Steroid Metabolome Analysis in Dichorionic Diamniotic Twin Pregnancy.

Steroid hormones have diverse roles in pregnancy; some help stabilise pregnancy and influence the stability of pregnancy and the onset of labour. Changes and disorders in steroidogenesis may be involved in several pregnancy pathologies. To date, only a few studies have performed a very limited steroid analysis in multiple pregnancies. Our teams investigated multiple pregnancies regarding the biosynthesis, transport, and effects of steroids. We recruited two groups of patients: pregnant women with multiple pregnancies as the study group, and a control singleton pregnancies group. Blood samples were drawn from the participants and analysed. Information about the mother, foetus, delivery, and newborn was extracted from medical records. The data were then analysed. The gestational age of twin pregnancies during delivery ranged from 35 + 3 to 39 + 3 weeks, while it was 38 + 1 to 41 + 1 weeks for the controls. Our findings provide answers to questions regarding the steroidome in multiple pregnancies. Results demonstrate differences in the steroidome between singleton and twin pregnancies. These were based on the presence of two placentae and two foetal adrenal glands, both with separate enzymatic activity. Since every newborn was delivered by caesarean section, analysis was not negatively influenced by changes in the steroid metabolome associated with the spontaneous onset of labour.

Steroid metabolome and multiple pregnancy

Steroid biosynthesis occurs in adrenal, gonadal, brain, liver, and placental tissues. Depending on the location of their activity, steroids can be divided into two groups - intracellular and extracellular. Intracellular ones act as transcription factors, suppressing or activating gene expression - they have a so-called genomic effect and therefore their onset of action is slow. Steroids acting extracellularly (non-genome effect) bind to neurotransmitter receptors located on the cytoplasmic cell membrane and thus affect the permeability of the ion channels, the effect of which is much faster, and we refer to them as neuroactive steroids or neurosteroids. While neuroactive steroids can be produced in different tissues of the body, or can be administered externally, neurosteroids are synthetized in cells of the nervous system. Some neuroactive steroids whose levels are extremely elevated in pregnancy (progesterone and its metabolites) are crucial in stabilizing pregnancy and changes in their concentration may influence the onset of parturition. Steroidogenic disorders may be involved in a number of pregnancy pathologies such as premature birth, pre-eclampsia, intrahepatic cholestasis in pregnancy, etc. Our research in collaboration with the Department of Steroids and Proteofactors of the Institute of Endocrinology in Prague also focuses on the investigation of multiple pregnancies in terms of biosynthesis, transport, and the effects of steroids. Studies available in the literature so far have not provided a comprehensive analysis of the steroidome in children and mothers in multiple pregnancies. The aim of our research is therefore to clarify the relationships between fetuses and mothers and between fetuses from the point of view of steroid synthesis and transport as well as the physiology and pathophysiology of human pregnancy and childbirth.

Perinatal and 2-year neurodevelopmental outcome in late preterm fetal compromise: the TRUFFLE 2 randomised trial protocol.

INTRODUCTION: Following the detection of fetal growth restriction, there is no consensus about the criteria that should trigger delivery in the late preterm period. The consequences of inappropriate early or late delivery are potentially important yet practice varies widely around the world, with abnormal findings from fetal heart rate monitoring invariably leading to delivery. Indices derived from fetal cerebral Doppler examination may guide such decisions although there are few studies in this area. We propose a randomised, controlled trial to establish the optimum method of timing delivery between 32 weeks and 36 weeks 6 days of gestation. We hypothesise that delivery on evidence of cerebral blood flow redistribution reduces a composite of perinatal poor outcome, death and short-term hypoxia-related morbidity, with no worsening of neurodevelopmental outcome at 2 years. METHODS AND ANALYSIS: Women with non-anomalous singleton pregnancies 32+0 to 36+6 weeks of gestation in whom the estimated fetal weight or abdominal circumference is <10th percentile or has decreased by 50 percentiles since 18-32 weeks will be included for observational data collection. Participants will be randomised if cerebral blood flow redistribution is identified, based on umbilical to middle cerebral artery pulsatility index ratio values. Computerised cardiotocography (cCTG) must show normal fetal heart rate short term variation (≥4.5 msec) and absence of decelerations at randomisation. Randomisation will be 1:1 to immediate delivery or delayed delivery (based on cCTG abnormalities or other worsening fetal condition). The primary outcome is poor condition at birth and/or fetal or neonatal death and/or major neonatal morbidity, the secondary non-inferiority outcome is 2-year infant general health and neurodevelopmental outcome based on the Parent Report of Children's Abilities-Revised questionnaire. ETHICS AND DISSEMINATION: The Study Coordination Centre has obtained approval from London-Riverside Research Ethics Committee (REC) and Health Regulatory Authority (HRA). Publication will be in line with NIHR Open Access policy. TRIAL REGISTRATION NUMBER: Main sponsor: Imperial College London, Reference: 19QC5491. Funders: NIHR HTA, Reference: 127 976. Study coordination centre: Imperial College Healthcare NHS Trust, Du Cane Road, London, W12 0HS with Centre for Trials Research, College of Biomedical & Life Sciences, Cardiff University. IRAS Project ID: 266 400. REC reference: 20/LO/0031. ISRCTN registry: 76 016 200.

