Uterine perivascular epithelioid cell tumors (PEComa) and the accuracy of proposed classification systems in predicting the malignant versus non-malignant behavior.

OBJECTIVE: To compare the accuracy of available classification systems (Folpe, modified Folpe, Bennet, and Schoolmester) in predicting the behavior of uterine Perivascular Epithelioid Cell tumors (PEComas). METHODS: We reviewed the pathology registry to identify all uterine PEComas treated at our center. We conducted a systematic literature review searching electronic databases from inception to November 2023. We included all references reporting at least one case of uterine PEComa; cases associated with tuberous sclerosis complex were excluded. Patient-level data were extracted by identified records. Survival analysis was used to assess the accuracy of all proposed classification systems to classify uterine PEComas as malignant versus non-malignant. RESULTS: Six uterine PEComas were treated at our center. The literature search identified 101 uterine PEComas from 32 studies. Eighty-five out of 107 PEComas (28 studies and our series) reported enough follow-up data and details to apply all four classifications. The modified Folpe classification demonstrated the highest hazard ratio (HR) for relapse (HR:8.63; 95% confidence interval [CI] 2.06-36.1) and death due to PEComa (HR:6.8, 95%CI:0.89-51.6) for malignant versus non-malignant PEComas. Changing the cut-off of PEComa size to ≥8 cm and mitotic figures per 50 high power fields to ≥5, the HR for recurrence lowered (HR:6.26; 95% CI 2.20-17.80), but HR for death increased (HR:10.3; 95% CI 1.35-77.80). CONCLUSIONS: The modified Folpe classification was the most accurate in predicting the PEComa behavior. Changing the cut-off of PEComa size and number of mitotic figures may improve the accuracy in predicting death due to disease.

Clinician perspectives on hysterectomy versus uterine preservation in pelvic organ prolapse surgery: A systematic review and meta-analysis.

BACKGROUND: Previous reviews on hysterectomy versus uterine-sparing surgery in pelvic organ prolapse (POP) repair did not consider that the open abdominal approach or transvaginal mesh use have been largely abandoned. OBJECTIVES: To provide up-to-date evidence by examining only studies investigating techniques currently in use for POP repair. SEARCH STRATEGY: MEDLINE and Embase databases were searched from inception to January 2023. SELECTION CRITERIA: We included randomized and non-randomized studies comparing surgical procedures for POP with or without concomitant hysterectomy. Studies describing open abdominal approaches or transvaginal mesh implantation were excluded. DATA COLLECTION AND ANALYSIS: A random effect meta-analysis was conducted on extracted data reporting pooled mean differences and odds ratios (OR) between groups with 95% confidence intervals (CI). MAIN RESULTS: Thirty-eight studies were included. Hysterectomy and uterine-sparing procedures did not differ in reoperation rate (OR 0.93; 95% CI 0.74-1.17), intraoperative major (OR 1.34; 95% CI 0.79-2.26) and minor (OR 1.38; 95% CI 0.79-2.4) complications, postoperative major (OR 1.42; 95% CI 0.85-2.37) and minor (OR 1.18; 95% CI 0.9-1.53) complications, and objective (OR 1.38; 95% CI 0.92-2.07) or subjective (OR 1.23; 95% CI 0.8-1.88) success. Uterine preservation was associated with a shorter operative time (-22.7 min; 95% CI -16.92 to -28.51 min), shorter hospital stay (-0.35 days, 95% CI -0.04 to -0.65 days), and less blood loss (-61.7 mL; 95% CI -31.3 to -92.1 mL). When only studies using a laparoscopic approach for both arms were considered, no differences were observed in investigated outcomes between the two groups. CONCLUSIONS: No major differences were observed in POP outcomes between procedures with and without concomitant hysterectomy. The decision to preserve or remove the uterus should be tailored on individual factors.

A mitochondrial regulator protein, MNRR1, is elevated in the maternal blood of women with preeclampsia.

