Vaginal dysbiosis - the association with reproductive outcomes in IVF patients: a systematic review and meta-analysis.

PURPOSE OF REVIEW: To examine impact of vaginal dysbiosis (VD), including bacterial vaginosis (BV) and aerobic vaginitis (AV) on reproductive outcomes of in vitro fertilization (IVF) patients. RECENT FINDINGS: BV-bacteria (e.g. Gardnerella ) and AV-bacteria (e.g. Streptococci and Enterococci ) have been identified in the endometrium. However, there is inconclusive evidence whether IVF patients with VD have lower success rates. SUMMARY: The present systematic review and meta-analysis of PubMed/Medline, until December 2023 included 25 studies, involving 6835 IVF patients. Overall VD was defined as an approximation of community state type IV, including BV and AV-type dysbiosis based on either molecular or microscopy methods. Outcomes were live birth rate (LBR), early pregnancy loss (EPL), clinical pregnancy rate (CPR), and biochemical pregnancy rate (BPR).Vaginal dysbiosis prevalence was 19% [1271/6835, 95% confidence interval (CI) 18-20%]. Six studies examined AV-type dysbiosis with a prevalence of 4% (26/628, 95% CI 3-6%). Vaginal dysbiosis correlates with a higher EPL [relative risk (RR) = 1.49, 95% CI 1.15-1.94] and lower CPR (RR = 0.82, 95% CI 0.70-0.95). No statistically significant impact of VD, BV, or AV was found on LBR and BPR.Thus, the association between VD and reproductive outcome remains puzzling as it is difficult to explain how VD impacts CPR and EPL but not LBR and BPR.

The relationship of total progressive motile sperm count with the outcome of IUI? An analysis of 5171 cycles.

Background: The role of motile sperm count in intrauterine insemination (IUI) success rate is controversial. This retrospective cohort study performed among unselected infertile couples undergoing IUI was to explore the association between the total progressive motile sperm count (TPMSC) and the live birth rate (LBR) following IUI.Methods: The total cohort of 5363 cycles, 2666 infertile couples between January 2015 and December 2018 and finally 5171 cycles, 2647 couples were included for analysis in Sun Yat-sen memorial hospital of Sun Yat-sen University. The primary outcome was LBR per cycle. And the secondary outcome measure was clinical pregnancy rate (CPR) per cycle.Results: From the receiver operating characteristic (ROC) analysis of female age predicting live birth, female age cutoff was defined as 28 years. With a female age of ≤28 years, the CPRs were 11.5%, 14.9%, 16.1%, and 15.8% in quartile groups of pre-wash TPMSC, respectively. For the LBRs the values were 9.4%, 12.9%, 14.4%, and 11.3%, and there were also no significant differences in quartile groups of pre-wash TPMSC with ≤24 million (M), [24M-50M], [50M-97M], >97M. No statistically significant differences in the CPRs (p = .051) and LBRs (p = .088) were also observed in the quartiles groups of post-wash TPMSC. With a female age of >28 years, the CPR in couples with post-wash TPMSC ≤22.32 M was significantly lower than with post-wash TPMSC >81.0 M (p = .007). There was an obvious trend in which CPRs and LBRs increased with the post-wash TPMSC during the <81 M interval in women >28 years.Conclusions: The optimal female age cutoff for live birth was 28 years in IUI cycles. Pre-wash and post-wash TPMSC were not significantly associated with CPR and LBR per cycle. When female age >28 years, there was a better outcome with post-wash TPMSC >22.32 million.

The combined effect of lifestyle intervention and antioxidant therapy on sperm DNA fragmentation and seminal oxidative stress in IVF patients: a pilot study.

