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Siara Teelucksingh,1,* Renuka Murali Govind,1,* Ruth Dobson,2,3 Catherine Nelson-Piercy,1,4 Caroline Ovadia4,5 1Department of Obstetric Medicine, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK; 2Preventive Neurology Unit, Queen Mary University of London, London, UK; 3Department of Neurology, Royal London Hospital, London, UK; 4Department of Women and Children’s Health, King’s College London, London, UK; 5Department of Obstetrics and Gynaecology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK*These authors contributed equally to this workCorrespondence: Caroline Ovadia, Department of Women and Children’s Health, King’s College London, 10th Floor North Wing, St. Thomas’ Hospital, London, SE1 7EH, UK, Email caroline.ovadia@kcl.ac.ukAbstract: Vestibular migraine is a leading cause of vertigo in pregnancy and, although not a distinct migraine subtype, is an episodic syndrome associated with migraine. Vestibular migraine is associated with diverse symptoms such as vertigo, aura, allodynia, osmophobia, nausea, vomiting and tinnitus, many of which may be exacerbated by, masked or even dismissed in pregnancy. Vestibular migraine is likely an underdiagnosed and undertreated condition in pregnancy. The aetiology of vestibular migraine remains incompletely understood, although various theories have been proposed, including genetic predisposition, neurochemical dysregulation and pro-inflammatory mechanisms, all of which are derived from the pathophysiology of classical migraine. Physiologic changes to the endocrine, haematologic and vascular systems in pregnancy may affect pathophysiological processes in vestibular migraine, and can alter the course of symptoms experienced in pregnancy. These changes also predispose to secondary headache disorders, which may have similar presentations. There has been considerable progress in therapeutic advances in vestibular migraine prophylaxis and treatment outside of pregnancy. There is currently no significant evidence base for acute treatment or prophylaxis for pregnant patients, with treatment recommendations extrapolated from studies on classical migraine, and offered on a benefit versus risk basis. Challenges commonly encountered include difficulty establishing a diagnosis, in addition to recognising and treating neuropsychiatric and gestational co-morbidities. Anxiety, depression, hypertensive disorders and cardiovascular disease are closely associated with migraine, and important contributors to morbidity and mortality during pregnancy. Identifying and treating vestibular migraine during pregnancy offers a unique opportunity to impact future patient health through screening and early treatment of associated co-morbidities. There have been innovations in classical migraine therapy that may confer benefit in vestibular migraine in pregnancy, with emphasis on lifestyle modification, effective prophylaxis, abortive therapies, cognitive behaviour therapy and management of vestibular migraine-related comorbidities.Keywords: vestibular, migraine, dizziness, vertigo, pregnancy

Objective: Around 80% of women with endometriosis have superficial endometriosis (SE) rather than ovarian or deep endometriosis (DE). However, to date, advances in non‐invasive, imaging‐based diagnosis have been limited to DE or ovarian disease. The objective of this study was to determine whether we can detect SE on transvaginal ultrasound scan (TVS) by assessing the peritoneum of the pouch of Douglas (POD). Methods: This was a retrospective diagnostic test study following a change in practice to include POD peritoneum assessment for SE during TVS at a tertiary London hospital. Eligible patients underwent TVS by a single clinician trained in endometriosis scanning and a subsequent surgical procedure (laparoscopy) between April 2018 and September 2021. Participants formed a consecutive series. The TVS findings were compared with those of laparoscopy as the gold standard. Comparison of TVS findings with intraoperative findings was performed by calculating the diagnostic test performance measures (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive and negative likelihood ratios). Results: The study included a total of 100 patients. We found that 43/100 (43.0%) patients had no endometriosis, 33/100 (33.0%) had SE and 24/100 (24.0%) had DE on laparoscopy. SE was correctly detected on TVS in 17/33 patients, with a sensitivity of 51.5% (95% CI, 33.5–69.2%), specificity of 94.0% (95% CI, 85.4–98.4%), PPV of 81.0% (95% CI, 60.8–92.1%) and NPV of 79.7% (95% CI, 73.4–84.9%). DE was correctly diagnosed in 20/24 cases, including all ovarian cases, with a sensitivity of 83.3% (95% CI, 62.3–95.3%), specificity of 97.4% (95% CI, 90.8–99.7%), PPV of 90.9% (95% CI, 71.6–97.5%) and NPV of 94.9% (95% CI, 88.3–97.8%). The detection of SE on TVS was most accurate in the POD (sensitivity, 50.0%; specificity, 96.4%; PPV, 76.9%; NPV, 88.9%). Conclusions: This study shows that the detection of SE in the POD is possible using routine TVS. While negative TVS does not reliably confirm the absence of disease or replace diagnostic laparoscopy, positive TVS facilitates non‐invasive diagnosis for a much larger group of women than was previously possible. This should help to reduce the time from the onset of symptoms to diagnosis and enable initiation of medical treatment without the risk, cost and delay associated with a surgical diagnosis. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Linked article: This is a mini commentary on Z Xu et al., pp. 367–377 in this issue. To view this article visit https://doi.org/10.1111/1471-0528.16968 [ABSTRACT FROM AUTHOR]

