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.

The management of care for a pregnant woman with recurrent pregnancy losses and proven immunodeficiency from the obstetricians point of view.

Recurrent pregnancy losses represent sensitive issue not only for the couple, but also for all healthcare professionals involved. In a broader context, they include not only recurrent miscarriages, but also the issue of periviable preterm birth with subsequent neonatal death and unexplained fetal death. This area requires an interdisciplinary approach. The field of reproductive immunology best answers questions related to pregnancy complications. However, there is currently no accurate recommendation as to who should care for such women. In this article I summarize the current state of knowledge about the issue, current experience with care management, including case studies.

Serum mannose-binding lectin (MBL) concentrations are reduced in non-pregnant women with previous adverse pregnancy outcomes.

Mannose-binding lectin (MBL) is an important component of the innate immunity, and it is responsible not only for opsonization of micro-organisms, but also for efferocytosis. The aim of this study was to investigate whether MBL concentrations and lectin complement pathway activity are altered in non-pregnant women with previous adverse pregnancy outcomes. Patients were divided into four groups on the basis of their history of pregnancy complications, including control patients who had uncomplicated pregnancies and term deliveries (control, n = 33), and three groups of patients with a history of pregnancy complications, including preterm labour (n = 29), recurrent miscarriage (n = 19) or unexplained intrauterine foetal death (IUFD; n = 17). All women enrolled in the study had an interval of three to six months following their previous pregnancy, and they agreed to have a blood sample taken. We found significantly higher MBL concentrations and functional activity of the lectin complement pathway in healthy controls who had previous uneventful term pregnancies (1341 ng/mL; activity 100% (IQR: 62%-100%)), compared to women with the history of IUFD (684 ng/mL, P = .008; activity 8.5% (IQR: 0%-97.8%), P = .011), recurrent miscarriage (524 ng/mL, P = .022; activity 44% (IQR: 4%-83%), P = .011) or preterm labour (799 ng/mL, P = .022; activity 62.5% (IQR: 0%-83%), P = .003). Our results suggest that inadequate function of the complement lectin pathway is associated with a higher risk of preterm labour, recurrent miscarriage and unexplained intrauterine foetal death.

Kinetics of Helios(+) and Helios(-) T regulatory cell subsets in the circulation of healthy pregnant women.

Regulatory T cells (Tregs) play a critical role in the maintenance of a pregnancy. While the kinetics of the number of peripheral blood Tregs has been satisfactorily described in mouse models, analysis of these cell populations in human pregnancy is complicated by high variability in the quantity of Tregs and inconsistencies in the markers used for detecting different types of Treg. In the light of this, we set out to investigate the kinetics of various types of Treg, including CD45RA, GARP and PD-1(+) Tregs, in the peripheral blood of pregnant women in the first, second and third trimester, and at the time of delivery. Tregs, defined as a CD4(+)CD25(++)CD127(dim)Foxp3(+) population of leucocytes, were detected using flow cytometry. Natural thymus-derived Tregs and induced Tregs in the peripheral blood were distinguished by the expression or absence of a Helios marker, respectively. Our results showed that during normal pregnancy the sizes of various Treg subpopulations varied across women and also in an individual woman did not remain constant but varied significantly, most notable being the decrease observed at the time of delivery. Helios(-) cells were significantly less frequent in the peripheral blood of healthy pregnant women than Helios(+) cells, and the majority of Tregs were Helios(+)PD-1(+) Tregs.

Proactive approach at the limits of viability improves the short-term outcome of neonates born after 23 weeks' gestation.

OBJECTIVE: The aim of this single-center study was to identify factors that affect the short-term outcome of newborns delivered around the limits of viability. METHODS: A group of 137 pregnant women who gave birth between 22+0/7 and 25+6/7 weeks of gestation was retrospectively studied. The center supports a proactive approach to infants around the limits of viability. Perinatal and neonatal characteristics were obtained and statistically evaluated. RESULTS: A total of 166 live-born infants were enrolled during a 6-year period; 162 (97.6%) of them were admitted to the neonatal intensive care unit (ICU) and 119 (73.5%) survived until discharge. The decrease in neonatal mortality was associated with an advanced gestational age (P<0.001) and a completed course of corticosteroids (P=0.002). Neonatal morbidities were common among infants of all gestational ages. The incidence of severe intraventricular hemorrhage significantly depended on gestational age (P<0.001) and a completed course of corticosteroids (P=0.002). Survival without severe neonatal morbidities was 39.5% and occurred mostly after 24+0/7 weeks of gestation. CONCLUSION: The short-term outcome of newborns delivered around the limits of viability is mostly affected by gestational age and antenatal corticosteroid treatment. A consistently proactive approach improves the survival of infants at the limits of viability. This is most pronounced in cases where the delivery is delayed beyond 24 completed gestational weeks.

