Estimulación ovárica en síndrome de Mayer-Rokitansky: reporte de caso y revisión de la literatura / Controlled ovarian stimulation in Mayer-Rokitansky syndrome: case report and literature review

Resumen El síndrome de Mayer-Rokitansky-Küster-Hauser (SMRKH) es una anomalía del tracto genital femenino caracterizada por ausencia congénita del útero y porción superior de la vagina. Ocurre en uno de cada 4,500 nacimientos y se diagnostica normalmente durante la adolescencia al presentarse amenorrea primaria. Su función ovárica está preservada, pero la información actual respecto al potencial reproductivo de estas pacientes es limitada. Se presenta el caso de una mujer con diagnóstico de SMRKH sometida a estimulación ovárica para transferencia de embriones a útero subrogado y se discute su potencial reproductivo: técnicas de reproducción asistida, intervenciones e impacto psicológico.

Abstract Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a congenital anomaly of the female genital tract characterized by congenital absence of the uterus and upper part of the vagina. It occurs in 4,500 female births and diagnosis is usually made during adolescence when primary amenorrhea presents. They have functioning ovaries but data regarding their reproductive potential is limited. We hereby report the case of a woman diagnosed with MRKH syndrome in whom assisted reproductive techniques were used to try to achieve pregnancy by gestational surrogacy and their reproductive potential is discussed: assisted reproductive techniques, procedures, and psychological impact.

Live Birth Rate Following Bed Rest Versus Early Mobilization After Embryo Transfer: A Systematic Review And Meta-Analysis.

Embryo transfer (ET) is the final step of in vitro fertilization (IVF). Different strategies have been proposed to increase the likelihood of implantation, such as post-transfer bed rest. The objective of this manuscript was to compare the clinical outcomes of embryo transfers after IVF of patients offered rest vs. early ambulation. The patient, intervention, comparison, and outcome(s) (PICO) model was used to select the study population, which included women/couples submitted to IVF and prescribed bed rest or early ambulation. Only studies including live birth (LB) as an outcome were included (www.crd.york.ac.uk/PROSPERO/CRD42020188716) A systematic search for studies was conducted on MEDLINE, ClinicalTrials.gov, PubMed, and the Cochrane Library. A librarian coordinated the searches in May 2020, which considered articles published since 1995. All original peer-reviewed articles in English were included, regardless of study design. The search retrieved 27 citations, of which 14 were eligible for full-text analysis and four accepted for inclusion. The studies included data on 21,598 patients/cycles (rest: 20,138; early ambulation: 1,460). Patients prescribed bed rest had an LB rate of 43.6% vs. 52.5% in the individuals not offered bed rest. The meta-analysis yielded an odds ratio of 0.77 (95% CI 0.5-1.2), which means patients on bed rest were 23% less likely to have a LB; nevertheless, this difference was not statistically significant. Considering that there is no difference between the two strategies, there is no evidence to recommend bed rest after embryo transfer.

El Microbioma del tracto reproductivo: una revisión narrativa de la literatura / The reproductive Microbiome: a narrative review of the literature

Antecedentes: Históricamente, el enfoque de la investigación en torno al microbioma se ha centrado en patología, mientras que su fisiología se ha ignorado en gran medida. La importancia de este papel fi- siológico se demostró cuando el proyecto del genoma humano se publicó en 2001. Objetivo: Discutir la investigación actual sobre el microbioma del tracto reproductivo femenino, con el fin de proporcionar una opinión experta sobre cómo utilizar este conocimiento en la práctica clínica del diagnóstico y tra- tamiento en el área de la ginecología, la obstetricia y la infertilidad. Material y metodos: En septiembre de 2020, se realizó una búsqueda electrónica en las bases de datos: PubMed y Google Scholar. La es- trategia de búsqueda incluyó palabras clave relacionadas con la literatura científica sobre el microbioma del tracto reproductivo femenino, como (sólo o en combinación): microflora, microbiota, tracto genital, reproducción, semen, vagina, útero, cervical, placenta, concepción, reproducción asistida y microbioma urogenital. La búsqueda se limitó a ensayos clínicos, estudios de cohorte (prospectivos y retrospectivos) y transversales, revisiones sistemáticas y revisiones de la literatura publicados entre 2000 y agosto de 2020. Resultados: Se reunieron 109 artículos de los que se eliminaron 73 por duplicidad y 4 no cum- plieron los criterios de inclusión; al final se analizaron 32 artículos. Tras la revisión de la literatura, se exponen los conceptos más relevantes para entender el impacto de la microbiota y su microbioma tanto en el área de la obstetricia, como de la ginecología y de la medicina reproductiva. AU)

