Objective: To investigate the association between hysterectomy with conservation of one or both adnexa and ovarian and tubal cancer. Design: Prospective cohort study. Setting: 13 NHS Trusts in England, Wales and Northern Ireland. Population: 202,506 postmenopausal women recruited between 2001-2005 to the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and followed up until 31 December 2014. Methods: Multiple sources (questionnaires, hospital notes, Hospital Episodes Statistics, national cancer/death registries, ultrasound reports) were used to obtain accurate data on hysterectomy (with conservation of one or both adnexa) and outcomes censored at bilateral oophorectomy, death, ovarian/tubal cancer diagnosis, loss to follow-up or 31 December 2014. Cox proportional hazards regression models were used to assess the association. Main outcome measures: Invasive epithelial ovarian and tubal cancer (WHO 2014) on independent outcome review. Results: Hysterectomy with conservation of one or both adnexa was reported in 41,912 (20.7%; 41,912/202,506) women. Median follow up was 11.1years (IQR 9.96-12.04), totalling >2.17million women-years. Among women who had undergone hysterectomy, 0.55% (231/41912) were diagnosed with ovarian/tubal cancer, compared with 0.59% (945/160594) of those with intact uterus. Multivariable analysis showed no evidence of an association between hysterectomy and invasive epithelial ovarian/tubal cancer (RR=0.98, 95%CI 0.85-1.13, p=0.765). Conclusions: This large cohort study provides further independent validation that hysterectomy is not associated with alteration of invasive epithelial ovarian and tubal cancer risk. This data is important both for clinical counselling and for refining risk prediction models.

Objective: To estimate the effect of oestrogen-only and combined hormone replacement therapy (HRT) on the hazards of overall and age-specific all-cause mortality in healthy women aged 46 to 65 at first prescription. Design: Matched cohort study.  Setting: Electronic primary care records from The Health Improvement Network (THIN) database, UK (1984−2017). Population: 105,199 HRT users (cases) and 224,643 non-users (controls) matched on age and general practice. Methods: Weibull-Double-Cox regression models adjusted for age at first treatment, birth cohort, type 2 diabetes, hypertension and hypertension treatment, coronary heart disease, oophorectomy/hysterectomy, body mass index, smoking, and deprivation status. Main outcome measures: All-cause mortality. Results: A total of 21,751 women died over an average of 13.5 years follow-up per participant, of whom 6,329 were users and 15,422 non-users. The adjusted hazard ratio (HR) of overall all-cause mortality in combined HRT users was 0.91 (95%CI 0.88−0.94), and in oestrogen-only users was 0.99 (0.93−1.07), compared to non-users. Age-specific adjusted HRs for participants aged 46-50, 51-55, 56-60, and 61-65 years at first treatment were 0.98 (0.92−1.04), 0.87 (0.82−0.92), 0.88 (0.82−0.93), and 0.92 (0.85−0.98), for combined HRT users compared to non-users, and 1.01 (0.84−1.21), 1.03 (0.89−1.18), 0.98 (0.86−1.12), and 0.93 (0.81−1.07) for oestrogen-only users, respectively. Conclusions: Combined HRT was associated with a 9% lower risk of all-cause mortality and oestrogen-only formulation was not associated with any significant changes.  Funding: IFoA. Keywords: Hormone replacement therapy, menopause, mortality, primary care records, THIN. Tweetable abstract: Oestrogen-only HRT is not associated with all-cause mortality and combined HRT reduces the risks.

