ABSTRACT
BACKGROUND & AIMS: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of stillbirth. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in patients with ICP who were or were not treated with ursodeoxycholic acid (UDCA). METHODS: Bile acid profiles and NT-proBNP, a marker of ventricular dysfunction, were assayed in umbilical venous serum from 15 controls and 76 ICP cases (36 untreated, 40 UDCA-treated). Fetal electrocardiogram traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability (HRV) parameters were measured in 2 behavioral states (quiet and active sleep). RESULTS: In untreated ICP, fetal total serum bile acid (TSBA) concentrations (r = 0.49, p = 0.019), hydrophobicity index (r = 0.20, p = 0.039), glycocholate concentrations (r = 0.56, p = 0.007) and taurocholate concentrations (r = 0.44, p = 0.039) positively correlated with fetal NT-proBNP. Maternal TSBA (r = 0.40, p = 0.026) and alanine aminotransferase (r = 0.40, p = 0.046) also positively correlated with fetal NT-proBNP. There were no significant correlations between maternal or fetal serum bile acid concentrations and fetal HRV parameters or NT-proBNP concentrations in the UDCA-treated cohort. Fetal PR interval length positively correlated with maternal TSBA in untreated (r = 0.46, p = 0.027) and UDCA-treated ICP (r = 0.54, p = 0.026). Measures of HRV in active sleep and quiet sleep were significantly higher in untreated ICP cases than controls. HRV values in UDCA-treated cases did not differ from controls. CONCLUSIONS: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterized by increased NT-proBNP concentration, PR interval length and HRV. UDCA treatment partially attenuates this phenotype. LAY SUMMARY: The risk of stillbirth in intrahepatic cholestasis of pregnancy (ICP) is linked to the level of bile acids in the mother which are thought to disrupt the baby's heart rhythm. We found that babies of women with untreated ICP have abnormally functioning hearts compared to those without ICP, and the degree of abnormality is closely linked to the level of harmful bile acids in the mother and baby's blood. Babies of women with ICP who received treatment with the drug UDCA do not have the same level of abnormality in their hearts, suggesting that UDCA could be a beneficial treatment in some ICP cases, although further clinical trials are needed to confirm this.
Subject(s)
Alanine Transaminase/blood , Bile Acids and Salts/blood , Cholestasis, Intrahepatic , Fetal Heart/physiopathology , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Pregnancy Complications , Ursodeoxycholic Acid/therapeutic use , Ventricular Dysfunction , Adult , Biomarkers/blood , Cholagogues and Choleretics/therapeutic use , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/drug therapy , Correlation of Data , Electrocardiography/methods , Female , Fetal Blood , Humans , Pregnancy , Pregnancy Complications/blood , Pregnancy Complications/diagnosis , Pregnancy Complications/drug therapy , Risk Assessment , Stillbirth/epidemiology , Treatment Outcome , Ventricular Dysfunction/blood , Ventricular Dysfunction/diagnosis , Ventricular Dysfunction/drug therapyABSTRACT
BACKGROUND: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. METHODS: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. FINDINGS: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165â136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163â947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 µmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 µmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 µmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). INTERPRETATION: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 µmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. FUNDING: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.
Subject(s)
Bile Acids and Salts/blood , Cholestasis, Intrahepatic/blood , Pregnancy Complications/blood , Premature Birth/blood , Stillbirth , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Bilirubin/blood , Biomarkers/blood , Case-Control Studies , Cholestasis, Intrahepatic/epidemiology , Cohort Studies , Female , Humans , Infant, Newborn , Perinatal Death , Pregnancy , Pregnancy Complications/epidemiology , Premature Birth/epidemiology , ROC Curve , Randomized Controlled Trials as Topic , Risk Factors , Stillbirth/epidemiologyABSTRACT
INTRODUCTION: Intrahepatic cholestasis of pregnancy is characterised by pruritus and elevated serum bile acids. The pruritus can be severe, and pharmacological options achieve inconsistent symptomatic improvement. Raised bile acids are linearly associated with adverse fetal outcomes, with existing management of limited benefit. We hypothesised that therapeutic plasma exchange removes pruritogens and lowers total bile acid concentrations, and improves symptoms and biochemical abnormalities in severe cases that have not responded to other treatments. METHODS: Four women with severe pruritus and hypercholanemia were managed with therapeutic plasma exchange. Serial blood biochemistry and visual analogue scores of itch severity were obtained. Blood and waste plasma samples were collected before and after exchange; individual bile acids and sulfated progesterone metabolites were measured with HPLC-MS, autotaxin activity and cytokine profiles with enzymatic methods. Results were analysed using segmental linear regression to describe longitudinal trends, and ratio t tests. RESULTS: Total bile acids and visual analogue itch scores demonstrated trends to transiently improve following plasma exchange, with temporary symptomatic benefit reported. Individual bile acids (excluding the drug ursodeoxycholic acid), and the sulfated metabolites of progesterone reduced following exchange (P = .03 and P = .04, respectively), whilst analysis of waste plasma demonstrated removal of autotaxin and cytokines. CONCLUSIONS: Therapeutic plasma exchange can lower potentially harmful bile acids and improve itch, likely secondary to the demonstrated removal of pruritogens. However, the limited current experience and potential complications, along with minimal sustained symptomatic benefit, restrict its current use to women with the most severe disease for whom other treatment options have been exhausted.
