aspartate aminotransferase values and APRI scores were significantly higher in the ICP group in all trimesters (P < 0.001). The optimal cutoff values of APRI scores to predict ICP for the first, second, and third trimesters were 0.101 (79.7% sensitivity, 79.6% specificity), 0.103 (78.4% sensitivity, 76.3% specificity), and 0.098 (72.5% sensitivity, 72% specificity), respectively. APRI scores were statistically higher in patients with ICP with composite adverse outcomes in all trimesters (P values of 0.03, 0.04, and 0.01, respectively). APRI score was found to be a valuable predictor of ICP and its adverse outcomes during the entire pregnancy.

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.

The comparison of systemic inflammatory response markers and Doppler ultrasound parameters between pregnancies with intrahepatic cholestasis and control cases

Objective: This study aims to detect a relationship between inflammatory markers, ductus venosus (DV) pulsatility index (PI), middle cerebral artery (MCA) PI, and umbilical artery (UA) systole to diastole ratio (S/D) and PI between pregnancies with intrahepatic cholestasis and control cases. Methods: This prospective study included 82 cases having intrahepatic cholestasis of pregnancy (ICP) and 80 gestational age-matched healthy control cases. The Doppler measurements (DV PI, MCA PI, and UA S/D and PI), inflammatory markers (neutrophil to lymphocyte ratio [NLR], platelet to lymphocyte ratio [PLR], mean platelet volume [MPV], and red blood cell distribution width [RDW]), and fetal and maternal outcomes were compared. Results: Patients with ICP had increased PLR value (p=0.019) and decreased lymphocyte count (p=0.004) compared to control cases. Also, there was a positive correlation between PLR value and the presence of ICP (χ2=5.774, p=0.016). There were no significant differences between ICP and control groups concerning NLR, RDW, MPV, and UA PI values. We found higher UA S/D, and DV PI values and lower MCA PI values in pregnancies with ICP compared to controls (p&lt;0.001, p=0.026, and p=0.003, respectively). Conclusion: In ICP cases, the PLR value was significantly increased than the controls, but the NLR, RDW, MPV, and UA PI values were found to be similar to control cases. The UA S/D, and DV PI values were increased, and MCA PI was significantly decreased in the ICP group compared to healthy pregnancies. However, we could not demonstrate the benefit of Doppler measurements in predicting neonatal outcomes in ICP cases.

Fetuin B may be a potential marker for predicting maternal and neonatal outcomes in intrahepatic cholestasis: Prospective case-control study.

To investigate the levels of serum fetuin B in healthy pregnant women and women with intrahepatic cholestasis of pregnancy (IHCP) and their association with pregnancy outcomes. This was a prospective case-control study, we included sixty singleton pregnant women with IHCP and sixty healthy-matched pregnant women in their third trimester. The serum fetuin B levels of these patients were analyzed. All the patients were followed up prospectively until delivery and data related to maternal, perinatal, and neonatal outcomes were obtained. Total bile acid levels and liver function tests were significantly higher in the IHCP group than in the control group (p<0.0001 and <0.0001, respectively). The serum fetuin B concentrations were higher in the IHCP group than in the control group, without any significant group difference (p=0.105). Preterm delivery, iatrogenic preterm delivery, and birth weight ≤2.500 gm are only significantly associated with serum fetuin B levels respectively (p<0.05). The diagnostic performance of serum bile acids [area under the curve (AUC)=0.998] was significantly better than that of fetuin B (AUC=0.586) (DeLong's test p≤0.001). We neither noted a significant difference between the IHCP and control groups concerning the serum fetuin B levels nor could we correlate its levels with adverse maternal and perinatal outcomes except with birth weight, thereby serum fetuin B was not an effective marker for use in shedding light on the pathophysiology of IHCP.

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.

The impact of intrahepatic cholestasis on pregnancy outcomes: a retrospective cohort study

BackgroundThis study analyzed the pregnancy outcomes of patients with intrahepatic cholestasis of pregnancy (ICP) in Hangzhou, China.MethodsCases of pregnant women monitored by antepartum testing at Hangzhou Women’s Hospital from January 2018 to December 2020 were reviewed. Subjects were classified into two groups according to whether they had ICP: 688 cases of ICP were assigned to an exposure group while 38,556 cases of non-ICP were assigned to a non-exposed group. Univariate analysis was performed on qualitative or quantitative data using the Chi-Squared test or Mann–Whitney U test, and the adjusted odds ratio (aOR) and 95% confidence interval (CI) of the two groups of related variables were calculated by multivariate binary logistic regression analysis.ResultsThe incidence rate of ICP was 1.75%. Pregnant women with hepatitis B virus were correlated with ICP. Hepatitis B carriers (aOR = 3.873), preeclampsia (PE, aOR = 3.712), thrombocytopenia (aOR = 1.992), gestational hypertension (GH, aOR = 1.627), hyperlipidemia (aOR = 1.602) and gestational diabetes mellitus (GDM, aOR = 1.265) were all risk factors for ICP. In contrast, Body Mass Index (BMI) ≥ 30 kg/m2 (aOR = 0.446), 25 m2 < maternal BMI < 29.9 kg/m2 (aOR = 0.699) and parity ≥ 1 (aOR = 0.722) were protective factors for ICP. Pregnant women in the ICP group had an increased risk of gestation days < 259 days (aOR = 4.574) and cesarean delivery (aOR = 1.930) after ICP, and a decreased risk of longer gestational days (aOR = 0.105), premature rupture of membranes (aOR = 0.384) and fetal macrosomia (aOR = 0.551).ConclusionsBy analyzing a Chinese population with ICP, we identified that pregnant women who are hepatitis B carriers or with PE, thrombocytopenia, GH, hyperlipidemia, and GDM are at higher risk of ICP. Moreover, ICP is associated with adverse pregnancy outcomes; in particular, ICP may increase the incidence of shorter gestational days and non-vaginal delivery methods such as cesarean section but reduce the incidence of premature rupture of membranes and fetal macrosomia.

Expression and clinical significance of short-chain fatty acids in pregnancy complications.

To investigate the expression of short-chain fatty acids (SCFAs)-metabolites of intestinal flora-in gestational complications of gestational diabetes mellitus (GDM), preeclampsia (PE), and intrahepatic cholestasis of pregnancy (ICP), and its clinical significance. Targeted metabonomics was used to detect SCFAs in the serum of 28 GDM pregnant women, 28 PE pregnant women, 29 ICP pregnant women, and 27 healthy pregnant women (NP); their expression changes were observed; the correlation between SCFAs and clinical characteristics was studied; and their potential as biomarkers for clinical diagnosis was evaluated. There were significant differences in the SCFA metabolic spectrum between the GDM, PE, ICP, and NP groups. Quantitative analysis showed that the content of isobutyric acid in the three pregnancy complications groups (the GDM, PE, and ICP groups) was significantly higher than that in the NP group (p < 0.05), and other SCFAs also showed significant differences in the three pregnancy complications groups compared with the NP group (p < 0.05). Receiver operating characteristic (ROC) curve analysis of the generalized linear model showed that multiple SCFAs were highly sensitive and specific as diagnostic markers in the pregnancy complications groups, where isobutyric acid was highly predictive in GDM (area under the ROC curve (AUC) = 0.764) and PE (AUC = 1), and caproic acid was highly predictive in ICP (AUC = 0.968), with potential clinical application. The metabolic products of intestinal flora, SCFAs, during pregnancy are closely related to pregnancy complications (GDM, PE, and ICP), and SCFAs can be used as potential markers of pregnancy complications.