The Impact of the Female Genital Microbiota on the Outcome of Assisted Reproduction Treatments.

The vaginal microbiota plays a critical role in the health of the female genital tract, and its composition contributes to gynecological disorders and infertility. Lactobacilli are the dominant species in the female genital tract: their production of lactic acid, hydrogen peroxide, and bacteriocins prevents the invasion and growth of pathogenic microorganisms. Several factors such as hormonal changes, age of reproduction, sexual practices, menstrual cycle, pregnancy, and antimicrobial drugs use can cause imbalance and dysbiosis of the vaginal microbiota. This review aims to highlight the impact of the vaginal microbiota in Assisted Reproductive Technology techniques (ART) and it examines the factors that influence the vaginal microbiota, the consequences of dysbiosis, and potential interventions to restore a healthy female genital tract.

Identifying Predictive Bacterial Markers from Cervical Swab Microbiota on Pregnancy Outcome in Woman Undergoing Assisted Reproductive Technologies.

BACKGROUND AND AIMS: Failure of the embryo to implant causes about three-fourths of lost pregnancies. Female genital tract microbiota has been associated to Assisted Reproductive Technologies (ART) outcomes. The objective of this study was to analyze the microbiota of human cervical swab and to correlate these findings with the ART outcomes. MATERIALS AND METHODS: In this study, 88 cervical swabs were collected from women undergoing ART cycles, with various causes of infertility, at the beginning of the ART protocols. After microbial DNA extraction, V3-V4 variable regions of the 16S rRNA gene were amplified and sequenced on the Illumina MiSeq platform. PEnalized LOgistic Regression Analysis (PELORA) was performed to identify clusters of bacterial populations with differential abundances between patients with unfavorable and favorable pregnancy outcome groups, respectively. RESULTS: We identified a core of microorganisms at lower taxonomic levels that were predictive of women's pregnancy outcomes. Statistically significant differences were identified at species levels with Lactobacillus salivarius, Lactobacillus rhamnosus among others. Moreover the abundance of Lactobacillus crispatus and iners, respectively increased and decreased in favorable group as compared to unfavorable group, resulted within the core of microorganisms associated to positive ART outcome. Although the predominance of lactobacilli is generally considered to be advantageous for ART outcome, we found that also the presence of Bifidobacterium (together with the other lactobacilli) was more abundant in the favorable group. DISCUSSION: Cervix is colonized by microorganisms which can play a role in ART outcomes as seen by an overall decrease in embryo attachment rates and pregnancy rates in both fertile and infertile women. If confirmed in a larger cohort, the abundance of these bacteria can be useful not only as a marker of unfavorable pregnancy outcome but also they may open the way to new interventional strategies based on genital tract microbiota manipulation in order to increase the pregnancy rates in woman undergoing assisted reproductive technologies.

High Rates of Hidden HCV Infections among Hospitalized Patients Aged 55-85.

BACKGROUND AND AIMS: The WHO has solicited all countries to eliminate HCV by 2030. The Italian government started routine screening for HCV infection in January 2021, initially targeting subjects born between 1969 and 1989. With the aim of achieving micro-elimination, we designed a hospital-wide project focusing on inpatients born from 1935 to 1985 and conducted it in our institution. METHOD: All inpatients aged 35 to 85, admitted from 10 February 2020 to 9 February 2021 for many different diseases and conditions underwent HCV antibody (HCVAb) testing by third-generation ELISA. When positive, reflex HCV RNA testing and genotyping were performed. Clinical history, fibrosis diagnosis, laboratory data and concomitant medications were available for all. RESULTS: The HCV screening rate of inpatients was 100%. In total, 11,748 participants were enrolled, of whom 53.50% were male. The HCVAb positivity rate was 3.03%. The HCVAb rate increased with age and was higher for patients born between 1935 and 1944 (4.81%). The rate of HCV RNA positivity was 0.97%. The vast majority (80.70%) of HCV RNA-positive participants were 55 or older; in about 40% of cases, HCV RNA-positive patients were unaware of their infection. Although 16 patients died after HCV chronic infection diagnosis (two due COVID-19) or HCV treatment prescription (one due to COVID-19), 74.56% of patient HCV diagnoses were linked to HCV treatment, despite their co-morbidities. All patients older than 65 who died had an active HCV infection. CONCLUSION: The present study revealed a rate of active HCV infections among inpatients lower than what has been reported in the past in the general population; this appears to be a result of the widespread use of pangenotypic direct-acting antiviral agents (DAAs). The overall rate of active infection was lower than the rate observed in the 1935-1954 cohort. The high rate of inpatients unaware of HCV infections and the high number of deaths among subjects with an active HCV infection born from 1935 to 1954, suggest that, at least in southern Italy, targeted screening of this birth cohort may be required to reduce the number of undiagnosed cases and hidden infections.

