Whole-genome sequencing of patients with rare diseases in a national health system.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Serum bile acid measurements in women of European and South Asian ethnicity with or without gestational diabetes mellitus: A cohort study.

OBJECTIVE: Investigation of serum bile acid profiles in pregnancies complicated by gestational diabetes mellitus (GDM) in a multi-ethnic cohort of women who are lean or obese. DESIGN: Prospective cohort study. SETTING: UK multicentre study. POPULATION: Fasting serum from participants of European or South Asian self-reported ethnicity from the PRiDE study, between 23 and 31 weeks of gestation. METHODS: Bile acids were measured using ultra-performance liquid chromatography-tandem mass spectrometry. Log-transformed data were analysed using linear regression in STATA/IC 15.0. MAIN OUTCOME MEASURES: Total bile acids (TBAs), C4, fasting glucose and insulin. RESULTS: The TBAs were 1.327-fold (1.105-1.594) increased with GDM in European women (P = 0.003). Women with GDM had 1.162-fold (1.002-1.347) increased levels of the BA synthesis marker C4 (P = 0.047). In South Asian women, obesity (but not GDM) increased TBAs 1.522-fold (1.193-1.942, P = 0.001). Obesity was associated with 1.420-fold (1.185-1.702) increased primary/secondary BA ratio (P < 0.001) related to 1.355-fold (1.140-1.611) increased primary BA concentrations (P = 0.001). TBAs were positively correlated with fasting glucose (P = 0.039) in all women, and with insulin (P = 0.001) and the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (P = 0.001) in women with GDM. CONCLUSIONS: Serum BA homeostasis in late gestation depends on body mass index and GDM in ethnicity-specific ways. This suggests ethnicity-specific aetiologies may contribute to metabolic risk in European and South Asian women, with the relationship between BAs and insulin resistance of greater importance in European women. Further studies into ethnicity-specific precision medicine for GDM are required.

Pregnancy-Associated Liver Diseases.

The liver disorders unique to pregnancy include hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, acute fatty liver of pregnancy, and preeclampsia-associated hepatic impairment, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome (HELLP). Their importance lies in the significant maternal and fetal/neonatal morbidity and mortality. Expeditious diagnosis and clinical evaluation is critical to ensure timely, appropriate care and minimize risks to the pregnant woman and her fetus/baby. A multidisciplinary approach is essential, including midwives, maternal-fetal-medicine specialists, anesthetists, neonatologists, and hepatologists.

Race, Insurance, and Sex-Based Disparities in Access to High-Volume Centers for Pancreatectomy.

BACKGROUND: With a large body of literature demonstrating positive volume-outcome relationships for most major operations, minimum volume requirements have been suggested for concentration of cases to high-volume centers (HVCs). However, data are limited regarding disparities in access to these hospitals for pancreatectomy patients. METHODS: The 2005-2018 National Inpatient Sample (NIS) was queried for all elective adult hospitalizations for pancreatectomy. Hospitals performing more than 20 annual cases were classified as HVCs. Mixed-multivariable regression models were developed to characterize the impact of demographic factors and case volume on outcomes of interest. RESULTS: Of an estimated 127,527 hospitalizations, 79.8% occurred at HVCs. Patients at these centers were more frequently white (79.0 vs 70.8%; p < 0.001), privately insured (39.4 vs 34.2%; p < 0.001), and within the highest income quartile (30.5 vs 25.0%; p < 0.001). Adjusted analysis showed that operations performed at HVCs were associated with reduced odds of in-hospital mortality (adjusted odds ratio [AOR], 0.43; 95% confidence interval [CI], 0.34-0.55), increased odds of discharge to home (AOR, 1.17; 95% CI, 1.04-1.30), shorter hospital stay (ß, -0.81 days; 95% CI, -1.2 to -0.40 days), but similar costs. Patients who were female (AOR, 0.88; 95% CI, 0.79-0.98), non-white (black: AOR, 0.66; 95% CI, 0.59-0.75; Hispanic: AOR, 0.56; 95% CI, 0.47-0.66; reference, white), insured by Medicaid (AOR, 0.63; 95% CI, 0.56-0.72; reference, private), and within the lowest income quartile (AOR, 0.73; 95% CI, 0.59-0.90; reference, highest) had decreased odds of treatment at an HVC. CONCLUSIONS: For those undergoing pancreatectomies, HVCs realize superior clinical outcomes but treat lower proportions of female, non-white, and Medicaid populations. These findings may have implications for improving access to high-quality centers.

