Embryo Transfer Procedural Parameters Do Not Predict IVF Cycle Outcome.

BACKGROUND: this study aims to assess the effect of embryo transfer (ET) performance parameters of a technical nature on IVF outcome. METHODS: A total of 1417 ETs from a single IVF center were included in this prospective observational study. The parameters investigated were as follows: the presence of cervical mucus post catheter withdrawal, the presence of blood, catheter reload, the employment of a tenaculum and stylet, catheter resistance as experienced by the physician and patient discomfort. RESULTS: When ET performance parameters were associated with clinical outcomes on a singular level, none of the ET parameters presented with any statistical significance. The evaluation of covariates indicated that the number and the quality of transferred embryos, as well as maternal age, exerted a statistically significant effect on clinical outcomes. In a multivariate analysis, only the presence of mucus along with significant catheter resistance presented with statistical significance; however, when adjusting for covariates, this combination showed no statistically significant effect on clinical outcomes. CONCLUSIONS: the results indicate that the time-consuming process of recording and analyzing ET performance parameters fails to offer any additional value in predicting the cycle's outcome, while factors like embryo quality and number, as well as maternal age, seem to be the sole robust predictive factors of an IVF cycle.

Commercially Available Molecular Approaches to Evaluate Endometrial Receptivity: A Systematic Review and Critical Analysis of the Literature.

Despite the advances in the field of reproductive medicine, implantation failure represents a challenging condition affecting 10-30% of patients subjected to in vitro fertilization (IVF). Research has focused on the identification of molecules playing crucial roles in endometrial receptivity, with the aim of designing predictive tools for efficient detection of the implantation window. To that end, novel molecular genomic and transcriptomic approaches have been introduced as promising tools to enable personalized approaches with the aim of optimizing embryo transfer dating. However, the clinical value of these approaches remains unclear. The aim of this study is to provide a systematic review and critical analysis of the existing evidence regarding the employment of commercially available novel approaches to evaluate endometrial receptivity. An Embase and PubMed/Medline search was performed on 1 February 2022. From the 475 articles yielded, only 27 were included and analyzed. The considerable heterogeneity of the included articles indicates the uniqueness of the implantation window, showcasing that the optimal time for embryo transfer varies significantly between women. Moreover, this study provides information regarding the technical aspects of these advanced molecular tools, as well as an analysis of novel possible biomarkers for endometrial receptivity, providing a basis for future research in the field.

Development of a predictive model for luteal phase oocyte retrieval in poor responders undergoing natural cycle IVF.

The aim of this study is the development of a prediction model indicating successful application of Oocyte Retrieval performed during the Luteal Phase (LuPOR) in poor responders, as defined by the retrieval of at least one MII oocyte. Recruitment included 1688 poor responders diagnosed as per Bologna Criteria, undergoing natural cycle ICSI between 2012 and 2020. Oocyte collections were performed during the follicular phase and during the luteal phase similarly. Antral Follicle Count (AFC), Estradiol (E2) levels evaluated on both trigger days prior to Follicular Phase Oocyte Retrieval (FoPOR) and LuPOR, and the number of small follicles 8-12 mm that were not aspirated during FoPOR were identified as predictive factors indicative of an efficient LuPOR practice with an Area Under the Curve (AUC) of 0.86, 0.86, 0.89 as well as 0.82 respectively. The combination of the above-mentioned characteristics into a prediction model provided an AUC of 0.88, specificity and a sensitivity of 0.73 and 0.94 respectively and an accuracy of 0.89. The model provided a positive predictive value (PPV) of 93.5% and a negative predictive value (NPV) of 46.8%. The clinical conclusion of the present study aims to be of added value to the clinician, by providing a prediction model defining the POR population benefiting from LuPOR. The high PPV of this model may renders this tool helpful for the practitioner that considers LuPOR.

Reporting on the Value of Artificial Intelligence in Predicting the Optimal Embryo for Transfer: A Systematic Review including Data Synthesis.

