Female smoking does not affect live birth rate after frozen thawed blastocyst transfer cycle.

PURPOSE: The development of vitrification and blastocyst culture have recently led to a rapidly growing number of single frozen thawed blastocyst transfer (FBT) cycles worldwide. Although the impact of female smoking on spontaneous fertility is well established, its effect on assisted reproductive technologies (ART) outcome is still controversial, and no study has specifically evaluated its effect on FBT cycles' outcome. METHODS: This retrospective study was conducted in all consecutive FBT cycles conducted between 2012 and 2021 in a single University-based ART centre. Endometrial preparation was standard and based on hormonal replacement therapy. One or two blastocysts were transferred according to couple's history and embryo quality. Female smoking status was recorded for each cycle, and the association between female smoking status and Live Birth Rate (LBR) after FBT cycle was evaluated with univariate and multivariate analysis. RESULTS: A total of 1537 FBT cycles performed in non-smoking women and 397 FBT cycles performed in smoking women were included in the analysis. No independent association between female smoking status and LBR in FBT cycles was found after logistic regression (OR=1.07 [0.79-1.45], p = 0.649). CONCLUSION: Our study suggests that female smoking might not impair endometrial receptiveness in non-stimulated FBT cycles. Further studies should nevertheless consider assessing more precisely the current smoking exposure.

[Pre-implantation genetic testing: Comparison between cleavage stage and blastocyst biopsy]. / Le diagnostic préimplantatoire : comparaison des stratégies de biopsie embryonnaire au stade clivé et au stade blastocyste.

OBJECTIVES: Preimplantation genetic testing (PGT) refers to the set of techniques for testing whether embryos obtained through in vitro fertilization have genetic defect. There is a lack of global standardization regarding practices between countries or even from one center to another. In ours, biopsies are preferably performed on day 3 embryos, but also at the blastocyst stage on day 5. The blastocyst biopsy often requires systematic freezing of the embryos before obtaining the genetic results, whereas day 3 biopsy allows fresh embryo transfer of the healthy or balanced embryo after getting the genetic results. We wanted to compare the chances of success for couples performing PGT in our center according to the day of the biopsy. METHODS: For this, we carried out a retrospective monocentric study including all PGT cycles performed between 2016 and 2019 divided into two groups: day 3 or day 5 biopsy. RESULTS: There was no significant difference in terms of live birth rate (P=0.7375) after fresh embryo transfers, as well for pregnancy rates, clinical pregnancy rates, implantation rates and miscarriage rates. On the other hand, we observed higher live birth rates after frozen-thawed embryo transfer when the biopsy was performed on day 5 rather on day 3 (P=0.0001). We also wanted to assess what was the most efficient biopsy strategy in our laboratory. Our rates of useful embryos were similar regardless of the day of the biopsy (34% in D3 and 37.7% in D5, P=0.244). No statistical difference was found in the number of unnecessarily biopsied embryos in the two groups. But still, the percentage of embryos biopsied on D5 and immediately frozen was 42.8% (118 blastocysts), while no embryo biopsied on D3 led to this case. CONCLUSION: Therefore, our results are in favor of generalization of the D5 biopsy as the international standard. However, the organizational, financial and logistical implications that this technic would impose make it unsystematic in our center.

IVF outcomes in patients with a history of bariatric surgery: a multicenter retrospective cohort study.