Background:Historically, the focus of research around the microbiome has been on pathology, while its physiology hasbeen largely ignored. The importance of this physiological role was demonstrated when the Human Genome Project waspublished in 2001. Objective:To discuss current research on the female reproductive tract microbiome, in order to providean expert opinion on how to use this knowledge in the clinical practice in the area of gynecology, obstetrics and infertility.Material and methods:In September ‘20, an electronic search was carried out in PubMed and Google Scholar. Thesearch strategy included keywords related to the scientific literature on the female reproductive tract microbiome, such as(alone or in combination): microflora, microbiota, genital tract, reproduction, semen, vagina, uterus, cervical, placenta,conception, assisted reproduction and the urogenital microbiome. The search was limited to clinical trials, cohort studies(prospective and retrospective) and cross-sectional, systematic reviews, and reviews of the literature published between2000 and August 2020. Results:A total of 109 articles were identified after the search, of which 73 were eliminated dueto duplication, and 4 did not meet the inclusion criteria. In the end, 32 articles were analyzed. After thoroughly reviewingthe literature, the most relevant concepts are exposed to understand the impact of the microbiota and its microbiome bothin the area of obstetrics, gynecology and reproductive medicine. Conclusions:A comprehensive understanding of therole of the reproductive microbiome guarantees improvements in fertility treatments and of the reproductive health in ge-neral. Although the field is new, there are already ways to use what is known to improve clinical practice and achievebetter results in the different facets of a woman's life. (AU)

Association of ovarian stimulation and embryonic aneuploidy in in vitro fertilization cycles with preimplantation genetic testing: A narrative systematic review.

The impact of gonadotropins used for COS on the rate of embryo aneuploidy in patients without the negative effects of age as a confounding factor, is still a subject of lively debate. We ran a systematic search for studies in MEDLINE, PubMed, Google Scholar and the Cochrane Library. A librarian coordinated the search in December of 2020. We included all original peer-reviewed papers in English, irrespective of study-design. There were no restrictions concerning method of amplification or platform used to analyze the amplified DNA. We used the PICO model to select the study population. We included women/couples submitted to COS for IVF with the intention to genetically analyze her/their embryos through PGT. The primary outcome was the rate of aneuploidy. We used the Newcastle-Ottawa scale (NOS) score to evaluate the quality of the studies included. The search yielded 73 citations, and 14 were eligible for analysis, which included data on 4805 cycles. Media quality NOS score was 8. Although it has been demonstrated that natural cycles are associated with aneuploidy, it does seem that more robust stimulations are indeed associated with a higher proportion of aneuploidy. Nevertheless, a higher response is associated with an increased number of euploid embryos available for transfer, which translates into more embryo-transfer cycles with a prospective higher cumulative live birth rate. Further evidence is needed to ascertain if there is a negative impact of COS, especially at the cellular level.

Do ovarian endometriomas affect ovarian response to ovarian stimulation for IVF/ICSI?

RESEARCH QUESTION: Does the presence of ovarian endometriomas affect ovarian response to ovarian stimulation after adjusting for age and ovarian reserve markers? DESIGN: This retrospective cross-sectional study compared the ovarian response between patients with ovarian endometriomas and women with other infertility factors undergoing their first ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). An age-specific nomogram model for the number of oocytes retrieved was built for both groups, and ovarian response was compared after adjusting for age, gonadotrophin dose, anti-Mullerian hormone (AMH) concentration and antral follicle count (AFC). RESULTS: A total of 923 patients were included: 101 women with at least one ovarian endometrioma, and 822 patients with other infertility factors. Comparisons of the nomograms for the number of oocytes retrieved demonstrated that response was significantly lower for women with endometrioma when the results were adjusted for age the z-score for the number of oocytes retrieved (-0.49 ± 0.71 versus -0.20 ± 0.86; 95% confidence interval [CI] -0.47 to -0.12) and also after adjustment for the total dose of gonadotrophins and AMH values (z-score mean difference -0.338; 95% CI -0.54, -0.14). When the z-score was adjusted for gonadotrophin dose and AFC, the number of oocytes retrieved was comparable between the two groups (z-score mean difference -0.038; 95% CI -0.34 to 0.27). CONCLUSIONS: Ovarian response after ovarian stimulation for IVF/ICSI in women with endometriomas is significantly lower than in controls after adjusting for age, gonadotrophin dose and AMH. Dose and protocol selection for ovarian stimulation in patients with endometrioma should be based on AFC rather than AMH, as the latter may be overestimated.

The effect of type of oral contraceptive pill and duration of use on fresh and cumulative live birth rates in IVF/ICSI cycles.