Artificial intelligence (AI) has been gaining support in the field of in vitro fertilization (IVF). Despite the promising existing data, AI cannot yet claim gold-standard status, which serves as the rationale for this study. This systematic review and data synthesis aims to evaluate and report on the predictive capabilities of AI-based prediction models regarding IVF outcome. The study has been registered in PROSPERO (CRD42021242097). Following a systematic search of the literature in Pubmed/Medline, Embase, and Cochrane Central Library, 18 studies were identified as eligible for inclusion. Regarding live-birth, the Area Under the Curve (AUC) of the Summary Receiver Operating Characteristics (SROC) was 0.905, while the partial AUC (pAUC) was 0.755. The Observed: Expected ratio was 1.12 (95%CI: 0.26-2.37; 95%PI: 0.02-6.54). Regarding clinical pregnancy with fetal heartbeat, the AUC of the SROC was 0.722, while the pAUC was 0.774. The O:E ratio was 0.77 (95%CI: 0.54-1.05; 95%PI: 0.21-1.62). According to this data synthesis, the majority of the AI-based prediction models are successful in accurately predicting the IVF outcome regarding live birth, clinical pregnancy, clinical pregnancy with fetal heartbeat, and ploidy status. This review attempted to compare between AI and human prediction capabilities, and although studies do not allow for a meta-analysis, this systematic review indicates that the AI-based prediction models perform rather similarly to the embryologists' evaluations. While AI models appear marginally more effective, they still have some way to go before they can claim to significantly surpass the clinical embryologists' predictive competence.

The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature.

Recurrent implantation failure (RIF) is a multifactorial condition affecting 10-15% of in vitro fertilization (IVF) couples. Data suggest that functional dysregulation of the endometrial immune system constitutes one of the main pathophysiological mechanisms leading to RIF. The aim of this article is to provide a thorough presentation and evaluation of the role of interleukins (ILs) in the pathogenesis of RIF. A comprehensive literature screening was performed summarizing current evidence. During implantation, several classes of ILs are secreted by epithelial and stromal endometrial cells, including IL-6, IL-10, IL-12, IL-15, IL-18, and the leukemia inhibitory factor. These ILs create a perplexing network that orchestrates both proliferation and maturation of uterine natural killer cells, controls the function of regulatory T and B cells inhibiting the secretion of antifetal antibodies, and supports trophoblast invasion and decidua formation. The existing data indicate associations between ILs and RIF. The extensive analysis performed herein concludes that the dysregulation of the ILs network indeed jeopardizes implantation leading to RIF. This review further proposes a mapping of future research on how to move forward from mere associations to robust molecular data that will allow an accurate profiling of ILs in turn enabling evidence-based consultancy and decision making when addressing RIF patients.

The Current Evidence Regarding COVID-19 and Pregnancy: Where Are We Now and Where Should We Head to Next?

Despite the volume of publications dedicated to unraveling the biological characteristics and clinical manifestations of SARS-CoV-2, available data on pregnant patients are limited. In the current review of literature, we present an overview on the developmental course, complications, and adverse effects of COVID-19 on pregnancy. A comprehensive review of the literature was performed in PubMed/Medline, Embase, and Cochrane Central databases up to June 2021. This article collectively presents what has been so far reported on the identified critical aspects, namely complications during pregnancy, delivery challenges, neonatal health care, potential routes of viral transmission, including vertical transmission or breastfeeding, along with the risks involved in the vaccination strategy during pregnancy. Despite the fact that we are still largely navigating uncharted territory, the observed publication explosion in the field is unprecedented. The overwhelming need for data is undoubtable, and this serves as the driver for the plethora of publications witnessed. Nonetheless, the quality of data sourced is variable. In the midst of the frenzy for reporting on SARS-CoV-2 data, monitoring this informational overload is where we should head to next, considering that poor quality research may in fact hamper our attempts to prevail against this unparalleled pandemic outbreak.

The Role of Uterine Natural Killer Cells on Recurrent Miscarriage and Recurrent Implantation Failure: From Pathophysiology to Treatment.