OBJECTIVE: Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative stress and an anti-angiogenic state play a crucial role. Mitochondria are a major source of cellular reactive oxygen species. Abnormalities in mitochondrial structures, proteins, and functions have been observed in the placentae of patients with preeclampsia, thus mitochondrial dysfunction has been implicated in the mechanism of the disease. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a newly characterized bi-organellar protein with pleiotropic functions. In the mitochondria, this protein regulates cytochrome c oxidase activity and reactive oxygen species production, whereas in the nucleus, it regulates the transcription of a number of genes including response to tissue hypoxia and inflammatory signals. Since MNRR1 expression changes in response to hypoxia and to an inflammatory signal, MNRR1 could be a part of mitochondrial dysfunction and involved in the pathologic process of preeclampsia. This study aimed to determine whether the plasma MNRR1 concentration of women with preeclampsia differed from that of normal pregnant women. METHODS: This retrospective case-control study included 97 women with preeclampsia, stratified by gestational age at delivery into early (<34 weeks, n = 40) and late (≥34 weeks, n = 57) preeclampsia and by the presence or absence of placental lesions consistent with maternal vascular malperfusion (MVM), the histologic counterpart of an anti-angiogenic state. Women with an uncomplicated pregnancy at various gestational ages who delivered at term served as controls (n = 80) and were further stratified into early (n = 25) and late (n = 55) controls according to gestational age at venipuncture. Maternal plasma MNRR1 concentrations were determined by an enzyme-linked immunosorbent assay. RESULTS: 1) Women with preeclampsia at the time of diagnosis (either early or late disease) had a significantly higher median (interquartile range, IQR) plasma MNRR1 concentration than the controls [early preeclampsia: 1632 (924-2926) pg/mL vs. 630 (448-4002) pg/mL, p = .026, and late preeclampsia: 1833 (1441-5534) pg/mL vs. 910 (526-6178) pg/mL, p = .021]. Among women with early preeclampsia, those with MVM lesions in the placenta had the highest median (IQR) plasma MNRR1 concentration among the three groups [with MVM: 2066 (1070-3188) pg/mL vs. without MVM: 888 (812-1781) pg/mL, p = .03; and with MVM vs. control: 630 (448-4002) pg/mL, p = .04]. There was no significant difference in the median plasma MNRR1 concentration between women with early preeclampsia without MVM lesions and those with an uncomplicated pregnancy (p = .3). By contrast, women with late preeclampsia, regardless of MVM lesions, had a significantly higher median (IQR) plasma MNRR1 concentration than women in the control group [with MVM: 1609 (1392-3135) pg/mL vs. control: 910 (526-6178), p = .045; and without MVM: 2023 (1578-8936) pg/mL vs. control, p = .01]. CONCLUSIONS: MNRR1, a mitochondrial regulator protein, is elevated in the maternal plasma of women with preeclampsia (both early and late) at the time of diagnosis. These findings may reflect some degree of mitochondrial dysfunction, intravascular inflammation, or other unknown pathologic processes that characterize this obstetrical syndrome.

Intrauterine manipulator during hysterectomy for endometrial cancer: a systematic review and meta-analysis of oncologic outcomes.

OBJECTIVE: This study aimed to assess the effects on oncologic outcomes of intrauterine manipulator use during laparoscopic hysterectomy for endometrial cancer. DATA SOURCES: A systematic literature search was performed by an expert librarian in multiple electronic databases from inception to January 31, 2023. STUDY ELIGIBILITY CRITERIA: We included all studies in the English language that compared oncologic outcomes (recurrence-free, cause-specific, or overall survival) between endometrial cancer patients who underwent total laparoscopic or robotic hysterectomy for endometrial cancer with vs without the use of an intrauterine manipulator. Studies comparing only peritoneal cytology status or lymphovascular space invasion were summarized for completeness. No selection criteria were applied to the study design. METHODS: Four reviewers independently reviewed studies for inclusion, assessed their risk of bias, and extracted data. Pooled hazard ratios with 95% confidence intervals were estimated for oncologic outcomes using the random effect model. Heterogeneity was quantified using the I2 tests. Publication bias was assessed by funnel plot and Egger test. RESULTS: Out of 350 identified references, we included 2 randomized controlled trials and 12 observational studies for a total of 14 studies and 5,019 patients. The use of an intrauterine manipulator during hysterectomy for endometrial cancer was associated with a pooled hazard ratio for recurrence of 1.52 (95% confidence interval, 0.99-2.33; P=.05; I2=31%; chi square P value=.22). Pooled hazard ratio for recurrence was 1.48 (95% confidence interval, 0.25-8.76; P=.62; I2=67%; chi square P value=.08) when only randomized controlled trials were considered. Pooled hazard ratio for overall survival was 1.07 (95% confidence interval, 0.65-1.76; P=0.79; I2=44%; chi square P value=.17). The rate of positive peritoneal cytology or lymphovascular space invasion did not differ using an intrauterine manipulator. CONCLUSION: Intrauterine manipulator use during hysterectomy for endometrial cancer was neither significantly associated with recurrence-free and overall survival nor with positive peritoneal cytology or lymphovascular space invasion, but further prospective studies are needed.

Major vessel resection for complete cytoreduction in primary advanced and recurrent ovarian malignancies: A case series and systematic review of the literature - pushing the boundaries in oncovascular surgery.

INTRODUCTION: Oncovascular surgery (the removal of major blood vessels infiltrated by cancer) is challenging but can be key to achieve complete cytoreduction in patient with advanced ovarian cancer. The aim of this study was to review the literature on oncovascular surgery in ovarian cancer and to report the details of all the cases performed at our institution. METHODS: We retrospectively reviewed the database of ovarian cancer patients who underwent debulking surgery at the Department of Obstetrics and Gynecology of Verona University between January 2021 and 2023. Patients with at least one major vessel resection during cytoreduction were identified. We then systematically review the literature searching Pubmed and Embase from inception to January 2023 to report all cases of surgery for ovarian cancer with concomitant major vessel resection. RESULTS: Five patients with advanced/recurrent ovarian cancer underwent major vascular resection at our institution. Vascular involvement was preoperatively identified in all cases and no case of vascular resection was performed after accidental injury. The major vessels removed were the inferior vena cava (n = 2), the common iliac veins (n = 2), the external iliac arteries (n = 2), the left common iliac artery (n = 1), and the left external iliac vein (n = 1). All patients underwent other non-gynecological cytoreductive procedures prior to vessel removal and had R0 obtained. Three (60%) patients experienced one or more postoperative complications. The literature search identified a total of seven cases of major vessels resection in ovarian cancer surgery. A single or multiple major vessels were removed in two (28.6%) and five (72.4%) cases, respectively. All the seven patients underwent vascular reconstruction. Four (57.1%) patients reported postoperative complications. Overall, 66.7% of the 12 total identified patients were free from disease at the last follow-up [median 15.5 months (range 5-25)]. CONCLUSIONS: Oncovascular surgery is feasible in selected patients with ovarian cancer, provided that a multidisciplinary approach with customized care is available.