STUDY QUESTION: Are there any differences in the fresh (LB) and cumulative live birth rates (CLBR) of women undergoing controlled ovarian stimulation (COS) for IVF/ICSI following pretreatment with different types of oral contraceptive pills (OCP) for different durations as compared to no-OCP? SUMMARY ANSWER: OCP administration for an interval of 12- to 30-day treatment period and with a 5-day washout period does not affect clinical pregnancy, LB nor cumulative LB in patients undergoing COS for an IVF cycle. WHAT IS KNOWN ALREADY: The use of OCP is an effective way of treatment planning in IVF/ICSI cycles, but published evidence about its effect on pregnancy and LBR is inconsistent, some studies finding decreased rates but others no difference. STUDY DESIGN, SIZE, DURATION: This is a retrospective analysis carried out in a University-affiliated tertiary centre between January 2009 and December 2017. Overall, 4116 infertile women between 18 and 45 years, who underwent their first ovarian stimulation cycle in our centre, were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were categorised into two groups as receiving OCP (n = 3517) or not (no OCP, n = 599). All patients with OCP pretreatment initiated controlled ovarian stimulation (COS) 5 days post-pill. Overall, two types of OCP were used at the study's centre: ethinylestradiol (EE) 30 µg/desogestrel 150 µg, a third-generation progesterone; or EE 30 µg/drospirenone 3 mg, a fourth-generation progestin with mild antiandrogenic activity. MAIN RESULTS AND THE ROLE OF CHANCE: A total of n = 4116 patients were analysed, (OCP n = 3517 and non-OCP n = 599). The use of OCP was independently associated with a small increase in the number of oocytes retrieved after adjusting for age, BMI, use of OCP, cause of infertility, initial dose (IU), type of gonadotropin, stimulation days, total stimulation units (total IU) (ß 0.22, 95% CI 0.12-0.31). Cumulative LBRs were comparable between groups OCP versus non-OCP (32.4 versus 31.6%, P = 0.712). Following adjustment for age, BMI, infertility diagnosis, starting and total dose, type of gonadotropin, total days of stimulation, type of insemination, number of oocytes retrieved, day of transfer and number of embryos transferred in a multiple logistic analysis, patients using OCPs had a similar probability of achieving a LB as compared with patients not-using OCPs following fresh embryo transfer (ORadj 0.89, 95% CI 0.69-1.15) and a similar probability for CLBR after the use of fresh and frozen embryos (ORadj 0.94, 95% CI 0.73-1.21). No differences were observed in ovarian stimulation and clinical outcomes between drospirenone and desogestrel OCP groups. LIMITATIONS, REASONS FOR CAUTION: Limitations are related to the retrospective nature of the study; despite the sample size, the adjustments and the multivariable regression analysis conducted, we cannot exclude the presence of confounding bias. OCP administration was not randomly assigned, not allowing to exclude the presence of selection bias. Lastly, we only used two types of OCP with durations and washout periods as per institution protocol. Therefore, we cannot exclude that longer duration of administration, a different type of OCP or different pill-free interval might have had an alternative effect on LBR or CLBR; thus, the generalizability of this study's results should be considered with caution. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides reassuring evidence that the use of 12-30 days OCP for cycle programming, prior to IVF, does not decrease the chance of live birth and cumulative live birth rates. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for this study. This research was performed under the auspices of 'Càtedra d'Investigació en Obstetrícia I Ginecologia' of the Department of Obstetrics, Gynaecology and Reproductive Medicine, Hospital Universitario Dexeus, Universitat Autònoma de Barcelona. The authors report no conflict of interest associated with the current study. TRIAL REGISTRATION NUMBER: NA.

Conceptos básicos en inmunología de la reproducción: revisión narrativa de la bibliografía / Basic concepts in reproductive immunology: a narrative review of the literature

Resumen: ANTECEDENTES: La inmunología de la reproducción no es un área nueva: siempre ha estado relacionada con el aborto recurrente y con la falla repetida en la implantación, sobre todo en el contexto de una fertilización in vitro. Recientemente emergieron nuevos conceptos importantes que los ginecoobstetras deben considerar. OBJETIVO: Interrelacionar los conceptos básicos de inmunología, embriología y reproducción asistida para comprender mejor lo que la primera puede resolver y lo que no. METODOLOGÍA: Estudio retrospectivo efectuado con base en la búsqueda electrónica, llevada a cabo en febrero de 2020 en las bases de datos: PubMed y Google Scholar con los siguientes términos (MeSH): abortion, spontaneous/immunology; embryo implantation/immunology; HLA-c antigens/immunology; immune tolerance/immunology; immunity, maternally-acquired/immunology; uterus/immunology; killer cells, natural/immunology; placentation/immunology; receptors, kir/immunology; antigen presentation/genetics; antigen presentation/immunology; maternal-fetal exchange/genetics; maternal-fetal exchange/immunology. RESULTADOS: Se reunieron 289 artículos y se eliminaron 248 por no cumplir con los criterios de inclusión; solo se analizaron 41. Los artículos identificados sirvieron de base para actualizar la situación de la inmunología en el contexto de la medicina de la reproducción. Durante el proceso se revisaron otros artículos que sirvieran de soporte bibliográfico a los conceptos descritos en esta revisión. CONCLUSIONES: Debido al destacado interés en el estudio de la genética de los embriones, la medicina de la reproducción se enfocó más en ella y dejó de lado a la inmunología. Sin embargo, como la genética sigue sin poder explicar de manera adecuada las fallas en la implantación, la inmunología de la reproducción vuelve a cobrar impulso.