Uterine natural killer (uNK) cells constitute a unique uterine leucocyte subpopulation facilitating implantation and maintaining pregnancy. Herein, we critically analyze current evidence regarding the role of uNK cells in the events entailed in recurrent implantation failure (RIF) and recurrent miscarriages (RM). Data suggest an association between RIF and RM with abnormally elevated uNK cells' numbers, as well as with a defective biological activity leading to cytotoxicity. However, other studies do not concur on these associations. Robust data suggesting a definitive causative relationship between uNK cells and RIF and RM is missing. Considering the possibility of uNK cells involvement on RIF and RM pathophysiology, possible treatments including glucocorticoids, intralipids, and intravenous immunoglobulin administration have been proposed towards addressing uNK related RIF and RM. When considering clinical routine practice, this study indicated that solid evidence is required to report on efficiency and safety of these treatments as there are recommendations that clearly advise against their employment. In conclusion, defining a causative relationship between uNK and RIF-RM pathologies certainly merits investigation. Future studies should serve as a prerequisite prior to proposing the use of uNK as a biomarker or prior to targeting uNK cells for therapeutic purposes addressing RIF and RM.

Molecular Drivers of Developmental Arrest in the Human Preimplantation Embryo: A Systematic Review and Critical Analysis Leading to Mapping Future Research.

Developmental arrest of the preimplantation embryo is a multifactorial condition, characterized by lack of cellular division for at least 24 hours, hindering the in vitro fertilization cycle outcome. This systematic review aims to present the molecular drivers of developmental arrest, focusing on embryonic and parental factors. A systematic search in PubMed/Medline, Embase and Cochrane-Central-Database was performed in January 2021. A total of 76 studies were included. The identified embryonic factors associated with arrest included gene variations, mitochondrial DNA copy number, methylation patterns, chromosomal abnormalities, metabolic profile and morphological features. Parental factors included, gene variation, protein expression levels and infertility etiology. A valuable conclusion emerging through critical analysis indicated that genetic origins of developmental arrest analyzed from the perspective of parental infertility etiology and the embryo itself, share common ground. This is a unique and long-overdue contribution to literature that for the first time presents an all-inclusive methodological report on the molecular drivers leading to preimplantation embryos' arrested development. The variety and heterogeneity of developmental arrest drivers, along with their inevitable intertwining relationships does not allow for prioritization on the factors playing a more definitive role in arrested development. This systematic review provides the basis for further research in the field.

Introducing intrauterine antibiotic infusion as a novel approach in effectively treating chronic endometritis and restoring reproductive dynamics: a randomized pilot study.

The chronic nature of Chronic Endometritis (CE) along with the challenging management and infertility entailed, call for cutting-edge therapeutic approaches. This study introduces the novel treatment of intrauterine antibiotic infusion (IAI) combined with oral antibiotic administration (OAA), and it assesses respective performance against the gold standard treatment of OAA. Data sourced herein reports on treatment efficiency and fertility restoration for both patients aiming to conceive naturally or via In Vitro fertilization. Eighty CE patients, 40 presenting with recurrent implantation failure, and 40 with recurrent pregnancy loss, were enrolled in the IVF and the natural conception arm respectively. Treatment was subjected to randomization. Effectively treated patients proceeded with either a single IVF cycle or were invited to conceive naturally over a 6-month period. Combination of IAI and OAA provided a statistically significant enhanced effectiveness treatment rate (RR 1.40; 95%CI 1.07-1.82; p = 0.01). No statistically significant difference was observed regarding the side-effects rate (RR 1.33; 95%CI 0.80-2.22; p = 0.52). No statistically significant difference was observed for either arm regarding live-birth rate. Following an intention-to-treat analysis, employment of IAI corresponds to improved clinical pregnancy rate-albeit not reaching statistical significance. In conclusion, complimentary implementation of IAI could provide a statistically significant enhanced clinical treatment outcome.

Investigating the Role of the microRNA-34/449 Family in Male Infertility: A Critical Analysis and Review of the Literature.