Sulfated progesterone metabolites (PMxS) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by pruritus and elevated serum bile acids. PMxS interact with bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1) to cause itch. We investigated whether PMxS could undergo enterohepatic recycling and stimulate intestinal GPBAR1-mediated release of gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). PMxS were quantified in pre-/postprandial serum samples (n=21) and feces (n=18) by ultra-performance liquid chromatography-tandem mass spectrometry in prospectively recruited third trimester of pregnancy outpatients with uncomplicated pregnancy or ICP. Ussing chambers were used to evaluate colonic ion secretion changes (ΔIsc) in wildtype, GPBAR1 -/- , and PYY -/- mice by PMxS metabolites, PM3S and PM5S, and in wildtype mice with or without apical sodium bile acid transporter (ASBT) inhibition (n=6/condition). PM3S/PM5S stimulation of GLP-1 release from wildtype and GPBAR1 -/- murine crypts and human colonoids was measured by ELISA (n=3). Serum PMxS increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxS are present in feces. Apical and basolateral PM3S and PM5S stimulated PYY-mediated -ΔIsc in wildtype (p<0.01) but not GPBAR1 -/- or PYY -/- colons. PM3S and PM5S caused GLP-1 secretion in murine crypts and human colonoids (p<0.001). ASBT inhibition blunted -ΔIsc by 68% after apical PM3S and PM5S addition (p<0.001). Serum PMxS, elevated in women with ICP and particularly postprandially, can undergo ASBT-mediated intestinal reuptake and activate GPBAR1 to stimulate gut hormone release. PMxS may therefore augment GPBAR1-mediated metabolic responses during pregnancy.

This primigravid pregnant woman had a new diagnosis of primary biliary cholangitis (PBC) that was treated with a combination of ursodeoxycholic acid (UDCA) and bezafibrate. Pregnancy may unmask underlying chronic hepatic disorders in susceptible women and, in some cases, the associated abnormalities of liver function or increased serum bile acids (hypercholanaemia) can result in significant fetal and maternal risk. Maternal pruritus, with associated sleep deprivation, may cause considerable distress. To our knowledge, this is the first reported case of a new diagnosis of PBC in pregnancy treated with a combination of both UDCA and a fibrate. The case demonstrates the importance of accurate and efficient diagnosis alongside effective multidisciplinary team working to initiate appropriate, timely treatment to minimise the risk to fetus and mother. Early assessment, risk stratification and cautious surveillance is paramount in managing evolving or coexisting pathology plus individualised delivery planning, aiming to optimise fetal and maternal outcomes., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CO consults for Mirum Pharmaceuticals and has received travel and accommodation expenses from the Falk Foundation. CW is a consultant for Mirum Pharmaceuticals., (© The Author(s) 2024.)