COVID-19 and Pregnancy: An Updated Review about Evidence-Based Therapeutic Strategies.

The COVID-19 pandemic posed a significant challenge for clinicians in managing pregnant women, who were at high risk of virus transmission and severe illness. While the WHO declared in May 2023 that COVID-19 is no longer a public health emergency, it emphasized that it remains a global health threat. Despite the success of vaccines, the possibility of new pandemic waves due to viral mutations should be considered. Ongoing assessment of the safety and effectiveness of pharmacological therapies is crucial in clinical practice. This narrative review summarizes the evidence-based therapeutic strategies for pregnant women with COVID-19, considering over three years of pandemic experience. The review discusses the safety and effectiveness of various drug regimens (antivirals, anticoagulants, corticosteroids, immunoglobulins, monoclonal antibodies, and therapeutic gases) and procedures (prone positioning and extracorporeal membrane oxygenation). Drugs with contraindications, inefficacy during pregnancy, or unknown adverse effects were excluded from our evaluation. The aim is to provide healthcare professionals with a comprehensive guide for managing pregnant women with COVID-19 based on lessons learned from the pandemic outbreak.

The Role of Micronutrients in Human Papillomavirus Infection, Cervical Dysplasia, and Neoplasm.

There is evidence that diet and nutrition are modifiable risk factors for several cancers. In recent years, attention paid to micronutrients in gynecology has increased, especially regarding Human papillomavirus (HPV) infection. We performed a review of the literature up until December 2022, aiming to clarify the effects of micronutrients, minerals, and vitamins on the history of HPV infection and the development of cervical cancer. We included studies having as their primary objective the evaluation of dietary supplements, in particular calcium; zinc; iron; selenium; carotenoids; and vitamins A, B12, C, D, E, and K. Different oligo-elements and micronutrients demonstrated a potential protective role against cervical cancer by intervening in different stages of the natural history of HPV infection, development of cervical dysplasia, and invasive disease. Healthcare providers should be aware of and incorporate the literature evidence in counseling, although the low quality of evidence provided by available studies recommends further well-designed investigations to give clear indications for clinical practice.

Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein.

OBJECTIVE: Mitochondrial dysfunction was observed in acute systemic inflammatory conditions such as sepsis and might be involved in sepsis-induced multi-organ failure. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2), also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1), a bi-organellar protein located in the mitochondria and the nucleus, is implicated in cell respiration, survival, and response to tissue hypoxia. Recently, the reduction of the cellular CHCHD2/MNRR1 protein, as part of mitochondrial dysfunction, has been shown to play a role in the amplification of inflammatory cytokines in a murine model of lipopolysaccharide-induced systemic inflammation. The aim of this study was to determine whether the plasma concentration of CHCHD2/MNRR1 changed during human normal pregnancy, spontaneous labor at term, and clinical chorioamnionitis at term. METHODS: We conducted a cross-sectional study that included the following groups: 1) non-pregnant women (n = 17); 2) normal pregnant women at various gestational ages from the first trimester until term (n = 110); 3) women at term with spontaneous labor (n = 50); and 4) women with clinical chorioamnionitis at term in labor (n = 25). Plasma concentrations of CHCHD2/MNRR1 were assessed by an enzyme-linked immunosorbent assay. RESULTS: 1) Pregnant women at term in labor with clinical chorioamnionitis had a significantly higher plasma CHCHD2/MNRR1 concentration than those in labor without chorioamnionitis (p = .003); 2) CHCHD2/MNRR1 is present in the plasma of healthy non-pregnant and normal pregnant women without significant differences in its plasma concentrations between the two groups; 3) there was no correlation between maternal plasma CHCHD2/MNRR1 concentration and gestational age at venipuncture; and 4) plasma CHCHD2/MNRR1 concentration was not significantly different in women at term in spontaneous labor compared to those not in labor. CONCLUSIONS: CHCHD2/MNRR1 is physiologically present in the plasma of healthy non-pregnant and normal pregnant women, and its concentration does not change with gestational age and parturition at term. However, plasma CHCHD2/MNRR1 is elevated in women at term with clinical chorioamnionitis. CHCHD2/MNRR1, a novel bi-organellar protein located in the mitochondria and the nucleus, is released into maternal plasma during systemic inflammation.

