Optimizing intrauterine insemination: A systematic review and meta-analysis of the effectiveness and safety of clinical treatment add-ons.

INTRODUCTION: Intrauterine insemination (IUI) is one of the most widespread fertility treatments. However, IUI protocols vary significantly amongst fertility clinics. Various add-on interventions have been proposed to boost success rates. These are mostly chosen arbitrarily or empirically. The aim of this systematic review and meta-analysis is to assess the effectiveness and safety of add-on interventions to the standard IUI protocol and to provide evidence-based recommendations on techniques used to optimize the clinical outcomes of IUI treatment. MATERIAL AND METHODS: Systematic review and meta-analyses were performed in accordance with PRISMA guidelines. A computerized literature search was performed from database inception to May 2023. Randomized controlled trials (RCTs) were included reporting on couples/single women undergoing IUI with any protocol for any indication using partner's or donor sperm. A meta-analysis based on random effects was performed for each outcome and add-on. Three authors independently assessed the trials for quality and risk of bias and overall certainty of evidence. Uncertainties were resolved through consensus. Primary outcomes were ongoing pregnancy rate (OPR) or live birth rate (LBR) per cycle/per woman randomized. Registration number PROSPERO: CRD42022300857. RESULTS: Sixty-six RCTs were included in the analysis (16 305 participants across 20 countries). Vaginal progesterone as luteal phase support in stimulated cycles was found to significantly increase LBR/OPR (RR 1.37, 95% CI 1.09-1.72, I2 = 4.9%) (moderate/low certainty of the evidence). Endometrial scratch prior/during stimulated IUI cycles may increase LBR/OPR (RR 1.44, 95% CI 1.03-2.01, I2 = 1.8%), but evidence is very uncertain. Results from two studies suggest that follicular phase ovarian stimulation increases LBR/OPR (RR 1.39, 95% CI 1.00-1.94, I2 = 0%) (low certainty of evidence). No significant difference was seen for the primary outcome for the other studied interventions. CONCLUSIONS: The findings of this systematic review and meta-analysis suggest that vaginal luteal phase progesterone support probably improves LBR/OPR in stimulated IUI treatments. In view of moderate/low certainty of the evidence more research is needed for solid conclusions. Further research is also recommended for the use of endometrial scratch and ovarian stimulation. Future studies should report on results according to subfertility background as it is possible that different add-ons could benefit specific patient groups.

Impact of double trophectoderm biopsy on reproductive outcomes following single euploid blastocyst transfer.

OBJECTIVES: To study the effect of double trophectoderm biopsy on clinical outcomes following single euploid blastocyst transfer. STUDY DESIGN: Retrospective cohort study of 2046 single euploid frozen-thawed blastocyst transfers from January 2015 to June 2022 in a single centre. All patients undergoing a frozen-thawed embryo transfer (FTET) cycle with euploid blastocysts, biopsied for any indication, were included. The outcomes were compared for blastocysts which were biopsied and vitrified once (Group 1, n = 1684), biopsied once but vitrified twice (Group 2, n = 312) and biopsied and vitrified twice (Group 3n = 50). We adjusted for confounders and performed subgroup analysis for PGT-A, PGT-M and PGT-SR cycles. The primary outcome was live birth rate. Secondary outcomes included pregnancy, clinical pregnancy, birthweight and sex ratio. RESULTS: After adjusting for confounders (previous failed euploid implantations, embryo quality and day of biopsy), embryos which were biopsied twice had lower OR for clinical pregnancy (0.48, CI 0.26-0.88, p = 0.019) and for live birth (0.50 CI 0.27-0.92, p = 0.025) compared to controls. Embryos which were biopsied once but vitrified twice had no different ORs for all reproductive outcomes compared to controls. No significant difference was observed for neonatal birthweight or sex ratio amongst the three groups. This is a retrospective single centre study with inherent bias and results may not be transferable to all settings. CONCLUSION: This study is the largest to date assessing the outcomes of FTET cycles following double trophectoderm biopsy. The results are in keeping with the existing literature and can be incorporated into patient counselling. Whilst double biopsy seems to adversely impact LBR, it is only one of the many factors that can affect success rates. The subfertility background and embryo characteristics should not be overlooked. This study provides reassuring evidence since double biopsied embryos still result in live births with no difference in sex ratio or birthweight. However, long term follow up of the off-springs is lacking and should be reported in future studies.

The definition of unexplained infertility: A systematic review.

