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Purpose of reviewReview the latest research on the female urogenital microbiome as a predictor of successful implantation.Recent findingsLactobacillus crispatus seems to be beneficial species in a healthy female genital tract, although the presence of anaerobic bacteria and their impact has yet to be determined. The vaginal microbiome is associated with assisted reproductive technology (ART) outcome in terms of successful implantation and pregnancy. Approaches restoring a dysbiotic vaginal microbiome seem promising. It is questionable if a unique endometrial microbiome exists, given the low bacterial biomass, the invasiveness of endometrial sampling, and its associated high contamination risk. Future studies should focus on the whole microbiome using proteomics and metabolomics, as well as the virome to get a more holistic understanding of its role in reproduction.SummaryThe vaginal and endometrial compartments are being studied to determine a healthy and unhealthy microbiome composition. Defining a healthy composition could provide insight into physiological processes related to the success of embryo implantation. The vaginal microbiome is easily accessible and its composition can be reliably assessed and can be associated with ART outcome. The existence of an endometrial or uterine microbiome is still debated, due to the combination of low biomass and unavoidable high risk of contamination during sampling.

Research question: What is the influence of ethnicity on the outcome of ovulation induction with clomifene citrate in women with polycystic ovary syndrome (PCOS)? Design: This was a retrospective cohort study. In total, 420 women diagnosed with PCOS who were of Northern European, Mediterranean, African, South-East Asian or South American descent, and who started ovulation induction treatment with clomifene citrate, were included. All women were treated with clomifene citrate according to a standardized treatment regimen. The minimal effective dose of clomifene citrate and prevalence of clomifene resistance (CRA) were assessed, and the chance of becoming ovulatory was predicted. Results: Differences were observed in body mass index (P = 0.008), waist circumference (P = 0.036) and serum LH, insulin and androgen concentrations (all P < 0.001) in women of different ethnicities with PCOS. Compared with women of Northern European descent, the minimal effective dose of clomifene citrate in women of other ethnic groups was not significantly different. The prevalence of CRA (P = 0.574) was similar in all ethnic groups A similar chance of ovulation (P = 0.504) was predicted for the different ethnic groups. Conclusions: This is the first study aiming to link ethnicity to ovulation induction outcome in PCOS. Although women of different ethnicities who have PCOS exhibit a variation in phenotypic expression, there do not appear to be differences in the prevalence of clomifene-resistant anovulation or the minimal effective dose of clomifene citrate. Furthermore, a prediction model revealed no significant differences in the predicted chance of ovulation. A larger cohort is needed to validate these findings.

This analysis of secondary outcome measures of a randomized controlled trial was conducted to study the effect of a one-year three-component (cognitive behavioural therapy, diet, exercise) lifestyle intervention (LSI), with or without additional Short Message Service (SMS) support, on physical activity and aerobic capacity in overweight or obese women with polycystic ovary syndrome (PCOS). Women diagnosed with PCOS and a BMI > 25 kg/m2 were randomly assigned to LSI with SMS support (SMS+, n = 60), LSI without SMS support (SMS−, n = 63) or care as usual (CAU, n = 60) in order to lose weight. Based on results from the International Physical Activity Questionnaire (IPAQ), we found a significant within-group increase after one year for SMS+ in the high physical activity category (+31%, p < 0.01) and sitting behaviour decreased (Δ −871 min/week, p < 0.01). Moreover, the peak cycle ergometer workload increased within SMS+ (Δ +10 watts, p < 0.01). The SMS+ group also demonstrated a significantly different increase in walking metabolic equivalent of task minutes (METmin)/week compared with CAU after one year (Δ 1106 METmin/week, p < 0.05). Apart from this increase in walking activity, no other between-group differences were found in this trial. Overall, based on within-group results, SMS support seemed to help with improving physical activity and aerobic capacity and decreasing sedentary behaviour.

