Calcineurin inhibitors in the management of recurrent miscarriage and recurrent implantation failure: Systematic review and meta-analysis.

Recurrent miscarriage (RM) affects up to 2.5% of couples of reproductive age. Up to 10% of couples using assisted reproductive technology experience recurrent implantation failure (RIF). Immunosuppressive drugs, such as calcineurin inhibitors (CNIs), has been proposed for RM and RIF management. This systematic review and meta-analysis (SRMA) aimed to evaluate the efficacy and safety of CNIs in RM and RIF treatment. We searched in the three databases. Review Manager 5.4.1 was used for statistical analysis. This review included 8 studies involving 1042 women (485 women in the CNIs group and 557 women in the control group). CNI treatment (cyclosporine [CsA] and tacrolimus [TAC]) increases live birth rate (LBR, odds ratio [OR]: 2.52; 95% confidence interval [CI]: 1.93-3.28, p < 0.00001) and clinical pregnancy rate (OR: 2.25; 95% CI: 1.54-4.40, p < 0.0001) and decreases miscarriage rate (OR: 0.45 95% CI: 0.32-0.63, p < 0.00001) when compared to the control. Side effects and obstetric and neonatal complications was similar in both groups. In conclusion, CNIs increased LBR in women with RM and RIF but there is a moderate risk of bias. Subgroup analysis revealed that CNIs improved LBR in women with RM with a low risk of bias. However, in women with RIF, with moderate to high risk of bias. The use of CsA and TAC, in low doses and for a short period, for managing reproductive failures in women seems to be safe, not causing serious side effects nor increasing the risk of obstetric and neonatal complications.

Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system.

Currently, obesity is considered a global public health problem. It is the main risk factor for noncommunicable diseases and reproductive complications, such as recurrent miscarriage (RM). RM affects approximately 1% of couples of reproductive age, and recent studies suggest that its prevalence is increasing. Immunological abnormalities may be responsible for a significant number of cases of unexplained RM. Obesity is recognized as a chronic low-grade inflammatory condition. The accumulation of fat in obese adipose tissue promotes changes in the local and systemic immune response. Adipokines, exosomes, micro-RNAs, lipids, and other factors released or secreted by adipose tissue are responsible for the interconnection between obesity and the immune system. Obesity-induced dysregulation of the innate and acquired immune response is also involved in the immunopathology of pregnancy loss in patients with unexplained RM. Therefore, understanding the communication pathways between maternal adipose tissue and the immune response in women living with obesity and RM is an important objective. Thus, diagnostic tools and new immunomodulatory therapies may be proposed for the management of patients with concurrent obesity and RM.

The use of immunotherapies for recurrent miscarriage: An overview of systematic reviews and meta-analysis.

Immunotherapies have been a treatment proposed for recurrent miscarriages (RMs). The use of immunotherapies remains not recommended in the management of couples with RM. This overview of systematic reviews and meta-analysis (SRs-MAs) aims to identify and evaluate the quality of SRs-MAs that studied the effectiveness of immunotherapies in the treatment of RM patients. SRs-MAs were searched in PubMed/Medline, Embase, and Web of Science. SRs-MAs were analyzed using AMSTAR-2, PRISMA 2020, Risk of Bias in Systematic (ROBIS), and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools to evaluate the methodological quality, reporting quality, risk of bias, and evidence quality of included SRs-MAs, respectively. This review included 20 SRs-MAs that evaluated the following immunotherapies: intravenous immunoglobulin (13 publications), lymphocyte immunotherapy (6 publications), corticosteroids (3 publications), and lipid emulsion (1 publication). SRs-MAs were rated as high methodological, moderate, and critically low quality in 14 (70 %), 1 (5 %), and 5 (25 %) SRs-MAs and high reporting, moderate, and low quality in 13 (65 %), 4 (20 %), and 3 (5 %) SRs-MAs, respectively. The overall risk of bias revealed a low risk of bias for three-quarters of the SRs-MAs. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) analysis resulted in 23 outcomes, of which 4, 3, 5, and 11 results were of high, moderate, low, and very low quality, respectively. An improvement has been observed over the past few years in the quality of systematic reviews (SR)-MAs that have investigated the efficacy of intravenous immunoglobulin, lymphocyte immunotherapy, lipid emulsion therapy, and corticosteroids as a therapy for RM.

Self-made transvaginal ultrasound simulator: new training equipment in ultrasound evaluation of controlled ovarian stimulation and oocyte retrieval.

