Investigating the Association of Assisted Reproduction Techniques and Adverse Perinatal Outcomes.

BACKGROUND: Infertility affects about 80 million individuals worldwide and 10-15% of couples at reproductive age will seek medical assistance. There is increasing evidence that pregnancies after Assisted Reproduction Techniques (ART) are associated with pre-term birth, low birthweight, congenital defects, and increased mortality rates. The aim of this review is to assess all the published literature and provide an updated review on the effect of assisted conception and perinatal and neonatal outcomes. METHODS: Comprehensive research on Pubmed/Medline, Scopus, and Google scholar electronic databases was conducted from July 2023 up to September 2023, using the terms assisted reproductive techniques, ART, in vitro fertilization, IVF, intracytoplasmic sperm injection, ICSI, preterm birth, PTB, low birth weight, LBW, chromosomal defects, congenital defects, and hypospadias. In total, 87 full text articles were retrieved and after a careful evaluation, 31 studies were selected for data extraction. RESULTS: Our review demonstrated a higher risk of congenital and chromosomal defects, and a higher incidence of male genital tract defects and heart defects in ART pregnancies. Regarding pre-term birth, our results were contradictory. CONCLUSIONS: Although assisted reproduction techniques are associated with increased risks, they are safe regarding perinatal outcomes and couples should not be discouraged from utilizing them. Our results aim to alert clinicians to these specific outcomes and offer more personalized care and counseling to infertile couples and their children.

The Contribution of Proteomics in Understanding Endometrial Protein Expression in Women with Recurrent Implantation Failure.

Recurrent implantation failure (RIF) poses a significant challenge in assisted reproductive technology (ART) outcomes. The endometrium plays a crucial role in embryo implantation, and its protein expression profile is integral in determining receptivity. Proteomics has emerged as a valuable tool in unraveling the molecular intricacies underlying endometrial receptivity and RIF. The aim of the present review is to analyze the contribution of proteomics to the understanding of endometrial protein expression in women with RIF, based on the results of significant proteomic studies. Medline/Pubmed databases were searched using keywords pertaining to proteomics combined with terms related to RIF. 15 studies were included in the present review. Several proteins have been found to exbibit differential expression in endometrial biopsies and fluid samples between fertile women and women with RIF during the receptive endometrial phase. The profile of endometrial proteins varied significantly among the studies. Nevertheless, similar changes in the expression levels of annexin-6, progesterone receptor, MMP-2, and MMP-9 in the endometrium of women with RIF, were found in more than one study indicating that certain proteins could potentially be effective biomarkers of endometrial receptivity. Proteomics contributes significantly to the understanding of protein expression in the endometrium of women with RIF and the analysis of proteins in endometrial fluid are promising for improving the clinical management of RIF.

Association between cytokine polymorphisms and recurrent pregnancy loss: A review of current evidence.

Cytokines are a type of protein that play an important role in the immune response and can also affect many physiological processes in the body. Cytokine polymorphisms refer to genetic variations or mutations that occur within the genes that code for cytokines, which may affect the level of cytokine production and function. Some cytokine polymorphisms have been associated with an increased risk of developing certain diseases, while others may be protective or have no significant effect on health. In recent years, the role of cytokine polymorphisms in the development of recurrent pregnancy loss (RPL) has been studied. RPL or miscarriage is defined as the occurrence of two or more consecutive pregnancy losses before the 20th week of gestation. There are diverse causes leading to RPL, including genetic, anatomical, hormonal, and immunological factors. With regard to cytokine polymorphisms, a few of them have been found to be associated with an increased risk of RPL, for instance, variations in the genes that code for interleukin-6, tumor necrosis factor-alpha, and interleukin-10. The exact mechanisms by which cytokine polymorphisms affect the risk of recurrent miscarriage are still being studied, and further research is essential to fully understand this complex condition. This brief review aims to summarize the recent literature on the association between cytokine polymorphisms and RPL.

The Expression of microRNAs and Their Involvement in Recurrent Pregnancy Loss.