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.

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.

A global perspective on management of bacterial infections in pregnancy: a systematic review of international guidelines.

INTRODUCTION: Maternal sepsis is a leading cause of maternal and neonatal mortality. Despite the availability of management protocols, there is disparity in case fatality rates for pregnancy-related sepsis compared to other maternity-related complications. The main aim of this systematic review was to assess concordance between international evidence-based guidelines for the prevention and management of childbirth-related bacterial infections. MATERIAL AND METHODS: The PRISMA statement was followed during the conduct and reporting of this review. PubMed was searched electronically from 2009 to November 2019 for clinical guidelines covering the topic of childbirth-related infections and specific searches for relevant guidelines on the websites of the top five international professional bodies most commonly identified by our searches. We did not apply any language restrictions. Guidelines were included if they provided any information about the prevention or management of childbirth-related bacterial infections irrespective of whether the guideline stated a recommendation or not. Two independent reviewers undertook study selection, decisions about inclusion of selected guidelines and data extraction. Extracted information was synthesized under the following topics: Asymptomatic bacteriuria; group B streptococcal infection (GBS); preterm premature rupture of membranes (P-PROM); intrauterine infection; procedures; maternal sepsis; miscellaneous. Concordance was defined as absence of contradictory information between the different guidelines with regards to a specific topic, subtopic or recommendation. Quality of included guidelines was assessed against the AGREE II guideline reporting domains. RESULTS: A total of 43 guidelines were selected of which 11 were excluded leaving 32 guidelines that fulfilled our inclusion criteria. None of the guidelines fulfilled all the quality assessment domains and 11 (34%) of the guidelines satisfied 1-2 of domains only. Two guidelines covered the topic of asymptomatic bacteriuria, nine for GBS, five for P-PROM and three covered each of intra-amniotic infections maternal sepsis, obstetric procedures and interventions topics. The remaining guidelines covered miscellaneous topics. CONCLUSIONS: There was concordance between guidelines with regards to several aspects in the prophylaxis and treatment of bacteriological infections in pregnancy. Nevertheless, there were several areas of discordance, some of which reached the extent of contradictory information as in the case of antenatal screening for GBS.

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.

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.

Low maternal serum matrix metalloproteinase (MMP)-2 concentrations are associated with preterm labor and fetal inflammatory response.

OBJECTIVES: to assess the relationship between maternal and umbilical serum concentrations of matrix metalloproteinases (MMP)-2,8,9, the soluble receptor for advanced glycation end products (sRAGE) and IL-10 and premature delivery and fetal inflammation. METHODS: maternal serum levels of MMPs, sRAGE, IL-10 and C-reactive protein (CRP) were determined in 67 women with preterm labor and in 38 healthy pregnant women of similar gestational age (GA). In the group with preterm labor we also determined umbilical concentrations of MMPs, IL-6 and sRAGE. The group with preterm labor was additionally divided based on the presence of funisitis and elevations of fetal umbilical IL-6 concentrations. RESULTS: maternal serum levels of MMP-2 and sRAGE were significantly lower in women with preterm labor compared to women with normal pregnancy. Additionally, within the group of women with preterm labor, maternal serum MMP-2 concentrations were significantly lower in the subgroup with funisitis and in the subgroup with elevated umbilical concentration of IL-6. CONCLUSION: our results demonstrate significantly different serum concentrations of MMP-2 and sRAGE in women with preterm labor compared to healthy pregnant patients of the same GA.

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.

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.

Diagnostic and prognostic value of presepsin in preterm deliveries.