Selective Extirpation of Tattooed Lymph Node in Combination with Sentinel Lymph Node Biopsy in the Management of Node-Positive Breast Cancer Patients after Neoadjuvant Systemic Therapy.

INTRODUCTION: Axillary dissection has little diagnostic and therapeutic benefit in node-positive breast cancer patients in whom axillary disease has been completely eradicated after neoadjuvant chemotherapy (ypN0). We sought to assess the efficacy of an algorithm used for the identification of the ypN0 patient consisting of intraoperative evaluation of sentinel and tattooed (initially positive) lymph nodes. METHODS: Included were T1 and T2 breast cancer patients with 1-3 positive axillary lymph nodes marked with carbon who were referred for neoadjuvant chemotherapy followed by a surgery. Axillary dissection was performed only in the patients with residual axillary disease after neoadjuvant chemotherapy on ultrasound or with metastases described in the sentinel or tattooed lymph nodes either intraoperatively or in the final histology. RESULTS: Out of 62 initially included node-positive patients, 15 (24%) were spared axillary dissection. The detection rate of tattooed lymph nodes after neoadjuvant chemotherapy was 81%. The ypN0 patients were identified with 91% sensitivity and 38% specificity using ultrasound and intraoperative assessment of both sentinel and tattooed lymph node according to the final histology. DISCUSSION/CONCLUSION: Lymph node marking with carbon dye is a useful and cost-effective method, which can be successfully implemented in order to reduce the number of patients undergoing axillary dissection. Low specificity of the presented algorithm was caused mostly by the overestimation of residual axillary disease on ultrasound.

Efficacy and safety of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy.

UNLABELLED:  Background and aims. Patients with intrahepatic cholestasis of pregnancy (ICP) benefit from ursodeoxycholic acid (UDCA) treatment. Since there is still certain reluctance to use UDCA in pregnant women, mainly due to warnings in the official SPC information in respective drug leaflets, our objective was to assess the efficacy and safety of UDCA during pregnancy. MATERIAL AND METHODS: Our retrospective multicentric study was performed on 191 consecutive pregnant women with ICP treated with UDCA. Any maternal and/or fetal complications of the UDCA treatment were searched for; healthy pregnant women (n = 256) served as controls. RESULTS: The UDCA treatment improved liver disease status in the majority of the affected women (86.1%). This treatment was well tolerated, with only negligible skin reactions (0.5%) and mild diarrhea (4.7%). No complications attributable to UDCA treatment were detected during the fetal life, delivery, or the early neonatal period. CONCLUSION: We confirmed the good efficacy and safety of UDCA treatment in pregnancy for both mothers and fetuses/neonates.

A Comprehensive Evaluation of Steroid Metabolism in Women with Intrahepatic Cholestasis of Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder, mostly occurring in the third trimester. ICP is defined as an elevation of serum bile acids, typically accompanied by pruritus and elevated activities of liver aminotransferases. ICP is caused by impaired biliary lipid secretion, in which endogenous steroids may play a key role. Although ICP is benign for the pregnant woman, it may be harmful for the fetus. We evaluated the differences between maternal circulating steroids measured by RIA (17-hydroxypregnenolone and its sulfate, 17-hydroxyprogesterone, and cortisol) and GC-MS (additional steroids), hepatic aminotransferases and bilirubin in women with ICP (n = 15, total bile acids (TBA) >8 µM) and corresponding controls (n = 17). An age-adjusted linear model, receiver-operating characteristics (ROC), and multivariate regression (a method of orthogonal projections to latent structure, OPLS) were used for data evaluation. While aminotransferases, conjugates of pregnanediols, 17-hydroxypregnenolone and 5ß-androstane-3α,17ß-diol were higher in ICP patients, 20α-dihydropregnenolone, 16α-hydroxy-steroids, sulfated 17-oxo-C19-steroids, and 5ß-reduced steroids were lower. The OPLS model including steroids measured by GC-MS and RIA showed 93.3% sensitivity and 100% specificity, while the model including steroids measured by GC-MS in a single sample aliquot showed 93.3% sensitivity and 94.1% specificity. A composite index including ratios of sulfated 3α/ß-hydroxy-5α/ß-androstane-17-ones to conjugated 5α/ß-pregnane-3α/ß, 20α-diols discriminated with 93.3% specificity and 81.3% sensitivity (ROC analysis). These new data demonstrating altered steroidogenesis in ICP patients offer more detailed pathophysiological insights into the role of steroids in the development of ICP.