Objective: Establish whether pregnancies complicated by gestational diabetes mellitus (GDM) are associated with a fetal cardiac phenotype that predisposes to arrhythmia; utilising measurements derived from non-invasive abdominal fetal ECG., Design: Prospective observational study., Setting: Three tertiary obstetric units, United Kingdom., Population: Women aged ≥ 16 years with either GDM or uncomplicated pregnancy (control) who were > 20 weeks gestational age., Methods: The MonicaAN24 non-invasive abdominal fetal ECG monitor was fitted for overnight recording., Main Outcome Measure: Calculation of the fetal heart rate (FHR) and fetal heart rate variability (HRV) time domain metrics standard deviation of normal-to-normal intervals (SDNN), root mean square of successive differences (RMSSD) and the PR, QRS, QT intervals was performed. Groups were compared using linear regression models (stratified by sleep state) and adjusted for fetal sex and ethnicity., Results: Ninety-six participants were included. For HRV in sleep state 1F, SDNN was higher for GDM than control participants 12.56 (10.45-16.62)ms versus 8.58 (5.83-9.73)ms [p = 0.01] [median (IQR)]. There were no differences in SDNN in sleep state 2F. No differences were identified in RMSSD in either sleep states or in the cardiac time intervals. We observed a negative correlation between HRV and body mass index/HbA1c and a positive correlation between FHR and body mass index/HbA1c in sleep states 1F/2F., Conclusions: Alterations of HRV and FHR rate may be associated with a diagnosis of GDM, likely secondary to altered autonomic function in utero., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Bile acid metabolism is partially regulated through the activity of the gut microbiota. Primary bile acids can be deconjugated and modified by bacteria expressing bile salt hydrolase and other enzymes, changing bile acid recycling by changing the interactions between enterocytes and hepatocytes. The modified bile acids can also activate signalling in cells regulating metabolism including colonic L-cells, skeletal muscle cells and brown adipocytes. In pregnancy, both bile acid metabolism and gut microbiota composition are altered. In women with intrahepatic cholestasis of pregnancy, the changes in bile acid metabolism are exacerbated and there is some evidence that the gut microbiota composition is also altered. Here we review the crosstalk between the liver and the gut especially in women with intrahepatic cholestasis of pregnancy, with a focus on the role of the gut microbiota in this crosstalk., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Reports of adverse pregnancy outcomes associated with maternal pruritus and liver impairment have circulated since the 1800s, yet the precise diagnosis and management of intrahepatic cholestasis of pregnancy have varied markedly. Recent evidence, including that from individual participant data meta-analyses, has provided an evidence that brings us closer to standardised, and optimal, management of the condition. Based upon increased adverse perinatal outcomes with higher bile acid concentrations, disease management should be according to severity (defined by peak bile acid concentration) in order to recommend appropriate gestation of birth. Similarly, the reduced spontaneous preterm birth rate for patients receiving ursodeoxycholic acid treatment suggests potential benefit for the treatment of patients with moderate-severe disease., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Fetal long QT syndrome (LQTS) may present with sinus bradycardia, functional 2:1 atrioventricular block (AVB), and ventricular arrhythmias (ventricular tachycardia [VT]/torsades de pointes [TdP]) and lead to fetal or postnatal death. We performed a systematic review and individual participant data meta-analysis of 83 studies reporting outcomes of 265 fetuses for which suspected LQTS was confirmed postnatally and determined risk of adverse perinatal and postnatal outcomes using logistic and stepwise logistic regression. A longer fetal QTc was more predictive of death than any other antenatal factor (receiver operating characteristic [ROC] area under the curve [AUC] 0.85; 95% confidence interval [CI] 0.66-1.00). Risk of death was significantly increased with fetal QTc >600 ms. Neither fetal heart rate nor heart rate z-score predicted death (ROC AUC 0.51; 95% CI 0.31-0.71; and ROC AUC 0.59; 95% CI 0.37-0.80, respectively). The combination of antenatal VT/TdP or functional 2:1 AVB and lack of family history of LQTS was also highly predictive of death (ROC AUC 0.82; 95% CI 0.76-0.88). Our data provide clinical screening tools to enable prediction and intervention for fetuses with LQTS at risk of death., (Copyright © 2022 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Neurologists increasingly use anti-CD20 therapies, including for women of childbearing age, despite these medications being unlicensed for use in pregnancy. Current evidence suggests that women can safely conceive while taking anti-CD20 therapy. Women should not be denied treatment during pregnancy when it is clinically indicated, although they should be counselled regarding live vaccinations for their infant. Women receiving regular ocrelizumab for multiple sclerosis should preferably wait 3 months before trying to conceive. There are few data around ofatumumab in pregnancy, and while there is probably a class effect across all anti-CD20 therapies, ofatumumab may need to be continued during pregnancy to maintain efficacy. We recommend that anti-CD20 therapies can be safely given while breast feeding. It is important to make time to discuss treatments with women of childbearing age to help them choose their most suitable treatment. Outcomes should be monitored in pregnancy registries., Competing Interests: Competing interests: RD, DR, KM, SH, ORP, HLF, NB-M, SW and PB are on the steering committee for the UK MS Pregnancy Register, which seeks to improve our understanding of the safety of DMT in pregnancy. RD has received honoraria for sitting on advisory boards from Roche and Novartis. She sits on the steering committee for the MINORE and SOPRANINO studies, which are examining the safety of ocrelizumab in pregnancy and breastfeeding. She receives grant support from the UK MS Society, BMA foundation, NIHR, MRC, NMSS, Horne Family Charitable Trust, Biogen, Celgene, and Merck. She has received honoraria for advisory boards and/or educational activities from Biogen, Teva, Sanofi, Merck, Janssen, Novartis, and Roche. DR has received honoraria for sitting on advisory boards and/or speaker fees from from Biogen, Celgene, Hikma, Janssen, MedDay, Merck Serono, Novartis, Roche, Sanofi, Teva Neuroscience. He is the UK Coordinating Investigator for Tecfidera, Aubagio and Lemtrada pregnancy registries. He has received research support, paid to his institution, from Actelion, Biogen, Janssen, Merck Serono, Mitsubishi, Novartis, Sanofi, Teva Neuroscience, TG Therapeutics. CO consults for Mirum Pharmaceuticals. KM reports honoraria for advisory boards/educational activities from Biogen, Roche, Merck, Teva, Novartis, Sanofi. ORP has received honoraria for advisory boards and/or educational activities from Biogen, Teva, Sanofi, Merck, Janssen, Novartis, and Roche. SH has received unrestricted educational grants or speaking honoraria from Biogen, Merck Serono, Novartis, Roche and Sanofi Genzyme. NB-M has nothing to declareSW reports honoraria for advisory boards and/or educational activities from Biogen, Sanofi, Merck, Janssen, Novartis, Roche and Celgene. CN-P reports speakers fees from UCB, Sanofi, Jansen, and Alexion. PB has received honoraria for advisory boards and/or educational activities from Merck, Biogen, Roche, MS Academy, Janssen, Sanofi-Genzyme, Teva and MedDay Pharmacuticals., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Each year in the UK, approximately 35,000 women develop gestational diabetes mellitus (GDM). The condition increases the risk of obstetric and neonatal complications for mother and child, including preeclampsia, preterm birth, and large for gestational age babies. Biochemical consequences include maternal hyperglycemia, neonatal hypoglycemia, and dyslipidemia. Metformin is the most commonly used firstline pharmacological treatment. However, there are concerns about its widespread use during pregnancy, due to its limited efficacy and potential safety concerns. Therefore, there is a need for additional therapies that improve both maternal-fetal glucose and lipid metabolism. Ursodeoxycholic acid (UDCA) is not currently used for treatment for GDM. However, it can improve glucose control in type 2 diabetes, and it improves fetal lipid profiles in gestational cholestasis. Consequentially, it is hypothesized that treatment with UDCA for women with GDM may improve both maternal metabolism and neonatal outcomes. The primary outcome of this trial is to assess the efficacy of UDCA compared with metformin to improve glucose levels in women with GDM., Methods: The trial is a two-armed, open-label, multi-center, randomized controlled trial. Women are eligible if they have been diagnosed with GDM by an oral glucose tolerance test between 24 + 0 and 30 + 6 weeks' gestation, and if they require pharmacological intervention. In total, 158 pregnant women will be recruited across seven NHS Trusts in England and Wales. Women who consent will be recruited and randomized to either metformin or UDCA, which will be taken daily until the birth of their baby. Maternal and neonatal blood samples will be taken to evaluate the impact of the treatments on maternal glucose control, and maternal and neonatal lipid metabolism. Maternal and fetal outcomes will be evaluated, and acceptability of UDCA compared with metformin will be assessed., Discussion: This trial has the potential to identify a potential new treatment for women with GDM. If successful, a future large multi-center trial will be designed to investigate where decisions can be personalized to identify which women will respond more effectively to UDCA than alternatives to improve maternal and baby outcomes., Trial Registration: ClinicalTrials.gov NCT04407650., (© 2022. The Author(s).)