Abstract: BACKGROUND: Reproductive immunology is not a new area in reproductive medicine, it has always been related to recurrent miscarriage and repeated implantation failure, especially in the context of IVF. Recently, new concepts have emerged that are important for OBGYN specialists to keep in mind. OBJECTIVE: Interrelating the basic concepts of immunology, embryology and assisted reproduction to better understand what the former can and cannot solve. METHODOLOGY: Retrospective study based on the electronic search, carried out in February 2020, in the databases: PubMed and Google Scholar with the following terms (MeSH) The following MeSH terms were used: Abortion, Spontaneous/immunology; Embryo Implantation/immunology; HLA-C Antigens/immunology; Immune Tolerance/immunology; Immunity, Maternally-Acquired/immunology; Uterus/immunology; Killer Cells, Natural/immunology; Placentation/immunology; Receptors, KIR/immunology; Antigen Presentation/genetics; Antigen Presentation/immunology; Maternal-Fetal Exchange/genetics; Maternal-Fetal Exchange/immunology. RESULTS: 289 articles were collected, and 248 articles were deleted because they did not meet the inclusion criteria; only 41 were analyzed. The articles identified served as a basis for updating the status of immunology in the context of reproductive medicine. During the process, other articles were reviewed to serve as bibliographic support for the concepts described in this review. CONCLUSIONS: Due to the outstanding interest in the study of embryo genetics, reproductive medicine focused more on it and left immunology aside. However, since genetics still cannot adequately explain implantation failures, reproductive immunology is gaining momentum again.

Desogestrel versus antagonist injections for LH suppression in oocyte donation cycles: a crossover study.

To study whether ovarian response to corifollitropin among oocyte donors (OD) is different when oral desogestrel (DSG) is used to block the luteinizing hormone (LH) surge when compared to GnRH-antagonist use. This is a retrospective, cohort study at a private, university-based, IVF center including 35 OD. Patients underwent two stimulation cycles under corifollitropin alfa (CFT), one under an antagonist and another under DSG, between February 2015 and May 2017. In antagonist cycles, daily ganirelix was administered since a leading follicle reached 14 mm. In the DSG cycles, daily oral DSG was prescribed. The main outcome measure was oocytes retrieved. Compared to antagonist cycles, cycles under DSG received fewer injections (10.3 ± 2.8 vs. 5.0 ± 2.1, p < .001), nominally lower total supplementary gonadotropin dose (497.4 ± 338.9I U vs. 442.9 ± 332.8 IU, p=.45) with a lower total cost of medication (1018.6 ± 191.0€ vs. 813.8 ± 145.9€, p<.001). There were no differences in the total number of retrieved oocytes between groups (17.4 ± 7.5 vs. 18.6 ± 8.9, p=.34). In the corresponding oocyte recipients, clinical pregnancy rate was similar between groups: 52.0% vs. 58.6%, respectively (p=.78). ODs' stimulation's response under DSG is similar when compared to (17.4 ± 7.5 vs. 18.6 ± 8.9, p=.34) but associated with less injections and lower medication costs. The main advantage of this strategy is its simplicity, an aspect of utmost importance in the management of ODs.

Ovarian response in oocyte donation cycles under LH suppression with GnRH antagonist or desogestrel progestin: retrospective and comparative study.

Here are investigated the serum hormones in ovarian stimulation cycles of oocyte donors (OD), under endogenous luteinizing hormone (LH) suppression with GnRH antagonist (antGnRH) vs. desogestrel (DSG) (progesterone-primed [PP]). OD underwent ovarian stimulation with gonadotropins at a private, university-based, infertility center between January 2017 and March 2018. Endogenous LH peak was controlled with either daily injections of antGnRH or with daily oral 75 mcg DSG (PP) until triggering. LH and progesterone were measured at trigger and the following day. A total of 404 OD cycles were included. There were no differences in age (26.7 ± 4.9 vs. 27.1 ± 4.8 years), AMH (3.7 ± 2.1 vs. 4.1 ± 2.7 ng/ml), and body mass index (BMI) (22.4 ± 2.8 vs. 22.1 ± 3.0 kg/m2) between PP and antGnRH groups, respectively. On the day of trigger, progesterone was lower in PP compared to antGnRH (0.9 ± 0.7, vs. 1.5 ± 1.2 ng/ml, p < .001), whereas no significant differences existed in estradiol or LH. On the day after trigger, lower progesterone in PP vs. antGnRH (10.8 ± 6.0 vs. 13.4 ± 7.9 ng/ml, p=.002) was observed. No differences were observed in the number of retrieved oocytes or the clinical pregnancies among recipients. Our study shows that endocrine response to DSG differs significantly as compared to antGnRH use for the control of endogenous LH without apparent impact on number of retrieved oocytes or the clinical pregnancies among recipients.

Androgen supplementation in assisted reproduction: where are we in 2019?