Objective To determine the prevalence of genital mycoplasma infection and the risk of spontaneous preterm birth (sPTB) in asymptomatic pregnant women. Design Prospective cohort. Setting Public and private health services in Ribeirão Preto-SP, Brazil. Population 1.349 asymptomatic women with a singleton pregnancy at 20-25 weeks of gestation (WG) recruited between 2010 and 2011. Methods Baseline data was assessed using a questionnaire, in addition to cervicovaginal fluid and blood samples, to analyze lower reproductive tract infections (RTIs) and immune mediators, respectively. The association between variables and the risk of sPTB was evaluated using logistic regression analysis to estimate the odds ratios (ORs). Main outcome measures Genital mycoplasma infection and prematurity. Results The prevalence of the sPTB and genital mycoplasma was 6.8% and 18%, respectively. The infection was not a risk factor for sPTB (aOR 0.66; 95% CI 0.32-1.35), even when associated with bacterial vaginosis (BV). However, it was associated with a low socioeconomic status (p=0.0470), cigarette use (p=0.0009), number of sexual partners (p=0.0019), and BV (p<.0001). Regarding the risk factors associated with sPTB, previous history of PTB (aOR 12.06; 95% CI 6.21-23.43) and a cervical length ≤ 2.5 cm (aOR 3.97; 95% CI 1.67-9.47) were significant. Conclusions The risk of sPTB was independently associated with the history of PTB and the cervical length but not with the genital mycoplasma infection. Funding: This work was founded by CNPq, FAPESP and CAPES. Keywords: Preterm birth, pregnancy, genital mycoplasma, bacterial vaginosis, risk factor

Medical Management of GDM – following the evidenceMini Commentary on 21-0353.R1 - “Changing Patterns in Medication Prescription for Gestational Diabetes During a Time of Guideline Change in the USA: A Cross-sectional Study ”Aaron B. Caughey, MD, PhDDepartment of Obstetrics and Gynecology; Oregon Health & Science University; Portland, ORCorrespondence:Aaron B. Caughey, MD, PhDProfessor and ChairDepartment of Obstetrics and GynecologyOregon Health & Sciences UniversityP: 503-494-2999F: 503-494-2391E: caughey@ohsu.eduGestational diabetes mellitus (GDM) is one of the most common pregnancy complications and is associated with numerous pregnancy complications including preeclampsia, preterm birth, stillbirth, cesarean delivery, fetal macrosomia, birth injury, neonatal hypoglycemia, childhood obesity in the offspring and other short- and long-term complications.(Sweeting AN, et al. Diabetes Care. 2016;39:75-81) Many of these complications appear to be associated with hyperglycemia, so tight control of maternal plasma glucose is the primary approach to management during pregnancy. The first line approach is usually a strict carbohydrate-controlled diet and exercise, but when this fails, medical therapy is indicated.For many years, the first-line medical approach was injectable insulin. However, an oral hypoglycemic agent, glyburide, was increasingly adopted after a trial of glyburide versus insulin demonstrated no statistical difference in the outcomes, though it was underpowered to do so.(Langer O, et al. N Engl J Med 2000;343:1134-8) Another oral agent, metformin, was studied in an adequately powered randomized trial that found no differences in outcomes between pregnancies treated with metformin versus insulin.(Rowan JA, et al. N Engl J Med 2008;358:2003-15) Perhaps because glyburide was already being used, or that metformin crosses the placenta, or an odd finding of a higher rate of preterm birth in the metformin group, there was little adoption of metformin after this trial. Other trials of these medications have been conducted and a systematic review in 2015 demonstrated that a number of outcomes were worse in women randomized to glyburide whereas there are no differences in women randomized to metformin.(Balsells M, et al. BMJ 2015;350:h102) These findings led the American College of Obstetricians and Gynecologists (ACOG) to change their recommendations to encourage insulin to be first-line treatment in 2017.(ACOG. Obstet Gynecol. 2017;130:e17-e37) A follow-up recommendation from ACOG broadened to include metformin as well.(ACOG. Obstet Gynecol. 2018 Feb;131(2):e49-e64)So, how have these data and the recommendations from ACOG changed practice patterns? In a paper published in BJOG this month, the authors examined the pharmacologic approaches to management in GDM.(Venkatesh KK, et al. BJOG, 2021) In a large cohort of over 10,000 individuals with GDM requiring medical therapy, they found that from 2015 to 2018, the use of insulin increased from 26% to 44%, the use of metformin increased from 17% to 29%, and the use of glyburide decreased from 58% to 27%. These data are from either side of the 2017 ACOG recommendation, but end in the same year as the follow-up recommendation. Given how long it can take for recommendations to be adopted by clinicians, one wonders how the practice patterns may have continued to evolve in 2019 and 2020.Recalling that the 2017 ACOG recommendation was to have insulin be first line for GDM, while the trend is in the right direction, it was still less than 50% as of 2018. While it is understandable that clinicians and patients want to prescribe an oral agent, insulin remains an effective medication with great safety data. Likely this is why it is recommended as first-line treatment by many organizations and hopefully, further trends towards its primary use will be seen.