PROBLEM: To evaluate the association between serum presepsin (soluble CD14 antigen subtype, sCD14-ST) levels soon after the appearance of signs of preterm delivery and preterm delivery within 48 h, before the 34th and 37th gestational weeks and the possible additional value of concurrently evaluated ultrasound vaginal cervicometry with serum presepsin measurement. METHODOLOGY: A total of 60 females were included. Serum presepsin was measured by a chemiluminescent immunoassay. Sonographic evaluation of cervical length in all females was conducted by transvaginal ultrasound. RESULTS: Patients who delivered within 48 h after analysis showed significantly higher presepsin concentrations compared to females with later deliveries. Higher presepsin was proven also for deliveries before/after weeks 34 and 37. A combined finding of cervical length shortening below 18 mm and presepsin level increasing above 623.5 pg/mL could point to the significantly high risk of preterm delivery. CONCLUSION: Elevated maternal serum concentration of sCD14-ST could be an independent and relevant risk factor for preterm delivery.

Agreement on intrapartum cardiotocogram recordings between expert obstetricians.

RATIONALE, AIMS AND OBJECTIVES: To evaluate obstetricians' inter- and intra-observer agreement on intrapartum cardiotocogram (CTG) recordings and to examine obstetricians' evaluations with respect to umbilical artery pH and base deficit. METHODS: Nine experienced obstetricians annotated 634 intrapartum CTG recordings. The evaluation of each recording was divided into four steps: evaluation of two 30-minute windows in the first stage of labour, evaluation of one window in the second stage of labour and labour outcome prediction. The complete set of evaluations used for this experiment is available online. The inter- and intra-observer agreement was evaluated using proportion of agreement and kappa coefficient. Clinicians' sensitivity and specificity was computed with respect to umbilical artery pH, base deficit and to Apgar score at the fifth minute. RESULTS: The overall proportion of agreement between clinicians reached 48% with 95% confidence intervals (CI) (CI: 47-50). Regarding the different classes, proportion of agreement ranged from 57% (CI: 54-60) for normal to 41% (CI: 36-46) for pathological class. The sensitivity of clinicians' majority vote to objective outcome was 39% (CI: 16-63) for the umbilical artery base deficit and 27% (CI: 16-42) for pH. The specificity was 89% (CI: 86-92) for both types of objective outcome. CONCLUSIONS: The reported inter-/intra-observer variability is large and this holds irrespective of clinicians' experience or work place. The results support the need of modernized guidelines for CTG evaluation and/or objectivization and repeatability by introduction of a computerized approach that could standardize the process of CTG evaluation within the delivery ward.

Progesterone, inflammation and preterm labor.

The initiation of human parturition is not fully understood to date. The data from animal experiments demonstrate that the primary impulse for the initiation of physiological labor arises from the fetal hypothalamo-pituitary-adrenal axis (HPA). HPA is responsible for the stimulation of steroid synthesis and prostaglandin production and, in turn, the cervical dilation and the beginning of myometrial contractions. Animal experiments, however, are only partly suitable for understanding the mechanism of human labor due to substantial species-specificity. In human, the changing levels of placental CRH control the production of fetal and placental steroids. The fundamental pathogenic manifestation of spontaneous preterm labor is inflammation and similar processes also underlie the full term one. While in full term labor it is not yet precisely known what starts this process, in the preterm one, several factors have been discussed like infection, uteroplacental ischemia, and hormonal abnormalities (progesterone- or CRH-related). Inflammatory processes affect both the mother and the fetus. Fetal inflammatory response (FIRS), which can be expected for children born preterm, is frequently associated with long-term complications, in particular neurological and pulmonary. Research in this field is therefore aimed at predicting preterm labor, and on predicting the fetal inflammatory response. The role of progesterone and its receptors in the pathophysiology of preterm labor are likewise intensively studied. Clinical results on the use of additive doses of progesterone in secondary prevention of preterm labor and current experimental studies point to progesterone and its receptors playing a key role in the pathophysiology of preterm labor. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.

The role of steroids in the development of post-partum mental disorders.