Globally, headache disorders are an important cause of disability in adults. As many types of headache (eg, migraine, tension-type and medication-overuse) are more common in women and have peak incidence in reproductive years, chronic headache disorders are highly prevalent in pregnant women. Some women with a history of migraine may find that it improves during pregnancy while others may find that their migraines become more unpredictable. Ideally, women with migraine and problematic headache disorder should be offered preconception counselling to address pregnancy-related concerns and advice on the use of medicines, which should be supported by high-quality information. For women with history of headache, the use of effective non-pharmacological options should be maximised, and the smallest number of the safest medicines at the lowest effective doses should be used while preparing for pregnancy and during pregnancy. This article forms part of the series of prescribing for pregnancy and discusses the impact of headache and migraine on pregnancy, the impact of pregnancy on headache and migraine and options for prophylaxis and treatment., Competing Interests: Competing interests: None declared. Refer to the online supplementary files to view the ICMJE form(s)., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Declaration of interests CO and H-UM are consultants for Mirum Pharmaceuticals. CW is a consultant for Mirum Pharmaceuticals and GlaxoSmithKline. KK is an unpaid consultant for Myriad Pharmaceuticals. WMH reports non-financial support from the Falk Foundation, during the conduct of the study, and is co-author of the Cochrane review on pharmacological interventions for treating intrahepatic cholestasis of pregnancy.(14) RMT reports grants from Tommy's and the Lauren Page Trust during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 The Authors(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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.