PURPOSE: Sperm DNA fragmentation (SDF) and seminal oxidative stress are emerging measurable factors in male factor infertility, which interventions could potentially reduce. We evaluated (i) the impact of lifestyle changes combined with oral antioxidant intake on sperm DNA fragmentation index (DFI) and static oxidation-reduction potential (sORP), and (ii) the correlation between DFI and sORP. MATERIALS AND METHODS: We conducted a prospective study involving 93 infertile males with a history of failed IVF/ICSI. Ten healthy male volunteers served as controls. Semen analysis was carried out according to 2010 WHO manual, whereas seminal sORP was measured using the MiOXSYS platform. SDF was assessed by sperm chromatin structure assay. Participants with DFI >15% underwent a three-month lifestyle intervention program, primarily based on diet and exercise, combined with oral antioxidant therapy using multivitamins, coenzyme Q10, omega-3, and oligo-elements. We assessed changes in semen parameters, DFI, and sORP, and compared DFI results to those of volunteers obtained two weeks apart. Spearman rank correlation tests were computed for sORP and DFI results. RESULTS: Thirty-eight (40.8%) patients had DFI >15%, of whom 31 participated in the intervention program. A significant decrease in median DFI from 25.8% to 18.0% was seen after the intervention (P <0.0001). The mean DFI decrease was 7.2% (95% CI: 4.8-9.5%; P <0.0001), whereas it was 0.42% (95%CI; -4.8 to 5.6%) in volunteers (P <0.00001). No differences were observed in sperm parameters and sORP. Based on paired sORP and DFI data from 86 patients, no correlation was observed between sORP and DFI values (rho=0.03). CONCLUSION: A 3-month lifestyle intervention program combined with antioxidant therapy reduced DFI in infertile men with elevated SDF and a history of failed IVF/ICSI. A personalized lifestyle and antioxidant intervention could improve fertility of subfertile couples through a reduction in DFI, albeit controlled trials evaluating reproductive outcomes are needed before firm conclusions can be made. Trial registration number and date: clinicaltrials.gov NCT03898752, April 2, 2019.

Analysing endometrial microbiome: methodological considerations and recommendations for good practice.

There is growing evidence that the upper female genital tract is not sterile, harbouring its own microbial communities. However, the significance and the potential effect of endometrial microorganisms on reproductive functions remain to be fully elucidated. Analysing the endometrial microbiome, the microbes and their genetic material present in the endometrium, is an emerging area of study. The initial studies suggest it is associated with poor reproductive outcomes and with different gynaecological pathologies. Nevertheless, studying a low-biomass microbial niche as is endometrium, the challenge is to conduct well-designed and well-controlled experiments in order to avoid and adjust for the risk of contamination, especially from the lower genital tract. Herein, we aim to highlight methodological considerations and propose good practice recommendations for future endometrial microbiome studies.

The exogenous progesterone-free luteal phase: two pilot randomized controlled trials in IVF patients.

RESEARCH QUESTION: Is the reproductive outcome similar after gonadotrophin-releasing hormone agonist (GnRHa) trigger followed by luteal human chorionic gonadotrophin (HCG) boluses compared with HCG trigger and a standard luteal phase support (LPS)? DESIGN: Two open-label pilot randomized controlled trials (RCT) with 250 patients from 2014 to 2019, with a primary outcome of ongoing pregnancy per embryo transfer. Patients with ≤13 follicles on the trigger day were randomized (RCT 1) to: Group A (n = 65): GnRHa trigger followed by a bolus of 1500 IU HCG s.c. on the oocyte retrieval day (ORD) and 1000 IU HCG s.c. 4 days later, and no vaginal LPS; or Group B (n = 65): 6500 IU HCG trigger, followed by a standard vaginal progesterone LPS. Patients with 14-25 follicles on the trigger day were randomized (RCT 2) to Group C (n = 60): GnRHa trigger followed by 1000 IU HCG s.c. on ORD and 500 IU HCG s.c. 4 days later, and no vaginal LPS; or Group D (n = 60): 6500 IU HCG trigger and a standard vaginal LPS. RESULTS: In RCT 1, the ongoing pregnancy rate was 44% (22/50) in the GnRHa group versus 46% (25/54) in the HCG trigger group (RR 0.95, 95% CI 0.62-1.45). No ovarian hyperstimulation syndrome (OHSS) was seen in Groups A or B. In RCT 2, the ongoing pregnancy rate was 51% (25/49) in the GnRHa group versus 60% (31/52) in the HCG trigger group (RR 0.86, 95% CI 0.60-1.22). The OHSS rates were 3.3% and 6.7%, respectively. CONCLUSIONS: Although a larger-scale study is needed before standard clinical implementation, the present study supports that the exogenous progesterone-free LPS is efficacious, simple and patient-friendly.