Subject(s)
Cholestasis, Intrahepatic/therapy , Plasma Exchange/methods , Pregnancy Complications/therapy , Bile Acids and Salts/blood , Cytokines/isolation & purification , Female , Humans , Phosphoric Diester Hydrolases/isolation & purification , Pregnancy , Pruritus/etiology , Treatment OutcomeABSTRACT
BACKGROUND & AIMS: Intrahepatic cholestasis of pregnancy (ICP) is defined by pruritus, elevated total fasting serum bile salts (TBS) and transaminases, and an increased risk of adverse fetal outcome. An accurate diagnostic marker is needed. Increased serum autotaxin correlates with cholestasis-associated pruritus. We aimed at unraveling the diagnostic accuracy of autotaxin in ICP. METHODS: Serum samples and placental tissue were collected from 44 women with uncomplicated pregnancies and 105 with pruritus and/or elevated serum transaminases. Autotaxin serum levels were quantified enzymatically and by Western blotting, autotaxin gene expression by quantitative PCR. RESULTS: Serum autotaxin was increased in ICP (mean ± SD: 43.5 ± 18.2 nmol ml(-1)min(-1), n=55, p<0.0001) compared to other pruritic disorders of pregnancy (16.8 ± 6.7 nmol ml(-1)min(-1), n=33), pre-eclampsia complicated by HELLP-syndrome (16.8 ± 8.9 nmol ml(-1)min(-1), n=17), and pregnant controls (19.6 ± 5.7 nmol ml(-1)min(-1), n=44). Longitudinal analysis during pregnancy revealed a marked rise in serum autotaxin with onset of ICP-related pruritus. Serum autotaxin was increased in women taking oral contraceptives. Increased serum autotaxin during ICP was not associated with increased autotaxin mRNA in placenta. With a cut-off value of 27.0 nmol ml(-1)min(-1), autotaxin had an excellent sensitivity and specificity in distinguishing ICP from other pruritic disorders or pre-eclampsia/HELLP-syndrome. Serum autotaxin displayed no circadian rhythm and was not influenced by food intake. CONCLUSIONS: Increased serum autotaxin activity represents a highly sensitive, specific and robust diagnostic marker of ICP, distinguishing ICP from other pruritic disorders of pregnancy and pregnancy-related liver diseases. Pregnancy and oral contraception increase serum autotaxin to a much lesser extent than ICP.
Subject(s)
Cholestasis, Intrahepatic , Phosphoric Diester Hydrolases , Pregnancy Complications , Adult , Biomarkers/blood , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/complications , Cholestasis, Intrahepatic/genetics , Diagnosis, Differential , Female , Humans , Phosphoric Diester Hydrolases/blood , Phosphoric Diester Hydrolases/genetics , Pregnancy , Pregnancy Complications/blood , Pregnancy Complications/genetics , Pruritus/blood , Pruritus/etiology , Sensitivity and Specificity , Transaminases/bloodABSTRACT
UNLABELLED: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, characterized by maternal pruritus and raised serum bile acids. Our objectives were to describe the epidemiology and pregnancy complications associated with severe ICP and to test the hypothesis that adverse perinatal outcomes are increased in these women. A prospective population-based case-control study with national coverage was undertaken using the UK Obstetric Surveillance System (UKOSS). Control data for comparison were obtained from women with healthy pregnancy outcome through UKOSS (n = 2,232), St Mary's Maternity Information System (n = 554,319), and Office for National Statistics (n = 668,195). The main outcome measures investigated were preterm delivery, stillbirth, and neonatal unit admission. In all, 713 confirmed cases of severe ICP were identified, giving an estimated incidence of 9.2 per 10,000 maternities. Women with severe ICP and a singleton pregnancy (n = 669) had increased risks of preterm delivery (164/664; 25% versus 144/2200; 6.5%; adjusted odds ratio [OR] 5.39, 95% confidence interval [CI] 4.17 to 6.98), neonatal unit admission (80/654; 12% versus 123/2192; 5.6%; adjusted OR 2.68, 95% CI 1.97 to 3.65), and stillbirth (10/664; 1.5% versus 11/2205; 0.5%; adjusted OR 2.58, 95% CI 1.03 to 6.49) compared to controls. Seven of 10 stillbirths in ICP cases were associated with coexisting pregnancy complications. These differences remained significant against national data. Risks of preterm delivery, meconium-stained amniotic fluid, and stillbirth rose with increasing maternal serum bile acid concentrations. CONCLUSION: In the largest prospective cohort study in severe ICP to date, we demonstrate significant increased risks of adverse perinatal outcomes, including stillbirth. Our findings support the case for close antenatal monitoring of pregnancies affected by severe ICP.