Aim: We sought to create and describe a self-made simulator designed and created for teaching purposes: a high-fidelity ultrasound phantom for demonstrating antral follicle count, ultrasound supervision of controlled of ovarian stimulation, and ultrasound-guided oocyte retrieval. Materials and methods: The uterus and ovaries of the ultrasound phantom were made from beef tongue, a male condom, latex gloves, cotton suture threads, bi-distilled water, and ultrasound gel. The components were placed in a pelvis created using three-dimensional (3D) printing. The phantom was presented to and evaluated by a group of 14 physicians pursuing a postgraduate course in reproductive medicine. Two training stations were structured: one to simulate antral follicle count and controlled ovarian stimulation and the other to simulate ultrasound-guided oocyte retrieval. Future specialists were requested to complete a feedback questionnaire evaluating the self-made simulator and the two practice stations. Results: The transvaginal ultrasound phantom was successfully created, making it possible to simulate antral follicle count, ultrasound control of ovarian hyperstimulation, and oocyte retrieval, and to capture ultrasound images. A review of the answers provided in the feedback questionnaire showed that the phantom had a good appearance and design, was realistic, helped to improve motor coordination, and could be a useful tool in the training of specialists in assisted reproduction. Conclusion: This phantom was designed to enable instruction and practice in the evaluation of ovarian follicles and ultrasound-guided oocyte retrieval in a supervised training environment. This self-made simulator is proposed as a training tool that could be included in the curricular structure of residency and postgraduate programs in reproductive medicine.

Screening for coronavirus disease 2019 in pregnant women admitted for delivery: an observational study.

OBJECTIVE: The aim of this study was to examine the impact of symptom-based screening on the prevalence and outcomes of neonatal coronavirus disease 2019 in pregnant women admitted for delivery. METHODS: A retrospective observational study was conducted from June to August 2020 at Gonzaga Mota of Messejana Hospital, Fortaleza, CE, Brazil. All pregnant women were screened for coronavirus disease 2019 based on symptoms. Reverse transcription-polymerase chain reaction or immunology assays for severe acute respiratory syndrome coronavirus 2 were performed when a patient reported a symptom. All newborns of symptomatic patients were submitted for Reverse transcription-polymerase chain reaction. Newborns were divided into groups according to the Reverse transcription-polymerase chain reaction results to identify the relationship between maternal symptoms and neonatal coronavirus disease 2019. RESULTS: A total of 55 (55/1,026, 5.4%) and 50 (50/1,026, 4.8%) pregnant women reported symptoms and had a positive confirmatory test, respectively. The most common symptom of coronavirus disease 2019 among the pregnant women with positive confirmatory test was cough (n=23, 46%). Seven newborns (7/50, 14%) of symptomatic mothers had positive Reverse transcription-polymerase chain reaction. Upon birth, no newborn had serious complications. CONCLUSION: Universal screening of pregnant women admitted for delivery can reduce the perinatal transmission of coronavirus disease 2019. Symptom-based screening can be an alternative for regions with a low prevalence of the disease where a better allocation of financial resources is necessary.

Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: a systematic review and meta-analysis.

Dysregulated natural killer (NK) cells have been associated with recurrent miscarriages (RM). Studies have suggested that high peripheral blood NK cell cytotoxicities (pNKCs) are associated with an increased risk of RM. The aim of this systematic review (SR) and meta-analysis (MAs) is to investigate the difference in pNKC between nonpregnant and pregnant women with RM and controls and determine whether pNKC is reduced by immunotherapy. We searched the PubMed/Medline, Embase, and Web of Science databases. The MAs were conducted to compare pNKCs between women with and without RM before and during pregnancy as well as pre- and post-immunotherapy. Risk of bias in nonrandomized studies was assessed by the Newcastle-Ottawa Scale. Statistical analysis was performed using the Review Manager software. A total of 19 studies were included in the SR and 14 studies in the MAs. The MAs revealed higher pNKCs among nonpregnant women with RM compared to controls (MD, 7.99 95 %CI 6.40-9.58; p < 0.00001). pNKCs were also higher in pregnant women with RM than in pregnant controls (MD, 8.21 95 %CI 6.08-10.34; p < 0.00001). Women with RM showed significantly decreased pNKCs after the immunotherapy compared to before (MD, -8.20 95 %CI -10.20 - -6.19; p < 0, 00001). Additionally, there is an association between high pNKCs and the risk of pregnancy loss in women with RM. However, included studies showed substantial heterogeneities regarding the inclusion criteria of patients, techniques measuring pNKC, and types of immunotherapies. More studies are needed to evaluate the clinical efficiency of pNKCs in managing RM.

Kisspeptin as a predictor of miscarriage: a systematic review.