There is a great body of evidence suggesting that in both humans and animal models the microRNA-34/449 (miR-34/449) family plays a crucial role for normal testicular functionality as well as for successful spermatogenesis, regulating spermatozoa maturation and functionality. This review and critical analysis aims to summarize the potential mechanisms via which miR-34/449 dysregulation could lead to male infertility. Existing data indicate that miR-34/449 family members regulate ciliogenesis in the efferent ductules epithelium. Upon miR-34/449 dysregulation, ciliogenesis in the efferent ductules is significantly impaired, leading to sperm aggregation and agglutination as well as to defective reabsorption of the seminiferous tubular fluids. These events in turn cause obstruction of the efferent ductules and thus accumulation of the tubular fluids resulting to high hydrostatic pressure into the testis. High hydrostatic pressure progressively leads to testicular dysfunction as well as to spermatogenic failure and finally to male infertility, which could range from severe oligoasthenozoospermia to azoospermia. In addition, miR-34/449 family members act as significant regulators of spermatogenesis with an essential role in controlling expression patterns of several spermatogenesis-related proteins. It is demonstrated that these microRNAs are meiotic specific microRNAs as their expression is relatively higher at the initiation of meiotic divisions during spermatogenesis. Moreover, data indicate that these molecules are essential for proper formation as well as for proper function of spermatozoa per se. MicroRNA-34/449 family seems to exert significant anti-oxidant and anti-apoptotic properties and thus contribute to testicular homeostatic regulation. Considering the clinical significance of these microRNAs, data indicate that the altered expression of the miR-34/449 family members is strongly associated with several aspects of male infertility. Most importantly, miR-34/449 levels in spermatozoa, in testicular tissues as well as in seminal plasma seem to be directly associated with severity of male infertility, indicating that these microRNAs could serve as potential sensitive biomarkers for an accurate individualized differential diagnosis, as well as for the assessment of the severity of male factor infertility. In conclusion, dysregulation of miR-34/449 family detrimentally affects male reproductive potential, impairing both testicular functionality as well as spermatogenesis. Future studies are needed to verify these conclusions.

Fine-tuning multiciliated cell differentiation at the post-transcriptional level: contribution of miR-34/449 family members.

Cell differentiation is a process that must be precisely regulated for the maintenance of tissue homeostasis. Differentiation towards a multiciliated cell fate is characterized by well-defined stages, where a transcriptional cascade is activated leading to the formation of multiple centrioles and cilia. Centrioles migrate and dock to the apical cell surface and, acting as basal bodies, give rise to multiple motile cilia. The concerted movement of cilia ensures directional fluid flow across epithelia and defects either in their number or structure can lead to disease phenotypes. Micro-RNAs (miRNAs; miRs) are small, non-coding RNA molecules that play an important role in post-transcriptional regulation of gene expression. miR-34b/c and miR-449a/b/c specifically function throughout the differentiation of multiciliated cells, fine-tuning the expression of many different centriole- and cilia-related genes. They strictly regulate the expression levels of genes that are required both for commitment towards the multiciliated cell fate (e.g. Notch) and for the establishment and maintenance of this fate by regulating the expression of transcription factors and structural components of the pathway. Herein we review miR-34 and miR-449 spatiotemporal regulation along with their roles during the different stages of multiciliogenesis.

PGT-A: who and when? Α systematic review and network meta-analysis of RCTs.

PURPOSE: Wide controversy is still ongoing regarding efficiency of preimplantation genetic testing for aneuploidy (PGT-A). This systematic review and meta-analysis, aims to identify the patient age group that benefits from PGT-A and the best day to biopsy. METHODS: A systematic search of the literature was performed on MEDLINE/PubMed, Embase and Cochrane Central Library up to May 2020. Eleven randomized controlled trials employing PGT-A with comprehensive chromosomal screening (CCS) on Day-3 or Day-5 were eligible. RESULTS: PGT-A did not improve live-birth rates (LBR) per patient in the general population (RR:1.11; 95%CI:0.87-1.42; n=1513; I2=75%). However, PGT-A lowered miscarriage rate in the general population (RR:0.45; 95%CI:0.25-0.80; n=912; I2=49%). Interestingly, the cumulative LBR per patient was improved by PGT-A (RR:1.36; 95%CI:1.13-1.64; n=580; I2=12%). When performing an age-subgroup analysis PGT-A improved LBR in women over the age of 35 (RR:1.29; 95%CI:1.05-1.60; n=692; I2=0%), whereas it appeared to be ineffective in younger women (RR:0.92; 95%CI:0.62-1.39; n=666; I2=75%). Regarding optimal timing, only day-5 biopsy practice presented with improved LBR per ET (RR: 1.37; 95% CI: 1.03-1.82; I2=72%). CONCLUSION: PGT-A did not improve clinical outcomes for the general population, however PGT-A improved live-birth rates strictly when performed on blastocyst stage embryos of women over the 35-year-old mark.