Subject(s)
Cholestasis, Intrahepatic/complications , Cholestasis, Intrahepatic/epidemiology , Outcome Assessment, Health Care , Pregnancy Complications/epidemiology , Pregnancy Outcome/epidemiology , Adult , Bile Acids and Salts/blood , Case-Control Studies , Cholestasis, Intrahepatic/blood , Cohort Studies , Female , Humans , Incidence , Pregnancy , Pregnancy Complications/blood , Premature Birth/epidemiology , Prospective Studies , Risk Factors , Stillbirth/epidemiology , United Kingdom/epidemiologyABSTRACT
OBJECTIVES: Intrahepatic cholestasis of pregnancy (ICP) has a complex etiology with a significant genetic component. Heterozygous mutations of canalicular transporters occur in a subset of ICP cases and a population susceptibility allele (p.444A) has been identified in ABCB11. We sought to expand our knowledge of the detailed genetic contribution to ICP by investigation of common variation around candidate loci with biological plausibility for a role in ICP (ABCB4, ABCB11, ABCC2, ATP8B1, NR1H4, and FGF19). METHODS: ICP patients (n=563) of white western European origin and controls (n=642) were analyzed in a case-control design. Single-nucleotide polymorphism (SNP) markers (n=83) were selected from the HapMap data set (Tagger, Haploview 4.1 (build 22)). Genotyping was performed by allelic discrimination assay on a robotic platform. Following quality control, SNP data were analyzed by Armitage's trend test. RESULTS: Cochran-Armitage trend testing identified six SNPs in ABCB11 together with six SNPs in ABCB4 that showed significant evidence of association. The minimum Bonferroni corrected P value for trend testing ABCB11 was 5.81×10(-4) (rs3815676) and for ABCB4 it was 4.6×10(-7)(rs2109505). Conditional analysis of the two clusters of association signals suggested a single signal in ABCB4 but evidence for two independent signals in ABCB11. To confirm these findings, a second study was performed in a further 227 cases, which confirmed and strengthened the original findings. CONCLUSIONS: Our analysis of a large cohort of ICP cases has identified a key role for common variation around the ABCB4 and ABCB11 loci, identified the core associations, and expanded our knowledge of ICP susceptibility.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , ATP-Binding Cassette Transporters/genetics , Cholestasis, Intrahepatic/genetics , Pregnancy Complications/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 11 , Case-Control Studies , Cholestasis, Intrahepatic/ethnology , Europe , Female , Genetic Association Studies , Genetic Predisposition to Disease , Heterozygote , Humans , Multidrug Resistance-Associated Protein 2 , Mutation , Polymorphism, Single Nucleotide , Pregnancy , Pregnancy Complications/ethnology , White People/geneticsABSTRACT
BACKGROUND & AIMS: Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons. METHODS: Cytosolic free calcium ([Ca(2+)](i)) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca(2+)](i)-inducing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device. RESULTS: Transient increases in neuronal [Ca(2+)](i) induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca(2+)](i) agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P < .0001) and cholestatic patients with versus without pruritus (P < .0001). Autotaxin activity correlated with intensity of pruritus (P < .0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or mu-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal. CONCLUSIONS: We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future therapeutic interventions.