BACKGROUND: There is no consensus on tests required to either diagnose unexplained infertility or use for research inclusion criteria. This leads to heterogeneity and bias affecting meta-analysis and best practice advice. OBJECTIVES: This systematic review analyses the variability of inclusion criteria applied to couples with unexplained infertility. We propose standardised criteria for use both in future research studies and clinical diagnosis. SEARCH STRATEGY: CINAHL and MEDLINE online databases were searched up to November 2022 for all published studies recruiting couples with unexplained infertility, available in full text in the English language. DATA COLLECTION AND ANALYSIS: Data were collected in an Excel spreadsheet. Results were analysed per category and methodology or reference range. MAIN RESULTS: Of 375 relevant studies, only 258 defined their inclusion criteria. The most commonly applied inclusion criteria were semen analysis, tubal patency and assessment of ovulation in 220 (85%), 232 (90%), 205 (79.5%) respectively. Only 87/220 (39.5%) studies reporting semen analysis used the World Health Organization (WHO) limits. Tubal patency was accepted if bilateral in 145/232 (62.5%) and if unilateral in 24/232 (10.3%). Ovulation was assessed using mid-luteal serum progesterone in 115/205 (56.1%) and by a history of regular cycles in 87/205 (42.4%). Other criteria, including uterine cavity assessment and hormone profile, were applied in less than 50% of included studies. CONCLUSIONS: This review highlights the heterogeneity among studied populations with unexplained infertility. Development and application of internationally accepted criteria will improve the quality of research and future clinical care.

Endogenous progesterone in unexplained infertility: a systematic review and meta-analysis.

PURPOSE: To investigate the possibility that altered actions of endogenous progesterone affect receptivity and contribute to unexplained infertility (UI). METHODS: Two authors electronically searched MEDLINE, CINAHL and Embase databases from inception to 6 July 2022 and hand-searched according to Cochrane methodology. We included all published primary research reporting outcomes related to endogenous progesterone in natural cycles in women with UI. Studies were assessed for risk of bias using a modified Newcastle-Ottawa Score or NHLBI Score. We pooled results where appropriate using a random-effects model. Findings were reported as odds ratios or mean differences. RESULTS: We included 41 studies (n = 4023). No difference was found between the mid-luteal serum progesterone levels of women with UI compared to fertile controls (MD 0.74, - 0.31-1.79, I2 36%). Women with UI had significantly higher rates of 'out-of-phase' endometrium than controls. Nine out of 10 progesterone-mediated markers of endometrial receptivity were significantly reduced in women with UI compared to fertile controls (the remaining 1 had conflicting results). Resistance in pelvic vessels was increased and perfusion of the endometrium and sub-endometrium reduced in UI compared to fertile controls in all included studies. Progesterone receptor expression and progesterone uptake were also reduced in women with unexplained infertility. CONCLUSIONS: End-organ measures of endogenous progesterone activity are reduced in women with UI compared to fertile controls. This apparently receptor-mediated reduction in response affects endometrial receptivity and is implicated as the cause of the infertility. Further research is required to confirm whether intervention could overcome this issue, offering a new option for treating unexplained infertility. TRIAL REGISTRATION: PROSPERO registration: CRD42020141041 06/08/2020.

Wnt4, Wnt6 and ß-catenin expression in human placental tissue - is there a link with first trimester miscarriage? Results from a pilot study.

BACKGROUND: Demystifying the events around early pregnancy is challenging. A wide network of mediators and signaling cascades orchestrate the processes of implantation and trophoblast proliferation. Dysregulation of these pathways could be implicated in early pregnancy loss. There is accumulating evidence around the role of Wnt pathway in implantation and early pregnancy. The purpose of this study was to explore alterations in the expression of Wnt4, Wnt6 and ß-catenin in placental tissue obtained from human first trimester euploid miscarriages versus normally developing early pregnancies. METHODS: The study group consisted of first trimester miscarriages (early embryonic demises and incomplete miscarriages) and the control group of social terminations of pregnancy (TOPs). The placental mRNA expression of Wnt4, Wnt6 and ß-catenin was studied using reverse transcription PCR and real time PCR. Only euploid conceptions were included in the analysis. RESULTS: Wnt4 expression was significantly increased in placental tissue from first trimester miscarriages versus controls (p = 0.003). No significant difference was documented in the expression of Wnt6 (p = 0.286) and ß-catenin (p = 0.793). There was a 5.1fold increase in Wnt4 expression for early embryonic demises versus TOPs and a 7.6fold increase for incomplete miscarriages versus TOPs - no significant difference between the two subgroups of miscarriage (p = 0.533). CONCLUSIONS: This is, to our knowledge, the first study demonstrating significant alteration of Wnt4 expression in human placental tissue, from failed early pregnancies compared to normal controls. Undoubtedly, a more profound study is needed to confirm these preliminary findings and explore Wnt mediators as potential targets for strategies to predict and prevent miscarriage.

Effects of metformin treatment on pregnancy outcomes in patients with polycystic ovary syndrome.

