Sperm DNA fragmentation index does not correlate with blastocyst aneuploidy or morphological grading.
Gat Itai,Tang Katelynn,Quach Kevin,Kuznyetsov Valeriy,Antes Ran,Filice Melissa,Zohni Khaled,Librach Clifford
High DNA fragmentation index (DFI) may be associated with poor outcome after IVF. Our aim was to determine whether DFI impacts blastocyst quality or clinical outcome. This retrospective study included 134 couples who underwent 177 IVF-ICSI and pre-implantation genetic screening (PGS) cycles during January 1st, 2014-March 31st, 2016 and had documented previous DFI. Group 1 (DFI>30%) encompassed 25 couples who underwent 36 cycles; Group 2 (DFI 15-30%) included 45 couples and 57 cycles; group 3 (DFI<15%) included 64 couples and 83 cycles. Male partners within group 1 were older (45.1 compared to 40.6 and 38.3 years, respectively, p<0.05), had higher BMI (32.4 compared to 26.6 and 25.8 respectively, p<0.05) and lower sperm count and motility (46*106/ml and 35.5%, respectively) compared to groups 2 (61.8*106/ml and 46.6%, respectively) and 3 (75.8*106/ml and 55.1%, respectively, p<0.05). Female parameters including ovarian reserve and response and embryo development were similar. Total numbers of biopsied blastocysts were 116, 175 and 259 in groups 1, 2 and 3, respectively. PGS for 24 chromosomes revealed comparable euploidy rate of 46-50.4%, with a similar morphological classification. No significant differences were found regarding pregnancy rates or pregnancy loss. It seems that DFI doesn't correlate with blastocyst aneuploidy or morphological grading.
Sperm DNA fragmentation index does not correlate with the sperm or embryo aneuploidy rate in recurrent miscarriage or implantation failure patients.
Bronet F,Martínez E,Gaytán M,Liñán A,Cernuda D,Ariza M,Nogales M,Pacheco A,San Celestino M,Garcia-Velasco J A
Human reproduction (Oxford, England)
BACKGROUND:The aneuploidy rate is higher in poor-quality sperm samples, which also have higher DNA fragmentation index values. The aim of this study was to assess the relationship between sperm DNA fragmentation in samples from infertile men belonging to couples with recurrent miscarriage or implantation failure and the aneuploidy rate in spermatozoa as well as in embryos from patients. METHODS:This prospective study evaluated DNA damage and the aneuploidy rate in fresh and processed (density gradient centrifugation) ejaculated sperm as well as the aneuploidy rate in biopsied embryos from fertility cycles. Fluorescence in situ hybridization was used for the aneuploidy analysis. Results were compared using linear regression and analysis of variance. RESULTS:A total of 154 embryos were evaluated from 38 patients undergoing PGD cycles; 35.2% of the embryos were chromosomally normal. Analysis of the same sperm samples showed an increased DNA fragmentation after sperm preparation in 76% of the patients. There was no correlation between DNA fragmentation and the aneuploidy rate in embryos or in fresh or processed sperm samples. CONCLUSIONS:Sperm DNA fragmentation is not related to chromosomal anomalies in embryos from patients with recurrent miscarriage or implantation failure. However, we cannot rule out the possibility that a relationship between DNA fragmentation and aneuploidy exists for other causes of infertility. Furthermore, the different methods used to evaluate DNA fragmentation may produce different results.
Adequate ovarian follicular status does not prevent the decrease in pregnancy rates associated with high sperm DNA fragmentation.
Frydman Nelly,Prisant Nadia,Hesters Laetitia,Frydman René,Tachdjian Gérard,Cohen-Bacrie Paul,Fanchin Rénato
Fertility and sterility
OBJECTIVE:Potential reparation of sperm DNA fragmentation in the oocyte may disturb any relationship between DNA-damaged sperm and the implantation ability of resulting embryos. To rule out this factor, we analyzed the consequences of sperm DNA fragmentation on IVF-ET outcome in women with healthy ovarian function. DESIGN:Prospective study. SETTING:Teaching hospital, France. PATIENT(S):All 117 women were <38 years old, who combined normal serum day-3 FSH and inhibin B levels with an adequate response to controlled ovarian hyperstimulation. INTERVENTION(S):The DNA fragmentation rate was determined in the raw sperm used for conventional IVF by flow cytometric terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Cycles were sorted into two groups according to whether DNA fragmentation exceeded (high fragmentation [HF], n = 52) or did not exceed (low fragmentation [LF], n = 65) the 50th percentile of values (35%). MAIN OUTCOME MEASURE(S):D2 embryo quality and implantation and ongoing pregnancy rates. RESULT(S):Patients' characteristics, raw semen parameters, fertilization rates, and embryology data were similar in HF and LF groups. Clinical (37.5% vs. 62.5%) and ongoing (23.5% vs. 57.8%) pregnancy rates per ET and implantation rates (24.5% vs. 42.4%) were lower in the HF group than in the LF group. CONCLUSION(S):High sperm DNA fragmentation spares fertilization and top embryo morphology rates but is associated with decreased IVF-ET outcome.