Insurance-Based Disparities in Congenital Cardiac Operations in the Era of the Affordable Care Act.

A body of literature has previously highlighted the impact of health insurance on observed disparities in congenital cardiac operations. With aims of improving access to healthcare for all patients, the Affordable Care Act (ACA) expanded Medicaid coverage to nearly all eligible children in 2010. Therefore, the present population-based study aimed to examine the association of Medicaid coverage with clinical and financial outcomes in the era the ACA. Records for pediatric patients (≤ 18 years) who underwent congenital cardiac operations were abstracted from the 2010-2018 Nationwide Readmissions Database. Operations were stratified using the Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) Category. Multivariable regression models were developed to evaluate the association of insurance status on index mortality, 30-day readmissions, care fragmentation, and cumulative costs. Of an estimated 132,745 hospitalizations for congenital cardiac surgery from 2010 to 2018, 74,925 (56.4%) were insured by Medicaid. The proportion of Medicaid patients increased from 57.6 to 60.8% during the study period. On adjusted analysis, patients with Medicaid insurance were at an increased odds of mortality (1.35, 95%CI: 1.13-1.60) and 30-day unplanned readmission (1.12, 95%CI: 1.01-1.25), experienced longer lengths of stay (+ 6.5 days, 95%CI 3.7-9.3), and exhibited higher cumulative hospitalization costs (+ $21,600, 95%CI: $11,500-31,700). The total hospitalization cost-burden for patients with Medicaid and private insurance were $12.6 billion and $8.06 billion, respectively. Medicaid patients exhibited increased mortality, readmissions, care fragmentation, and costs compared to those with private insurance. Our results of outcome variation by insurance status indicate the necessity of policy changes to attempt to approach equality in surgical out comes for this high-risk cohort. Baseline characteristics, trends, and outcomes by insurance status over the ACA rollout period 2010-2018.

Center Volume Impacts Readmissions and Mortality after Congenital Cardiac Surgery.

OBJECTIVE: To characterize the relationship between surgical volume and postoperative outcomes in congenital heart surgery, we used a national cohort to assess the costs, readmissions, and complications in children undergoing cardiac operations. STUDY DESIGN: The Nationwide Readmissions Database was used to identify pediatric patients (≤18 years) undergoing congenital cardiac surgery from 2010 to 2017. Hospitals were categorized based on deciles and tertiles of annual caseload with high-volume categorized as the highest tertile of volume. Multivariable regression models adjusting for patient and hospital characteristics were used to study the impact of volume on 30-day nonelective readmission, mortality, home discharge, and resource use. RESULTS: Of an estimated 69 448 hospitalizations included for analysis, 56 672 (82%) occurred at high-volume centers. After adjustment for key clinical factors, each decile increase in volume was associated with a 25% relative decrease in the odds of mortality, a 14% decrease in the odds of nonhome discharge, and a 4% relative decrease in the likelihood of 30-day nonelective readmission. After risk adjustment, each incremental increase in volume decile was associated with a one-half-day decrease in the hospital length of stay, but did not alter costs of the index hospitalization. However, after including all readmissions within 30 days of the index discharge, high-volume centers were associated with significantly lower costs compared with low-volume hospitals. CONCLUSIONS: Increased congenital cardiac surgery volume is associated with improved mortality, reduced duration of hospitalization, 30-day readmissions, and resource use. These findings demonstrate the inverse relationship between hospital volume and resource use and may have implications for the centralization of care for congenital cardiac surgery.

Association of Hospital Safety Net Status With Outcomes and Resource Use for Extracorporeal Membrane Oxygenation in the United States.