Evaluating different strategies for poor ovarian response management: a retrospective cohort study and literature review.

This retrospective study compares four different strategies for managing poor ovarian response (POR), namely, conventional stimulation (300 IUs) IVF-fresh embryo transfer (CONVF), mild stimulation (150 IUs) IVF-fresh embryo transfer (MILDF), mild stimulation embryo banking (MILDB), and embryo banking in natural cycles (NATB). In total, 796 POR patients were considered eligible. Statistical analysis revealed a shorter duration of stimulation and a lower required amount of gonadotropins in MILDF compared with CONVF (9.34 ± 1.17 versus 10.37 ± 1.14; 1402 ± 176 versus 3110 ± 343, P < 0.001). Comparing MILDF and MILDB, a higher number of available oocytes and embryos was observed in MILDB (2.36 ± 1.15 versus 6.58 ± 1.11; 1.72 ± 1.02 versus 3.51 ± 0.61, P < 0.001). Moreover, the MILDB presented with a lower number of required oocyte retrievals and a higher number of oocytes per oocyte retrieval compared with NATB (3.90 ± 1.56 versus 7.15 ± 1.80; 1.95 ± 0.74 versus 0.89 ± 0.20, P < 0.001). Data indicate that MILDF is equally efficient and associated with a shorter duration of stimulation and a lower required amount of gonadotropins compared with CONVF. Embryo accumulation may be more efficient compared with a fresh embryo transfer. MILDB may be a more efficient approach compared with NATB. To conclude, embryo accumulation following mild stimulation appears to form the optimal strategy for POR management. More studies are needed to verify these conclusions.

Getting to Know Endometriosis-Related Infertility Better: A Review on How Endometriosis Affects Oocyte Quality and Embryo Development.

Endometriosis-related infertility describes a case of deteriorated fecundity when endometriosis is diagnosed. Numerous mechanisms have been proposed in an effort to delineate the multifaceted pathophysiology that induces impairment of reproductive dynamics in patients with endometriosis. In this critical analysis, authors present the plethora of molecular events that are entailed and elaborate on how they potentially impair the oocyte's and embryo's competence in patients with endometriosis. Reactive oxygen species, dysregulation of the immune system and cellular architectural disruption constitute the crucial mechanisms that detrimentally affect oocyte and embryo developmental potential. The molecular level impairment of the reproductive tissue is discussed, since differentiation, proliferation and apoptosis constitute focal regulatory cellular functions that appear severely compromised in cases of endometriosis. Mapping the precise molecular mechanisms entailed in endometriosis-related infertility may help delineate the complex nature of the disorder and bring us a step closer to a more personalized approach in understanding, diagnosing and managing endometriosis-related infertility.

Investigating apoptotic, inflammatory, and growth markers in poor responders undergoing natural in vitro fertilization cycles: a pilot study.

This study investigates follicular fluid (FF) from patients with poor and normal ovarian response undergoing natural assisted reproductive technology cycles. We report about (1) cell-free DNA (cfDNA), which reflects apoptosis; (2) corticotropin-releasing hormone (CRH); (3) interleukin (IL)-15, which reflects inflammation; (4) granulocyte colony-stimulating factor (G-CSF); (5) vascular endothelial growth factor (VEGF); and (6) insulin-like growth factor I (IGF-I), which reflects follicular growth. Forty-four poor responders and 44 normal responders-according to the Bologna criteria-were recruited. FF samples were prepared for cfDNA quantification employing Q-PCR and for CRH, IL-15, G-CSF, VEGF, and IGF-I quantification employing ELISA. Statistically nonsignificant different levels of FF cfDNA, CRH, IL-15, VEGF, and IGF-I were observed. Interestingly, statistically significant higher G-CSF levels were observed in normal responders (302.48 ± 474.36 versus 200.10 ± 426.79 pg/mL, P = 0.003). Lower cfDNA integrity was observed in cycles resulting in clinical pregnancy for both groups (normal: 0.07 ± 0.04 versus 0.25 ± 0.17 ng/µL, P < 0.001; poor: 0.10 ± 0.06 versus 0.26 ± 0.12 ng/µL, P < 0.001). The results predominantly showcase similarities between normal and poor responders pertaining to inflammatory, apoptotic, and growth factors. This may be attributed to the employment of natural cycles in order to exclude controlled ovarian stimulation as a factor-indicating its detrimental effect. As G-CSF levels presented significantly higher in normal responders, its vital role in understanding a compromised ovarian response is highlighted.

