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.

Laboring Alone: Perinatal Outcomes during Childbirth without a Birth Partner or Other Companion during the COVID-19 Pandemic.

During the first wave of the COVID-19 pandemic in the spring of 2020, the government of the Czech Republic issued a nationwide ban on visitors to maternity wards. We studied whether the absence of a close person during labor due to this ban impacted perinatal indicators. This study was performed using an administrative observational questionnaire focused on absolute frequencies of events sent to maternity facilities across the Czech Republic. Completed answers were received from 33 facilities covering 4805 births during the study period in 2019 and 4514 births in 2020. The differences in individual parameters were tested using Pearson's chi-squared homogeneity test. There were no significant differences between the two periods in spontaneous pre-term births (p = 0.522) or in the number of cesarean sections (p = 0.536). No significant changes were seen in either local or systemic analgesia. Data showed a significantly shorter (p = 0.026) first stage of labor in 2020 compared to 2019, while there was no significant difference (p = 0.673) in the second stage of labor. There was no statistically significant difference found for newborn perinatal adaptation. There were also no significant differences in intrapartum maternal injuries. Overall, we found no significant differences in basic perinatal indicators during the first wave of COVID-19 in 2020 compared to 2019. Although the absence of a close person may cause stress for the laboring women, it does not impair objective clinical outcomes.

Ursodeoxycholic acid use in lactating female patients is associated with clinically negligible concentrations of this bile acid in breast milk.

In the literature on the safety of ursodeoxycholic acid (UDCA) during breastfeeding, insufficient data has been reported to date. Thus, the aim of our study was to analyze bile acid (BA) concentrations in breast milk in a cohort of patients, treated with UDCA, and with various cholestatic liver diseases. The study was carried out on a cohort of 20 patients with various cholestatic diseases. All the patients were treated with UDCA (500-1500 mg daily). Concentrations of BA, sampled on day 3 after delivery were analyzed using the GS-MS technique, and then compared to untreated women. Total BA concentrations in the breast milk of the UDCA-treated patients were equal to those of the untreated women controls (3.2 ± 1 vs. 3.2 ± 0.2 µmol/L, respectively). The UDCA concentrations in breast milk remained negligible in UDCA-treated patients (0.69 µmol/L), and in any event did not contribute to the newborn BA pool. No apparent side-effects of the maternal UDCA treatment were observed in any newborn infant, and no deterioration in postnatal development was observed during the routine 1-year follow-ups. Therapeutic administration of UDCA during lactation is safe for breastfed babies since UDCA only gets into breast milk in negligible amounts. UDCA treatment should be allowed and included into the guidelines for the therapy of cholestatic diseases in breastfeeding mothers.

Establishing the Optimal Time for Induction of Labor in Women with Diet-Controlled Gestational Diabetes Mellitus: A Single-Center Observational Study.

To determine the optimal week for labor induction in women with diet-controlled gestational diabetes mellitus by comparing differences in perinatal and neonatal outcomes of labor induction to expectant management at different gestational weeks. Methods: This was a retrospective analysis of a prospectively recruited cohort of 797 singleton pregnancies complicated by diet-controlled gestational diabetes mellitus that were diagnosed, treated, and delivered after 37 weeks in a tertiary, university-affiliated perinatal center between January 2016 and December 2021. Results: The incidence of neonatal complications was highest when delivery occurred at 37 weeks, whereas fetal macrosomia occurred mostly at 41 weeks (20.7%); the frequency of large for gestational age infants did not differ between the groups. Conversely, the best neonatal outcomes were observed at 40 weeks due to the lowest number of neonates requiring phototherapy for neonatal jaundice (1.7%) and the smallest proportion of neonates experiencing composite adverse neonatal outcomes defined as neonatal hypoglycemia, phototherapy, clavicle fracture, or umbilical artery pH < 7.15 (10.4%). Compared with expectant management, the risk for neonatal hypoglycemia was increased for induction at 39 weeks (adjusted odds ratio 12.29, 95% confidence interval 1.35−111.75, p = 0.026) and that for fetal macrosomia was decreased for induction at 40 weeks (adjusted odds ratio 0.11, 95% confidence interval 0.01−0.92, p = 0.041), after adjusting for maternal pre-pregnancy body mass index, nulliparity, and mean pregnancy A1c. Conclusions: The lowest rate of neonatal complications was observed at 40 weeks. Labor induction at 40 weeks prevented fetal macrosomia.