PURPOSE: Safety net hospitals (SNH) have been associated with inferior surgical outcomes and increased resource use. Utilization and outcomes for extracorporeal membrane oxygenation (ECMO), a rescue modality for patients with respiratory or cardiac failure, may vary by safety net status. We hypothesized SNH to be associated with inferior outcomes and costs of ECMO in a national cohort. MATERIALS AND METHODS: The 2008-2017 National Inpatient Sample was queried for ECMO hospitalizations and safety net hospitals were identified. Multivariable regression was used to perform risk-adjusted comparisons of mortality, complications and resource utilization at safety net and non-safety net hospitals. RESULTS: Of 36,491 ECMO hospitalizations, 28.2% were at SNH. On adjusted comparison SNH was associated with increased odds of mortality (AOR: 1.23), tracheostomy use (AOR: 1.51), intracranial hemorrhage (AOR: 1.39), as well as infectious complications (AOR: 1.21, all P < .05), with NSNH as reference. SNH was also associated with increased hospitalization duration (ß=+4.5 days) and hospitalization costs (ß=+$32,880, all P < .01). CONCLUSIONS: We have found SNH to be associated with inferior survival, increased complications, and higher costs compared to NSNH. These disparate outcomes warrant further studies examining systemic and hospital-level factors that may impact outcomes and resource use of ECMO at SNH.

Clinical and Financial Outcomes Associated With Vocal Fold Paralysis in Congenital Cardiac Surgery.

OBJECTIVES: Vocal fold paralysis (VFP) has proven to increase resource use in several surgical fields. However, its burden in congenital cardiac surgery, a specialty known to be associated with high resource use, has not yet been examined. The authors aimed to assess the impact of VFP on costs, lengths of stay, and readmissions following congenital cardiac surgery. DESIGN: A retrospective analysis of administrative data. SETTING: The 2010-2017 National Readmissions Database. PARTICIPANTS: All pediatric patients undergoing congenital cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Vocal fold paralysis was defined using International Classification of Diseases, Ninth and Tenth Revisions, diagnosis codes. The primary outcome of interest was 30-day nonelective readmissions and 90-day readmissions; costs, length of stay, and discharge status also were considered. Of an estimated 124,486 patients meeting study criteria, 2,868 (2.3%) were identified with VFP. Incidence of VFP increased during the study period (0.7% in 2010 to 3.2% in 2017, nptrend < 0.001). Rates of nonhome discharge (30.0% v 16.4%, p < 0.001), 30-day readmission (23.9% v 12.4%, p < 0.001), and 90-day readmission (8.3% v 4.4%, p = 0.03) were increased in the VFP cohort, as were lengths of stay (42.1 v 27.0 days, p < 0.001) and costs ($196,000 v $128,000, p < 0.001). After adjustment for patient and hospital factors, VFP was independently associated with greater odds of nonhome discharge (adjusted odds ratios [AOR], 1.66, 95% CI, 1.14-2.40), 30-day readmission (AOR, 1.58, 95% CI, 1.03-2.42), 90-day readmission (AOR, 2.07, 95% CI, 1.22-3.52), longer lengths of stay (+ 6.1 days, 95% CI, 1.3-10.8), and higher hospitalization costs (+$22,000, 95% CI, 3,000-39,000). CONCLUSIONS: Readmission rates after congenital cardiac surgery are significantly greater among those with VFP, as are costs, lengths of stay, and nonhome discharges. Therefore, further efforts are necessary to increase awareness and reduce the incidence of VFP in this vulnerable population to minimize the financial burden of congenital cardiac surgery on the US medical system.

Outcomes of Expedited Discharge After Isolated Coronary Artery Bypass Grafting.

