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Summary 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 We also included unpublished data from two UK hospitals.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 ca...

The uterus is a dynamic organ that undergoes distinct molecular and functional changes during the menstrual cycle, implantation, pregnancy and parturition. Steroid hormones are the predominant driving force for uterine transformation, but there is also a paracrine and autocrine contribution via the local release of cytokines from both immune (leucocytes, maternal and foetal macrophages, natural killer and T cells), and non-immune tissues (uterine epithelia, cervix and uterine smooth muscle). This review provides a brief overview of the role played by cytokines during pregnancy and parturition and begins to explore how disturbances in cytokine networks may lead to impaired reproductive success. We hope that by identifying key areas of interest and controversy in field, the review will serve as a useful starting point for readers. It is important to note that much of the literature originates from animal studies and, given the complexity of cytokine interactions, we would caution extrapolation between species. We have, where possible, referred to pertinent human data. Cytokines and their inflammatory networksCytokines are an extensive array of pleiotropic glycoproteins involved in the regulation of all biological processes. Although their traditional role is commonly perceived in relation to their immunoregulatory properties, cytokines also have a range of mitogenic and proapoptotic functions on non-immune cells (1). They operate as parts of highly complex integrated networks that exhibit marked multiple stimulatory ⁄ antagonistic interactions, synergism and a degree of functional redundancy. The complexity of their network regulation is due to the unique properties of cytokines, which include pleiotropism, where each cytokine has multiple target cells in an array of different organs, and where responses may differ according to cell type. Cytokines also act cooperatively to potentiate and modulate each other's actions in order to induce specific effects (2). They are also capable of mutual antagonism, wherein different cytokines have opposing actions (3). Finally, functional redundancy (whereby several different cytokines act individually on a cell type to induce the same response) is often mediated via a common receptor complex (4). Redundancy is of particular relevance in reproduction as a salvage pathways, highlighted by the fact that various knockout mouse models expected to be infertile actually maintain pregnancies to term and deliver normally (5). Individual cytokines are further able to induce different effects based on their exposure time and absolute concentration: for example, tumour necrosis factor (TNF)-a can trigger apoptotic pathways, while paradoxically also being able to induce opposing bio-regulatory effects, such Complex cytokine networks play an important role in a wide range of reproductive and pregnancy related processes. Here, we review the current knowledge concerning the impact of cytokines on uterine physiology and pathophysiology. Cytokines influence a range of uterine functions during t...

Objective To determine the nature and outcome of obstetric cholestasis in a United Kingdom population.Design Prospective analysis of clinical outcome in women diagnosed with obstetric cholestasis that is actively managed. Setting Antenatal population of three London hospitals between August 1999 and April 2001.Population Seventy women with obstetric cholestasis defined as abnormal liver function (one or more abnormality in gamma-glutamyl transpeptidase, alanine amino-transferase, aspartate amino-transferase and total bile acids) in a pregnant woman with pruritus, in the absence of other pathology. Methods All women were interviewed weekly regarding their symptoms. All were actively managed according to a standardised protocol, which included early delivery before 38 weeks. Obstetric outcome was recorded. Results Seventy women of mean age 30 (6) years delivered 73 infants. The median gestation at onset of pruritus was 30 (range 4-39) weeks and at diagnosis of obstetric cholestasis was 33.7 (range 21 -40.7) weeks. Asian women were more likely to be diagnosed with obstetric cholestasis. Pruritus was usually severe and generalised, and commonly worst on the palms and/or soles of the feet. There were no stillbirths or perinatal deaths. Twenty-five women required caesarean section (36%); only four (16%) were for fetal distress. Twelve women (17%) delivered before 37 weeks, of which eight (67%) were iatrogenic. Ten (14%) infants required admission to the special care baby unit of which four (40%) were ventilated. Conclusions Policies of active management result in increased intervention and associated complications. This must be balanced against possible reductions in perinatal mortality.