Background: Recurrent pregnancy loss refers to the spontaneous demise of two or more pregnancies before the 24 weeks of gestation. In almost half of the cases of recurrent miscarriages, the causes remain unknown since there is no reliable way of prognosis, early diagnosis, or treatment. Recent research has detected differential expression of certain miRNAs in reproductive system pathologies. Methods: The aim of the present review is to focus on microRNAs and their relationship with idiopathic recurrent miscarriages and to correlate miRNA expression with recurrent miscarriage and examine their potential role as biomarkers. Pubmed/Medline and Scopus databases were searched up to 31st January 2024 with terms related to recurrent pregnancy loss and miRNAs. Results: In total, 21 studies were selected for the review. A total of 75 different miRNAs were identified, showing a statistically significant differential expression. Around 40 miRNAs had increased expression, such as miR-520, miR-184 and miR-100-5p, 21 decreased, such as let-7c, and 14 had either increased or decreased expression depending on the study, such as miR-21. Conclusions: The dysregulation of miRNA expression is strongly associated with recurrent miscarriages. The circulating in the peripheral blood miRNAs, miR-100-5p and let-7c, might be utilized as biomarkers and establish a valuable non-invasive prognostic and diagnostic tool in the future.

Oocyte Maturation and miRNAs: Studying a Complicate Interaction to Reveal Possible Biomarkers for Female Infertility.

Cellular metabolism, apoptosis, fertilization, and proliferation of granulosa cells belong to a battery of processes where microRNAs can be detected and associated with infertility. The aim of the present review is to focus on mammalian oocyte maturation events and the association between oocyte growth and miRNA expression. PubMed/Medline, Google Scholar and Scopus databases were searched, and 33 studies were included. Regarding the correlation among miRNA expression and the regulation of granulosa cells and cumulus cells, the most important miRNAs were let-7b, let-7c and miR-21. Additionally, the loss of Dicer, an enzyme involved in miRNA biogenesis, is probably a crucial factor in oogenesis, oocyte maturation and embryogenesis. Furthermore, miRNAs interfere with different cellular mechanisms like apoptosis, steroidogenesis, genome integrity, angiogenesis, antioxidative response and, consequently, oocyte maturation. Hence, it is of major importance to clarify the role and mechanism of each miRNA as understanding its action may develop new tools and establish new diagnostic and treatment approaches for infertility and ovarian disorders.

Bridging the Gap between Galectin-3 Expression and Hypertensive Pregnancy Disorders: A Narrative Review.

Galectin-3 belongs to a family of soluble glycan-binding proteins, which are increasingly recognized as modulators of pregnancy-associated processes, including proper placental development. Gestational hypertension and preeclampsia are significant complications of pregnancy, affecting millions of women annually. Despite their prevalence, the underlying pathophysiological mechanisms remain poorly understood. Several theories have been proposed, including inflammation, placental insufficiency, disturbed placental invasion, and angiogenesis. The Scopus and PubMed/MEDLINE databases were utilized until the end of May 2024. In total, 11 articles with 1011 patients, with 558 in the control group and 453 in the preeclampsia group, were included. Seven articles investigated the expression of galectin-3 (Gal-3) in placental tissue samples, eight studies calculated the serum levels of Gal-3 in maternal blood samples, while one study referred to the possible correlation of galectin-3 levels in umbilical cord blood. The results were inconsistent in both the placental tissue and maternal serum; Gal-3 placental expression was found to be statistically increased in five studies compared to that in women without gestational hypertensive disorders, while two studies either mentioned decreased expression or no difference. Similarly, the Gal-3 maternal serum levels, compared to those in women without gestational hypertensive disorders, were found to be statistically increased in five studies, while three studies did not find any statistical difference. Gal-3 can play a crucial role in the pathogenesis of preeclampsia, and its expression is influenced by gestational age and placental insufficiency. A further investigation ought to be conducted to enlighten the correlation of Gal-3 with gestational hypertension and preeclampsia development.

The Effectiveness of Metabolic Bariatric Surgery in Preventing Gynecologic Cancer - from Pathophysiology to Clinical Outcomes.