OBJECTIVES: Expedited discharge after coronary artery bypass grafting (CABG) has been postulated as a possible solution for reducing hospitalization costs. This study aimed to evaluate the impact of expedited postoperative discharge on readmissions and costs in patients undergoing isolated CABG. DESIGN: Adults (≥18 years) who underwent isolated CABG were identified using the 2016-to-2019 Nationwide Readmission Database. Patients were classified as expedited or routine, with expedited patients being discharged on or before postoperative day 4. Those who experienced perioperative complications were excluded. SETTING: The Nationwide Readmissions Database. PARTICIPANTS: Patients ≥18 years old who underwent isolated CABG. MEASUREMENTS AND MAIN RESULTS: Of an estimated 187,591 patients meeting study criteria, 37.2% (n = 69,861) experienced expedited discharge. Expedited patients experienced lower index hospitalization costs ($28,543 v $34,114, p < 0.001), and were less likely to experience 30-day nonelective readmission (4.6% v 7.3%, p < 0.001) and 90-day nonelective readmission (5.6% v 8.7%, p < 0.001). After adjustment, expedited discharge remained independently associated with reduced odds of both 30-day (adjusted odds ratio [AOR]: 0.78, 95% CI: 0.71-0.85) and 90-day (AOR: 0.80, 95% CI: 0.74-0.87) nonelective readmission. In addition, expedited discharge was associated with an incremental decrease in index hospitalization costs (ß: -5,661, 95% CI: -5,894 to -5,429). CONCLUSIONS: Expedited discharge immensely decreases costs of care for patients undergoing isolated CABG, as well as readmission risks. Expedited discharge may be considered a strategy to both improve postoperative patient care and reduce hospitalization costs within the United States healthcare system.

Nuclear Receptors in Pregnancy and Outcomes: Clinical Perspective.

Pregnancy is characterised by profound hormonal and metabolic changes in the mother. Both oestrogen and progesterone, along with their respective nuclear receptors, have an important role in maintaining a healthy pregnancy. Equally, other nuclear receptors such as LXR, FXR and the PPARs play important roles in the gradual alterations in metabolism that ensure survival of mother and fetus. Disruptions in nuclear receptor signalling can result in pregnancy disorders such as gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, hypertensive disorders of pregnancy and preterm labour, all of which have both immediate and long-term implications for maternal and fetal health. By reviewing data from human studies and animal models, this chapter will describe the contribution of nuclear receptors to normal pregnancy, their role in gestational disorders and their potential as therapeutic targets.

Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations.

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.

National Trends in the Cost Burden of Pediatric Gunshot Wounds Across the United States.

OBJECTIVE: To characterize hospitalization costs attributable to gun-related injuries in children across the US. STUDY DESIGN: The 2005-2017 National Inpatient Sample was used to identify all pediatric admissions for gunshot wounds (GSW). Patients were stratified by International Classification of Diseases procedural codes for trauma-related operations. Annual trends in GSW hospitalizations and costs were analyzed with survey-weighted estimates. Multivariable regressions were used to identify factors associated with high-cost hospitalizations. RESULTS: During the study period, an estimated 36 283 pediatric patients were admitted for a GSW, with 43.1% undergoing an operative intervention during hospitalization. Admissions for pediatric firearm injuries decreased from 3246 in 2005 to 3185 in 2017 (NPtrend < .001). The median inflation-adjusted cost was $12 408 (IQR $6253-$24 585). Median costs rose significantly from $10 749 in 2005 to $16 157 in 2017 (P < .001). Compared with those who did not undergo surgical interventions, operative patients incurred increased median costs ($18 576 vs $8942, P < .001). Assault and self-harm injuries as well as several operations were independently associated with classification in the highest cost tertile. CONCLUSIONS: Admissions for pediatric firearm injuries were associated with a significant socioeconomic burden in the US, with increasing resource use over time. Pediatric gun violence is a major public health crisis that warrants further research and advocacy to reduce its prevalence and social impact.

Clinical and Financial Outcomes of Necrotizing Soft-Tissue Infections in Safety-Net Hospitals.