PCOS (polycystic ovary syndrome) is associated with overweight and obesity. Women with PCOS and overweight or obesity present with more pronounced reproductive derangements. Moreover, when pregnant, pregnancy complications such as gestational diabetes, hypertensive disorders and preterm birth seem to be more prevalent in this population. The present study is a one-year randomized controlled trial to investigate the effect of a three-component (cognitive behavioral therapy, healthy diet and physical therapy) lifestyle intervention (LSI) with or without Short Message Service (SMS) on pregnancy leading to live birth, pregnancy complications and outcomes within 24 months after the start of the lifestyle intervention compared to care as usual (CAU). We hypothesized that pre-pregnancy weight loss and the adoption of a healthy lifestyle would cause more pregnancies, shorter time to conception and less pregnancy complications. Women diagnosed with PCOS according to the Rotterdam 2003 criteria and a BMI above 25 kg/m2 were included. A total of 183 participants were randomly assigned to three groups: 1) three-component lifestyle intervention with SMS (LSI SMS+); 2) three-component lifestyle intervention without SMS (LSI SMS-); 3) care as usual (CAU): encourage to lose weight autonomously (control group). Pregnancy and neonatal outcomes were collected from the Dutch Bureau of Statistics (CBS) combined with the Dutch Perinatal registry (Perined). Within 24 months after the start of the intervention the pregnancy rate leading to live birth was 41.7% (25/60) within SMS+, 38.1% (24/63) within SMS- and 38.3% (23/60) within CAU. This was non-significant between the groups. Mean time to pregnancy for SMS+ was 18.3 months, 19.1 months for SMS- and 19.4 months for CAU (p=0.775). Gestational diabetes (LSI: 8.2% vs CAU: 21.7%, p=0.133), hypertensive disorders (LSI: 8.2% vs CAU: 13.0%, p=0.673) and preterm birth (LSI: 12.2% vs CAU: 17.4%, p=0.716) rates were all lower in the LSI groups (SMS+ and SMS- combined) compared to CAU. This trial demonstrated a non-significant positive trend in pregnancy outcomes in favor of the lifestyle intervention groups. We believe that a pre-pregnancy three-component lifestyle intervention in overweight or obese women with PCOS supports the attempts to get a healthy pregnancy by creating weight loss with positive effects on their physical and mental health. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Research question: What is the incidence of chromosomal mosaicism in human blastocysts and can a single trophectoderm (TE) biopsy accurately predict the chromosomal constitution of the inner cell mass (ICM)? Design: Observational study in 46 surplus cryopreserved preimplantation embryos of unknown chromosomal constitution. For each embryo, a TE biopsy was performed and the ICM was collected separately. Both samples underwent next-generation sequencing (NGS) for cytogenetic analysis and were classified as chromosomally normal, abnormal or mosaic. Mosaic samples were classified as low or high mosaic, based on the majority dominance of either normal or abnormal cells in the biopsied sample. Findings within each embryo were compared. Results: Chromosomal mosaicism was detected in 59% (n = 27/46) of the embryos, with a cytogenetic concordance rate between TE and corresponding ICM of 48% (n = 22/46). Concordance was higher from a clinical perspective: in 86% of embryos with a high-mosaic or abnormal TE, the ICM was also high-mosaic or abnormal. In 88% of the blastocysts with a normal or low-mosaic TE biopsy, a normal or low-mosaic ICM was observed. Conclusion: Despite the low cytogenetic concordance rate due to chromosomal mosaicism present in blastocysts, it was found that a single TE biopsy could correctly predict whether the ICM consists of mostly normal or abnormal cells in the majority of cases.

Post-bariatric weight loss can cause iatrogenic malnutrition and micronutrient depletion. In this study, we evaluated the impact of gastric bypass surgery (GB) and multivitamin supplement use on maternal micronutrient status before and across pregnancy. A retrospective medical chart review of 197 singleton pregnancies after GB with a due date between 2009 and 2019 was performed at a bariatric expertise center in the Netherlands. Hemoglobin, calcium, iron status, folate, vitamin D, vitamin B12 and ferritin levels were determined before and after GB during standard follow-up and at all gestational trimesters and analyzed using linear mixed models. Patients were prescribed standard multivitamin supplements or multivitamins specifically developed for post-bariatric patients (FitForMe WLS Forte (FFM)). Overall, hemoglobin and calcium levels decreased after surgery and during pregnancy, whereas folate, vitamin D, and vitamin B12 levels increased, and iron levels remained stable. FFM use was associated with higher hemoglobin, folate, vitamin D, and ferritin levels. In conclusion, through adequate supplementation and follow-up, GB does not have to result in impaired micronutrient status. Supplements developed specifically for post-bariatric patients generally result in higher micronutrient values than regular multivitamins before and during pregnancy. These data emphasize the urgent need for nutritional counseling including dietary and multivitamin supplement advise for post-bariatric women contemplating and during pregnancy.