Low anti-Müllerian hormone level is not a risk factor for early pregnancy loss in IVF/ICSI treatment.
Peuranpää P,Hautamäki H,Halttunen-Nieminen M,Hydén-Granskog C,Tiitinen A
Human reproduction (Oxford, England)
STUDY QUESTION:Is a low (<1.0 μg/L) or moderately low (1.0-1.9 μg/L) serum anti-Müllerian hormone (AMH) level a risk factor for early pregnancy loss in IVF/ICSI with a fresh or frozen-thawed embryo transfer (ET)? SUMMARY ANSWER:A low or moderately low serum AMH level does not associate with miscarriage, non-visualized pregnancy loss or overall early pregnancy loss rate in the IVF/ICSI treatment. WHAT IS KNOWN ALREADY:Low AMH predicts poor ovarian response and small oocyte yield in IVF/ICSI treatment, but its value in the evaluation of live birth rate (LBR) is modest. Little is known about the risk of early pregnancy loss in ART among women with low AMH. STUDY DESIGN, SIZE, DURATION:A retrospective cohort study on 1383 women undergoing their first oocyte retrieval for IVF/ICSI in Helsinki University Hospital in Helsinki, Finland, between 2012 and 2016, with all associated fresh (n = 1315) and frozen-thawed (n = 1418) ET cycles finished by August 2018. AMH was measured within 12 months before the IVF/ICSI stimulation. PARTICIPANTS/MATERIALS, SETTING, METHODS:Of all the women, 235 (17.0%) had low (<1.0 μg/L), 278 (20.1%) had moderately low (1.0-1.9 μg/L) and 870 (62.9%) had normal (≥2.0 μg/L) AMH. The primary outcomes were miscarriage, non-visualized pregnancy loss and early pregnancy loss (miscarriage and non-visualized pregnancy loss combined) after fresh or frozen-thawed ET. The impact of AMH on these outcomes was calculated in three populations: among all women who became pregnant, among women with AMH ≤6.0 μg/L and in a population weighted by the inverse probability of becoming pregnant (inverse probability weighting, IPW). The impact of AMH was also assessed on the secondary outcomes, cumulative pregnancy rate (cPR) and cumulative live birth rate (cLBR) across all ET cycles in the woman's first IVF/ICSI. Potential confounders (the woman's age, overweight, smoking, history of endometriosis and underlying medical conditions) adjusted the final results. MAIN RESULTS AND THE ROLE OF CHANCE:Of 1123 pregnancies, 285 (25.4%) ended in non-visualized pregnancy loss and 143 (12.7%) in miscarriage. The LBR was 24.6% per ET (673/2733). Low or moderately low AMH, compared with normal AMH, did not associate with miscarriage or non-visualized pregnancy loss in analyses among all women who became pregnant (adjusted relative risk (RR) for miscarriage vs live birth, 0.70 and 95% CI 0.42-1.17 in low AMH and adjusted RR, 1.00 and 95% CI, 0.68-1.49 in moderately low AMH; adjusted RR for non-visualized pregnancy loss vs live birth, 0.90 and 95% CI, 0.65-1.23 in low AMH and adjusted RR, 1.09 and 95% CI 0.85-1.41 in moderately low AMH), nor did low or moderately low AMH associate with the overall early pregnancy loss rate (adjusted RR for early pregnancy loss vs live birth, 0.86 and 95% CI, 0.68-1.10 in low AMH and adjusted RR, 1.01 and 95% CI, 0.86-1.27 in moderately low AMH). Results remained similar after restricting the analysis to women with AMH ≤6.0 μg/L. Women with low or moderately low AMH had fewer pregnancies and live births than women with normal AMH in their first IVF/ICSI (cPR/cLBR in women with low AMH 50.6/34.0%, moderately low AMH 59.0/36.3% and normal AMH 68.3/49.2%). When the lower probability for pregnancy was considered by using IPW, women with low or moderately low AMH did not have a higher risk for miscarriage, non-visualized pregnancy loss or overall early pregnancy loss compared with women with normal AMH. LIMITATIONS, REASONS FOR CAUTION:The number of miscarriages in women with low AMH was moderately small, limiting the power of the study. The real-world clinical setting of the study restricted the ability to control for all factors causing selection bias. WIDER IMPLICATIONS OF THE FINDINGS:The cLBR was higher among women with normal AMH than among women with low or moderately low AMH in their first IVF/ICSI treatment because these women had more oocytes and embryos. Women with low or moderately low AMH did not have an increased risk for early pregnancy loss. This information is reassuring for couples and useful in counseling. These results are also valuable when assessing the overall effectiveness of IVF/ICSI treatment. STUDY FUNDING/COMPETING INTEREST(S):Research funds from Helsinki University Hospital (no. TYH2018232), Hyvinkää Hospital (no. M3080TUT18) and the Emil Aaltonen Foundation for P.P. Grants from the Paulo Foundation and the Finnish Medical Foundation for H.H. The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER:HUS/138/2017.