Objective: To compare the host and biomechanical response to a fully absorbable poly-4-hydroxybutyrate (P4HB) scaffold to the response to PP mesh in an animal model of vaginal POP surgery. Design: A study employing a sheep model Setting: KU Leuven Center for Surgical Technologies Population: 14 parous female Mule sheep Methods: P4HB scaffolds were surgically implanted in the posterior vaginal wall of sheep. The comparative PP mesh data were obtained from an identical protocol. Main outcome measures: Gross necropsy, histological and biomechanical evaluation of explants, and the in vivo P4HB scaffold degradation were evaluated at 60- and 180-days post-implantation. Results: Gross necropsy revealed no implant related adverse events using P4HB scaffolds. The tensile stiffness of the P4HB explants increased at 180-days (12.498 ± 2.66 N/mm (P=0.019)) as compared to 60-days (4.585 ± 1.57 N/mm) post-implantation, while P4HB degraded gradually. P4HB scaffolds exhibited excellent tissue integration with dense connective tissue and a moderate initial host response. P4HB scaffolds induced a significantly higher M2/M1 ratio (1.70 ± 0.67 SD, score 0-4), as compared to PP mesh (0.99 ± 0.78 SEM, score 0-4) at 180-days. Conclusions: P4HB scaffold facilitated a gradual load transfer to vaginal tissue over time. The fully absorbable P4HB scaffold, in comparison to PP mesh, has a favorable host response with comparable load bearing capacity. If these results are also observed at longer follow-up, a clinical study for vaginal POP surgery may be warranted to demonstrate efficacy. Key words: Pelvic organ prolapse, vaginal surgery, Poly-4-hydroxybutyrate, degradable scaffold, host response, biomechanics.

Objective To describe the characteristics and outcomes of women with inherited bleeding disorder during pregnancy and birth. Design Retrospective cohort study. Setting Tertiary care hospitals, NSW and Victoria Australia. Population 100 women with inherited bleeding disorders, who birthed 134 live infants from 132 pregnancies. Methods Data was retrospectively obtained from the patient and neonatal medical records. Descriptive analysis was used to report maternal and pregnancy characteristics, birth and neonatal outcomes. Main outcome measures Factor replacement, neuraxial analgesia use and complications, post-partum haemorrhage and neonatal complications. Results PPH occurred in 22% of deliveries with primary PPH occurring in 20% and secondary PPH in 4% of births. 48% of PPHs were classified as major. PPHs occurred across the spectrum of IBD and was evenly distributed between women who had “normalised” their factor levels in pregnancy compared to those requiring factor at the time of birth. An obstetric cause was identified in more than half of PPHs. Conclusions Women with inherited bleeding disorders can deliver safely and receive neuraxial analgesia without complication when best practices are adhered to. PPH appears to occur at higher rates than the general population despite adequate factor levels or planned replacement. Whilst an obstetric cause was demonstrable in the many cases, these findings raise concern over the current definition of “adequate” factor levels at the time of birth.

Retained Products of Conception as an Etiology for EndometritisPietro Bortoletto, MD1, Phillip A. Romanski, MD1, Nina Schatz-Siemers, DO2, Steven D. Spandorfer, MD11 The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, 1305 York Ave, 7th Floor, New York, NY 10021, USA.2 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine-New York Presbyterian Hospital, New York, NY 10021, USA.

A document by Blair Wylie. Click on the document to view its contents.