Association between gestational diabetes mellitus and bioavailability of insulin-like growth factors and role of their binding proteins.

OBJECTIVE: Insulin-like growth factors (IGFs) are involved in regulating growth and metabolism and increase insulin sensitivity, improve glucose metabolism, and are potentially related to gestational diabetes mellitus (GDM) and its complications for mothers and fetuses. DESIGN: This study aimed to assess serum levels and cord blood levels of IGF system components in pregnant women with (39 participants) and without GDM (22 participants). Blood samples were obtained at 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. Cord blood samples were obtained during delivery. Results between both groups as well as between single visits were statistically compared. RESULTS: Both IGF1 and IGF2 maternal serum levels did not differ between the GDM and non-GDM groups. However, levels of IGF-binding proteins (IGFBPs) were different. IGFBP4 levels were decreased during pregnancy and after delivery in women with GDM, while IGFBP7 levels were increased during pregnancy in women with GDM. Cord blood IGFBP3 and IGFBP7 levels were increased (p < 0.001 for IGFBP3, p = 0.003 for IGFBP7), while IGFBP4 levels were decreased (p < 0.001) in the GDM group compared with the non-GDM group. CONCLUSIONS: Although IGF levels did not differ, changes in their function level could still persist possibly because of the effects of the binding proteins, especially their promoting or inhibitory effects on IGFs. These results should be considered in interpretation of IGF levels.

COVID-19, Vaccination, and Female Fertility in the Czech Republic.

The fast-track process to approve vaccines against COVID-19 has raised questions about their safety, especially in relation to fertility. Over the last 2 years, studies have appeared monitoring female fertility, especially from assisted reproduction centers or in animal experiments. However, studies monitoring healthy populations are still limited. The aim of our study was to monitor the relevant parameters of female fertility (sex and other steroids, LH, FSH, SHBG, Antimüllerian hormone and antral follicle count) before and then 2-4 months after the third dose of vaccination against COVID-19 in a group of 25 healthy fertile woman. In addition, anti-SARS-CoV-2 and anti-SARS-CoV-2S antibodies were determined. We did not observe significant changes in the measured parameters before and after the third dose of vaccination. By comparing levels of the analytes with antibodies indicating a prior COVID-19 infection, we found that women who had experienced the disease had statistically lower levels of estrone, estradiol, SHBG and 5α-dihydroprogesterone, and conversely, higher levels of androgen active dehydroepiandrosterone and dihydrotestosterone. Our results confirm that vaccination does not affect female fertility, and that what fertile women should be worried about is not vaccination, but rather COVID-19 infection itself.

Progesterone: A Steroid with Wide Range of Effects in Physiology as Well as Human Medicine.

Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial roles. While the discovery of its effects has a long history, over recent decades, various novel actions of this interesting steroid have been documented, of which its neuro- and immunoprotective activities are the most widely discussed. Discoveries of the novel biological activities of progesterone have also driven research and development in the field of progesterone analogues used in human medicine. Progestogen treatment has traditionally and predominately been used in maintaining pregnancy, the prevention of preterm labor, various gynecological pathologies, and in lowering the negative effects of menopause. However, there are also various other medical fields where progesterone and its analogues could find application in the future. The aim of this work is to show the mechanisms of action of progesterone and its metabolites, the physiological and pharmacological actions of progesterone and its synthetic analogues in human medicine, as well as the impacts of its production and use on the environment.