Objective: The objective of this study is to establish maternal reference values of AMH in a fertile multi-ethnic urban pregnant population and to evaluate the effect of gestational age. Design: The Generation R Study is an ongoing population-based prospective cohort study from early pregnancy onwards. Setting: Rotterdam, the Netherlands, out of hospital setting. Population: In 5806 women serum AMH levels were determined in early pregnancy (median 13.5 weeks; 95% range 10.5-17.2). Methods: The model-based AMH reference ranges for maternal age and gestational age were created using GAMLSS. Associations between AMH and several first trimester biomarkers were analyzed using multivariate linear regression analyses. Main outcome measures: AMH levels in early pregnancy and the association with placental biomarkers, hCG, sFLT, and PLGF. Results: A nomogram of AMH in early pregnancy was developed. Serum AMH levels showed a decline with advancing gestational age. Higher AMH levels were associated with a higher level of hCG and sFLT. This last association was predominantly mediated by hCG. AMH levels were negatively associated with PLGF levels. Conclusion: In this large study we show that AMH levels in the first trimester decrease with advancing gestational age. The association between AMH and the placental biomarkers hCG, sFLT and PLGF suggests a better placental development with a lower vascular resistance in mothers with higher AMH levels. AMH might be useful in predicting adverse pregnancy outcome due to impaired placental development. Keywords: Ovarian reserve, placental biomarker, nomogram, first trimester, human Choriogonadotrophin (hCG), soluble FMS-Like Tyrosine kinase-1 (sFLT), Placental Growth Factor (PLGF).

BACKGROUND Approximately 1 in 7 couples experience subfertility, many of whom have lifestyles that negatively affect fertility, such as poor nutrition, low physical activity, obesity, smoking, or alcohol consumption. Reducing lifestyle risk factors prior to pregnancy or assisted reproductive technology treatment contributes to the improvement of reproductive health, but cost-implications are unknown. OBJECTIVE The goal of this study was to evaluate reproductive, maternal pregnancy, and birth outcomes, as well as the costs of pre-conception lifestyle intervention programs in subfertile couples and obese women undergoing assisted reproductive technology. METHODS Using a hypothetical model based on quantitative parameters from published literature and expert opinion, we evaluated the following lifestyle intervention programs: (1) Smarter Pregnancy, an online tool; (2) LIFEstyle, which provides outpatient support for obese women; (3) concurrent use of both Smarter Pregnancy and LIFEstyle for obese women; (4) smoking cessation in men; and (5) a mindfulness mental health support program using group therapy sessions. The model population was based on data from the Netherlands. RESULTS All model-based analyses of the lifestyle interventions showed a reduction in the number of in vitro fertilization, intracytoplasmic sperm injection, or intrauterine insemination treatments required to achieve pregnancy and successful birth for couples in the Netherlands. Smarter Pregnancy was modeled to have the largest increase in spontaneous pregnancy rate (13.0%) and the largest absolute reduction in potential assisted reproductive technology treatments. Among obese subfertile women, LIFEstyle was modeled to show a reduction in the occurrence of gestational diabetes, maternal hypertensive pregnancy complications, and preterm births by 4.4%, 3.8%, and 3.0%, respectively, per couple. Modeled cost savings per couple per year were €41 (US $48.66), €360 (US $427.23), €513 (US $608.80), €586 (US $695.43), and €1163 (US $1380.18) for smoking cessation, mindfulness, Smarter Pregnancy, combined Smarter Pregnancy AND LIFEstyle, and LIFEstyle interventions, respectively. CONCLUSIONS Although we modeled the potential impact on reproductive outcomes and costs of fertility treatment rather than collecting real-world data, our model suggests that of the lifestyle interventions for encouraging healthier behaviors, all are likely to be cost effective and appear to have positive effects on reproductive, maternal pregnancy, and birth outcomes. Further real-world data are required to determine the cost-effectiveness of pre-conception lifestyle interventions, including mobile apps and web-based tools that help improve lifestyle, and their effects on reproductive health. We believe that further implementation of the lifestyle app Smarter Pregnancy designed for subfertile couples seeking assistance to become pregnant is likely to be cost-effective and would allow reproductive health outcomes to be collected.