Results of less radical fertility-sparing procedures with omitted parametrectomy for cervical cancer: 5years of experience.

OBJECTIVE: The aim of our study was to describe oncological and obstetrical outcomes in patients who underwent less radical fertility-sparing surgical (FSS) procedures with omitted parametrectomy for cervical cancer. METHODS: Included were women with cervical cancer stages IA2-IB2 who were under the age of 40 and desired future pregnancy. Patients underwent pelvic lymphadenectomy and sentinel lymph node biopsy. Node-negative cases underwent subsequent cervical surgery and were further analyzed. Neoadjuvant chemotherapy (NAC) was administered in patients with tumors >2cm and/or involving >2/3 of cervical stroma. Simple vaginal trachelectomy or needle conization were performed according to tumor extent and topography. The follow-up period started once free surgical margins were reached. RESULTS: Out of 44 women enrolled, 32 women (IA2=7, IB1=23, IB2=2) successfully completed FSS. NAC was administered in 9 (28.1%) cases. A simple trachelectomy was performed in 11 patients and needle conization in 21 patients. During the follow-up, 6 out of 32 women became pregnant. Of these, 1 miscarried and 5 successfully delivered. Disease recurred in 6 patients; 5 recurrences were central and 1 recurrence presented as an ovarian mass. Invasive cervical carcinoma, high-grade squamous intraepithelial (HSIL), and low-grade squamous intraepithelial (LSIL) lesions were detected in 4, 1 and 1 patients, respectively. Three of them received NAC. All events were detected within 16months after surgery. CONCLUSIONS: Nearly 27% of patients cannot complete FSS due to node positivity, progression during NAC, or involved margins. The total recurrence rate reached 18.8%, with the majority of invasive recurrences detected in patients after NAC followed by FSS. These patients represent cases at a higher risk of recurrence even if adequate free margins are reached by surgery. Nearly half of the cohort did not consider pregnancy in the near future because of personal reasons.

Prolonged progesterone administration is associated with less frequent cervicovaginal colonization by Ureaplasma urealyticum during pregnancy - Results of a pilot study.

BACKGROUND: Preterm birth is a leading cause of perinatal mortality and morbidity. Heavy cervicovaginal Ureaplasma colonization is thought to play a role in the pathogenesis of preterm birth. The administration of vaginal progesterone has been shown to reduce the incidence of preterm birth in women with short cervical length. Steroid hormones seem to modulate the presence of microorganisms in the vagina. The aim of this study was to assess whether the treatment with vaginal progesterone could reduce the incidence of preterm birth and cervicovaginal colonization by Ureaplasma urealyticum in a cohort of pregnant women with threatened preterm labor. METHODS: A cohort of 63 females who presented with regular contractions and/or short cervical length between 24-32 weeks of gestation were recruited into a prospective study. 70% of patients had been treated with vaginal progesterone prior to recruitment and these patients continued with the treatment until birth. All patients were tested for the presence of cervicovaginal Ureaplasma urealyticum colonization at admission. The primary endpoint was preterm birth before 37 weeks. RESULTS: The incidence of preterm delivery was significantly increased in patients who tested positive for Ureaplasma urealyticum. Prolonged vaginal progesterone administration was associated with less frequent cervicovaginal colonization by U. urealyticum. Cervicovaginal colonization by U. urealyticum and absence of progesterone treatment were identified as two independent risk factors for preterm delivery. CONCLUSIONS: Our results demonstrate the beneficial effects of progesterone administration in reducing the incidence of cervicovaginal colonization by Ureaplasma urealyticum.

Fetal complications due to intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder of pregnancy. Diagnosis is based on the clinical picture, particularly the presence of pruritus with a deterioration of liver function tests, and typically elevated serum levels of total bile acids. ICP manifests in the second half of pregnancy, predominantly during the third trimester. Symptoms of the disease resolve spontaneously after delivery. Etiology is still not fully understood. Genetic defects in specific transport proteins, elevated levels of sex hormones, and various environmental factors are thought to play a role in the development of this disorder. Although practically benign for the pregnant woman, ICP represents a serious threat to the fetus. It increases the risk of preterm delivery, meconium excretion into the amniotic fluid, respiratory distress syndrome, and sudden intrauterine fetal death. Identifying fetuses at risk of ICP complications remains challenging. The ideal obstetrical management of ICP needs to be definitively determined. The aim of this review is to summarize the current knowledge on fetal complications of ICP and describe management options for their prevention.