Onset of chronic myeloid leukemia with complex karyotype in a pregnant patient: case report and revision of literature.

Approximately 10%-12% of patients in chronic-phase chronic myeloid leukemia (CP-CML) have additional chromosomal aberrations at diagnosis; moreover, CML occurs in up to 10% of pregnancy-associated leukemias, with an annual incidence of 1 per 100,000 pregnancies. In this report we describe the case of a 36-year-old female with CP-CML diagnosed in the 18th week of pregnancy and with a new complex variant translocation t(4;9;22;21)(q24;q34;q11;q22) and an additional chromosomal aberration t(1;20)(p36;p11). In consideration of her pregnancy, the patient strictly monitored her blood cell count without any specific treatment. At 32 weeks of pregnancy, the patient delivered via cesarean section a healthy baby girl. After 10 days from childbirth, dasatinib was started at a standard dosage of 100 mg/day and 3 months later complete cytogenetic response and major molecular response were obtained, with the achievement of an optimal response according to European Leukemia Net recommendations and showing efficacy of this tyrosine kinase inhibitor (TKI) in the presence of a complex karyotype.

Modulation of factors involved in placental haemostasis and angiogenesis by low-molecular-weight-heparins.

PURPOSE: In placentae from uneventful pregnancies a direct relationship between expression of tissue factor (TF) and tissue-factor pathway inhibitor type 2 (TFPI2) was found, as well as between TF and vascular endothelial growth factor (VEGF). Furthermore, placentae from gestational vascular complications (GVCs) lack these correlations. Aims of the present study are (1) to evaluate a possible role of low-molecular-weight-heparins (LMWHs) in the modulation of the expression of TF, TFPI, TFPI2 and VEGF in placentae from thrombophilic women and (2) to study the possible role of endothelium in the placental expression of markers involved in haemostasis and angiogenesis. METHODS: Fourteen pregnancies in thrombophilic women and 11 uneventful pregnancies in non-thrombophilic women were studied and placentae collected. From each placenta total RNA was obtained. Expression of TF, TFPI, TFPI2 and VEGF was evaluated. Human Vein Endothelial Cells were incubated with increasing doses of LMWH and expression of TF, TFPI and VEGF was measured. RESULTS: Expression of all the markers analyzed in placentae from treated pregnancies was similar to that observed in placentae from uneventful ones. A significant direct relationship between TF and TFPI2, as well as TF and VEGF, was observed in cases treated with LMWHs and controls. Furthermore, the expression of TF and its inhibitors and VEGF in endothelial cells was modulated by LMWH. CONCLUSION: Present data suggest that LMWH during pregnancy in thrombophilic women restores the relationship between markers of haemostasis and angiogenesis. Furthermore, the endothelium is likely to play an important role in this phenomenon.

Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications.