OBJECTIVE: A highly accurate serum marker for predicting viable pregnancy needs to be developed. Recent studies have demonstrated that kisspeptin is a potential biomarker for this purpose. METHODS: This systematic review evaluated the available data in the literature on the role of kisspeptin as a miscarriage biomarker. A literature search was conducted in the PubMed/Medline, Embase, Web of Science, and Scopus databases using the following keywords: (kisspeptin) AND (miscarriage OR pregnancy loss OR spontaneous abortion OR reproductive failure). RESULTS: Seven case-control studies were selected for the systematic review. The included papers described the potential role of kisspeptin as a putative biomarker of pregnancy loss. Furthermore, two studies reported that changes in kisspeptin levels may be associated with unexplained infertility and low rates of embryo implantation in women undergoing assisted reproductive technology. CONCLUSION: Kisspeptin might be used as a potential biomarker of pregnancy viability in the near future. However, studies with better evidence are needed to establish the applicability of kisspeptin as a diagnostic and prognostic tool.

Ovarian aging in humans: potential strategies for extending reproductive lifespan.

Ovarian reserve is a term used to estimate the total number of immature follicles present in the ovaries. Between birth and menopause, there is a progressive decrease in the number of ovarian follicles. Ovarian aging is a continuous physiological phenomenon, with menopause being the clinical mark of the end of ovarian function. Genetics, measured as family history for age at the onset of menopause, is the main determinant. However, physical activity, diet, and lifestyle are important factors that can influence the age of menopause. The low estrogen levels after natural or premature menopause increased the risk for several diseases, resulting in increased mortality risk. Besides that, the decreasing ovarian reserve is associated to reduced fertility. In women with infertility undergoing in vitro fertilization, reduced markers of ovarian reserve, including antral follicular count and anti-Mullerian hormone, are the main indicators of reduced chances of becoming pregnant. Therefore, it becomes clear that the ovarian reserve has a central role in women's life, affecting fertility early in life and overall health later in life. Based on this, the ideal strategy for delaying ovarian aging should have the following characteristics: (1) be initiated in the presence of good ovarian reserve; (2) maintained for a long period; (3) have an action on the dynamics of primordial follicles, controlling the rate of activation and atresia; and (4) safe use in pre-conception, pregnancy, and lactation. In this review, we therefore discuss some of these strategies and its feasibility for preventing a decline in the ovarian reserve.

Screening for coronavirus disease 2019 in pregnant women admitted for delivery: an observational study

SUMMARY OBJECTIVE: The aim of this study was to examine the impact of symptom-based screening on the prevalence and outcomes of neonatal coronavirus disease 2019 in pregnant women admitted for delivery. METHODS: A retrospective observational study was conducted from June to August 2020 at Gonzaga Mota of Messejana Hospital, Fortaleza, CE, Brazil. All pregnant women were screened for coronavirus disease 2019 based on symptoms. Reverse transcription-polymerase chain reaction or immunology assays for severe acute respiratory syndrome coronavirus 2 were performed when a patient reported a symptom. All newborns of symptomatic patients were submitted for Reverse transcription-polymerase chain reaction. Newborns were divided into groups according to the Reverse transcription-polymerase chain reaction results to identify the relationship between maternal symptoms and neonatal coronavirus disease 2019. RESULTS: A total of 55 (55/1,026, 5.4%) and 50 (50/1,026, 4.8%) pregnant women reported symptoms and had a positive confirmatory test, respectively. The most common symptom of coronavirus disease 2019 among the pregnant women with positive confirmatory test was cough (n=23, 46%). Seven newborns (7/50, 14%) of symptomatic mothers had positive Reverse transcription-polymerase chain reaction. Upon birth, no newborn had serious complications. CONCLUSION: Universal screening of pregnant women admitted for delivery can reduce the perinatal transmission of coronavirus disease 2019. Symptom-based screening can be an alternative for regions with a low prevalence of the disease where a better allocation of financial resources is necessary.

The Dietary Inflammatory Index as a predictor of pregnancy outcomes: Systematic review and meta-analysis.