PURPOSE OF REVIEW: The purpose of this review is to provide an overview of androgen supplementation in ART with the most updated evidence, from animal studies to its clinical applications in poor ovarian responders (POR) and the future studies to be published. RECENT FINDINGS: Animal studies, has shown that testosterone supplementation, can be an option to increase the recruitable follicular pool in POR. However, the potential mechanism of action, dose, and duration of treatment is still under investigation. Early studies in humans reported promising results in favor of androgens [dehydroepiandrosterone (DHEA) or testosterone] in POR. Nevertheless, recent evidence does not appear to follow the initial results, whereas the type, dose, and duration of testosterone administration appear to be crucial for treatment effect. SUMMARY: Testosterone seems to play an essential role in regulating ovarian function. However, it is worrisome that androgens are used off-label, despite that the available evidence is weak. Although testosterone supplementation may be beneficial in POR, published studies have used inconsistent doses and duration of administration. An ongoing trial (T-TRANSPORT trial) for the first time aims to provide conclusive evidence on whether transdermal testosterone administration can improve the reproductive outcomes in patients undergoing IVF/ICSI.

Ultrasonographically diagnosed dermoid cysts do not influence ovarian stimulation response in an in vitro fertilization cycle.

To determine if patients with a DC respond similarly to ovarian stimulation when compared to patients without a DC. Infertility patients with a DC that underwent IVF between January 2009 and December 2016 were included. A cystic mass with mixed echogenicity, internal echoes similar to thick bands, fatty-fluid level, or an echogenic tubercle with acoustic shadow (Rokitansky nodule) within two years of the cycle characterized the diagnosis. The z-score compared the standard deviations (SDs) in patients with/without a DC and were compared to a nomogram (expected oocytes minus oocytes obtained divided by the SD), adjusted for age and number of oocytes retrieved, built utilizing cycles from noninfertile female patients. Thirty-nine patients with DC and 7839 patients without DC were identified. The mean number of oocytes (8.6 ± 5.8 vs. 8.5 ± 7.7, p = .43) and MIIs (6.7 ± 4.7 vs. 7.0 ± 6.7, p = .74) retrieved were similar. When cycles with and without a DC were compared to the nomogram (z-score of 0), cycles with a DC presented a z-score for ovarian response of 0.1921 SDs from the mean, and patients without DC presented a z-score of -0.2065 SDs from the mean (similar and less than -1.0). After building a population 'normal' response as a template, patients with and without a DC responded similar to COS.

Ovarian stimulation for preimplantation genetic testing.

A narrative review of the management of controlled ovarian stimulation in patients undergoing preimplantation genetic testing is presented. An electronic search was performed to identify research publications that addressed ovarian stimulation and preimplantation genetic testing published until December 2017. Studies were classified in decreasing categories: randomized controlled trials, prospective controlled trials, prospective non-controlled trials, retrospective studies and experimental studies. The aim of controlled ovarian stimulation has shifted from obtaining embryos available for transfer to yielding the maximum embryos available for biopsy to increase the odds of achieving one euploid embryo available for transfer, without the distress of inducing ovarian hyperstimulation syndrome or inadequate endometrium receptivity as vitrification and deferred embryo transfer usually will be planned. The present narrative review summarizes all treatment-related variables as well as stimulation strategies after controlled ovarian stimulation that could help patients undergoing an in vitro fertilization cycle coupled with preimplantation genetic testing, including the number of oocytes needed to achieve one healthy live birth, oral contraceptive pill usage, the role of mild ovarian stimulation or random-start stimulation, the stimulation protocol and type of gonadotropin of choice, the novel progesterone protocols, agonist or dual trigger as a final oocyte maturation trigger, the accumulation of oocytes/embryos and the optimal interval before proceeding with a subsequent controlled ovarian stimulation or the optimal medication to link stimulation cycles. The discussion is being presented according to how questions are posed in clinical practice. The aim of ovarian stimulation has shifted from obtaining embryos available for transfer to yielding the maximum embryos available for biopsy to increase the odds of achieving one euploid embryo available for transfer.

Can anti-Müllerian hormone predict success outcomes in donor sperm inseminations?

Anti-Müllerian hormone (AMH) is a useful biomarker to predict the ovarian response to controlled ovarian stimulation (COS) for IVF. However, currently there is a lack of evidence for the role of ovarian reserve markers when there is no need of COS. The aim of this study was to evaluate the usefulness of AMH to predict the outcomes of donor sperm insemination cycles in non-infertile women. A retrospective study including 139 healthy women, who underwent 348 intrauterine insemination (IUI) cycles with donor sperms under the stimulated or natural cycles, was conducted. All patients had an AMH evaluation performed before starting the first IUI attempt. AMH levels were similar in both, women who conceived and those who did not (2.00 ± 1.52 vs. 1.88 ± 1.64 ng/ml; p = .45). The area under the ROC curve in predicting pregnancy for AMH was 0.53. After adjusting for other confounding variables, the multivariate analysis revealed that AMH was not associated with pregnancy (aOR 0.89; 95% CI 0.57-1.37). We conclude that AMH is not predictive of pregnancy in healthy non-infertile women who perform IUI with donor sperm. These findings suggest the low capability of AMH to predict fertility when no COS is needed.