Objective: To estimate the association between maternal origin and obstetric anal sphincter injury (OASI), and assess if associations differed by length of residence. Design: Population-based cohort study. Setting: The Medical Birth Registry of Norway. Population: Primiparous women with vaginal livebirth of a singleton cephalic fetus between 2008 and 2017 (n=188 658). Methods: Multivariable logistic regression models estimated aORs for OASI with 95% CI by maternal region of origin and birthplace. We stratified models on length of residence and paternal birthplace. Main outcome measures: OASI. Results: Overall 6 373 cases of OASI were identified (3.4% of total cohort). Women from South Asia were most likely to experience OASI (6.2%; aOR 2.24, 95% CI 1.93–2.60), followed by those from Southeast/East Asian/Pacific (5.7%; 1.83, 1.64–2.04), and Sub-Saharan Africa (5.2%; 1.97, 1.72–2.26), compared to women originating from Norway. Among women born in the same region, those with short length of residence in Norway (0–4 years), showed higher odds of OASI. Migrant women across most regions of origin had reduced risk of OASI if they had a Norwegian compared to foreign-born partner. Conclusions: Primiparous women from Asian regions and Sub-Saharan Africa had up to two-fold risk of OASI, compared to women originating from Norway. Migrants with short residence and those with a foreign-born partner had higher risk of OASI, implying that some of the risk differential is due to sociocultural factors. Some migrants, especially new arrivals, may benefit from special attention during labour to reduce morbidity and achieve equitable outcomes.

Objective To estimate the pregnancy rates and outcomes for women with cystic fibrosis (wwCF) in the UK compared to the general population and to explore the impact of the introduction of disease modifying treatments on pregnancy rates. Design A population-based cross-sectional study. Setting Electronic records of UK CF Registry Data (~99% of all CF), and conceptions data for England and Wales (E&W). Population All women aged 15-44 years who were pregnant between 2003-2017. Methods We calculated 3-yearly crude and age-specific pregnancy rates per 1,000 women years (wys), pregnancy rates for wwCF with a G551D mutation before and after Ivacaftor was introduced in 2012 and compared live birth rates. Main outcome measures Crude rates, age specific fertility, and maternal morbidity. Results The overall pregnancy rate was 23.5 (95% CI 21.9-25.3) per 1,000 wys, ~3.4fold difference to E&W women (77.7). This pattern was evident in the age specific rates, except for those aged 40-44 years where the difference in rates was much less (wwCF 8.2 per 1,000 wys vs. 13.3 in E&W). LB rate differences mirrored pregnancy rates (wwCF 17.4 per 1000 wys vs. 61.4 E&W women). Following the introduction of Ivacaftor, pregnancy rates in wwCF with G551D increased from 29.5 to 56.9 per 1000wys (2012-2014 to 2015-2017). Conclusions Pregnancy rates in wwCF are about a third of the rates in the general population but on the rise following the introduction of Ivacaftor. There is no indication that there is a reduced chance of a live birth in wwCF who become pregnant.

BJOG commentary for BJOG-21-0466 A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study

