Background Preterm birth (PTB) disproportionately affects women from ethnic minority backgrounds, yet these communities remain underrepresented in genomic research. The PRESTIGE-PTB study uses whole genome sequencing to investigate genetic determinants of spontaneous PTB and embeds patient and public involvement and engagement (PPIE) to promote inclusivity, acceptability, and responsiveness to lived experience. Methods Monthly online PPIE meetings were conducted with three contributors from ethnically diverse backgrounds between December 2024 and September 2025. Activities included co-development of participant materials, discussion of recruitment challenges, and refinement of communication strategies. Meeting minutes and evaluation forms from contributors and researchers were analysed descriptively. Reporting was guided by the GRIPP2 short-form checklist. Results Nine PPIE meetings were held. Contributor feedback led to revisions of posters and social media materials, improved cultural sensitivity in recruitment communication, and targeted outreach through charities and community groups, contributing to increased self-referrals. Contributors reported increased knowledge, confidence, and sense of value, while researchers described enhanced awareness of inclusivity and patient experience. Limitations included late introduction of PPIE and restricted influence on foundational study documents. Conclusions Regular, well-supported PPIE enhanced study materials, communication, and inclusivity in genomic PTB research. Early involvement, broader diversity, and sustained funding are essential to maximise the impact of PPIE in future maternal and genomic research. Trial registration Not applicable.

Background: Gestational diabetes mellitus (GDM) is associated with metabolic disturbance and subclinical cardiovascular changes during pregnancy and after birth. Optimal glycaemic control remains challenging for many patients despite existing management strategies. Ursodeoxycholic acid (UDCA) has shown potential metabolic effects, including enhanced insulin sensitivity and anti-inflammatory effects. Previously, we demonstrated that UDCA improves glycaemic control in women achieving higher circulating UDCA concentrations; however, its effect on maternal cardiac function remains unknown. The objective was to evaluate whether treatment with UDCA compared with placebo is associated with differences in maternal cardiac function in pregnancies complicated by GDM. Methods: In this randomized, placebo-controlled trial, 113 women with GDM were recruited, with 56 allocated to UDCA and 57 to placebo (IMIB-GU-2019-02, registration date: 17 June 2020; first participant enrolled: 3 March 2021). After measurement of maternal blood UDCA levels, 43 participants in the treatment group with levels ≥ 0.5 μmol/L were included in a per-protocol analysis. Participants had cardiac assessments at baseline, in the late third trimester (36 weeks) and postpartum. Detailed left ventricular systolic and diastolic functional indices were assessed using conventional pulse and tissue Doppler indices as well as strain imaging. Right ventricular systolic function was also assessed. Results: Baseline maternal characteristics and cardiac functional indices were comparable between the UDCA and placebo groups. In the third trimester, women treated with UDCA showed more negative left atrial strain during atrial contraction (LASct_AC) compared with placebo (p = 0.016), while no significant between-group differences were observed in conventional left ventricular systolic or diastolic parameters. In the postpartum period, UDCA treatment was associated with higher left atrial reservoir function, reflected by increased LASr_ED (p = 0.041) and LASr_AC (p = 0.036), as well as more negative left atrial conduit strain at end-diastole (LAScd_ED; p = 0.043). No consistent differences were observed in left ventricular systolic function, haemodynamic indices, or right ventricular functional parameters between the two groups. Conclusions: These findings are associated with small and time-dependent differences in reducing atrial dysfunction and improving cardiac efficiency during late pregnancy and postpartum. However, given the lack of long-term follow-up, further research is needed to determine the long-term cardiovascular relevance of UDCA in this population.