Inherited or acquired thrombophilias have been largely explored as a cause of pregnancy complications. However, pathogenesis of obstetric complications, as fetal loss and pregnancy-related hypertensive disorders is still partly unexplained. Recently, a common haplotype (M2) within the annexin A5 (ANXA5) gene has been described as a risk factor in recurrent fetal losses (RFL). It has been demonstrated to reduce the promoter activity of the ANXA5 promoter in luciferase reporter assays. Aim of this study was to investigate the prevalence of M2 haplotype in three different settings of women with previous obstetric complications: RFL, intra-uterine fetal death (IUFD) and pregnancy-related hypertension (gestational hypertension [GH] and pre-eclampsia [PE]). One hundred three patients with previous RFL, 54 with IUFD, 158 with hypertensive disease (67 GH, 91 PE) were investigated. As controls, 195 women from the same ethnic background with uneventful pregnancies were enrolled. Logistic regression, correcting for age, gravidity and parity showed that the ANXA5 haplotype is significantly and independently associated with the occurrence of RFL (3.1; 95%CI: 1.1-9.5; p = 0.047) and pregnancy-related hypertensive disorders (2.1; 95%CI: 1.2-3.5; p = 0.008). The M2 haplotype might be a new and relevant risk factor for obstetric complications.

Homocysteine levels in amniotic fluid. Relationship with birth-weight.

Hyperhomocysteinemia could play a similar role in the placenta to that played in adults at risk of thrombosis. Moreover, hyperhomocysteinemia in women is described to be associated with the birth of small for gestational age (SGA) newborns, although there are discrepancies on this issue. To date, there is no biochemical marker predictive of SGA in a given pregnancy. We verified the presence of a relationship between homocysteine in amniotic fluid at mid-pregnancy and birth-weight. Amniotic fluid was obtained from 459 healthy women undergoing midtrimester amniocentesis (17.1 +/- 1.2 weeks) because of maternal age. Homocysteine levels were measured in 434 (10 twin) pregnancies. In addition, femur length (FL) and biparietal diameter (BPD) were measured. Outcome of pregnancy was recorded. 233 (53.7%) foetuses were males, 201 (46.3%) females. The mean homocysteine concentration was 1.04 +/- 0.72 microM, (95% C.I. 0.43-2.41). An univariate analysis showed the presence of an association with gestational age, FL, BPD. A multiple linear regression showed that homocysteine levels were significantly associated with FL (p < 0.001) and BPD (p = 0.011). After excluding twin pregnancies, 31 newborns (7.3%) were classified as SGA. Mean birth-weight was 2390 g in SGA, whereas it was 3360 g in 393 adequate for gestational age (AGA) newborns (p < 0.001). The adjusted mean level of homocysteine was significantly lower in AGA (1.01 microM; 95% C.I: 0.94-1.08) than that recorded in pregnancies resulting in a SGA (1.29 microM; 95% CI: 1.05-1.51; p = 0.03). In a large setting, these data provide reference values for homocysteine in amniotic fluids. Moreover, they suggest that homocysteine levels in amniotic fluids may be higher in pregnancies with a SGA newborn.

Preventing adverse obstetric outcomes in women with genetic thrombophilia.

OBJECTIVE: To improve fetomaternal outcomes in women with obstetric complications and inherited causes of thrombophilia. DESIGN: Clinical trial. SETTING: Thrombophilic women with previous unexplained adverse outcomes. PATIENT(S): Twenty-five women with previous severe obstetric complications were treated during and after pregnancy. INTERVENTION(S): Low fixed dose of heparin or aspirin. MAIN OUTCOME MEASURE(S): Fetomaternal outcome. RESULT(S): Low fixed dose of heparin were administered to 24 pregnant women, aspirin to 7. Overall, among 31 treated pregnant women, 28 (90.3%) compared to 4 of 58 (6.9%) in previous pregnancies had a good obstetric outcome. Two fetal losses <14 weeks gestation and a fetal growth restriction were registered. All newborns, except one, were in the tenth centile or above. All babies were discharged in good clinical status. In the treated pregnancies, no thrombosis or pharmacological side effect was recorded. CONCLUSION(S): Heparin prophylaxis at fixed low doses and possibly aspirin could be efficacious in preventing adverse outcomes in women carrying inherited thrombophilia with previous poor obstetric outcomes.