Research and business - the yin and yang in modern medicine.

Yin and yang is a concept of dualism in Chinese philosophy, describing how opposite or contrary forces may be complementary, interconnected and interdependent, and how they may give rise to each other as they interrelate with one another. In line with this, modern clinical research and business can definitely be described as yin and yang. With the increasing need for funding, researchers at a very early stage during the development of a new concept may be forced or tempted to enter the business world. Furthermore, researchers are encouraged and supported by their own universities to collaborate with possible future business partners, not only to acquire funding, but also to explore potential patenting. This collaboration between the business world and research can definitely be very fruitful and provide benefit for both parties, patients and society as a whole, but it may also introduce the risk of premature materialization.

Novel Physiology and Definition of Poor Ovarian Response; Clinical Recommendations.

Poor ovarian response (POR) to controlled ovarian stimulation (OS) presents a major challenge in assisted reproduction. The Bologna criteria represented the first serious attempt to set clear criteria for the definition of POR. However, the Bologna criteria were questioned because of the persistent heterogeneity among POR patients and the inability to provide management strategies. Based on these facts, a more recent classification, the POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) classification, was developed to provide a homogeneous and refined definition of POR that significantly reduces the heterogeneity of the Bologna criteria definition of POR and helps in the clinical handling and counseling of patients. In this review, we discuss the impact of the POSEIDON classification on the clinical management of patients with POR.

Vaginal Microbiota and In Vitro Fertilization Outcomes: Development of a Simple Diagnostic Tool to Predict Patients at Risk of a Poor Reproductive Outcome.

BACKGROUND: Female reproductive tract microbiota may affect human reproduction. The current study considered whether a more detailed characterization of the vaginal microbiota could improve prediction of risk of poor reproductive outcome in patients undergoing in vitro fertilization (IVF). METHODS: Vaginal samples from 120 patients undergoing IVF were sequenced using the V4 region of the 16S ribosomal RNA gene with clustering of Gardnerella vaginalis genomic clades. Abnormal vaginal microbiota was defined by microscopy and quantitative polymerase chain reaction (qPCR) for G. vaginalis and/or Atopobium vaginae above a threshold. RESULTS: Three major community state types with abundance of Lactobacillus crispatus, Lactobacillus iners, and a diverse community type were identified, including 2 subtypes, characterized by a high abundance of L. crispatus and L. iners, respectively, but in combination with common diversity type operational taxonomic units. No significant association between community state type and the reproductive outcome could be demonstrated; however, abnormal vaginal microbiota by qPCR and a grouping based on high Shannon diversity index predicted the reproductive outcome equally well. CONCLUSIONS: The predictive value of 16S ribosomal RNA gene sequencing was not superior to the simpler and less expensive qPCR diagnostic approach in predicting the risk of a poor reproductive outcome in patients undergoing IVF. CLINICAL TRIALS REGISTRATION: NCT02042352.

Bureaucratic overheating is a parasite hampering modern clinical research - a viewpoint from the 'belly of the beast'.

Clinical researchers in Europe are experiencing an increasing amount of bureaucracy, which in our eyes has now reached surrealistic heights, hampering the future of research, and thus, the development of new treatment regimens and advances in clinical research. In the long term, the current approval and control processes will negatively impact patient care, education, academia and the health economy of our countries. Thus, a debate is necessary including not only healthcare workers, but also politicians and patients.