Obesity and cancer represent two pandemics of current civilization, the progression of which has followed parallel trajectories. To time, thirteen types of malignancies have been recognized as obesity-related cancers, including breast (in postmenopausal women), endometrial, and ovarian cancer. Pathophysiologic mechanisms that connect the two entities include insulin resistance, adipokine imbalance, increased peripheral aromatization and estrogen levels, tissue hypoxia, and disrupted immunity in the cellular milieu. Beyond the connection of obesity to carcinogenesis at a molecular and cellular level, clinicians should always be cognizant of the fact that obesity might have secondary impacts on the diagnosis and treatment of gynecologic cancer, including limited access to effective screening programs, resistance to chemotherapy and targeted therapies, persisting lymphedema, etc. Metabolic bariatric surgery represents an attractive intervention not only for decreasing the risk of carcinogenesis in high-risk women living with obesity but most importantly as a measure to improve disease-specific and overall survival in patients with diagnosed obesity-related gynecologic malignancies. The present narrative review summarizes current evidence on the underlying pathophysiologic mechanisms, the clinical data, and the potential applications of metabolic bariatric surgery in all types of gynecologic cancer, including breast, endometrial, ovarian, cervical, vulvar, and vaginal.

Detection of zeb1 Gene in Granulosa Cells in Women Undergoing IVF Treatment.

BACKGROUND: ZEB1 plays a role in epithelial-to-mesenchymal transition and acts as a repressor of E-cadherin, TGF-ß, and Wnt/ß-catenin. Since ZEB1 protein is expressed in estrogen-responsive tissues, and expression of the gene in the normal ovary and endometrium is positively correlated with high estrogen levels, we performed a direct analysis of granulosa cell samples to determine whether there are any significant changes in zeb1 expression during folliculogenesis. METHODS: ZEB1 expression levels were measured in the granulosa cells of 56 infertile women undergoing IVF treatment. RNA extraction from granulosa cells was performed along with reverse transcription quantitative polymerase chain reaction (RT-qPCR) with SYBR Green I to determine zeb1 gene expression levels. Statistical analysis was performed by using t-test, while possible correlations of the expression of ZEB1 protein with body mass index (BMI), age, number of oocytes, and oocyte maturation were investigated. RESULTS: Zeb1 gene expression levels correlate significantly with body mass index (BMI) and age, but not with oocyte number and oocyte maturation stage. Obese women demonstrate a higher expression level of zeb1 gene compared to normal and overweight women. Moreover, zeb1 gene is overexpressed in women aged 35-40 years old and is under-expressed in women >40 years old. CONCLUSIONS: ZEB1 expression should be further investigated as it may unveil new potential findings of the zeb1 gene's role in female fertility and its use as a biomarker in fertility workups.

Association of GSTM1 Polymorphism and Redox Potential with Idiopathic Male Infertility.

BACKGROUND: The aim of this case-control study is to investigate possible associations between GSTM1 polymorphism and redox potential with sperm parameters. METHODS: The study group consisted of sperm samples from 51 infertile men according to the WHO guidelines. The control group included 39 samples from men with normal seminal parameters. DNA was extracted and genotyped for the detection of the GSTM1 polymorphism. An evaluation of the static redox potential (sORP) using the MiOXSYSTM system was conducted. RESULTS: The frequency of the GSTM1-null genotype was higher in infertile male individuals (60.78%) than in the controls (41.03%) and was associated with a 2.228-fold increased risk for male infertility. Fertile controls carrying the GSTM1-null genotype presented a lower percentage of typical sperm morphology and lower slow progressive motility. An excess of redox potential was observed in infertile males compared to fertile ones. In the control group higher sORP values had a positive correlation with immotility percentage and a negative correlation regarding total motility. In the study group sORP values had a negative correlation with total count, concentration, and slow progressive motility. CONCLUSIONS: The present study highlights that GSTM1 polymorphism and redox potential affect both fertile and in fertile males. Moreover, redox potential levels could be used as an additional indicator along with the routine semen analysis for a comprehensive screening between infertile and fertile men.

Eco-Friendly and COVID-19 Friendly? Decreasing the Carbon Footprint of the Operating Room in the COVID-19 Era.