Neonatal Outcomes of Water Delivery versus Land Delivery: A Retrospective Propensity Score Weighted Study.

OBJECTIVE: Recent evidence has shown that water delivery is safe for the mother, but high-quality evidence is not available for the newborn. Therefore, obstetric guidelines do not support it. This retrospective study aimed to contribute to the available evidence on maternal and neonatal outcomes associated with water delivery. STUDY DESIGN: Retrospective cohort study from prospectively collected birth registry data from 2015 to 2019. A total of 144 consecutive water deliveries and 265 land deliveries eligible for waterbirth were identified. The inverse probability of treatment weighting (IPTW) method was applied to address for confounders. RESULTS: We identified 144 women who delivered in water (water group) and 265 women who delivered on land (land group). One (0.7%) neonatal death was observed in the water delivery group. After IPTW adjustment, water delivery was significantly associated with a higher risk of maternal fever in puerperium (odds ratio [OR]: 4.98; 95% confidence interval [CI]: 1.86-17.02; p = 0.004), of neonatal cord avulsion (OR: 20.73; 95% CI: 2.63-2,674; p = 0.001), and of positive neonatal C-reactive protein (CRP > 5 mg/L; OR: 2.59; 95% CI: 1.05-7.24; p = 0.039); delivering in water was associated with lower maternal blood loss (mean difference: 110.40 mL; 95% CI: 191.01-29.78; p = 0.007), a lower risk of major (≥1,000 mL) postpartum hemorrhage (OR: 0.96; 95% CI: 0.92-0.99; p = 0.016), lower risk of manual placenta delivery (OR: 0.18; 95% CI: 0.03-0.67; p = 0.008) and curettage (OR: 0.24; 95% CI: 0.08-0.60; p = 0.002), lower use of episiotomy (OR: 0.02; 95% CI: 0-0.12; p < 0.001), and lower risk of neonatal ward admission (OR: 0.35; 95% CI: 0.25-0.48; p < 0.001). CONCLUSION: The present study showed that differences are present between water and land delivery, and among them is the risk of cord avulsion, a severe and potentially fatal event. In women choosing to deliver in water, a trained staffmust be present and immediate recognition of cord avulsion is key for a prompt management to avoid possible serious complications. KEY POINTS: · High-quality evidence is not available for neonatal safety of waterbirth; therefore, retrospective studies still represent the main body of evidence.. · Differences are present between water and land delivery, and among them, the increased risk of cord avulsion is a potentially fatal event.. · A trained staff must assist women who chose to deliver in water and cord avulsion must be promptly recognized and managed to avoid severe neonatal complications..

Meconium-stained amniotic fluid.

Green-stained amniotic fluid, often referred to as meconium-stained amniotic fluid, is present in 5% to 20% of patients in labor and is considered an obstetric hazard. The condition has been attributed to the passage of fetal colonic content (meconium), intraamniotic bleeding with the presence of heme catabolic products, or both. The frequency of green-stained amniotic fluid increases as a function of gestational age, reaching approximately 27% in post-term gestation. Green-stained amniotic fluid during labor has been associated with fetal acidemia (umbilical artery pH <7.00), neonatal respiratory distress, and seizures as well as cerebral palsy. Hypoxia is widely considered a mechanism responsible for fetal defecation and meconium-stained amniotic fluid; however, most fetuses with meconium-stained amniotic fluid do not have fetal acidemia. Intraamniotic infection/inflammation has emerged as an important factor in meconium-stained amniotic fluid in term and preterm gestations, as patients with these conditions have a higher rate of clinical chorioamnionitis and neonatal sepsis. The precise mechanisms linking intraamniotic inflammation to green-stained amniotic fluid have not been determined, but the effects of oxidative stress in heme catabolism have been implicated. Two randomized clinical trials suggest that antibiotic administration decreases the rate of clinical chorioamnionitis in patients with meconium-stained amniotic fluid. A serious complication of meconium-stained amniotic fluid is meconium aspiration syndrome. This condition develops in 5% of cases presenting with meconium-stained amniotic fluid and is a severe complication typical of term newborns. Meconium aspiration syndrome is attributed to the mechanical and chemical effects of aspirated meconium coupled with local and systemic fetal inflammation. Routine naso/oropharyngeal suctioning and tracheal intubation in cases of meconium-stained amniotic fluid have not been shown to be beneficial and are no longer recommended in obstetrical practice. A systematic review of randomized controlled trials suggested that amnioinfusion may decrease the rate of meconium aspiration syndrome. Histologic examination of the fetal membranes for meconium has been invoked in medical legal litigation to time the occurrence of fetal injury. However, inferences have been largely based on the results of in vitro experiments, and extrapolation of such findings to the clinical setting warrants caution. Fetal defecation throughout gestation appears to be a physiologic phenomenon based on ultrasound as well as in observations in animals.

Pregnancy-specific responses to COVID-19 revealed by high-throughput proteomics of human plasma.