Linking back-to-back stimulation cycles with oral contraceptives or progestins in women undergoing embryo accumulation for preimplantation genetic testing, a retrospective study.

This retrospective study was carried out to determine which strategy is associated with improved outcomes in two back-to-back cycles when undergoing embryo accumulation. Eighty patients with two stimulation cycles performed with <45 days between retrievals between Jan'16-Mar'17 were included. Patients were segregated according to the strategy used to link stimulations: spontaneous menses (SM), vaginal micronized progesterone (VMP) or oral contraceptive pills (OCP). Main outcome measure was oocytes retrieved. The oocytes retrieved difference between cycles was -0.9 in SM, -1.5 in VMP and +0.4 in OCPs. Although not statistically significant, more oocytes retrieved were observed in the 2ndcycle when OCPs were used (9.0 ± 3.7 vs. 9.4 ± 4.1)? whereas fewer oocytes retrieved were observed when SM (9.4 ± 3.9 vs. 8.5 ± .0) or VMP (9.8 ± 5.7 vs. 8.2 ± 4.4) were used. After adjusting for age, gonadotropins and stimulation days (2nd cycle) and treatment group in an ANCOVA model, no treatment was associated with a higher average number of oocytes retrieved (power: 14.9%) or a higher difference of oocytes retrieved (power: 22.3%). Although no statistical significance was reached, OCPs were observed to achieve higher average and positive difference of oocytes retrieved in the 2nd cycle.

Clinical success of IUI cycles with donor sperm is not affected by total inseminated volume: a RCT.

STUDY QUESTION: What is the impact on live birth rates (LBR) when a donor IUI (dIUI) cycle is performed with an insemination volume of 0.5 mL versus the usual 0.2 mL? SUMMARY ANSWER: LBR after a dIUI cycle is no different when performed with 0.5 versus 0.2 mL. WHAT IS ALREADY KNOWN: An IUI has an important role in the treatment of severe male infertility, and is often used in same-sex female couples and single parents. Different variables have been studied to determine factors correlated with clinical outcomes (IUI scheduling, ovarian stimulation, sperm parameters) but little is known about the inseminated volume. The use of conical bottom test tubes could contribute substantially to the loss of inseminated spermatozoa because it precludes the total recovery of the sample. Additionally, the insemination catheter could uphold this reduction causing sperm adhesion on the inner walls of the insemination catheter, decreasing even more the total inseminated volume. It is expected that utilizing an IUI approach that increases sperm volume in the fallopian tubes (0.5 mL rather than 0.2 mL) at the time of ovulation will lead to higher LBRs. To avoid bias related to sperm quality, the study population was restricted to dIUI cycles. STUDY DESIGN SIZE AND DURATION: A parallel-group, double-blinded, RCT, including patients undergoing natural or stimulated dIUI, was performed between March 2013 and April 2015. dIUI cycles (n = 293) were randomized through a computer-generated list to undergo insemination with 0.2 mL (control group) or 0.5 mL (study group), of which 24 were excluded (protocol deviation) and 269 received the allocated intervention. Patients with the presence of tubal factor infertility, grades III-IV endometriosis, >3 previous dIUI cycles or with ≥3 follicles >14 mm were excluded. The study was designed with 80% power to detect a 5% difference in LBR with a reference of 15% and a two-tailed 5% significance level. The required sample size was 118 per group. PARTICIPANTS/MATERIALS SETTING AND METHOD: There were 143 cycles (0.2 mL group) and 126 cycles (0.5 mL group). The primary end-point of the trial was LBR per dIUI cycle in both treatment groups. Clinical pregnancy rate and miscarriage rate were evaluated as secondary outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: No adverse events were reported during the study trial. Study groups (0.2 versus 0.5 mL, respectively) were similar in age (35.8 ± 3.9 versus 35.4 ± 4.0 years: mean±SD), and had similar anti-Mullerian hormone levels (2.2 ± 1.8 versus 2.0 ± 1.5 ng/mL), basal antral follicle count (13.2 ± 6.4 versus 13.6 ± 6.0), BMI (23.5 ± 3.9 versus 23.7 ± 4.1 kg/m2), number of follicles >17 mm (1.1 ± 0.5 versus 1.1 ± 0.5), total gonadotrophin dose (553.1 ± 366.3 versus 494.6 ± 237.1 IU), and total motile sperm count (8.22 ± 7.1 versus 7.7 ± 5.7 million). Similar clinical pregnancy rates (18.9% (27/143) versus 19.8% (25/126), NS), LBRs (15.4% (22/143) versus 19.0% (24/126), NS) and miscarriage rates (18.5% (5/27) versus 4.0% (1/25), NS) were observed between groups. LIMITATIONS REASONS FOR CAUTION: The study was not powered to detect differences in the secondary outcomes, clinical pregnancy and miscarriage rates. The randomization was performed at the dIUI cycle level, therefore, the results are reported as success rate per dIUI cycle rather than per patient. WIDER IMPLICATIONS OF THE FINDINGS: This is the first RCT to show that the inseminated volume is not correlated with the probability of a live birth. The miscarriage rate was higher in the 0.2 mL group, although this difference was not statistically significant. If the lower miscarriage rate observed in the 0.5 mL group is confirmed, this could be related to the presence of uterine contractions similar of those generated during sexual intercourse, which may be implicated in the inception of early biochemical embryo-endometrium communication. STUDY FUNDING/COMPETING INTERESTS: All authors declare having no conflict of interest with regard to this trial. No funding was received for this study. This research was performed under the auspices of 'Càtedra d'Investigació en Obstetrícia I Ginecologia' of the Department of Obstetrics, Gynaecology and Reproductive Medicine, Hospital Universitari Quiron-Dexeus, Universitat Autònoma de Barcelona. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (Identifier: NCT03006523).