Surgery is one of the most energy-intensive branches of healthcare. Although the COVID-19 pandemic has reduced surgical volumes, infection control protocols have increased the ecological footprint of surgery owing to the extensive use of personal protective equipment, sanitation, testing and isolation resources. The burden of environmental diseases requiring surgical care, the international commitment towards environmental sustainability and the global efforts to return to the pre-pandemic surgical workflow call for action towards climate-friendly surgery. The authors have searched the peer-reviewed and gray literature for clinical studies, reports and guidelines related to the ecological footprint of surgical care and the available solutions and frameworks to reduce it. Numerous studies concede that surgery is associated with a high rate of energy utilization and waste generation that is comparable to major non-medical sources of pollution. Recommendations and research questions outlining environmentally sustainable models of surgical practices span from sanitation and air quality improvement systems to the allocation of non-recyclable consumables and energy-efficient surgical planning. The latter are particularly relevant to infection control protocols for COVID-19. Paving the way towards climate-friendly surgery is a worthy endeavor with a major potential to improve surgical practice and outcomes in the long term.

Effects of endocrine disrupting compounds on female fertility.

Endocrine Disrupting Compounds or Chemicals (EDCs) constitute an extensive and varied group of mostly non-natural chemicals that have the ability to imitate any aspect of hormone action, perturbing many physiological functions in humans and animals. As for female fertility, several EDCs are associated with adverse effects in the regulation of steroidogenesis, higher miscarriage rates as well as lower fertilization and embryo implantation rates and some of them are considered to decrease the number of high-quality embryos in assisted reproductive technology (ART) pregnancy. The most common EDCs are pesticides, hexachlorobenzene (HCB), hexachlorocyclohexane (HCH) and especially phthalates and bisphenols which are used in thousands of products as plasticizers. Among all, Bisphenol A (BPA) is one of the most permeating and well-studied EDCs. BPA's action resembles that of estradiol affecting negatively the female reproductive system in various ways. This review summarizes the most recent literature on the impact of EDCs in female fertility.

Association between COVID-19 Infection and Miscarriages, What We Really Know?

BACKGROUND: COVID-19 is a modern worldwide pandemic that affected and continues to affect millions of people around the world. Since the discovery that angiotensin-converting enzyme 2 (ACE2) is the binding site for COVID-19 to achieve cell entry, there has been a continuous debate about the effect of COVID-19 infection in first and second trimester abortions. The aim of this review is to investigate the impact of COVID-19 infection on the incidence of miscarriage. Furthermore, we seek to identify potential pathophysiological mechanisms of early pregnancy loss present in infected women. METHODS: A literature review was conducted on different databases, including PubMed, Google Scholar, Ovid, Science Direct, Scopus, and Cochrane library, between 1 January 2020 and 31 August 2023. A total of 364 articles were identified and 32 articles were ultimately included in the review. RESULTS: There are several case studies that provide evidence that early pregnancy loss is associated with COVID-19 infection. These findings are not further confirmed by the majority of systematic reviews and meta-analyses, which demonstrate that the total number of miscarriages do not differ significantly between infected and non-infected groups. Furthermore, there are also case reports that associate COVID-19 infection with late second trimester abortions. CONCLUSIONS: Given that the virus persists globally, it is important to gain a better understanding of its associated risks in the reproductive process, and larger, more homogeneous, and controlled studies are required to obtain more robust data that can be meta-analyzed to obtain an overview of this potential relationship.

ANRIL rs4977574 Gene Polymorphism in Women with Recurrent Pregnancy Loss.