BACKGROUND: Pregnant women are at greater risk of adverse outcomes, including mortality, as well as obstetrical complications resulting from COVID-19. However, pregnancy-specific changes that underlie such worsened outcomes remain unclear. METHODS: Plasma samples were collected from pregnant women and non-pregnant individuals (male and female) with (n = 72 pregnant, 52 non-pregnant) and without (n = 29 pregnant, 41 non-pregnant) COVID-19. COVID-19 patients were grouped as asymptomatic, mild, moderate, severe, or critically ill according to NIH classifications. Proteomic profiling of 7,288 analytes corresponding to 6,596 unique protein targets was performed using the SOMAmer platform. RESULTS: Herein, we profile the plasma proteome of pregnant and non-pregnant COVID-19 patients and controls and show alterations that display a dose-response relationship with disease severity; yet, such proteomic perturbations are dampened during pregnancy. In both pregnant and non-pregnant state, the proteome response induced by COVID-19 shows enrichment of mediators implicated in cytokine storm, endothelial dysfunction, and angiogenesis. Shared and pregnancy-specific proteomic changes are identified: pregnant women display a tailored response that may protect the conceptus from heightened inflammation, while non-pregnant individuals display a stronger response to repel infection. Furthermore, the plasma proteome can accurately identify COVID-19 patients, even when asymptomatic or with mild symptoms. CONCLUSION: This study represents the most comprehensive characterization of the plasma proteome of pregnant and non-pregnant COVID-19 patients. Our findings emphasize the distinct immune modulation between the non-pregnant and pregnant states, providing insight into the pathogenesis of COVID-19 as well as a potential explanation for the more severe outcomes observed in pregnant women.

Pregnant COVID-19 patients are at increased risk of experiencing complications and severe outcomes compared to the general population. However, the reasons for this heightened risk are still unclear. We measured the proteins present in the blood of pregnant and non-pregnant patients with COVID-19 and compared these to healthy individuals. We found that some COVID-19-associated proteins were present at lower levels in pregnant women, which could help to protect the fetus from harmful inflammation, the body's natural response to infection. While some proteins affected by COVID-19 are shared between pregnant and non-pregnant patients, others were distinctly affected only in pregnant women, providing a potential explanation for the more severe outcomes in this group.

Evidence for the participation of CHCHD2/MNRR1, a mitochondrial protein, in spontaneous labor at term and in preterm labor with intra-amniotic infection.

OBJECTIVE: Intra-amniotic inflammation (IAI), associated with either microbe (infection) or danger signals (sterile), plays a major role in the pathophysiology of preterm labor and delivery. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2) [also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1)], a mitochondrial protein involved in oxidative phosphorylation and cell survival, is capable of sensing tissue hypoxia and inflammatory signaling. The ability to maintain an appropriate energy balance at the cellular level while adapting to environmental stress is essential for the survival of an organism. Mitochondrial dysfunction has been observed in acute systemic inflammatory conditions, such as sepsis, and is proposed to be involved in sepsis-induced multi-organ failure. The purpose of this study was to determine the amniotic fluid concentrations of CHCHD2/MNRR1 in pregnant women, women at term in labor, and those in preterm labor (PTL) with and without IAI. METHODS: This cross-sectional study comprised patients allocated to the following groups: (1) mid-trimester (n = 16); (2) term in labor (n = 37); (3) term not in labor (n = 22); (4) PTL without IAI who delivered at term (n = 25); (5) PTL without IAI who delivered preterm (n = 47); and (6) PTL with IAI who delivered preterm (n = 53). Diagnosis of IAI (amniotic fluid interleukin-6 concentration ≥2.6 ng/mL) included cases associated with microbial invasion of the amniotic cavity and those of sterile nature (absence of detectable bacteria, using culture and molecular microbiology techniques). Amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations were determined with a validated and sensitive immunoassay. RESULTS: (1) CHCHD2/MNRR1 was detectable in all amniotic fluid samples and women at term without labor had a higher amniotic fluid CHCHD2/MNRR1 concentration than those in the mid-trimester (p = 0.003); (2) the amniotic fluid concentration of CHCHD2/MNRR1 in women at term in labor was higher than that in women at term without labor (p = 0.01); (3) women with PTL and IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those without IAI, either with preterm (p < 0.001) or term delivery (p = 0.01); (4) women with microbial-associated IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those with sterile IAI (p < 0.001); (5) among women with PTL and IAI, the amniotic fluid concentration of CHCHD2/MNRR1 correlated with that of interleukin-6 (Spearman's Rho = 0.7; p < 0.001); and (6) no correlation was observed between amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations among women with PTL. CONCLUSION: CHCHD2/MNRR1 is a physiological constituent of human amniotic fluid in normal pregnancy, and the amniotic concentration of this mitochondrial protein increases during pregnancy, labor at term, and preterm labor with intra-amniotic infection. Hence, CHCHD2/MNRR1 may be released into the amniotic cavity by dysfunctional mitochondria during microbial-associated IAI.

A biomarker for bacteremia in pregnant women with acute pyelonephritis: soluble suppressor of tumorigenicity 2 or sST2.