BACKGROUND: Unfavorable post-partum changes to mental well-being affect more than half of all women, and are a risk to the health of both mother and baby. Their effects place strains on health and social systems. Currently, no generally accepted theory exists of the causes and mechanisms of post-partum mental disorders. METHODS: Literature search up to 2012, using PubMed and search words: neuroactive steroids, post-partum mental disorders, depression, corticotropin-releasing hormone and estrogens. RESULTS: There are several theories for post-partum depression. One is that autoimmune diseases are involved. Others revolve around genes responsible or that lead to increased disposition to the disorder. It is likely however that the process is associated with the separation of the placenta and the fetal zone of fetal adrenal gland, the main sources of corticotropin-releasing hormone and sexual and neuroactive steroids during pregnancy, and the ability of the receptor system to adapt to these changes. The central nervous system is able to produce neurosteroids, but the drop in levels of peripheral steroids likely leads to a sudden deficit in neuroinhibitory steroids modulating ionotropic receptors in the brain. CONCLUSIONS: Post-partum depression is a multifactorial disease with unknown etiology. It is probably associated with sudden changes in the production of hormones influencing the nervous system, and on the other hand the ability of the receptor system to adapt to these changes. When the relative changes in concentrations of hormones, rather than their absolute levels, is likely more important.

Low levels of circulating T-regulatory lymphocytes and short cervical length are associated with preterm labor.

Recent discoveries suggest that T-regulatory lymphocytes (Treg) might play an important role in the pathophysiology of preterm labor. The aim of this study was to assess the relationship among the levels of maternal circulating Treg cells, uterine cervical length, and the risk of preterm labor. Sixty women with regular contractions and/or cervical incompetence at 24-32 weeks' gestation were recruited into a prospective study. Each patient underwent transvaginal ultrasound examination of the cervical length, and regulatory T cells were quantified in peripheral blood samples by flow cytometry. Patients with cervical incompetence were prescribed vaginal progesterone until birth. Measurements of Treg levels and cervical length correlated with the timing of labor. The risk of preterm labor happening within 48 h of testing was demonstrated to be almost 35 times higher (OR=35.21, CI 13.3; 214, p<0.001) in the group with simultaneously low Treg values (<0.031 × 10(9)/L) and a shortened uterine cervix (<17.5mm), compared with the situation where both of these values were normal. Similar results were found in predicting preterm delivery before 34 weeks, or between 34 and 37 weeks. A statistically nonsignificant trend toward increased cervical length and increased Treg count was noted in the women on progesterone treatment. We show for the first time that the combined assessment of Treg cell count and cervical length is a much better predictor of preterm delivery than either parameter used on its own. This combined approach may offer clinical application in patients who present with risk factors for preterm labor.

Steroid profiling in pregnancy: a focus on the human fetus.

In this review we focused on steroid metabolomics in human fetuses and newborns and its role in the physiology and pathophysiology of human pregnancy and subsequent stages of human life, and on the physiological relevance of steroids influencing the nervous systems with regards to their concentrations in the fetus. Steroid profiling provides valuable data for the diagnostics of diseases related to altered steroidogenesis in the fetal and maternal compartments and placenta. We outlined a potential use of steroid metabolomics for the prediction of reproductive disorders, misbalance of hypothalamic-pituitary-adrenal axis, and impaired insulin sensitivity in subsequent stages of human life. A possible role of steroids exhibiting a non-genomic effect in the development of gestational diabetes and in the neuroprotection via negative modulation of AMPA/kainate receptors was also indicated. Increasing progesterone synthesis and catabolism, declining production of tocolytic 5ß-pregnane steroids, and rising activities of steroid sulfotransferases with the approaching term may be of importance in sustaining pregnancy. An increasing trend was demonstrated with advancing gestation toward the production of ketones (and 3ß-hydroxyl groups in the case of 3α-hydroxy-steroids) was demonstrated in the fetus on the expense of 3α-hydroxy-, 17ß-hydroxy-, and 20α-hydroxy-groups weakening in the sequence C17, C3, and C20. There was higher production of active progestogen but lower production of active estrogen and GABAergic steroids with the approaching term. Rising activities of placental CYP19A1 and oxidative isoforms of HSD17B, and of fetal CYP3A7 with advancing gestation may protect the fetus from hyperestrogenization. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.