Hatching status before embryo transfer is not correlated with implantation rate in chromosomally screened blastocysts.

STUDY QUESTION: Do the reproductive outcomes from the transfer of fully hatched (FH) blastocysts differ from those of not fully hatched (NFH) blastocysts? SUMMARY ANSWER: Biochemical pregnancy rate (BPR), implantation rate (IR), live birth rate (LBR) and early pregnancy loss (EPL) rate are similar in FH and NFH single euploid blastocyst embryo transfers. WHAT IS KNOWN ALREADY: The use of extended culture and PGS often leads to transfer of an embryo that is well developed and frequently FH from the zona pellucida. Without the protection of the zona, an FH embryo could be vulnerable to trauma during the transfer procedure. To date, no other study has evaluated the reproductive competence of an FH blastocyst transfer. STUDY DESIGN, SIZE, DURATION: The retrospective study included 808 patients who underwent 808 cycles performed between September 2013 and July 2015 at a private academic IVF center. Of these, 436 cycles entailed transfer of a NFH blastocyst (n = 123 fresh transfer, n = 313 frozen/thawed embryo transfer (FET)) and 372 cycles entailed transfer of an FH blastocyst (n = 132 fresh, 240 FET). Fresh and FET cycles and associated clinical outcomes were considered separately. LBR was defined as the delivery of a live infant after 24 weeks of gestation. PARTICIPANTS/MATERIALS, SETTING, METHOD: Trophectoderm biopsies were performed on Day 5 (d5) or 6 (d6) for embryos meeting morphology eligibility criteria (set at ≥3BC). Morphologic grading was determined using a modified Gardner-Schoolcraft scale prior to transfer. A single euploid embryo was selected for transfer per cycle on either the morning of d6, for fresh transfers or 5 days after progesterone supplementation for patients with transfer in an FET cycle. Embryos were classified as NFH (expansion Grade 3, 4 or 5) or FH (expansion Grade 6) cohorts. The main outcome measure was IR. MAIN RESULTS AND THE ROLE OF CHANCE: In the fresh transfer group, IR was similar between NFH and FH cycles (53.7% versus 55.3%, P = 0.99, odds ratio (OR) 0.9; 95% confidence interval (CI) 0.6-1.5). Secondary outcomes were also statistically similar between groups: BPR (65.9% versus 66.7%, OR 1.0; 95% CI: 0.6-1.6), LBR (43.1% versus 47.7%, P = 0.45, OR 1.2; 95% CI: 0.7-1.9) and EPL rate (22.8% versus 18.2%, OR 1.3; 95% CI: 0.7-2.4). After adjusting for age, BMI, endometrial thickness at the LH surge and oocytes retrieved in a logistic regression (LR) model, the hatching status remained not associated with IR (P > 0.05). In the FET cycles, IR was similar between NFH and FH cycles (62.6% versus 61.7%, OR 1.0; 95% CI: 0.7-1.5). Secondary outcomes were similar between groups: BPR (74.1% versus 72.9%, respectively, OR 1.1; 95% CI: 0.7-1.6), LBR (55.0% versus 50.0%, OR 0.8; 95% CI: 0.6-1.1) and EPL rate (18.9% versus 22.9%, respectively, OR 0.8; 95% CI: 0.5-1.2). After adjusting for age, BMI, endometrial thickness at the LH surge and oocytes retrieved in an LR model, the hatching status was not shown to be associated with implantation (P > 0.05). LIMITATIONS, REASONS FOR CAUTION: Limitations include the retrospective design and data from a single institution. Additionally, the study was limited to patients that developed high-quality blastocysts suitable for biopsy. WIDER IMPLICATIONS OF THE FINDINGS: The results suggest that FH embryos are not more fragile or less likely to implant when compared to NFH counterparts. We found no evidence of altered IR or other clinical outcomes in the transfer of FH euploid embryos. STUDY FUNDING/COMPETING INTERESTS: JG is funded by MSTP grant T32 GM007280 (NIH). No additional funding was received. There are no conflicts of interest to declare..