Objective: Sepsis is a leading cause of maternal death, and its diagnosis during the golden hour is critical to improve survival. Acute pyelonephritis in pregnancy is a risk factor for obstetrical and medical complications, and it is a major cause of sepsis, as bacteremia complicates 15-20% of pyelonephritis episodes in pregnancy. The diagnosis of bacteremia currently relies on blood cultures, whereas a rapid test could allow timely management and improved outcomes. Soluble suppression of tumorigenicity 2 (sST2) was previously proposed as a biomarker for sepsis in non-pregnant adults and children. This study was designed to determine whether maternal plasma concentrations of sST2 in pregnant patients with pyelonephritis can help to identify those at risk for bacteremia.Study design: This cross-sectional study included women with normal pregnancy (n = 131) and pregnant women with acute pyelonephritis (n = 36). Acute pyelonephritis was diagnosed based on a combination of clinical findings and a positive urine culture. Patients were further classified according to the results of blood cultures into those with and without bacteremia. Plasma concentrations of sST2 were determined by a sensitive immunoassay. Non-parametric statistics were used for analysis.Results: The maternal plasma sST2 concentration increased with gestational age in normal pregnancies. Pregnant patients with acute pyelonephritis had a higher median (interquartile range) plasma sST2 concentration than those with a normal pregnancy [85 (47-239) ng/mL vs. 31 (14-52) ng/mL, p < .001]. Among patients with pyelonephritis, those with a positive blood culture had a median plasma concentration of sST2 higher than that of patients with a negative blood culture [258 (IQR: 75-305) ng/mL vs. 83 (IQR: 46-153) ng/mL; p = .03]. An elevated plasma concentration of sST2 ≥ 215 ng/mL had a sensitivity of 73% and a specificity of 95% (area under the receiver operating characteristic curve, 0.74; p = .003) with a positive likelihood ratio of 13.8 and a negative likelihood ratio of 0.3 for the identification of patients who had a positive blood culture.Conclusion: sST2 is a candidate biomarker to identify bacteremia in pregnant women with pyelonephritis. Rapid identification of these patients may optimize patient care.

Proteomic profile of extracellular vesicles in maternal plasma of women with fetal death.

OBJECTIVES: Fetal death is a complication of pregnancy caused by multiple etiologies rather than being the end-result of a single disease process. Many soluble analytes in the maternal circulation, such as hormones and cytokines, have been implicated in its pathophysiology. However, changes in the protein content of extracellular vesicles (EVs), which could provide additional insight into the disease pathways of this obstetrical syndrome, have not been examined. This study aimed to characterize the proteomic profile of EVs in the plasma of pregnant women who experienced fetal death and to evaluate whether such a profile reflected the pathophysiological mechanisms of this obstetrical complication. Moreover, the proteomic results were compared to and integrated with those obtained from the soluble fraction of maternal plasma. METHODS: This retrospective case-control study included 47 women who experienced fetal death and 94 matched, healthy, pregnant controls. Proteomic analysis of 82 proteins in the EVs and the soluble fractions of maternal plasma samples was conducted by using a bead-based, multiplexed immunoassay platform. Quantile regression analysis and random forest models were implemented to assess differences in the concentration of proteins in the EV and soluble fractions and to evaluate their combined discriminatory power between clinical groups. Hierarchical cluster analysis was applied to identify subgroups of fetal death cases with similar proteomic profiles. A p-value of <.05 was used to infer significance, unless multiple testing was involved, with the false discovery rate controlled at the 10% level (q < 0.1). All statistical analyses were performed by using the R statistical language and environment-and specialized packages. RESULTS: Nineteen proteins (placental growth factor, macrophage migration inhibitory factor, endoglin, regulated upon activation normal T cell expressed and presumably secreted (RANTES), interleukin (IL)-6, macrophage inflammatory protein 1-alpha, urokinase plasminogen activator surface receptor, tissue factor pathway inhibitor, IL-8, E-Selectin, vascular endothelial growth factor receptor 2, pentraxin 3, IL-16, galectin-1, monocyte chemotactic protein 1, disintegrin and metalloproteinase domain-containing protein 12, insulin-like growth factor-binding protein 1, matrix metalloproteinase-1(MMP1), and CD163) were found to have different plasma concentrations (of an EV or a soluble fraction) in women with fetal death compared to controls. There was a similar pattern of change for the dysregulated proteins in the EV and soluble fractions and a positive correlation between the log2-fold changes of proteins significant in either the EV or the soluble fraction (ρ = 0.89, p < .001). The combination of EV and soluble fraction proteins resulted in a good discriminatory model (area under the ROC curve, 82%; sensitivity, 57.5% at a 10% false-positive rate). Unsupervised clustering based on the proteins differentially expressed in either the EV or the soluble fraction of patients with fetal death relative to controls revealed three major clusters of patients. CONCLUSION: Pregnant women with fetal death have different concentrations of 19 proteins in the EV and soluble fractions compared to controls, and the direction of changes in concentration was similar between fractions. The combination of EV and soluble protein concentrations revealed three different clusters of fetal death cases with distinct clinical and placental histopathological characteristics.

Acute pyelonephritis in pregnancy and plasma syndecan-1: evidence of glycocalyx involvement.