Background: APOL1 risk alleles are prevalent in individuals of West African ancestry and associated with increased risk of kidney disease. Although preeclampsia disproportionately affects women of Black ethnic backgrounds, evidence linking APOL1 alleles to preeclampsia remains conflicting. Objectives: The purpose of this study was to explore whether maternal APOL1 alleles contribute to preeclampsia risk and associated adverse pregnancy outcomes. Study design: We conducted a nested case-control study of 5210 pregnant women, including 745 preeclampsia cases and 949 controls of Black self-reported ethnicity, 1385 preeclampsia cases and 2131 controls of White self-reported ethnicity. APOL1 G1 and G2 risk alleles were directly genotyped on the Illumina Infinium Global Screening Array. Associations with preeclampsia, early preeclampsia, recurrent preeclampsia, birthweight centiles and gestational age at delivery were examined using regression models assuming a recessive mode of inheritance with adjustment for established risk factors and stratification by self-reported ethnicity and genetically-determined ancestry. Results: Presence of APOL1 risk alleles was almost exclusively observed in women of Black self-reported ethnicity. 168/949 controls (17.7%) and 133/745 cases (17.9%) carried two APOL1 risk alleles, and these women did not have a significantly increased risk of preeclampsia compared to those with zero or one APOL1 risk alleles in adjusted analyses (OR 1.00, 95% CI 0.76-1.29, p=0.972). When restricting analysis to women of Black self-reported ethnicity only, no association was observed between APOL1 genotype and preeclampsia risk (adjusted OR 0.94, 95% CI 0.61-1.25, p=0.673). When restricting analysis to women of pan-African genetically-determined ancestry only, also no association was observed between APOL1 genotype and preeclampsia risk (adjusted OR 1.00, 95% CI 0.76-1.32). No associations were found between number of APOL1 risk alleles and early preeclampsia, recurrent preeclampsia, birthweight centile or gestational age at delivery after adjustment for established risk factors and stratification by self-reported ethnicity or genetically-determined ancestry. Conclusions: Maternal APOL1 risk alleles do not independently influence preeclampsia risk or related adverse outcomes in a multi-ethnic pregnancy study. Future studies should examine whether fetal APOL1 genotypes, alone or in interaction with maternal genotypes, contribute to preeclampsia risk. ### Competing Interest Statement FCR receives part-time salary contribution as Chief Medical Officer at MEGI Health UK Ltd and receives consulting fees for advisory services provided through Option 5 Health Limited, Revena Limited and Gerson Lehrman Group Limited (GLG). The remaining authors have nothing to disclose. ### Funding Statement This study was supported by a grant from the Fetal Medicine Foundation. FCR is supported by the Medical Research Council (MR/V006835/1). LCC is supported by an NIHR Senior Investigator Award. PH is supported by BrightFocus, US (G2021011S) and US NIH (R21AI177219). AdM is supported by the Fetal Medicine Foundation (495237). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the NHS Research Ethics Committee (REC reference: 02-03-033) on 11th March 2003. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Intrahepatic cholestasis of pregnancy (ICP), characterised by elevated maternal serum bile acids (BAs), increases risk of preterm labour that may be mitigated by ursodeoxycholic acid (UDCA) treatment. How different BA species, including UDCA, affect myometrial function remains imperfectly understood. Primary human myometrial cells were isolated from women with uncomplicated pregnancy and treated with taurocholic acid (TCA, 150µmol/l), tauro-UDCA (TUDCA, 150µmol/l) or both TCA and TUDCA (75µmol/l each); some were stimulated oxytocin (10nmol/l, 6 h). Gene expression was determined using real-time quantitative PCR, and IL-6 protein in supernatant using ELISA. TCA increased OXTR mRNA expression after 4, 10, 18 and 24 h. Following overnight BA pre-treatment, 6-hour combined treatment with TCA and TUDCA led to highest OXTR (p < 0.01 vs. control) and increased oxytocin-induced COX-2 (p < 0.05) and IL-6 mRNA (p = 0.06) expression. IL-6 protein was increased by TCA but not TUDCA. This indicates elevated BAs in maternal serum may alter expression of oxytocin-responsive genes by upregulating OXTR expression. Combined exposure to high TCA and TUDCA increased expression of OXTR, COX-2 and IL-6, but not IL-6 protein, while TUDCA alone had no effect. Altered OXTR expression and downstream gene expression changes may contribute to ICP-associated myometrial contractility and preterm birth risk, meriting further study.

Background:Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality, and a major contributor to low birth weight. Beta blockers (BB) and calcium channel blockers (CCB) are the most commonly recommended agents to treat hypertension in pregnancy. Yet it remains unknown whether these agents alter the risk of preeclampsia (PE), and if so, whether effects arise through maternal physiology or through direct fetal mechanisms. Objectives:To use drug-target Mendelian randomization (MR) to estimate the effects of genetically-proxied inhibition of beta-adrenergic and L-type calcium-channel targets on PE risk, birth weight, partitioned into maternal and fetal genetic components, and gestational age (GA). Methods:We constructed instruments from genome-wide significant, LD-independent variants within prespecified windows around systolic blood pressure (SBP) modulating drug targets in addition to a genome-wide SBP instrument (European ancestry). Outcomes comprised of PE (16,349 cases / 595,135 controls), maternal and fetal genetic effects on birth weight (n≈210,267 and n≈298,142), and GA (n≈151,987). Two-sample MR estimated effects per 5mmHg decrease in SBP. Bayesian colocalization assessed shared causal variants. Multiple testing was controlled with Benjamini-Hochberg correction. Results:Genetically lower SBP was associated with reduced PE risk and modest increases in birth weight and GA. BB (ADRB1) target inhibition showed no convincing reduction in PE risk but was associated with lower birth weight, with associations predominantly through direct fetal genetic effects and strong colocalization at ADRB1 with fetal birth-weight signals. In contrast, CCB targets collectively associated with lower PE risk without consistent evidence of fetal growth impairment; colocalization support for individual CCB loci was limited. Sensitivity analyses (heterogeneity, pleiotropy) did not materially alter these patterns where instrument counts permitted. Conclusions:Drug-target MR suggests that BB pathways are unlikely to meaningfully reduce PE and are linked to reduced fetal growth - chiefly via direct fetal mechanisms. In contrast, CCB pathways are associated with lower PE risk and largely neutral fetal growth effects. These findings support prioritizing CCBs for evaluation in comparative trials of PE prevention.