STUDY QUESTION: How does a history of dramatic weight loss linked to bariatric surgery impact IVF outcomes? SUMMARY ANSWER: Women with a history of bariatric surgery who had undergone IVF had a comparable cumulative live birth rate (CLBR) to non-operated patients of the same BMI after the first IVF cycle. WHAT IS KNOWN ALREADY: In the current context of increasing prevalence of obesity in women of reproductive age, weight loss induced by bariatric surgery has been shown to improve spontaneous fertility in obese women. However, little is known on the clinical benefit of bariatric surgery in obese infertile women undergoing IVF. STUDY DESIGN, SIZE, DURATION: This exploratory retrospective multicenter cohort study was conducted in 10 287 IVF/ICSI cycles performed between 2012 and 2016. We compared the outcome of the first IVF cycle in women with a history of bariatric surgery to two age-matched groups composed of non-operated women matched on the post-operative BMI of cases, and non-operated severely obese women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The three exposure groups of age-matched women undergoing their first IVF cycle were compared: Group 1: 83 women with a history of bariatric surgery (exposure, mean BMI 28.9 kg/m2); Group 2: 166 non-operated women (non-exposed to bariatric surgery, mean BMI = 28.8 kg/m2) with a similar BMI to Group 1 at the time of IVF treatment; and Group 3: 83 non-operated severely obese women (non-exposed to bariatric surgery, mean BMI = 37.7 kg/m2). The main outcome measure was the CLBR. Secondary outcomes were the number of mature oocytes retrieved and embryos obtained, implantation and miscarriage rates, live birth rate per transfer as well as birthweight. MAIN RESULTS AND THE ROLE OF CHANCE: No significant difference in CLBR between the operated Group 1 patients and the two non-operated Groups 2 and 3 was observed (22.9%, 25.9%, and 12.0%, in Groups 1, 2 and 3, respectively). No significant difference in average number of mature oocytes and embryos obtained was observed among the three groups. The implantation rates were not different between Groups 1 and 2 (13.8% versus 13.7%), and although lower (6.9%) in obese women of Group 3, this difference was not statistically significant. Miscarriage rates in Groups 1, 2 and 3 were 38.7%, 35.8% and 56.5%, respectively (P = 0.256). Live birth rate per transfer in obese patients was significantly lower compared to the other two groups (20%, 18%, 9.3%, respectively, in Groups 1, 2 and 3, P = 0.0167). Multivariate analysis revealed that a 1-unit lower BMI increased the chances of live birth by 9%. In operated women, a significantly smaller weight for gestational age was observed in newborns of Group 1 compared to Group 3 (P = 0.04). LIMITATIONS, REASONS FOR CAUTION: This study was conducted in France and nearly all patients were Caucasian, questioning the generalizability of the results in other countries and ethnicities. Moreover, 950 women per group would be needed to achieve a properly powered study in order to detect a significant improvement in live birth rate after bariatric surgery as compared to infertile obese women. WIDER IMPLICATIONS OF THE FINDINGS: These data fuel the debate on the importance of pluridisciplinary care of infertile obese women, and advocate for further discussion on whether bariatric surgery should be proposed in severely obese infertile women before IVF. However, in light of the present results, infertile women with a history of bariatric surgery can be reassured that surgery-induced dramatic weight loss has no significant impact on IVF prognosis. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by unrestricted grants from FINOX-Gédéon Richter and FERRING Pharmaceuticals awarded to the ART center of the Clinique Mathilde to fund the data collection and the statistical analysis. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NCT02884258.

Evolution of serum Anti-Müllerian Hormone (AMH) level in young women treated with chemotherapy for breast cancer according to basal AMH level.

OBJECTIVE: Serum AMH level has been shown to decrease in women treated for breast cancer in several studies. However, whether basal AMH status affects AMH dynamics during chemotherapy remains to be clarified. The objective of this study was to compare serum AMH dynamics in young women with either low, normal or high basal serum AMH level at diagnosis, during and after treatment with chemotherapy for breast cancer. STUDY DESIGN: In this secondary analysis of a prospective cohort study, serum AMH was measured during and after chemotherapy in 239 women of reproductive age diagnosed with breast cancer and treated with chemotherapy. The association between AMH dynamics throughout chemotherapy and during follow-up and basal AMH status, i.e. low AMH (<1 µg/l, <7 pmol/l), normal AMH (1-4.9 µg/l, 7-36 pmol/l) and high AMH (≥5 µg/l, >36 pmol/l), was evaluated. Menses occurrence was also recorded. RESULTS: A total of 21 women had low, 154 had normal and 64 had high basal AMH level. Serum AMH rapidly decreased during chemotherapy in all groups, and its variation during chemotherapy and follow-up was not significantly different between the 3 groups. CONCLUSION: No association was found between AMH variation during chemotherapy and follow-up, and basal AMH level at diagnosis. However, women with high basal AMH levels have significantly higher AMH levels throughout chemotherapy and follow-up than women with normal or low basal AMH levels at diagnosis.