Do elevated TSH levels predict early pregnancy loss in ART patients?

INTRODUCTION: The upper limit of normal TSH has been revised from 5 mIU/L to 2.5 mIU/L. We sought to evaluate IVF patients and the association between abnormal TSH and early pregnancy loss. METHODS: A retrospective study of patients who had TSH levels measured within the 2 weeks prior to their fresh autologous IVF cycles (2002-2014). Cohorts were stratified by oocyte age (<35, [35-38), [38-41), [41-43) and ≥43 years), and TSH level [(0-0.5], (0.5-2.5], (2.5-5], and (5-23) mIU/L]. Patients were followed until pregnancy loss or delivery. Model was assessed by chi-square of ANOVA with significance at p < 0.05. RESULTS: TSH was abnormally elevated (>5 mIU/L), mildly elevated ((2.5-5] mIU/L) or suppressed (≤0.5 mIU/L) in 46, 317 and 65 of the 1201 total cycles, respectively. Treatment resulted in 630 pregnancies, 524 clinical pregnancies and 409 deliveries. Pregnancy loss rates were increased in patients ≥38 yo (p < 0.001) but not [35-38) yo (p = 0.40) compared with those <35 yo. Early pregnancy loss rate was not associated with TSH level (p > 0.30) compared with euthyroid patients after adjusting for oocyte age. CONCLUSION: Early pregnancy loss rate in IVF patients appears to have no relation to recent TSH levels.

Reproductive outcome is optimized by genomic embryo screening, vitrification, and subsequent transfer into a prepared synchronous endometrium.

PURPOSE: The aim of this study is to compare implantation and live birth rates (LBR) between fresh euploid embryo transfers versus cryo-all cycles with a subsequent embryo transfer into a prepared endometrium. MATERIAL AND METHODS: This is a retrospective cohort study. Patients who underwent an IVF cycle with PGS with trophectoderm biopsy from January 2011 to July 2015 were included. Patients were divided into three groups: "Fresh Only," "Frozen Embryo Transfer ('FET) Only," and "Fresh ET then FET." For "Fresh Only" group (n = 345), PGS results were received within 24 h. For "FET Only" group (n = 514), results were expected after 24 h, and embryos were cryopreserved after biopsy; only FET was performed in this group (no fresh transfer). For "FET with a previous fresh ET" (n = 139) group, patients underwent a fresh ET with a subsequent FET, in which the same cohort of embryos was utilized. The main outcome measures were pregnancy rate (PR), clinical PR, implantation rate (IR), LBR, and early pregnancy loss rate. RESULTS: IRs were statistically higher in the "FET Only" group when compared to the "Fresh Only" group (59.5 vs. 50.6%, p < 0.01) and the "FET with a previous fresh ET" (59.5 vs. 50.6%, p < 0.05). LBR was statistically significant in the "FET Only" group when compared to the "Fresh Only" group (57.6 vs. 46.5 %, p < 0.005) but not when compared to "FET with a previous fresh ET" group (57.6 vs. 47.7%, p = 0.07). CONCLUSIONS: This analysis suggests euploid embryos to be more likely to implant and achieve a LBR in a synthetic FET cycle than in a fresh cycle.

Comparision of Letrozole with Timed Intercourse Versus Clomiphene Citrate with Intrauterine Insemination in Patients with Unexplained Infertility.

OBJECTIVE: To evaluate outcomes of patients with unexplained infertility who underwent letrozole (LET)- stimulated controlled ovarian stimulation (COS) with timed sexual intercourse (IC) as compared to patients treated with clomiphene citrate (CC) and intrauterine insemination (IUI). STUDY DESIGN: A non- randomized, retrospective study where unexplained in- fertility patients (n=7,764). underwent a COS cycle with both LET and timed IC or with CC and IUI from January 2010-June 2014. One group consisted of patients who completed a COS cycle with LET and were instructed to have sexual IC. The other included patients were treated with CC and underwent IUI. Pregnancy rates (PRs) were compared between groups. RESULTS: No statistical difference was observed in each group's age or serum follicule-stimulating hor- mone levels. A statistical significance in LET versus CC-stimulated groups was observed for mean endome- trial thickness (8.3 ± 1.7 vs. 7.9 ± 1.8 mm) and follicular response (2.0 ± 1.0 vs. 2.3 ± 1.3), respectively. Clinical PRs after timed IC were significantly higher in the LET versus CC-stimulated group (15.0% vs 11.8%). Clinical PRs after timed IUI were also significantly higher in the LET versus CC-stimulated group (12.3% vs. 11.5%). Moreover, clinical PRs in LET with IC were significant- ly higher than CC with IUI (15.0% vs. 11.5%). CONCLUSION: Unexplained infertility patients who underwent LET stimulation with IC werefound to have better pregnancy out- comes as compared to those who underwent timed IC.or IUI with CC stimulation.