Dual stimulation using corifollitropin alfa in 54 Bologna criteria poor ovarian responders - a case series.

RESEARCH QUESTION: What are the reproductive outcomes of Bologna criteria poor responders undergoing dual stimulation (DuoStim) and subsequent cryopreserved embryo transfer? DESIGN: Case series of patients treated during the period August 2015 to March 2018 in a public fertility clinic. The study included 54 Bologna criteria poor responder IVF patients younger than 42 years receiving a follicular stimulation (DuoStim 1) followed by a luteal phase stimulation (DuoStim 2) within the same cycle, both stimulations being performed with corifollitropin alfa followed by a subsequent cryopreserved embryo transfer cycle. The primary endpoint was the number of oocytes retrieved in DuoStim 1 compared with DuoStim 2. The secondary endpoint was ongoing pregnancy rate (OPR) at 12 weeks of gestation. RESULTS: The mean number of oocytes retrieved in DuoStim 1 and DuoStim 2 was 2.4 ± 2.1 versus 3.7 ± 2.6, respectively; thus, a total of 1.2 (95% CI, 0.46-1.96) more oocytes was retrieved in DuoStim 2 compared with DuoStim 1 (P = 0.002). The OPR at 12 weeks was 20% (11/54) in this poor ovarian response population with a mean age of 36.7 years. CONCLUSIONS: Luteal phase stimulation results in more oocytes in poor responders compared with follicular phase stimulation. DuoStim, using corifollitropin alfa followed by individualized FSH dosing, appears to be an alternative to conventional follicular phase stimulation, decreasing the risk of cycle cancellation.

Individualized controlled ovarian stimulation in expected poor-responders: an update.

Controlled ovarian stimulation with subsequent multi-follicular development continues to be a keystone in ART. Evidence supports an individualized approach to ovarian stimulation, usually involving combinations of ovarian reserve tests, body mass index and age to tailor the exogenous gonadotropin dose, and potentially adjuvant treatment aiming for high safety and a shortening of time to live birth. While stimulation and trigger concepts have been developed successfully in normo- and hyperresponder patients, the poor responder patient remains difficult to manage. However, recent advances in definition and classification of the expected poor ovarian responder patient might enable a more accurate and clinically useful interpretation of new treatment concepts in a more homogenous study population. In the present review, we discuss the classification of the expected poor ovarian responder patient as well as clinically useful measurements of efficacy for controlled ovarian stimulation, and finally, we discuss the evidence for clinical management of patients with expected poor ovarian response, including adjuvant treatments such as growth hormone, androgens, and LH activity.In conclusion, the best available evidence supports that the treatment of the expected poor ovarian response patient should be individualized in all steps of ART, including the choice of GnRH analogue, the gonadotropin type and dose, ovulation trigger, and the possible use of adjuvant therapies.

Progesterone levels on pregnancy test day after hormone replacement therapy-cryopreserved embryo transfer cycles and related reproductive outcomes.