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.

Altered Steroidome in Women with Gestational Diabetes Mellitus: Focus on Neuroactive and Immunomodulatory Steroids from the 24th Week of Pregnancy to Labor.

Gestational diabetes mellitus (GDM) is a complication in pregnancy, but studies focused on the steroidome in patients with GDM are not available in the public domain. This article evaluates the steroidome in GDM+ and GDM- women and its changes from 24 weeks (± of gestation) to labor. The study included GDM+ (n = 44) and GDM- women (n = 33), in weeks 24-28, 30-36 of gestation and at labor and mixed umbilical blood after delivery. Steroidomic data (101 steroids quantified by GC-MS/MS) support the concept that the increasing diabetogenic effects with the approaching term are associated with mounting progesterone levels. The GDM+ group showed lower levels of testosterone (due to reduced AKR1C3 activity), estradiol (due to a shift from the HSD17B1 towards HSD17B2 activity), 7-oxygenated androgens (competing with cortisone for HSD11B1 and shifting the balance from diabetogenic cortisol towards the inactive cortisone), reduced activities of SRD5As, and CYP17A1 in the hydroxylase but higher CYP17A1 activity in the lyase step. With the approaching term, the authors found rising activities of CYP3A7, AKR1C1, CYP17A1 in its hydroxylase step, but a decline in its lyase step, rising conjugation of neuroinhibitory and pregnancy-stabilizing steroids and weakening AKR1D1 activity.

Pregnancy of women with type 1 diabetes mellitus - the effect of preconception care on perinatal results. Ten years of experience.

INTRODUCTION: Despite the ever-improving medical care, pregnancies of women with type 1 diabetes mellitus (T1DM) are at increased risk of complications for both mother and child. Optimal compensation of diabetes before and during pregnancy is an essential protective factor reducing the risk of congenital malformations, pregnancy loss, and other complications. The pregnancy of women with T1DM should be planned, ideally at a time of optimal diabetes compensation. Target glycated hemoglobin (HbA1c) values until the range of 42-48 mmol/mol should be achieved at least three months before pregnancy. Our work aimed to evaluate the perinatal results of pregnancies in women with T1DM and the eff ect of preconception counseling and adequate T1DM compensation before pregnancy on perinatal outcomes. METHODS AND RESULTS: Retrospective analysis of pregnancy and perinatal outcomes of women with T1DM were followed up at the Department of Gynecology and Obstetrics, General University Hospital in Prague and First Faculty of Medicine, Charles University between 2008 to 2018. A total of 221 women with T1DM were included in the analysis. Adequate (HbA1c  48 mmol/mol at least 3 months before conception) and inadequate diabetes compensation at the beginning of the pregnancy had 59 (26.7%) and 162 (72.3%) women, respectively. Pregnancies of women with adequate diabetes compensation were more often planned (55.9 vs. 24.7%; P  95th percentile; 22.0 vs. 35.8%; P = 0.027). CONCLUSION: The pregnancy of women with T1DM is burdened by a number of perinatal and neonatal complications. In the study group, most women with T1DM became pregnant unintentionally at a time of inadequate diabetes compensation. Women who achieved adequate diabetes compensation before pregnancy had a lower incidence of perinatal complications. Therefore, it is advised that women with T1DM should plan their pregnancy, attend preconception and antenatal care, and give birth in perinatal centers, which provide coordinated care from diabetologists, gynecologists, obstetricians, and neonatologists.

The role of endocannabinoids in pregnancy.