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 (UDCA) treatment can reduce itch and lower endogenous serum bile acids in intrahepatic cholestasis of pregnancy (ICP). We sought to determine how it could influence the gut environment in ICP to alter enterohepatic signalling. The gut microbiota and bile acid content were determined in faeces from 35 pregnant women (14 with uncomplicated pregnancies and 21 with ICP, 17 receiving UDCA). Faecal bile salt hydrolase activity was measured using a precipitation assay. Serum fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) concentrations were measured following a standardised diet for 21 hours. Women with a high ratio of Bacteroidetes to Firmicutes were more likely to be treated with UDCA (Fisher's exact test p = 0.0178) than those with a lower ratio. Bile salt hydrolase activity was reduced in women with low Bacteroidetes:Firmicutes. Women taking UDCA had higher faecal lithocholic acid (p < 0.0001), with more unconjugated bile acids than women with untreated ICP or uncomplicated pregnancy. UDCA-treatment increased serum FGF19, and reduced C4 (reflecting lower bile acid synthesis). During ICP, UDCA treatment can be associated with enrichment of the gut microbiota with Bacteroidetes. These demonstrate high bile salt hydrolase activity, which deconjugates bile acids enabling secondary modification to FXR agonists, enhancing enterohepatic feedback via FGF19.

Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia., (© 2019 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

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 165 136 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 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I 2 =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., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2018 Wiley Periodicals, Inc.)

Intrahepatic cholestasis of pregnancy, also known as obstetric cholestasis, is a pruritic condition of pregnancy characterized by an underlying elevation in circulating bile acids and liver derangement, and associated with adverse fetal outcomes, such as preterm labor and stillbirth. Limited understanding of the underlying pathophysiology and mechanisms involved in adverse outcomes has previously restricted treatment options and pregnancy management. Recent advances in these research fields provide tantalizing targets to improve the care of pregnant women affected by this condition., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice., Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP., (© 2015 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.

The incidence of gestational diabetes is increasing, with higher obesity in the pregnant population, lifestyle changes and migration thought to underlie this. Recent large studies, such as the MiG, HAPO and ACHOIS trials, have furthered our understanding of both the implications of the disease and the management options available. Previous CEMACH (Confidential Enquiries into Maternal and Child Health) studies of diabetes in pregnancy have shown a significant proportion of patients receiving sub-optimal care. We aim to summarise the current standard of management strategies in pregnancy, whilst acknowledging controversies and limitations in the existing evidence. Antenatal management involves service organisation to provide multi-disciplinary team reviews to address glycaemic control, fetal monitoring and associated conditions such as obesity and hypertensive disorders of pregnancy. The use of diet, exercise, oral hypoglycaemic agents and insulins will be discussed, along with specific considerations for the management of preterm labour and administration of corticosteroids for fetal lung maturity. The timing and management of labour, including mechanisms of delivery, will be covered, including neonatal considerations and the use of breast feeding. Finally, a discussion of appropriate post delivery care will consider the prevention of, and screening for, the development of type 2 diabetes.

Background: Patient surveys are becoming increasingly common and already are an obligatory activity to qualify for a Better Practice Program Grant. Strategies to increase return rates remain unevaluated in Australian general practice., Aim: To evaluate the effectiveness of an instant lottery ticket as a response-aiding technique in patient surveys., Method: A random sample of adult patients was selected from an age-sex-disease register, stratified by sex and randomised to receive an instant lottery ticket with the self-administered questionnaire mailed out in December 1994., Results: There was no significant difference by group either for women (P = 0.68), men (P = 0.88) or both sexes combined (P = 0.68). However, irrespective of inclusion of the lottery ticket, men were significantly less likely to return questionnaires than women (P = 0.02)., Conclusions: Instant lottery tickets do not increase return rates to questionnaires and are not recommended. Other strategies need to be tested, particularly to involve male patients in general practice research.

The Central Sydney Area Health Service has developed and piloted a Hospital in the Home program as an alternative to inpatient admission. Hospital in the Home offers the opportunity for increased productivity of existing hospital services, and advantages for patients in terms of satisfaction and improved or comparable clinical outcomes. Having developed treatment protocols and established a core Hospital in the Home team, a wider demonstration project across three hospitals within the Central Sydney Area Health Service is proposed.