Background Prior work has demonstrated inferior outcomes for a multitude of medical and surgical conditions at hospitals with high burdens of underinsured patients (safety-net). The present study aimed to evaluate trends in incidence, clinical outcomes and resource utilization in the surgical management of necrotizing soft-tissue infections (NSTI) at safety-net hospitals. Materials and methods Adults requiring surgical debridement/amputation following NSTI-related hospitalizations were identified in the 2005-2018 National Inpatient Sample. Safety-net status (SNH) was assigned to institutions in the top tertile for annual proportion of underinsured patients. Logistic multivariable regression was utilized to evaluate the association of SNH with mortality, hospitalization duration (LOS), costs and discharge disposition. Results Of an estimated 212,692 patients, 76,719 (36.1%) were managed at SNH. The annual incidence of NSTI admissions increased overall while associated mortality declined. After adjustment, SNH status was associated with greater odds of mortality (adjusted odds ratios: 1.14, 95% CI: 1.03-1.26), LOS (ß: +1.8 d, 95% CI: 1.3-2.2) and costs (ß: +$4,400, 95% CI: 2,900-5,800). SNH patients had similar rates of amputation but lower likelihood of care facility or home health discharge. Conclusion With a rising incidence and overall reduction in mortality, safety-net hospitals persistently exhibit greater mortality and resource use for surgical NSTI admissions. Variation in access, disease presentation and timeliness of operative intervention may explain the observed findings.

Association of donor hypertension and outcomes in orthotopic heart transplantation.

The present study examined the impact of donor hypertension on recipient survival and offer acceptance practices in the United States. This was a retrospective study of all patients undergoing OHT from 1995 to 2019 using the United Network for Organ Sharing and Potential Transplant Recipient file databases. Hypertensive donors were stratified by Short (0-5 years) and Prolonged (> 5 years) hypertension. Multivariable logistic regression was used to analyze offer acceptance practices while Cox proportional-hazards models were used to compare mortality across groups. Of 38,338 heart transplants meeting study criteria, 5662 were procured from hypertensive donors (69% Short and 31% Prolonged). After adjustment, Prolonged donor hypertension was associated with increased mortality (hazard ratio, HR, 1.31, 95% confidence interval, CI, 1.04-1.64), while recipients of Short donors experienced no decrement in post-transplant survival. Both Short and Prolonged hypertension were independently associated with decreased odds of offer acceptance (odds ratio, OR .92 95%CI: .88-.96 and OR .93 95%CI: .88-.99, respectively). While prolonged untreated hypertension in OHT donors is associated with a slight decrement in recipient survival, donors with ≤5 years of hypertension yielded similar outcomes. Donor hypertension was associated with reduced organ offer acceptance, highlighting a potential source of organ underutilization.

The 2018 adult heart allocation policy change benefits low-volume transplant centers.

INTRODUCTION: The effect of the 2018 adult heart allocation policy change at an institution-level remains unclear. The present study assessed the impact of the policy change by transplant center volume. METHODS: The United Network for Organ Sharing database was queried for all adults undergoing isolated heart transplantation from November 2016 to September 2020. Era 1 was defined as the period before the policy change and Era 2 afterwards. Hospitals were divided into low-(LVC) medium-(MVC) and high-volume (HVC) tertiles based on annual transplant center volume. Competing-risks regressions were used to determine changes in waitlist death/deterioration, while post-transplant mortality was assessed using multivariable Cox proportional-hazards models. RESULTS: A total of 3531 (47.0%) patients underwent heart transplantation in Era 1 and 3988 (53.0%) in Era 2. At LVC, Era 2 patients were less likely to experience death/deterioration on the waitlist (subhazard ratio .74, 95% CI .63-.88), while MVC and HVC patients experienced similar waitlist death/deterioration across eras. After adjustment, transplantation in Era 2 was associated with worse 1-year mortality at MVC (hazard ratio, HR, 1.42 95% CI 1.02-1.96) and HVC (HR 1.42, 95% CI 1.02-1.98) but not at LVC. CONCLUSION: Early analysis shows that LVC may be benefitting under the new allocation scheme.

Outcomes and resource use for liver transplantation in the United States: Insights from the 2009-2017 National Inpatient Sample.