OBJECTIVE: In this paper, we summarize the role of the endocannabinoid system in relation to pregnancy and childbirth and its potential for dia-gnosis of preterm birth. METHODS: Review of articles in peer-reviewed journals using the PubMed database. RESULTS: Endocannabinoid system plays a significant role in embryo development, transport and implantation as well as in placentation. It consists of numerous endogenous ligands; however, in relation to pregnancy there are mainly two studied representatives: anandamide and 2-arachidonoylglycerol. There is increasing evidence, in addition to early pregnancy events, that anandamide plays a regulatory role in pregnancy maintenance and the timing of labour. The activity of anandamide depends on its metabolic pathway and the enzymatic activity that ensures its conversion. Ultimately, changes in anandamide concentration lead to increased production of prostaglandins or prostamides, with inverse effects on pregnancy. The abuse of exogenous cannabinoids in pregnancy has substantial impact on the unborn child in many ways and may result in detrimental effects including preterm birth. CONCLUSION: Measuring anandamide concentration and the prostaglandin to prostamide ratio could be a useful tool in assessing the risk of preterm birth.

Chronic kidney disease and pregnancy outcomes.

Pregnancy complicated by CKD is currently not fully understood topic. Outcome of pregnancy in patients with CKD is related to impaired glomerular filtration rate and the degree of proteinuria. In our study we evaluated the association of serum creatinine level and proteinuria with both maternal and fetal outcomes in the cohort of 84 pregnant patients with CKD. In CKD group we confirmed negative correlation of highest serum creatinine level in pregnancy to fetal weight (p value < 0.001) and gestation period (p value < 0.001). Likewise, negative correlation of preconception serum creatinine to fetal weight (p value < 0.001) and gestation period (p value 0.002). Negative correlation of proteinuria to gestation period (p value < 0.001) and fetal weight (p value < 0.001) was also demonstrated. CKD is serious risk factor for pregnancy outcome. Proteinuria and serum creatinine level should be examined before pregnancy and regularly monitored during pregnancy. Higher serum creatinine levels and higher proteinuria predispose to shorter gestation period and lower birth weight of the neonate.

Endocannabinoids.

OBJECTIVE: Overview of current knowledge in the field of the endocannabinoid system with emphasis on the relationships between endocannabinoids and exocannabinoids. The endocannabinoid system consists of cannabinoid receptors 1 and 2, ligands of these receptors, especially two classical; endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoyl-glycerol. Transport systems that ensure the entry of endocannabinoids into cells, where they are degraded by fatty acid amide hydrolase or monoacylglycerol lipase. The endocannabinoid system is a signaling pathway for the regulation of a number of physiological or pathological conditions. So far, it is one of the less explored ways of regulation, as evidenced by the recent explosive increase in the number of published works. Dysregulation of endocannabinoid systems is a possible cause of many diseases. It can occur both in the genetic polymorphism of its individual components, but also in therapy with certain drugs or natural substances, typically cannabinoids. Due to the wide overlap of the regulation of physiological functions by the endocannabinoid system, a considerable number of drugs are being developed, the aim of which is to correct the dysregulation of the endocannabinoid system. CONCLUSION: The endocannabinoid system is one of the most important regulatory systems with a very broad intervention in physiological and pathological conditions. The resulting specific regulations intersect the interplay of many enzymes involved in the production and degradation of endocannabinoids, transport systems involved in the entry of endocannabinoids into cells, cannabinoid receptors and exogenous cannabinoids, or natural substances acting at various sites in the endocannabinoid system. Knowledge in this area can contribute to improving health care and increasing the safety of its provision.

The role of the microbiome in pregnancy.

OBJECTIVE: To provide a comprehensive overview of the available information on the maternal microbio-me and its effect on pregnancy and preterm birth. METHODS: Systematic review of available literature on the topic was done using the PubMed database. CONCLUSION: Etiology of preterm labor is multifactorial. Individual setting of humoral and cellular immune response is key; however, lately the focus has shifted to the role of the microbio-me, especially the vaginal one. The role of additional microbio-mes and the relationship between different compartments are the focus of intensive research. Mainly the differences in the maternal and neonatal microbio-me depend on the method of delivery and administration of different antibio-tics during pregnancy and labor. The uterine cavity is no longer thought to be without colonization and the formation of the fetal microbio-me begins early in pregnancy.