Mini-Commentary on Manuscript # BJOG-20-2493A Biomarker for Amniotic Fluid Embolism: The Search ContinuesWord count: 495Research into the pregnancy associated cytokine storm-like condition historically known as amniotic fluid embolism (AFE) has been hampered by a lack of unique diagnostic criteria. In its classic form, the clinical presentation of this condition is unmistakable. In less classic presentations, each of the clinical hallmarks of AFE (depressed ventricular function, lung injury and coagulopathy) may, in isolation, be seen in other obstetric conditions. Indeed, much of the confusion arising from previously published case series purporting to describe women with AFE appears to be the result of the inclusion of patients with other conditions. (Clark SL et al Obstet Gynecol 2014:123: 337-48) Identification of a reliable, objective biomarker specific to AFE is badly needed.It is against this background that the work of Bouvet et al is especially welcome. These investigators examined the use of insulin-like growth factor binding protein -1, a protein found in high concentration in amniotic fluid, as a potential biomarker of AFE in women suspected to have this condition. Unfortunately, the results were negative, leading the authors to question the usefulness of this assay.Although the results were negative, the major importance of this study may be as an example of how to properly conduct a search for AFE biomarkers. These authors avoided several pitfalls that have invalidated most previous biomarker publications. First, they used 2 objective, internationally recognized clinical criteria sets for identifying women with AFE. Their finding that only about half of women suspected to have AFE actually had the condition based on either of the identified criteria sets emphasizes the importance of insisting on inclusion criteria more stringent than “someone thought the patient had AFE,” so common in current literature. Secondly, in their use of women with suspected AFE these investigators avoided another common pitfall in biomarker research, namely the use of normal pregnant women, rather than critically ill women as controls. Presumably the women without AFE had some other form of critical illness. This distinction is particularly important in investigating the potential of various inflammatory mediators as specific markers for AFE.Finally, the authors’ data support 2 additional important conclusions beyond the original intent of the paper. The finding that 100% of AFE patients identified by the SMFM criteria also met the UK diagnostic criteria serve as additional validation of the ability of the former criteria to reliably identify a group of women who, for research purposes, do have the disease, while excluding some others with less typical forms of AFE. (Clark et al, Am J Obstet Gynecol 2016:408-12.) Secondly, the authors’ findings of no difference in levels of ILGFBP-1 in women with and without clinical AFE, despite high levels of this protein in amniotic fluid, supports the current belief that amniotic fluid per se is unrelated to the condition known as amniotic fluid embolism.It is generally accepted by the scientific community that AFE is unpreventable. It is hoped that additional quality research such as that of Bouvet et al may someday change this unfortunate fact.

Professor PEP Petros DSc DS (UWA) PhD (Uppsala) MB BS MD (Syd) FRCOG (Lond)31/93 Elizabeth Bay Rd, Elizabeth Bay NSW 2011 AUSTRALIAReconstructive Pelvic Floor Surgeon and Certified Urogynaecologist (retired)Formerly University of NSW Professorial Dept of Surgery, St Vincent’s Hospital Sydney (retired)Adjunct Professor, University of Western Australia School of Mechanical and Chemical Engineering, Perth WA (current)Tel 61 2 9361 3853 Cellphone (AUST) 61 411 181 731Email pp@kvinno.com website www.integraltheory.org

Objective: to evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. Design and setting: multicentre retrospective cohort study between 2008-2021 Population: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis Methods and main outcome measures: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. Results: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 at term age (79% of live births and 60% of pregnancies). No maternal deaths were observed, one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. Conclusions: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contra-indication for pregnancy. Individualized, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population.

BJOG-20-2353.R2 What should we believe when systematic reviews disagree?For many years, uterine balloon tamponade (UBT) has been used to treat severe postpartum haemorrhage (PPH), despite a lack of randomised trials to demonstrate its effectiveness. With commercial devices being expensive, clinicians in low resource settings have made their own using 2 low-cost, widely available items (Foley catheters and condoms). Public health experts have been so confident of their benefit that large programmes have been set up to disseminate the necessary skills worldwide.Recently, however, the global maternal health community has been thrown into disarray when not one, but two randomised controlled efficacy trials suggested that outcomes with condom catheter UBTs were actuallyworse than normal care in low resource settings. The Cochrane meta-analysis concluded that “in [low resource] settings, balloon tamponade [should be] only introduced alongside multi‐system improvements in PPH care” (Kellie et al. Cochrane Database of Systematic Reviews 2020(7): CD013663).Systematic reviews may be the pinnacle of evidence-based medicine, but even they can differ in how to interpret evidence. And so, proponents of the condom catheter conducted their own systematic review with far wider inclusion criteria – they not only included the randomised trials but examined success rates from 15 non-randomised trials and 69 case series (Suarez et al. Am J Obstet Gynecol 2020;222(4):293.e1–e52). Furthermore, the primary outcome was the success rate of the technique (overall 86%) rather than the risk of morbidity and mortality compared to controls, as used in the Cochrane review. This is problematic, as reported ‘success rates’ without controls can be very difficult to interpret: in initial case series misoprostol showed similar success rates against life-threatening haemorrhage before RCTs eventually showed it to be less effective than oxytocin.A third version of the same review is published today by a WHO team (Pingray et al. BJOG 2021;XXX,XXX). This time they include only 4 high quality studies in which UBT was compared to standard care. With a composite maternal morbidity / mortality outcome, they found no evidence of benefit and concluded that “the effect … is unclear, as is the role of the type of device and the setting”. WHO studies are now underway to address this uncertainty.But why is this all so important? The difficulty comes because the World Health Organisation has been updating its guidance on PPH management, and had to declare a position on UBT. The recently-published guideline, drawn up by independent experts, accepts the validity of the RCTs but recognises that there is wide acceptability of the technique and that the evidence of harm is only for condom catheters and onlyin resource-poor settings. They put a high emphasis on minimising harm and conclude that UBTs should only be used in settings where there is already a good standard of care, including recourse to blood transfusion and surgery if needed (WHO. Geneva: World Health Organization; 2021).Until further studies are published, the debate will continue. But this episode shows how the choice of inclusion criteria and outcomes in systematic reviews are critical, both for their conclusions, and for global policy.