Subject(s)
Cholestasis, Intrahepatic/blood , Liver Cirrhosis, Biliary/blood , Lysophospholipids/blood , Neurons/metabolism , Pregnancy Complications/blood , Pruritus/etiology , Adult , Aged , Animals , Calcium/metabolism , Cell Line, Tumor , Cholestasis, Intrahepatic/complications , Cholestasis, Intrahepatic/therapy , Chromatography, High Pressure Liquid , Disease Models, Animal , Drainage , Female , Fluorometry , Humans , Injections, Intradermal , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/therapy , Lysophospholipids/administration & dosage , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Middle Aged , Multienzyme Complexes/blood , Phosphodiesterase I/blood , Phosphoric Diester Hydrolases , Pregnancy , Pregnancy Complications/therapy , Pruritus/blood , Pruritus/chemically induced , Pyrophosphatases/blood , Severity of Illness Index , Time Factors , Up-RegulationABSTRACT
BACKGROUND/AIMS: Intrahepatic cholestasis of pregnancy (ICP) is complicated by spontaneous preterm labor, fetal anoxia and unexplained fetal death. We aim to evaluate the mechanisms by which raised fetal bile acids cause placental abnormalities and fetal cardiac pathology. METHODS: The study was performed using placental samples taken from ICP pregnancies, placental explant culture, neonatal and adult cardiomyocytes, and murine and human embryonic stem cell-derived cardiomyocytes. RESULTS: Maternal cholestasis causes a placental phenotype with histological abnormalities. This can be evaluated using placental explant cultures. Taurocholate, the principal bile acid raised in the fetal compartment in ICP, causes abnormal cardiomyocyte contraction, rhythm and desynchronization of calcium dynamics. To extend our observations that the muscarinic M2 receptor plays a role in bile acid-induced arrhythmia in cardiomyocytes, we are developing a model containing mixed cell populations to represent the fetal and maternal hearts. This will be used to evaluate the underlying mechanisms to explain fetal arrhythmia in the presence of cholestasis. CONCLUSION: Bile acids signal via a spectrum of pathways in the placenta and the fetal heart.
Subject(s)
Bile Acids and Salts/metabolism , Cholestasis, Intrahepatic/metabolism , Fetus/metabolism , Pregnancy Complications/metabolism , Signal Transduction , Female , Fetal Heart , Humans , Maternal-Fetal Exchange , PregnancyABSTRACT
BACKGROUND: Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. METHODS: In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 µmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. FINDINGS: The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35-3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04-2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86-1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39-0·91; p=0·016). INTERPRETATION: Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment. FUNDING: Tommy's, the Wellcome Trust, ICP Support, and the National Institute for Health Research.
Subject(s)
Cholestasis, Intrahepatic/drug therapy , Pregnancy Complications/drug therapy , Ursodeoxycholic Acid/therapeutic use , Cholagogues and Choleretics/therapeutic use , Female , Humans , PregnancySubject(s)
Cholestasis, Intrahepatic/therapy , Pregnancy Complications/therapy , Female , Humans , PregnancyABSTRACT
Liver disease in pregnancy, either pre-existing or pregnancy specific, can be associated with a significant risk of maternal and fetal morbidity and mortality. Here, we review the presentation, management and perinatal outcomes of common causes of liver disease.
Subject(s)
Liver Diseases/diagnosis , Liver Diseases/therapy , Pregnancy Complications/diagnosis , Pregnancy Complications/therapy , Antiviral Agents/therapeutic use , Cholangitis, Sclerosing/drug therapy , Cholangitis, Sclerosing/physiopathology , Cholestasis, Intrahepatic/diagnosis , Chronic Disease , Contraindications , Fatty Liver/diagnosis , Female , Hepatitis, Autoimmune/drug therapy , Hepatitis, Viral, Human/therapy , Hepatitis, Viral, Human/transmission , Humans , Infectious Disease Transmission, Vertical/prevention & control , Pregnancy , Pregnancy OutcomeABSTRACT
OBJECTIVE: To describe the use of combined ursodeoxycholic acid (UDCA) and rifampicin treatment in intrahepatic cholestasis of pregnancy (ICP). STUDY DESIGN: A questionnaire survey of 27 women with 28 affected pregnancies identified via the UK and International Obstetric Medicine forum. The clinical case notes of women with ICP treated with combined UDCA and rifampicin therapy were reviewed, and data regarding maternal and perinatal outcomes extracted. RESULTS: Serum bile acids remained high whilst taking UDCA as monotherapy. In 14 pregnancies (54%) serum bile acids decreased following the introduction of rifampicin. In 10 pregnancies (38%), there was a 50% reduction in serum bile acids. There were no adverse effects reported with either drug. CONCLUSIONS: This is the first report of the use of rifampicin in ICP. The data suggest that combined treatment with UDCA and rifampicin is an effective way of treating women with severe ICP who do not respond to treatment with UDCA alone.