Is It Possible to Personalize the Diagnosis and Treatment of Breast Cancer during Pregnancy?

The main goal of precision medicine in patients with breast cancer is to tailor the treatment according to the particular genetic makeup and the genetic changes in the cancer cells. Breast cancer occurring during pregnancy (BCP) is a complex and difficult clinical problem. Although it is not very common, both maternal and fetal outcome must be always considered when planning treatment. Pregnancy represents a significant barrier to the implementation of personalized treatment for breast cancer. Tailoring therapy mainly takes into account the stage of pregnancy, the subtype of cancer, the stage of cancer, and the patient's preference. Results of the treatment of breast cancer in pregnancy are as yet not very satisfactory because of often delayed diagnosis, and it usually has an unfavorable outcome. Treatment of patients with pregnancy-associated breast cancer should be centralized. Centralization may result in increased experience in diagnosis and treatment and accumulated data may help us to optimize the treatment approaches, modify general treatment recommendations, and improve the survival and quality of life of the patients.

The possible role of endocrine dysfunction of adipose tissue in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is diabetes that is first diagnosed in the second or third trimester of pregnancy in patients who did not have a history of diabetes before pregnancy. Consequences of GDM include increased risk of macrosomia and birth complications in the infant and an increased risk of maternal type 2 diabetes mellitus (T2DM) after pregnancy. There is also a longer-term risk of obesity, T2DM, and cardiovascular diseases in the child. GDM is the result of impaired glucose tolerance due to pancreatic ß-cell dysfunction on a background of insulin resistance that physiologically increases during pregnancy. The strongest clinical predictors of GDM are overweight and obesity. The fact that women with GDM are more likely to be overweight or obese suggests that adipose tissue dysfunction may be involved in the pathogenesis of GDM, similarly to T2DM. Adipose tissue is not only involved in energy storage but also functions as an active endocrine organ secreting adipokines (specific hormones and cytokines) with the ability to alter insulin sensitivity. Recent evidence points to a crucial role of numerous adipokines produced by fat in the development of GDM. The following text summarizes the current knowledge about a possible role of selected adipokines in the development of GDM.

Subclinical Inflammation and Adipose Tissue Lymphocytes in Pregnant Females With Gestational Diabetes Mellitus.

CONTEXT: Gestational diabetes mellitus (GDM) is accompanied by subclinical inflammation; however, little is known about local inflammation in adipose tissue and placenta. OBJECTIVE: To analyze systemic and local subclinical inflammation and adipose tissue lymphocyte content and phenotype in pregnant women with and without GDM. DESIGN: Observational study. SETTINGS: Academic hospital. PATIENTS: Twenty-one pregnant women with GDM (GDM group), 16 pregnant women without GDM (non-GDM group) and 15 nonpregnant control women (N group). INTERVENTIONS: Serum samples taken at 28 to 32 (visit 1 [V1]) and 36 to 38 (V2) gestational weeks and 6 to 12 months after delivery (V3) in the GDM and non-GDM group and before elective gynecological surgery in the N group. Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained during cesarean delivery or surgery. MAIN OUTCOME MEASURES: Serum levels and adipose tissue expression of proinflammatory cytokines, adipose tissue lymphocyte content and phenotype (for a subset of GDM and non-GDM subjects). RESULTS: Accented proinflammatory state in GDM was documented by increased circulating tumor necrosis factor-α (TNF-α) levels. In both groups of pregnant females total lymphocytes were higher in VAT compared to SAT. In GDM subjects B cells and NKT cells were higher in SAT compared to VAT and T helper cells were increased relative to SAT of non-GDM group, while no intercompartmental adipose tissue differences were seen in non-GDM women. CONCLUSIONS: Pregnant females had higher total lymphocyte count in VAT relative to SAT regardless of GDM. In addition to increased systemic subclinical inflammation, GDM was associated with significant differences in lymphocyte composition between subcutaneous and visceral adipose tissue depots.