Intrahepatic cholestasis of pregnancy (ICP) presents with cholestatic pruritus, elevated sBA and increased risk of adverse perinatal outcomes. Volixibat is a minimally absorbed IBAT inhibitor that interrupts enterohepatic recirculation. We describe four patients with ICP with pruritus and sBA > ULN treated with volixibat (20 or 80 mg BID orally until delivery), with dose modifications permitted for tolerability. Daily pruritus scores, sBA, liver enzymes, perinatal outcomes and TEAEs were assessed. Over 1000 patients were invited to participate; 26 were screened, and four received volixibat. Three patients experienced reductions in pruritus from baseline regardless of volixibat dose, with intermittent relief coinciding with resumption of dosing when doses were interrupted. sBA nadir values all reached < 6 μmol/L following volixibat. No clinically meaningful changes in laboratory parameters were observed. All patients had healthy live births. Most frequent TEAEs were gastrointestinal. Volixibat demonstrated improvements in pruritus and sBA in patients with ICP. Trial Registration: NCT04718961.

Abstract Intrahepatic Cholestasis of Pregnancy (ICP) is the most common pregnancy-related liver disorder. ABCB4 heterozygous variants are implicated in ICP, but interpretation of rare variants remains challenging, leading to many variants of uncertain significance. This study compares predictions from multiple in silico tools on nine heterozygous missense variants identified in women with ICP. Using the Genomics England Research Environment, 253 women with ICP and whole-genome sequencing data were analysed. Variants with minor allele frequency < 0.05 were filtered, and nine rare missense variants were assessed using SIFT, PolyPhen, CADD, Vasor ( ABCB4 -specific), and AlphaMissense. Only 44% (4/9) of variants had consistent classification across all tools. Published functional studies often conflicted with predictions. For example, T175A showed no detectable effect in HepG2/HEK293 cells but was classified as likely pathogenic by Vasor and benign by AlphaMissense. Similarly, N510S impacted protein stability functionally and was deemed likely pathogenic by Vasor but benign by AlphaMissense. In silico tools show conflicting predictions for ABCB4 rare variants, highlighting the difficulty of classification without functional or segregation data as well as the heavy reliance on computational predictions.

OBJECTIVE:To define standardised outcomes, the Core Outcome Set (COS) for reporting in studies of Intrahepatic Cholestasis of Pregnancy (ICP). DESIGN:e-Delphi survey and consensus process. SETTING:International. POPULATION:155 individuals from Asia, Europe, Oceania, North and South America: 31 patients (20%), 121 clinicians (78%), and 3 researchers (2%). METHODS:Maternal and perinatal outcomes reported in studies of ICP were collated. Stakeholders in ICP research and clinical care scored the importance of each outcome using a 9-point Likert scale over three rounds; short-listed outcomes were ranked during face-to-face consensus meetings. The final COS was agreed by the Study Steering Committee. The study was registered prospectively with Core Outcome Measures in Effectiveness Trials. Ethical approval was granted by the King's College London Research Ethics Committee (KCL MRA-23/24-39574). MAIN OUTCOME MEASURES:From 54 manuscripts, 97 individual clinical outcomes were attributed to ICP. Twenty three outcomes were shortlisted by the e-Delphi surveys, the ranking of which enabled selection of 10 core outcomes. RESULTS:Maternal core outcomes comprise: total maternal bile acid (BA) concentration (maximum), gestational age at peak BA concentration, and itch impact on maternal wellbeing. Birth core outcomes comprise: stillbirth, gestational age at birth, and spontaneous preterm birth versus induced preterm birth. Neonatal core outcomes comprise: perinatal death within 7 days of birth, perinatal asphyxia, neonatal unit admission, and mechanical ventilation. CONCLUSIONS:Given the heterogeneity of reported outcomes, we have confirmed the need for a COS in ICP, standardising the minimum reported outcomes to reduce outcome reporting bias and research wastage.