BACKGROUND: Acute pyelonephritis, a risk factor for maternal sepsis, adult respiratory distress syndrome, and preterm labor, is a frequent cause of hospitalization. This condition is characterized by excessive intravascular inflammation and endothelial cell activation and dysfunction. Syndecan-1, a major component of the glycocalyx, is a gel-like layer that covers the luminal surface of healthy endothelial cells, preserving and mediating many endothelial functions. During pregnancy, there is an additional potential source of syndecan-1, the "syncytiotrophoblast glycocalyx," which lines the intervillous space. Insults that damage the glycocalyx lead to a shedding of syndecan-1 into the circulation. Hence, syndecan-1 has been proposed as a marker of endothelial injury in conditions such as sepsis, trauma, cardiovascular disease, and diabetes mellitus. OBJECTIVE: The objective of this study was to determine whether the plasma syndecan-1 concentration changes in women with acute pyelonephritis in the presence or absence of bacteremia. STUDY DESIGN: This cross-sectional study included three groups: (1) non-pregnant women (n = 25); (2) women with an uncomplicated pregnancy from whom samples were collected preterm (n = 61) or at term (n = 69); and (3) pregnant women diagnosed with acute pyelonephritis from whom samples were collected at the time of diagnosis during the second and third trimesters (n = 33). The diagnosis of acute pyelonephritis was based on clinical findings and a positive urine culture for bacteria. Blood culture results were available in 85% (28/33) of women with acute pyelonephritis. Plasma concentrations of syndecan-1 were determined by a validated immunoassay. RESULTS: (1) Women with an uncomplicated pregnancy had a higher plasma concentration of syndecan-1 than non-pregnant women. The geometric mean (95% confidence interval [CI]) of syndecan-1 concentration was 51.0 (12.1-216.1) ng/mL in non-pregnant controls; 1280 (365-4487) ng/mL in normal preterm gestations; and 1786 (546-5834) ng/mL in normal term gestations (adjusted p < .005 for all three between group comparisons); (2) plasma syndecan-1 concentrations increased with gestational age among women with a normal pregnancy (p < .001, R2 = 0.27); (3) syndecan-1 multiple of the mean (MoM) values in pregnant patients with acute pyelonephritis were higher than those in normal pregnant women based on second- and third-trimester samples (p = .048, 1.26-fold change). The increase was driven primarily by cases with a positive blood culture (p = .009, 1.74-fold change); (4) when data from third-trimester samples were compared, overall differences in syndecan-1 MoM values between cases and controls were slightly larger (p = .03, 1.36- fold change), which were especially contributed to by cases with a positive blood culture (p = .023, fold change 1.79-fold change). CONCLUSIONS: Plasma syndecan-1 concentration is higher in pregnant women and increases as a function of gestational age. Patients with acute pyelonephritis have a higher plasma concentration of syndecan-1, and this is particularly the case in the presence of bacteremia.

Maternal plasma syndecan-1: a biomarker for fetal growth restriction.

OBJECTIVE: The identification of fetal growth disorders is an important clinical priority given that they increase the risk of perinatal morbidity and mortality as well as long-term diseases. A subset of small-for-gestational-age (SGA) infants are growth-restricted, and this condition is often attributed to placental insufficiency. Syndecan-1, a product of the degradation of the endothelial glycocalyx, has been proposed as a biomarker of endothelial damage in different pathologies. During pregnancy, a "specialized" form of the glycocalyx-the "syncytiotrophoblast glycocalyx"-covers the placental villi. The purpose of this study was to determine whether the concentration of maternal plasma syndecan-1 can be proposed as a biomarker for fetal growth restriction. STUDY DESIGN: A cross-sectional study was designed to include women with normal pregnancy (n = 130) and pregnant women who delivered an SGA neonate (n = 50). Doppler velocimetry of the uterine and umbilical arteries was performed in women with an SGA fetus at the time of diagnosis. Venipuncture was performed within 48 h of Doppler velocimetry and plasma concentrations of syndecan-1 were determined by a specific and sensitive immunoassay. RESULTS: (1) Plasma syndecan-1 concentration followed a nonlinear increase with gestational age in uncomplicated pregnancies (R2 = 0.27, p < .001); (2) women with a pregnancy complicated with an SGA fetus had a significantly lower mean plasma concentration of syndecan-1 than those with an appropriate-for-gestational-age fetus (p = .0001); (3) this difference can be attributed to fetal growth restriction, as the mean plasma syndecan-1 concentration was significantly lower only in the group of women with an SGA fetus who had abnormal umbilical and uterine artery Doppler velocimetry compared to controls (p = .00071; adjusted p = .0028). A trend toward lower syndecan-1 concentrations was also noted for SGA with abnormal uterine but normal umbilical artery Doppler velocimetry (p = .0505; adjusted p = .067); 4) among women with an SGA fetus, those with abnormal umbilical and uterine artery Doppler findings had a lower mean plasma syndecan-1 concentration than women with normal Doppler velocimetry (p = .02; adjusted p = .04); 5) an inverse relationship was found between the maternal plasma syndecan-1 concentration and the umbilical artery pulsatility index (r = -0.5; p = .003); and 6) a plasma syndecan-1 concentration ≤ 850 ng/mL had a positive likelihood ratio of 4.4 and a negative likelihood ratio of 0.24 for the identification of a mother with an SGA fetus who had abnormal umbilical artery Doppler velocimetry (area under the ROC curve 0.83; p < .001). CONCLUSION: Low maternal plasma syndecan-1 may reflect placental diseases and this protein could be a biomarker for fetal growth restriction. However, as a sole biomarker for this condition, its accuracy is low.