INTRODUCTION: Liver transplantation (LT) is a life-saving treatment for end-stage liver disease patients that requires significant resources. We used national data to evaluate LT outcomes and factors associated with hospital resource use. METHODS: Using the National Inpatient Sample, we identified all patients undergoing LT from 2009 to 2017 and defined high-resource use (HRU) as having costs ≥ 90th percentile. Hierarchical regression models were used to assess factors associated with length of stay (LOS) and HRU. RESULTS: Over the study period, approximately 53,000 patients underwent LT, increasing from 5,582 in 2009 to 7,095 in 2017 (nptrend < 0.001). Morbidity and mortality were 42.2% and 3.9%, respectively, with a median post-LT LOS of 10 days. Hospitalization costs increased from $106,866 to $145,868 (nptrend < 0.001). Acute kidney injury (ß:4.7 days, P < .001) and end-stage renal disease (ESRD) with dialysis (ß:4.3 days, P < .001) were associated with greater LOS while the Northeast region (AOR:5.2, P < .001), ESRD with dialysis (AOR:3.4, P < .001), heart failure (AOR:2.5, P < .001), and fulminant liver disease (AOR:1.8, P = .01) were associated with HRU. CONCLUSION: The cost of LT has increased over time. Renal dysfunction, regional practice patterns, and patient acuity were associated with greater resource use. Transplanting patients before health deterioration may help contain costs, mitigate resource use, and improve LT outcomes.

The BACH project protocol: an international multicentre total Bile Acid Comparison and Harmonisation project and sub-study of the TURRIFIC randomised trial.

OBJECTIVES: Multicentre international trials relying on diagnoses derived from biochemical results may overlook the importance of assay standardisation from the participating laboratories. Here we describe a study protocol aimed at harmonising results from total bile acid determinations within the context of an international randomised controlled Trial of two treatments, URsodeoxycholic acid and RIFampicin, for women with severe early onset Intrahepatic Cholestasis of pregnancy (TURRIFIC), referred to as the Bile Acid Comparison and Harmonisation (BACH) study, with the aims of reducing inter-laboratory heterogeneity in total bile acid assays. METHODS: We have simulated laboratory data to determine the feasibility of total bile acid recalibration using a reference set of patient samples with a consensus value approach and subsequently used regression-based techniques to transform the data. RESULTS: From these simulations, we have demonstrated that mathematical recalibration of total bile acid results is plausible, with a high probability of successfully harmonising results across participating laboratories. CONCLUSIONS: Standardisation of bile acid results facilitates the commutability of laboratory results and collation for statistical analysis. It may provide the momentum for broader application of the described techniques in the setting of large-scale multinational clinical trials dependent on results from non-standardised assays.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated maternal circulating bile acid levels and associated dyslipidemia. ICP leads to accumulation of bile acids in the fetal compartment, and the elevated bile acid concentrations are associated with an increased risk of adverse fetal outcomes. The farnesoid X receptor agonist obeticholic acid (OCA) is efficient in the treatment of cholestatic conditions such as primary biliary cholangitis. We hypothesized that OCA administration during hypercholanemic pregnancy will improve maternal and fetal bile acid and lipid profiles. Female C57BL/6J mice were fed either a normal chow diet, a 0.5% cholic acid (CA)-supplemented diet, a 0.03% OCA-supplemented diet, or a 0.5% CA + 0.03% OCA-supplemented diet for 1 wk before mating and throughout pregnancy until euthanization on day 18. The effects of CA and OCA feeding on maternal and fetal morphometry, bile acid and lipid levels, and cecal microbiota were investigated. OCA administration during gestation did not alter the maternal or fetal body weight or organ morphometry. OCA treatment during hypercholanemic pregnancy reduced bile acid levels in the fetal compartment. However, fetal dyslipidemia was not reversed, and OCA did not impact maternal bile acid levels or dyslipidemia. In conclusion, OCA administration during gestation had no apparent detrimental impact on maternal or fetal morphometry and improved fetal hypercholanemia. Because high serum bile acid concentrations in ICP are associated with increased rates of adverse fetal outcomes, further investigations into the potential use of OCA during cholestatic gestation are warranted.NEW & NOTEWORTHY We used a mouse model of gestational hypercholanemia to investigate the use of obeticholic acid (OCA), a potent FXR agonist, as a treatment for the hypercholanemia of intrahepatic cholestasis of pregnancy (ICP). The results demonstrate that OCA can improve the fetal bile acid profile. This is relevant not only to women with ICP but also for women who become pregnant while receiving OCA treatment for other conditions such as primary biliary cholangitis and nonalcoholic steatohepatitis.

Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial.

BACKGROUND: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. METHODS: We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. FINDINGS: Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. INTERPRETATION: Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation Programme.