Children of mothers with intrahepatic cholestasis of pregnancy (ICP) are more likely to develop metabolic disease later in life. Using a mouse model of gestational cholestasis, we previously found that 18-week-old offspring had metabolic alterations that were exacerbated in female offspring when challenged with a Western diet (WD). Microbiota changes are emerging as a potential mechanism for developmental programming, and the maternal gut microbiota is known to be altered in pregnancy and in ICP. We hypothesized that, in our model, the offspring gut microbiota is altered by maternal gestational disease, potentially impacting future offspring metabolic health. Female mice were fed a cholic acid (CA)-supplemented diet for 1 week preceding and throughout pregnancy to mimic gestational hypercholanemia. Female offspring were challenged with a WD from 12 to 18 weeks of age and cecal contents were collected for metataxonomics and metabolomic profiling. Maternal CA dietary supplementation was associated with markedly increased cecal sulfated bile acid species (up to 387-fold increase). Whilst WD-feeding of offspring was associated with a greater proportion of primary to secondary bile acids, and more tauro-conjugated bile acids than for offspring fed a normal diet, this adaptation to WD-feeding was not evident for those whose mothers were fed a CA-supplemented diet. Indeed, WD-fed offspring of CA-supplemented mothers had a >2-fold reduction in CA and dehydrocholic acid levels compared to those from NC-fed mothers. This corresponded with an altered profile of cecal microbiota, with clear separation of microbiotal profiles according to maternal diet in the WD-fed, but not NC-fed, offspring. This observational mouse study has shown that exposure to maternal hypercholanemia can significantly impact the effects of an obesogenic diet on offspring intestinal bile acid metabolism and gut microbiota, likely increasing their vulnerability to metabolic dysfunction when exposed to the “second hit” of an unhealthy postnatal environment.

Background:Pruritus is a common symptom of intrahepatic cholestasis of pregnancy (ICP) and significantly reduces patients' quality of life (QoL). Methods:A multinational survey administered through ICP patient support groups was conducted in women with current or previous ICP. Results:In total, 697 women from the UK, USA, Australia, Canada, New Zealand, and Ireland responded to the survey. 94% had ICP in a previous pregnancy. The median worst itch score (0-10) was 9. Pruritus severity was associated with a higher degree of sleep disturbance, fatigue, and mood changes. 59% reported that pruritus led to disruption of daily activities. 33% reported missing school or work. Most patients were taking ≥2 antipruritic medications and achieved only partial resolution of pruritus. Conclusion:The results underscore the negative impact of pruritus on QoL in patients with ICP and substantiate the high unmet need for developing safe and effective antipruritic therapies in ICP. Trial Registration:Trial registration is not applicable because this was not an interventional study.

OBJECTIVE:To determine whether the gestation at which severe ICP (bile acids ≥100 µmol/L) developed or peaked is associated with the risk of stillbirth. STUDY DESIGN:Observational cohort study, including patients with singleton pregnancies and severe ICP, likely enriched for those experiencing stillbirths. The association between peak serum bile acid concentration and stillbirth risk was determined using logistic regression. Participants were dichotomized according to the gestation at which serum bile acid concentrations first became severe, or peaked, and stillbirth rates compared using Mann-Whitney and logistic regression. RESULTS:Of 198 participants, 15 (7.6 %) pregnancies ended in stillbirth. The gestation of peak bile acid concentration was associated with stillbirth risk (OR 1.28 per advancing week, 95 %CI 1.06-1.56); patients with stillbirths first developed severely elevated bile acids later than those with livebirths (p = 0.029). Of those with first bile acid concentration ≥100 μmol/L after 28 weeks', 13/133 (9.8 %) babies were stillborn, whilst 2/65 (3.1 %) stillbirths occurred for those with severe disease onset before 28 weeks' (OR 3.47, 95 %CI 0.77-15.74). For 11/15 patients experiencing stillbirth, bile acids rose markedly in the five days prior to stillbirth. CONCLUSIONS:A later gestation at which serum bile acids first rise over 100 μmol/L, and a later gestation at which bile acid concentration peaks, are both associated with a higher risk of stillbirth. A marked increase in bile acid concentration immediately prior to stillbirth may herald increased risk. These findings underline the benefit of repeat testing and surveillance of serum bile acids to support individualized recommendations regarding birth gestation.

Preterm birth is a central determinant of infant morbidity and mortality. Efforts to reduce its incidence must address the disparate underlying causes.

Nausea and vomiting of pregnancy (NVP) affects up to 90