Female obesity does not impact live birth rate after frozen-thawed blastocyst transfer.

STUDY QUESTION: Does female obesity affect live birth rate after frozen-thawed blastocyst transfer? SUMMARY ANSWER: Live birth rate was not statistically different between obese and normal weight patients after frozen-thawed blastocyst transfer (FBT). WHAT IS KNOWN ALREADY: Obesity is a major health problem across the world, especially in women of reproductive age. It impacts both spontaneous fertility and clinical outcomes after assisted reproductive technology. However, the respective impact of female obesity on oocyte quality and endometrial receptivity remains unclear. While several studies showed that live birth rate was decreased in obese women after fresh embryo transfer in IVF cycle, only two studies have evaluated the effects of female body mass index (BMI) on pregnancy outcomes after frozen-thawed blastocyst transfer (FBT), reporting conflicting data. STUDY DESIGN, SIZE, DURATION: This retrospective case control study was conducted in all consecutive frozen-thawed autologous blastocyst transfer (FBT) cycles conducted between 2012 and 2017 in a single university-based centre. A total of 1415 FBT cycles performed in normal weight women (BMI = 18.5-24.9 kg/m2) and 252 FBT cycles performed in obese women (BMI ≥ 30 kg/m2) were included in the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Endometrial preparation was standard and based on hormonal replacement therapy. One or two blastocysts were transferred according to couple's history and embryo quality. MAIN RESULTS AND THE ROLE OF CHANCE: Female and male age, smoking status, basal AMH level and type of infertility were comparable in obese and normal weight groups. Concerning FBT cycles, the duration of hormonal treatment, the stage and number of embryos (84% single blastocyst transfer and 16% double blastocysts transfer) used for transfer were comparable between both groups. Mean endometrium thickness was significantly higher in obese than in normal weight group (8.7 ± 1.8 vs 8.1 ± 1.6 mm, P < 0.0001). Concerning FBT cycle outcomes, implantation rate, clinical pregnancy rate and live birth rate were comparable in obese and in normal weight groups. Odds ratio (OR) demonstrated no association between live birth rate after FBT and female BMI (OR = 0.92, CI 0.61-1.38, P = 0.68). LIMITATIONS, REASONS FOR CAUTION: Anthropometric parameters such as hip to waist ratio were not used. Polycystic ovarian syndrome status was not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: Our study showed that live birth rate after frozen-thawed blastocyst transfer was not statistically different in obese and in normal-weight women. Although this needs confirmation, this suggests that the impairment of uterine receptivity observed in obese women after fresh embryo transfer might be associated with ovarian stimulation and its hormonal perturbations rather than with oocyte/embryo quality. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Prospective evaluation of serum anti-Müllerian hormone dynamics in 250 women of reproductive age treated with chemotherapy for breast cancer.

AIM: Women of reproductive age with breast cancer generally receive gonadotoxic chemotherapy. Fertility issues are of great concern for them. However, little is known on ovarian damage during chemotherapy and its evolution during long-term follow-up. The aim of this study was to provide a detailed description of serum anti-Müllerian hormone (AMH) evolution during chemotherapy and 24-month follow-up. METHODS: This prospective cohort study was conducted in 250 patients, aged 18-39 years, diagnosed with breast cancer and treated with adjuvant/neoadjuvant chemotherapy. Each patient underwent blood AMH measurement at each chemotherapy cycle, and at 6, 12 and 24 months after chemotherapy. Menses occurrence was also recorded. RESULTS: Mean basal AMH level was 4.19 ± 4.84 ng/mL, and was negatively correlated with age. Serum AMH level rapidly decreased in all patients after each chemotherapy cycle to undetectable levels in most of them, and slowly increased in 45% of the patients during the 24-month follow-up. AMH decrease was significantly associated with age and basal AMH level, but not with cyclophosphamide dose and tamoxifen use. The prevalence of chemotherapy-related amenorrhoea was 92.4% at the end of chemotherapy; women with amenorrhoea being significantly older and having lower basal AMH than women who resumed menses. CONCLUSIONS: Our study confirms rapid and deep ovarian reserve alteration in young women receiving chemotherapy for breast cancer, and shows moderate AMH recovery in some patients. Although AMH cannot alone predict fertility potential, these new data emphasise the need for post-treatment ovarian insufficiency follow-up, strongly support the use of fertility preservation strategies and may provide new tools for improved counselling.