BACKGROUND: ANRIL rs4977574 gene polymorphism has been associated with arterial thrombosis and cardiovascular disease development. ANRIL rs4977574 gene polymorphism could also be associated with recurrent pregnancy loss (RPL) since there is increasing evidence in favor of a potential shared pathophysiological mechanism with cardiovascular disease, potentially through arterial thrombosis. This study's goal is to investigate the differences in ANRIL rs4977574 gene polymorphism between women with and without RPL, if any, as well as a potential association with the number of pregnancy losses. METHODS: DNA was isolated from peripheral blood samples, and the sequence containing the polymorphism of interest was amplified with PCR. Results were visualized under UV light following electrophoresis in 3% agarose gel with ethidium bromide. ANRIL rs4977574 (A>G) prevalence was compared between 56 women with and 69 without RPL. Results were adjusted for women's age and BMI, while a stratified analysis was performed according to number of pregnancy losses. RESULTS: Allele A was significantly more prevalent in the control group compared to RPL women [31 (44.9%) vs. 14 (25%), p = 0.021]. Although not reaching statistical significance, a gradually decreasing prevalence of allele A with an increasing number of pregnancy losses was observed [31 (44.9%) in control, eight (30.7%) with two, six (23.1%) with three, and 0 (0.0%) with four pregnancy losses, p = 0.078]. Results were also similar following adjustment. CONCLUSIONS: This is the first study that demonstrates an association between RPL presence and ANRIL rs4977574 gene polymorphism (lower prevalence of allele A), while a difference according to the number of pregnancy losses cannot be excluded.

Inguinal Lymph Node Metastasis as Sole Manifestation of Ovarian / Fallopian Tube Cancer: a Review of the Literature.

Background: Ovarian/fallopian tube cancer is the deadliest gynecological malignancy. Most cases are diagnosed at an advanced stage, typically after the cancer has spread to the peritoneal cavity, or via lymphatic drainage. The presence of distant lymph node metastasis in the inguinal region is a rare manifestation of lymphatic metastasis. Since the 2014 FIGO staging revision, ovarian cancer patients with inguinal metastasis are classified as stage IVB. However, the clinical significance of such an upstaging remains under investigation. Materials and Methods: Both Scopus and PubMed / MEDLINE databases were utilized, by inputting the following combination of keywords: (Ovarian cancer OR Fallopian tube cancer) AND (Inguinal lymph node AND Metastasis) on June 31st, 2023. The time of publication and text availability were not considered when searching the databases and all relevant articles in English were initially accepted. Results: Twelve patients from equal number of case reports were included in our review. Mean age of diagnosis was 56,5 years old, with 3 out of 12 women to be premenopausal at the time of diagnosis. Regarding the histologic type, 67% (8 out of 12) of the cases were serous adenocarcinoma and 4 patients (33%) were diagnosed with fallopian tube malignancy. All patients, except one, were treated with primary cytoreductive surgery. In all patients optimal cytoreductive surgery was achieved. All patients, except one, received adjuvant chemotherapy. Regarding the disease-free survival, mean DFS is calculated approximately at 2 years (23,1 months). Conclusion: Inguinal lymph node metastases from ovarian / fallopian tube malignancy as initial site of metastasis is extremely rare. However, patients with inguinal masses should be investigated for ovarian / fallopian malignancy. Further investigation ought to be conducted to enlighten the pathway and the oncological significance of inguinal lymph node metastasis in ovarian cancer patients.

Detection of GSTM1-null Genotype in Women Undergoing IVF Treatment.

BACKGROUND: Glutathione S-transferase (GST) M1 belongs to a family of detoxification enzymes and deficiency in enzyme activity is due to a homozygous deletion of the GSTM1 gene. Several studies reveal a possible correlation between female infertility and GSTM1 polymorphisms. The aim of this study is to investigate the effect of the GSTM1-null polymorphism in female infertility as well as in IVF parameters. METHODS: In the study group 125 women were classified as infertile according to WHO and 49 women with at least one successful pregnancy and no miscarriages, as control group. Genomic DNA from blood samples was isolated and PCR amplification was applied to determine the presence of GSTM1-null genotype. RESULTS: Data analysis demonstrated a statistically significant higher presence of GSTM1-null variant in the infertile group compared to the control group. In a subgroup analysis of the infertile group, the estradiol levels, the number of fertilized oocytes as well as the number and the quality of the cumulus-oocyte complex, were statistically significant higher in women detected with the wildtype of GSTM1 gene compared to those who had the GSTM1 null genotype (deletion). CONCLUSIONS: Our study results propose a possible involvement of GMST1 in female infertility and may help elucidate possible interactions between the microenvironment of oocytes and the oxidative stress.