Effects of neuraxial analgesia technique on labor and maternal-fetal outcomes: a retrospective study.

PURPOSE: To compare the effects of epidural analgesia (EA) and combined spinal epidural analgesia (SEA) on labor and maternal-fetal outcomes. METHODS: We retrospectively identified and included 1499 patients with a single cephalic fetus who delivered at the study center from January 2015 to December 2018 and received neuraxial analgesia at the beginning of the active phase of labor (presence of regular painful contractions and cervical dilatation between 4 and 6 cm). Data including analgesia, labor characteristics, and maternal-fetal outcomes were retrieved from the prospectively collected delivery room database and medical records. RESULTS: SEA was associated with a shorter first stage of labor than EA, with a median difference of 60 min. On multivariable ordinal logistic regression analysis, neuraxial analgesia, gestational age, fetal weight, labor induction, and parity were independently associated with the first stage length: patients in the EA group were 1.32 times more likely to have a longer first stage of labor (95% CI 1.06-1.64, p = 0.012) than those in the SEA group. Additionally, a significantly lower incidence of fundal pressure was performed among patients who underwent SEA (OR 0.55, 95% CI 0.34-0.9, p = 0.017). No associations were observed between the used neuraxial analgesia technique and other outcomes. CONCLUSIONS: SEA was associated with a shorter length of the first stage of labor and a lower rate of fundal pressure use than EA. Further studies confirming the effects of SEA on labor management and clarifying differences in maternal-fetal outcomes will allow concluding about the superiority of one technique upon the other.

Maternal plasma cytokines and the subsequent risk of uterine atony and postpartum hemorrhage.

OBJECTIVES: To determine whether the maternal plasma concentrations of cytokines are higher in pregnant women with postpartum hemorrhage (PPH) compared to pregnant women without PPH. METHODS: A retrospective case-control study included 36 women with PPH and 72 matched controls. Cases and controls were matched for gestational age at delivery, labor status, delivery route, parity, and year of sample collection. Maternal plasma samples were collected up to 3 days prior to delivery. Comparison of the plasma concentrations of 29 cytokines was performed by using linear mixed-effects models and included adjustment for covariates and multiple testing. A false discovery rate adjusted p-value <0.1 was used to infer significance. Random forest models with evaluation by leave-one-out and 9-fold cross-validation were used to assess the combined value of the proteins in predicting PPH. RESULTS: Concentrations of interleukin (IL)-16, IL-6, IL-12/IL-23p40, monocyte chemotactic protein 1 (MCP-1), and IL-1ß were significantly higher in PPH than in the control group. This difference remained significant after adjustment for maternal age, clinical chorioamnionitis, and preeclampsia. Multi-protein random forest proteomics models had moderate cross-validated accuracy for prediction of PPH [area under the ROC curve, 0.69 (0.58-0.81) by leave-one-out cross validation and 0.73 (0.65-0.81) by 9-fold cross-validation], and the inclusion of clinical and demographic information did not increase the prediction performance. CONCLUSIONS: Pregnant women with severe PPH had higher median maternal plasma concentrations of IL-16, IL-6, IL-12/IL-23p40, MCP-1, and IL-1ß than patients without PPH. These cytokines could serve as biomarkers or their pathways may be therapeutic targets.

Effects of transdermal versus oral hormone replacement therapy in postmenopause: a systematic review.

PURPOSE: To summarize available evidence comparing the transdermal and the oral administration routes of hormone replacement therapy (HRT) in postmenopausal women. METHODS: We performed a systematic review of the literature on multiple databases between January 1990 and December 2021. We included randomized controlled trials and observational studies comparing the transdermal and oral administration routes of estrogens for HRT in postmenopausal women regarding at least one of the outcomes of interest: cardiovascular risk, venous thromboembolism (VTE), lipid metabolism, carbohydrate metabolism, bone mineral density (BMD), and risk of pre-malignant and malignant endometrial lesions, or breast cancer. RESULTS: The systematic literature search identified a total of 1369 manuscripts, of which 51 were included. Most studies were observational and of good quality, whereas the majority of randomized controlled trials presented a high or medium risk of bias. Oral and transdermal administration routes are similar regarding BMD, glucose metabolism, and lipid profile improvements, as well as do not appear different regarding breast cancer, endometrial disease, and cardiovascular risk. Identified literature provides clear evidence only for the VTE risk, which is higher with the oral administration route. CONCLUSIONS: Available evidence comparing the transdermal and oral administration routes for HRT is limited and of low quality, recommending further investigations. VTE risk can be considered the clearest and strongest clinical difference between the two administration routes, supporting the transdermal HRT as safer than the oral administration route.