The Conundrum of Poor Ovarian Response: From Diagnosis to Treatment.

Despite recent striking advances in assisted reproductive technology (ART), poor ovarian response (POR) diagnosis and treatment is still considered challenging. Poor responders constitute a heterogeneous cohort with the common denominator of under-responding to controlled ovarian stimulation. Inevitably, respective success rates are significantly compromised. As POR pathophysiology entails the elusive factor of compromised ovarian function, both diagnosis and management fuel an ongoing heated debate depicted in the literature. From the criteria employed for diagnosis to the plethora of strategies and adjuvant therapies proposed, the conundrum of POR still puzzles the practitioner. What is more, novel treatment approaches from stem cell therapy and platelet-rich plasma intra-ovarian infusion to mitochondrial replacement therapy have emerged, albeit not claiming clinical routine status yet. The complex and time sensitive nature of this subgroup of infertile patients indicates the demand for a consensus on a horizontally accepted definition, diagnosis and subsequent effective treating strategy. This critical review analyzes the standing criteria employed in order to diagnose and aptly categorize POR patients, while it proceeds to critically evaluate current and novel strategies regarding their management. Discrepancies in diagnosis and respective implications are discussed, while the existing diversity in management options highlights the need for individualized management.

Early Onset Preeclampsia Diagnosis Prior to the 20th Week of Gestation in a Twin Pregnancy Managed via Selective Reduction of an Intrauterine Growth Restriction Fetus: A Case Report and Literature Review.

A single, healthy, 44-year-old perimenopausal woman pursuing a pregnancy, employed donor embryos, resulting to a dichorionic diamniotic twin pregnancy. In the 18th week of gestation severe symptoms indicated early onset preeclampsia reporting severe hypertension (BP 180/90 mmHg), intense headaches and nausea as well as elevated 24-h urine protein levels (1.5 g/day). Concurrently diagnosis of an IUGR fetus was concluded. Standard pharmaceutical administration for treating preeclampsia was ordered. Persistence of symptoms indicated recommendation for pregnancy termination, however the patient opted against this. Selective embryo reduction was performed as the last resort prior to pregnancy termination. Following selective reduction the headaches and nausea were successfully subdued and the patient's blood pressure was adjusted (mean BP 130/80 mmHg). This enabled further progression of pregnancy for an impressive 11 week-period, and a live birth on the 30th week. To conclude, only a few rare cases have been reported with diagnosis of early onset preeclampsia prior to the 20th week mark and none report live births. Albeit termination of pregnancy was recommended, the management of selective reduction of the IUGR fetus enabled successful treatment of preeclampsia coupled by a live birth of a healthy infant without any perinatal or postnatal complications reported.

Novel Approaches in Addressing Ovarian Insufficiency in 2019: Are We There Yet?

Ovarian insufficiency is described as a multifaceted issue typically encountered in the field of assisted reproduction. The three main identified diagnoses of ovarian insufficiency include premature ovarian failure (POF), poor ovarian response (POR), and advanced maternal age (AMA). Patient heterogeneity in the era of individualized medicine drives research forward leading to the emergence of novel approaches. This plethora of innovative treatments in the service of adequately managing ovarian insufficiency is called to undertake the challenge of addressing infertile patients exploring their reproductive options. This review provides an all-inclusive presentation and critical analysis on novel treatments that have not achieved routine clinical practice status yet, but have recently emerged as promising. In light of the lack of randomized controlled trials conveying safety and efficiency, clinicians are left puzzled in addressing the "how" and "for whom" these approaches may be beneficial. From ovarian injection employing platelet-rich plasma (PRP) or stem cells to artificial gametes and ovaries, ovarian transplantation, and mitochondrial replacement therapy, this descriptive review provides insight toward assisting the practitioner in decision making regarding these cutting-edge treatments. Biological mechanisms, invasiveness levels, efficiency, as well as possible complications, the current status along with bioethical concerns are discussed in the context of identifying future optimal treatment.