Unhealthy diets have been linked to low-grade chronic inflammation, a condition known to play a role in the pathophysiology of non-communicable diseases as well as pregnancy complications. The Dietary Inflammatory Index (DII) is a tool for evaluating the inflammatory potential of various diets. The goal of this systematic review and meta-analysis is to assess the current state of evidence on the use of DII as a predictor of pregnancy outcomes in pregnant women. This study was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PROSPERO, number CRD42021288966). DII was evaluated as a predictor of obstetric complications in observational studies. The search was conducted in PubMed/Medline, Embase, and Web of Science. Data from eligible studies were extracted independently by two reviewers. The Newcastle-Ottawa Scale was used to assess the methodological quality of the studies. A total of eight studies were eligible for the review. In a meta-analysis of continuous and categorical variables, DII was a predictor of any obstetric complications [mean difference: 0.39, 95 %CI 0.02-0.75, (p = 0.04); and odds ratio: 1.24, 95 %CI 1.11-1.40, (p = 0.0002)]. High DII was associated with pregnancy complications, particularly preeclampsia/hypertensive disorder of pregnancy and preterm birth. The DII is a tool that can assist in the food and therapeutic planning of pregnant women with obstetric risks. Well-designed clinical trials are necessary, especially studies that focus on recurrent pregnancy losses and implantation failures.

Extracorporeal membrane oxygenation support in children with severe coronavirus disease-2019: A case series.

Background: The coronavirus disease-2019 (COVID-19) pandemic has predominantly affected the adult population, but with a significantly lower prevalence in children. Most pediatric patients with COVID-19 have mild course; however, a small number progressed to acute respiratory distress syndrome, hypoxemia, despite optimized conventional therapies. Thus, this study aimed to report a series of six cases of children with severe acute respiratory syndrome coronavirus 2 infection who were supported by extracorporeal membrane oxygenation (ECMO) due to refractory hypoxemic respiratory failure. Methods: This observational, retrospective, and descriptive study reported a series of cases. Data were retrospectively collected from the medical records of patients who were admitted to the Pediatric Cardiologic Intensive Care of Hospital Dr. Carlos Alberto Studart Gomes and Hospital Regional da Unimed, between March 1, 2020, and June 30, 2021. Sociodemographic, clinical, and laboratory data were analyzed. Findings: The median age was 1.8 years (range: 0.4-14.5 years), 66.7% were males, and weight varied from 13 to 110 kg. The mean time between the onset of symptoms and cannulation, ECMO duration, and ventilation time were 15 days (range: 6-24 days)], 11 days (range: 6-19 days), and 20.5 days (range: 14-33 days), respectively. Five (83.3%) children were successfully decannulated and four survived with hospital discharge. One child died on ECMO support due to multiple organ dysfunction syndromes after 13 days and another one died 3 days after decannulation due to extensive hemorrhagic stroke. Our case series revealed a 33.3% in-hospital mortality rate. ECMO appears as a viable intervention in selected patients who failed conventional therapies in the pediatric population. Funding: This observational study received no funding.

Biomarkers of acute kidney injury in pediatric cardiac surgery.

Acute kidney injury (AKI) is characterized by a sudden decrease in kidney function. Children with congenital heart disease are a special group at risk of developing AKI. We performed a systematic review of the literature to search for studies reporting the usefulness of novel urine, serum, and plasma biomarkers in the diagnosis and progression of AKI and their association with clinical outcomes in children undergoing pediatric cardiac surgery. In thirty studies, we analyzed the capacity to predict AKI and poor outcomes of five biomarkers: Cystatin C, Neutrophil gelatinase-associated lipocalin, Interleukin-18, Kidney injury molecule-1, and Liver fatty acid-binding protein. In conclusion, we suggest the need for further meta-analyses with the availability of additional studies.

COVID-19 and miscarriage: From immunopathological mechanisms to actual clinical evidence.

The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the first half of pregnancy and pregnancy loss is still unknown. Infections by other coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), appear to increase the risk of miscarriage. The purpose of this study is to assess whether SARS-CoV-2 infection increases the risk of miscarriage. Firstly, a narrative review of the literature on animal and human studies was performed to analyze the immunopathological mechanisms of SARS-CoV-2 infection during preconception and early pregnancy, by which it may increase the risk of miscarriage. Secondly, a systematic review/meta-analysis of studies was conducted to assess the prevalence of miscarriage in COVID-19 patients diagnosed during pregnancy. Meta-analysis of proportions was used to combine data, and pooled proportions were reported. Seventeen case series and observational studies and 10 prevalence meta-analyses were selected for the review. The estimate of the overall miscarriage rate in pregnant women with COVID-19 was 15.3 % (95 % CI 10.94-20.59) and 23.1 (95 % CI 13.17-34.95) using fixed and random effect models, respectively. Based on the data in the current literature, the miscarriage rate (<22 weeks gestation) in women with SARS-CoV-2 infection is in the range of normal population. Well-designed studies are urgently needed to determine whether SARS-CoV-2 infection increases the risk of miscarriage during periconception and early pregnancy.