Anti-müllerian hormone levels and evolution in women of reproductive age with breast cancer treated with chemotherapy.

BACKGROUND: Long-term consequences of cancer treatments in young women, and especially fertility issues, are gaining attention as survival rates increase. Breast cancer is the most frequent malignancy in women of reproductive age. AIM: The purpose of this review is to describe serum anti-müllerian hormone (AMH) level at diagnosis and its evolution during and after chemotherapy in women of reproductive age treated for breast cancer. Second, the impact of taxanes on AMH, the association between AMH and amenorrhea, and the comparison of AMH with other hormonal markers of ovarian reserve were studied. METHODS: A systematic PubMed search was conducted on all articles, published up to April 2016 and related to AMH in women suffering from breast cancer using the following key words: AMH, müllerian-inhibiting substance, ovarian reserve, ovarian function, breast cancer, gonadotoxicity, ovarian toxicity, amenorrhea, chemotherapy, and menopause. RESULTS: AMH levels rapidly fall down to undetectable levels in most women during chemotherapy and generally persist at very low levels in most women after the treatment. Taxanes seem to impact negatively ovarian function, but data on ovarian reserve are scarce. AMH is a predictor of the occurrence of chemotherapy-related amenorrhea and is the most relevant hormonal marker of ovarian reserve. CONCLUSION: Serum AMH is a relevant tool for ovarian reserve assessment and follow-up during treatment in premenopausal women with breast cancer. Further large prospective studies are necessary to determine its predictive interest for post-treatment residual fertility, and eventually use it in fertility preservation counseling before treatment initiation.

[Congenital bilateral absence of vas deferens: From diagnosis to assisted reproductive techniques - the experience of three centers]. / Absence bilatérale des canaux déférents : du diagnostic à l'assistance médicale à la procréation. Expérience de 3 centres.

OBJECTIVES: To review the management with assisted reproductive technologies (ART) of men with congenital bilateral absence of vas deferens (CBAVD), associated with cystic fibrosis or not, after surgical retrieval [epididymal aspiration (MESA) or testicular biopsy (TESE)]. METHODS: Multicenter retrospective study made of 2 groups: CBAVD and cystic fibrosis (CF) or CBAVD only (CF-RD). Two centers performed MESA (Brest and Nantes) and one TESE (Rennes). Sperm numeration, motility, vitality, morphology and nuclear maturity were measured in both centers performing MESA. Fertilization rate (TF) and cumulated progressive pregnancy rate by retrieved oocyte (TGC) were compared between centers following ART. RESULTS: Ninety patients underwent surgical retrieval between January 1996 and March 2013, 30 in the CF group and 60 in the CF-RD group. Semen parameters were comparable between groups and centers. Fifty-eight (22 in the CF group and 36 in the CF-RD group) patients received ART between April 1996 and October 2014. TF was 50% and 52% and TGC 26% and 32% in the CF group and CF-RD groups, respectively. The results did not differ between groups but TGC was higher in Rennes than in the other two centers. CONCLUSION: Both semen parameters and ART results are comparable and similar to those reported in the literature. As shown by the results obtained in Rennes, TESE seems to be more effective.

Identification of genital tract markers in the human seminal plasma using an integrative genomics approach.