Subject(s)
Cholestasis, Intrahepatic/drug therapy , Pregnancy Complications/drug therapy , Rifampin/therapeutic use , Bile Acids and Salts/blood , Cholestasis, Intrahepatic/blood , Drug Therapy, Combination , Female , Gestational Age , Humans , Pregnancy , Pregnancy Complications/blood , Pregnancy Outcome , Rifampin/administration & dosage , Ursodeoxycholic Acid/administration & dosageABSTRACT
Intrahepatic cholestasis of pregnancy is the most common pregnancy-specific liver disease that typically presents in the third trimester. The clinical features are maternal pruritus in the absence of a rash and deranged liver function tests, including raised serum bile acids. Intrahepatic cholestasis of pregnancy is associated with an increased risk of adverse perinatal outcomes, including spontaneous preterm delivery, meconium staining of the amniotic fluid, and stillbirth. It is commonly treated with ursodeoxycholic acid. There is accumulating evidence to suggest that intrahepatic cholestasis of pregnancy has a lasting influence on both maternal and fetal health. We review the etiology, diagnosis, and management of this intriguing condition.
Subject(s)
Cholestasis, Intrahepatic/complications , Pregnancy Complications , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/drug therapy , Cholestasis, Intrahepatic/physiopathology , Female , Humans , Liver/physiopathology , Liver Function Tests , PregnancyABSTRACT
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 (nâ=â18), UDCA-treated ICP (nâ=â46) and uncomplicated pregnancy (nâ=â15) 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 (pâ=â<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 (pâ=â<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.
Subject(s)
Bile Acids and Salts/blood , Cholestasis, Intrahepatic/blood , Cholestasis, Intrahepatic/drug therapy , Maternal-Fetal Exchange , Pregnancy Complications/blood , Pregnancy Complications/drug therapy , Ursodeoxycholic Acid/therapeutic use , Case-Control Studies , Chromatography, High Pressure Liquid , Female , Glycine/blood , Humans , Mass Spectrometry , Pregnancy , Taurine/blood , Umbilical Arteries/metabolism , Umbilical Veins/metabolismSubject(s)
Cholestasis, Intrahepatic/complications , Pregnancy Complications , Female , Humans , PregnancyABSTRACT
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.
Subject(s)
Cholestasis, Intrahepatic/etiology , Cholestasis, Intrahepatic/physiopathology , Pregnancy Complications/physiopathology , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/epidemiology , Environment , Female , Fetal Death/prevention & control , Fetus/physiology , Humans , Liver/metabolism , Pregnancy , Pregnancy Outcome , Pregnancy Trimester, Third , Pruritus/etiologyABSTRACT
BACKGROUND AND AIMS: Intrahepatic cholestasis of pregnancy (ICP) is characterized by liver impairment, pruritus, and elevated maternal serum bile acids. It can cause premature delivery and intrauterine death. Bile acid synthesis, metabolism, and transport are regulated by the bile acid sensor FXR, and we hypothesized that genetic variation in FXR confers susceptibility to ICP. METHODS: The coding regions and intron/exon boundaries of FXR were sequenced in 92 British ICP cases of mixed ethnicity. Subsequently, a case-control study of allele frequencies of these variants in 2 independent cohorts of Caucasian ICP patients and controls was performed. Variants were cloned into an FXR expression plasmid and tested in functional assays. RESULTS: We identified 4 novel heterozygous FXR variants (-1g>t, M1V, W80R, M173T) in ICP. W80R was not present in Caucasians and M1V was detected uniquely in 1 British case. M173T and -1g>t occur both in Caucasian cases and controls, and we found a significant association of M173T with ICP (OR, 3.2; 95% confidence interval, 1.1-11.2; P = .02) when the allele frequencies of both Caucasian cohorts were analyzed together. We demonstrate functional defects in either translation efficiency or activity for 3 of the 4 variants (-1g>t, M1V, M173T). CONCLUSIONS: This is the first report of functional variants in FXR. We propose that these variants may predispose to ICP, and because FXR has a central role in regulating bile and lipid homeostasis they may be associated with other cholestatic and dyslipidemic disorders.