Herein, we present an overview of the recent microbiome research and findings within the field of reproductive medicine and its relation with the outcome of Assisted reproductive technology (ART). Analyses of the microbiome composition all throughout the female reproductive trace during the process of assisted reproductive techniques are discussed.Only the vaginal microbiome can be sampled without possible risks of contamination. Although this also seems to apply to the cervical microbiome, collection has to be performed with extreme caution. Because of the high risk of cross contamination, results of microbial composition of all other sites of the female reproductive tract have to be interpreted with caution. The vaginal composition prior to the start of hormonal treatment for ART seems to be predictive of in vitro fertilization/in vitro fertilization-intracytoplasmic sperm injection (IVF/IVF-ICSI) outcome, with mainly a highly negative predictive value.The local microbiota, especially the absence or presence of specific microbes, within parts of the female reproductive tract seem to be associated with the outcome of ART.

Serum concentrations of Anti-Müllerian hormone (AMH) and Inhibin B were used to assess potential fertility in survivors of childhood haematopoietic stem cell transplantation (HSCT) after three chemotherapy-conditioning regimens of differing intensity. Of 428 patients transplanted between 1990-2012 for leukaemia and immunodeficiency 121 surviving1 year after a single HSCT were recruited. Group A had a treosulfan-based regimen (low-toxicity); Group B had fludarabine/melphalan (Flu-Mel) (reduced-intensity) and Group C had busulphan/cyclophosphamide (Bu-Cy) (myelo-ablative). Mean age at HSCT and follow-up and length of follow-up were 3.6, 11.8 and 9.9 years. Mean AMH standard deviation scores (SDS) were significantly higher in Group A (-1.047) and Group B (-1.255) than Group C (-1.543), suggesting less ovarian reserve impairment after treosulfan and Flu-Mel than after Bu-Cy. Mean serum AMH concentration was significantly better with treosulfan (1.0 μg/l) than with Flu-Mel or Bu-Cy. In males, mean Inhibin B SDS was significantly higher in Group A (-0.506) than in Group B (-2.53) and Group C (-1.23) with the Flu-Mel group suffering greatest impairment. In conclusion, a treosulfan-based regimen confers a more favourable outlook for gonadal reserve than Flu-Mel or Bu-Cy in both sexes. Higher values of Inhibin B after Bu-Cy than after Flu-Mel may reflect recovery over time.

Involuntary loss of urine is a major health care problem, especially in women. The Conveen Continence Guard is a non-surgical treatment of stress incontinence. A possible risk of vaginal devices is introduction of changes in bacteriological flora of the vagina, especially after re-use of the guard. Moreover, vaginal devices can induce magnesium ion deficiency and thereby facilitate growth of Staphylococcus Aureus. This can lead to the production of toxin-1, eventually resulting in toxic shock syndrome.The first aim of this study was to investigate the capacity to absorp magnesium ions in an in-vitro study. Secondly, 14 patients with stress incontinence were examined for bacteriological changes in the vagina after re-using the continence guard for four days. After completing this study the patients were asked whether re-using the continence guard was as convenient as single use.The continence guard had no absorption capacity for magnesium ions. The vaginal bacteriological changes after re-use showed in 11% changes in bacterial growth and in 20% increased bacterial growth. Only one patient developed a vaginal colonization with Staphylococcus Aureus but had no symptoms of disease. The continence guard showed itself to be less effective in preventing stress incontinence after re-use.Although re-use of the continence guard is feasable from a bacteriological point of view, re-use renders the device less effective.

Serum anti-Mullerian hormone (AMH) concentrations decline with increasing age and constitute a Sensitive marker for ovarian ageing. In addition, basal serum AMH concentrations predict ovarian response during IVF cycles. Concomitantly, oocyte quantity and embryo quality decrease with advancing age. Hence, it was postulated that AMH in serum constitutes a marker for embryo quality. Women aged 37 years and younger with regular menstrual cycles, normal body mass index and partners with normal semen parameters were randomly assigned to either a standard or mild stimulation protocol for IVF treatment. Blood samples were drawn at cycle day 3 and at the day of human chorionic gonadotrophin administration. Embryo quality was assessed using embryo morphology score and preimplantation genetic screening. Serum AMH concentrations on cycle day 3 were correlated with the number of oocytes retrieved in both groups. AMH and embryo morphology were correlated after mild stimulation, but not after conventional ovarian stimulation. AMH and the chromosomal competence of embryos were not correlated. Serum AMH is predictive for ovarian response to stimulation. However, the lack of a consistent correlation with embryo morphology and embryo aneuploidy rate is not in favour of a direct relationship between oocyte quantity and embryo quality.