STUDY QUESTION: Can protein biomarkers of the male genital tract be identified in human seminal plasma? SUMMARY ANSWER: We identified potential biomarkers for each of the organs participating in the secretions of the human seminal plasma. WHAT IS KNOWN ALREADY: The seminal plasma fulfills critical functions for fertility by providing spermatozoa with a protective milieu, promoting their final maturation and modulating the immune responsiveness of the female reproductive tract. It is also considered to be a promising source of biomarkers of male infertility and/or pathologies of the male genital tract. STUDY DESIGN, SIZE, DURATION: This study combines proteomic analyses of normal seminal plasma together with transcriptomic gene expression profiling of human healthy tissues. MATERIALS, SETTING, METHODS: Non-liquefied seminal plasma proteins from a healthy donor were prefractionated using two sequential Proteominer™ libraries. Eight subproteome fractions were collected, trypsin digested and subjected to three successive mass spectrometry analyses for peptide characterization. The list of identified proteins was compared with and merged with other available data sets of the human seminal plasma proteome. The expression of corresponding genes was then investigated using tissue transcriptome profiles to determine where, along the male reproductive tract, these proteins were produced. Finally, tissue specificity of a selected subset of biomarker candidates was validated on human tissues. MAIN RESULTS AND THE ROLE OF CHANCE: We first performed a proteomic analysis of the human seminal plasma and identified 699 proteins. By comparing our protein list with other previous proteomic data sets, we found that 2545 unique proteins have been described so far in the human seminal plasma. We then profiled their expression at the gene level and identified 83 testis, 42 epididymis, 7 seminal vesicle and 17 prostate candidate protein markers. For a subset of testis-specific candidates, i.e. TKTL1, LDHC and PGK2, we further validated their germ cell expression and demonstrated that such markers could distinguish between semen from fertile and infertile men. LIMITATIONS, REASONS FOR CAUTION: While some of the markers we identified are well-known tissue-specific products, further dedicated studies to validate the biomarker status of new candidates will be required. Additionally, whether or not the abundance of these proteins is indeed decreased in some specific pathological situations remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS: Using an integrative genomics approach, we identified biomarker candidates for each of the organs participating in the seminal plasma production. In this study, we essentially focused on germ cell markers and their potential application for the diagnosis of male infertility. Other types of markers also deserve a focused attention given their potential predictive value for various reproductive disorders, notably for prostate cancers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Proteomics Core Facility at Biogenouest and was funded by Conseil Régional de Bretagne, IBiSA and Agence de la Biomédecine grants. The authors declare that there exists a competing financial interest in this work that is related to a patent application on the use of identified germ cell-specific proteins in an antibody-based assay (Fertichip™) to predict the successful testicular biopsy outcomes in human non-obstructive azoospermia.

[Ovarian cryopreservation: what future?]. / La congélation ovarienne: quel avenir?

Ovarian cortex cryobanking is a technique of fertility preservation that led to the birth of about 20 children in the world since 2004. Its main limitations are low follicular survival rate after thawing and transplantation and the risk of disease reintroduction. A lot of research is currently conducted in order to optimize both efficacy and safety of the graft and to develop alternative techniques to restore fertility. These advances will allow oncologists to offer this technique to a growing number of patients in the context of fertility preservation (for medical or social indications), but also in other indications such as puberty induction or menopause treatment.

[Sarcoidosis-like granulomatosis revealing a tertiary syphilis]. / Granulomatose pseudosarcoïdosique révélant une syphilis tertiaire.

Numerous disorders can cause a systemic granulomatosis. We report a patient who presented a biopsy proven granulomatous skin eruption, fever, and atypical thoracic pain. Electrocardiogram showed a first-degree atrioventricular heart bloc. During follow-up he developed a panuveitis and oral corticosteroids were started. A diagnosis of systemic sarcoidosis was considered. Because of unfavourable ophthalmologic outcome, investigations were enlarged and revealed a highly positive serology for syphilis and VDRL both in serum and cerebrospinal fluid. Clinical outcome with penicillin G therapy was favorable. This observation reminds us the clinical polymorphism of syphilis, which can be presented as a systemic granulomatosis.