INTRODUCTION: This review covers the current evidence regarding the use of metformin as a therapeutic intervention for optimizing pregnancy outcomes in women with polycystic ovary syndrome (PCOS). AREAS COVERED: After searching Medline, Embase and CINAHL, all important large clinical trials and observational studies plus systematic reviews, meta-analyses and Cochrane reviews have been summarized here. The results have been compared to culminate in a thorough review and discussion on the use of metformin in relation to reproductive outcomes for women with PCOS. The role of metformin in PCOS is explored both in terms of achieving conception and during pregnancy. The existing evidence around metformin use is summarized both during the preconceptual period and during pregnancy, in relation to reproductive outcomes. EXPERT OPINION: Metformin is a widely used medication, often prescribed to improve reproductive outcomes for women with PCOS. However, the evidence remains equivocal regarding its efficacy both in optimizing fertility and pregnancy outcomes. More research is required with special emphasis on metformin use within different populations, including ethnic groups and women with varying BMI ranges.

Preconception tests at advanced maternal age.

Pregnancies at an advanced reproductive age are increasingly common. However, the safety of pregnancy remains a concern as maternal age is a recognized independent factor for various obstetric complications. Also, age is a risk factor for most systematic health problems and older women are more likely to enter into pregnancy with pre-existing conditions. At the moment there is no separate, structured guidance on preconception tests at advanced maternal age. However, the preconceptual period offers an ideal window to recognize and address underlying health issues, social issues and harmful lifestyle behaviours in order to optimize maternal health ultimately reducing infertility, perinatal morbidity and mortality. Preconception tests should be clinically relevant aiming to identify risk factors and address them to predict and prevent infertility and pregnancy complications. The importance of preconception care is magnified for women of advanced age for whom the risks are higher and the potential benefits greater.

The curious case of premature luteinization.

PURPOSE: Premature luteinization (PL) affects 12.3-46.7% of fresh in vitro fertilization cycles, and there is accumulating evidence confirming its negative effect on success rates. However, despite its clinical significance, PL is poorly understood and defined. This narrative review aims to provide a fresh look at the phenomenon of PL by summarizing the existing evidence and re-evaluating fundamental issues. METHODS: A thorough electronic search was conducted covering the period from 1978 until January 2018 in PubMed, Embase, and Medline databases, and references of relevant studies were cross-checked. Meeting proceedings of the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine were also hand searched. RESULTS: In the curious case of PL, one should go back to the beginning and re-consider every step of the way. The pathogenesis, definition, measurement methods, clinical implications, and management strategies are discussed in detail, highlighting controversies and offering "food for thought" for future directions. CONCLUSIONS: Authors need to speak the same language when studying PL in order to facilitate comparisons. The terminology, progesterone cut-off, measurement methods and days of measurement should be standardized and globally accepted; otherwise, there can be no scientific dialog. Future research should focus on specific patient profiles that may require a tailored approach. Progesterone measurements throughout the follicular phase possibly depict the progesterone exposure better than an isolated measurement on the day of hCG. Adequately powered randomized controlled trials should confirm which the best prevention and management plan of PL is, before introducing any strategy into clinical practice.

IVF culture media: past, present and future.

BACKGROUND: The advances in the world of IVF during the last decades have been rapid and impressive and culture media play a major role in this success. Until the 1980s fertility centers made their media in house. Nowadays, there are numerous commercially available culture media that contain various components including nutrients, vitamins and growth factors. This review goes through the past, present and future of IVF culture media and explores their composition and quality assessment. METHODS: A computerized search was performed in PubMed regarding IVF culture media including results from 1929 until March 2014. Information was gathered from the websites of companies who market culture media, advertising material, instructions for use and certificates of analysis. The regulation regarding IVF media mainly in the European Union (EU) but also in non-European countries was explored. RESULTS: The keyword 'IVF culture media' gave 923 results in PubMed and 'embryo culture media' 12 068 results dating from 1912 until March 2014, depicting the increased scientific activity in this field. The commercialization of IVF culture media has increased the standards bringing a great variety of options into clinical practice. However, it has led to reduced transparency and comparisons of brand names that do not facilitate the scientific dialogue. Furthermore, there is some evidence suggesting that suboptimal culture conditions could cause long-term reprogramming in the embryo as the periconception period is particularly susceptible to epigenetic alterations. IVF media are now classified as class III medical devices and only CE (Conformité Européene)-marked media should be used in the EU. CONCLUSION: The CE marking of IVF culture media is a significant development in the field. However, the quality and efficiency of culture media should be monitored closely. Well-designed randomized controlled trials, large epidemiological studies and full transparency should be the next steps. Reliable, standardized models assessing multiple end-points and post-implantation development should replace the mouse embryo assay. Structured long-term follow-up of children conceived by assisted reproduction technologies and traceability are of paramount importance.