Is the patient choice the best choice?

Aortic balloon for the intraoperative management of placenta accreta spectrum: need for standardised methodology and safety dataIn 2003, Bell-Thomas et al (BJOG 2003;110:1120-1122) reported on the emergency use of a transfemoral aortic occlusion catheter to control massive haemorrhage in a case of caesarean hysterectomy for placenta percreta. This was only the second case published in the international literature on the use of an intra-abdominal aortic balloon occlusion (IABO) in the management of placenta accreta spectrum (PAS) (Paull et al. Anesth Intensive Care 1995;23:731-734). A non-exhaustive Pub-Med literature review of articles published in English on this the topic over the last 20 years, identifies 27 articles, 23 of which come from the Peoples Republic of China, where IABO seems to be increasingly popular in the management of PAS.In brief, IABO involves the insertion of a balloon catheter into the infrarenal abdominal aorta above the aortic bifurcation under fluoroscopy guidance. The procedure is performed in a hybrid operating room or interventional radiology (IR) suite with secondary transfer to the operating room. In all but one study (Zhu et al Biomed Res Int.2017:8604849), the balloon was inflated after delivery of the newborn.All publications so far have been retrospective and most are case-control studies, comparing the outcomes of IABO with those of routine surgical techniques with or without additional procedures such as intra-uterine tamponade. Recently, authors have also started to compare IABO with iliac artery balloon occlusion.Overall, these studies have shown that IABO is associated with reduced estimated blood loss and transfusion requirement, ICU admission and hysterectomy and suggested that IABO is more effective than iliac artery balloon occlusion, presumably as arterial occlusion is more effective.However, there is wide variation between studies in prenatal imaging and clinical selection criteria, intraoperative IR methodology and confirmation of the diagnosis of PAS at birth. For example, the pre-operative fluoroscopy time ranges between 2 and 25 minutes with fetal radiation exposure of 4 to 25 mGy; intraoperative balloon inflation/deflation time varies between 5-10/1 minutes and 45-80/10 minutes. The size of the balloon and the need for transfer between the IR room and the operative theatre is rarely described. Most studies lack histopathology confirmation of the diagnosis and/or stratification by PAS grade.Heterogeneity in methodology and design leads to a high risk of confounding, bias or chance. There is also a high risk that the relationship is not causal. One major concern is the risks-benefit ratio of the use of IABO for both mothers and fetuses, in particular if they do not have PAS. The most commonly reported post-operative complication associated with IABO are arterial thrombosis of the external iliac or the femoral artery. There are no data on the long-term follow of the children born after IABO.In 2018, the expert panel of the RCOG green top guidelines 27a (Jauniaux et al., BJOG.2019;126:e1-e48) concluded that larger studies are necessary to determine the safety and efficacy of IR before this technique can be advised in the routine management of PAS. The 10 new studies published in 2019-2010 on the use of IABO in the management of PAS are insufficient to change this statement.Word count: 499

New insights in diagnostic thresholds for total serum bile acid (TSBA) in intrahepatic cholestasis of pregnancy (ICP)