RESEARCH QUESTION: Do serum progesterone levels determine ongoing pregnancy rates (OPR) in hormone replacement therapy frozen-thawed embryo transfer (HRT-FET) cycles? DESIGN: A cohort study of 244 HRT-FET cycles from a Danish public fertility centre. Data from patients undergoing HRT-FET from January 2016 to December 2017 were extracted from a clinical database. All patients had transfer in HRT cycles of autologous embryos frozen on day 5 or 6. Endometrial preparation was performed using 6 mg oestradiol valerate daily from the second day of the cycle followed by vaginal micronized progesterone (90 mg/8 h). All patients had serum progesterone measurement during the artificial luteal phase. RESULTS: The optimal cut-off for ongoing pregnancy was 35 nmol/l based on sensitivity analysis of different progesterone levels as a factor variable and its association with ongoing pregnancy. No significant differences regarding number of embryos transferred, embryo quality, age, body mass index (BMI) or smoking were found in the two groups of progesterone < 35 nmol/l and ≥ 35 nmol/l, respectively. A total of 51% of patients had a serum progesterone < 35 nmol/l. The range of all measurements was 0.3 to 110 nmol/l. The unadjusted OPR was significantly lower in the < 35 nmol/l group compared with the ≥ 35 nmol/l group (38% versus 51%;P = 0.04). A logistic regression analysis, adjusting for smoking, age, BMI, number of embryos transferred and blastocyst age showed a significant decrease in OPR when progesterone was < 35 nmol/l of 44% (95% confidence interval [CI] 35-54%) compared with ≥ 35 nmol/l of 58% (95% CI 48-68%), risk difference of 14% (95% CI 2-26%,P = 0.02). CONCLUSIONS: Serum progesterone levels < 35 nmol/l decrease the chance of OPR in HRT-FET cycles.

Bio-equivalent doses of recombinant HCG and recombinant LH during ovarian stimulation result in similar oestradiol output: a randomized controlled study.

In nature, HCG is secreted by the implanting embryo from peri-implantation and onwards. In contrast, LH is mandatory for steroidogenesis and follicular development during the follicular phase, working in synergy with FSH. Moreover, LH is mandatory for the function of the corpus luteum. Although LH and HCG bind to the same receptor, significant molecular, structural and functional differences exist, inducing differences in bioactivity. This randomized controlled study compared the effect of recombinant FSH stimulation combined with daily either micro-dose recombinant HCG or recombinant LH supplementation in a 1:1 bioactivity ratio from day 1 of stimulation in a long gonadotrophin releasing hormone agonist down regulation protocol. A total of 100 patients from a public clinic completed the study. The primary end-point was the oestradiol level on the day of ovulation trigger and the median oestradiol level in the HCG supplemented group was 8662 pmol/l versus 9203 pmol/l in the recombinant LH supplemented group; therefore, no significant difference was found. Moreover, no differences were observed in the number of oocytes retrieved or in the live birth rate. We conclude that recombinant HCG and recombinant LH are equally effective in boosting oestradiol synthesis during ovarian stimulation when used in a 1:1 bioactivity ratio.

Treatment of bacterial vaginosis in pregnancy in order to reduce the risk of spontaneous preterm delivery - a clinical recommendation.

INTRODUCTION: Bacterial vaginosis (BV) is characterized by a dysbiosis of the vaginal microbiota with a depletion of Lactobacillus spp. In pregnancy, prevalence's between 7 and 30% have been reported depending on the study population and the definition. BV may be associated with an increased risk of spontaneous preterm delivery (sPTD). However, it is controversial whether or not BV-positive pregnant women will benefit from treatment to reduce the risk of sPTD. We could not identify any good-quality guideline addressing this issue. Consequently we aimed to produce this clinical recommendation based on GRADE. MATERIAL AND METHODS: Systematic literature searches were conducted in the following databases: Guidelines International Network: G-I-N, Medline, Embase, The Cochrane Database of Systematic Reviews, Web of Science and http://www.clinicaltrials.gov from 1999 to 3 October 2014. Hence, nine guidelines, 34 reviews, 18 randomized controlled trials and 12 observational studies were included. RESULTS: The GRADE quality of evidence was consistently low or very low, primarily because none of the risk ratios (RR) for the risk of sPTD at <37 weeks were statistically significant. Concerning treatment with metronidazole, RR was 1.11 (95% CI 0.93-1.34) in low-risk pregnancies and 0.96 (95% CI 0.78-1.18) in high risk pregnancies. Concerning treatment with clindamycin at any gestational age, the RR was 0.87 (95% CI 0.73-1.05). CONCLUSION: This systematic review gives a strong recommendation against treatment with metronidazole and a weak recommendation against treatment with clindamycin to reduce the sPTD rate in both high-risk and low-risk pregnancies with BV.