Basal Serum Anti-Müllerian Hormone Level as a Predictor of Clinical Outcomes in Freezing-all Embryo Transfer Program.
Li Xiao-Lan,Huang Rui,Fang Cong,Liang Xiao-Yan
Current medical science
As a novel biomarker, there is inconsistent evidence regarding the association between anti-Müllerian hormone (AMH) and live birth rate in freezing-all embryo transfer cycles. We aim to assess the prognostic effect of baseline AMH on clinical outcomes, especially live birth rate in freezing-all embryo transfer cycles. A total of 828 non-polycystic ovary patients that underwent their first frozen-thawed embryo transfers in our center between January 2010 and January 2015 were recruited in this retrospective analysis. Patients were stratified into three groups based on their baseline AMH concentration: low AMH group (<1.4 ng/mL), middle AMH group (1.4-5.8 ng/mL) and high AMH group (>5.8 ng/mL). The results showed that low AMH level was associated with adverse clinical outcomes. The differences in implantation rate (21.9% vs. 43.2% vs. 58.8%, P<0.001), clinical pregnancy rate (32.0% vs. 55.2% vs. 65.7%, P<0.001), live birth delivery rate (21.8% vs. 43.6% vs. 52.7%, P<0.001) and miscarriage rate (31.8% vs. 17.5% vs. 15.4%, P=0.014) among the three groups were statistically significant. After adjusting confounders (i.e. age, baseline FSH level, AFC, endometrium thickness, endometrium preparation protocols, number of embryos transferred, etiologies of infertility), differences in live birth rate, clinical pregnancy rate and implantation rate between groups remained significant. The further age subgroup analysis demonstrated that low AMH concentration was significantly associated with poor outcomes both in young and advanced patients. The area under the curve for serum AMH, age, AFC and FSH were 0.635, 0.634, 0.615 and 0.543 respectively, for predicting live birth. In conclusion, baseline AMH was an independent prognostic factor of live birth rate of freezing-all embryo transfers, but its predictive value on live birth rate was of limited clinical value.
Quality of embryos on day 7 after medium refreshment on day 6: a prospective trial.
Insogna Iris G,Lanes Andrea,Ginsburg Elizabeth S,Racowsky Catherine
Human reproduction (Oxford, England)
STUDY QUESTION:Are embryos that fail to meet biopsy or freezing criteria on day 6 (D6) more likely to meet these criteria on day 7 (D7) if cultured in fresh medium from D6 to D7? SUMMARY ANSWER:Refreshment of medium on D6 did not increase the proportion of usable embryos on D7, with an adverse effect for women ≥40 years old. WHAT IS KNOWN ALREADY:Embryo development in continuous single-step medium, from fertilization to the blastocyst stage, is equivalent to that using a sequential media protocol. However, there remains a theoretical benefit of refreshing the culture environment by transitioning slowly developing D6 embryos to a fresh medium droplet of the same composition, with a renewed source of nutrients and a milieu free of metabolic toxins. STUDY DESIGN, SIZE, DURATION:This was a prospective trial of culture media exposure in which embryos were randomized on D6 to remain in the same culture medium from D3 to D7 (continuous, n = 620) or be moved to fresh medium (fresh, n = 603) on D6, with re-evaluation on D7. Data were collected from IVF cycles, with or without ICSI, between 29 March 2019 and 17 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS:Embryos from 298 women, aged 18-44 years, from cycles with or without preimplantation genetic testing (PGT) that did not meet criteria for biopsy and/or freeze on D6 were included in the study. Embryos were only included if there was a minimum of two embryos meeting the inclusion criteria in any cohort. Only the first cycle undertaken by each woman in the study period from which embryos were randomized was included. MAIN RESULTS AND THE ROLE OF CHANCE:A total of 1254 embryos were randomized from 312 cycles (209 non-PGT and 103 PGT) including 200 women undergoing IVF without PGT and 98 women who underwent PGT. The proportion of usable blastocysts on D7 did not differ between groups: 10.1% (61/603) in fresh versus 9.7% (60/620) in continuous medium (relative risk (RR) 1.05, 95% CI 0.74-1.47)). Embryos from women ≥40 years old had a significantly decreased likelihood of achieving a usable blastocyst on D7 after culture in fresh versus continuous medium: 3.5% versus 12.2%; RR 0.29, 95% CI 0.08-0.98. In total, 9.9% of embryos otherwise discarded on D6 met the criteria for biopsy and/or freeze on D7. LIMITATIONS, REASONS FOR CAUTION:Future work investigating implantation, clinical pregnancy and miscarriage rates with D7 embryos is still needed. WIDER IMPLICATIONS OF THE FINDINGS:Refreshment of medium on D6 did not increase the proportion of usable embryos on D7 overall. Younger women were more likely to develop D7 embryos after refreshment of medium on D6, while an adverse effect was seen in women ≥40 years old. However, by extending the culture of embryos to D7, additional blastocysts become available for clinical use. STUDY FUNDING/COMPETING INTEREST(S):Funding was provided through the Department of Obstetrics and Gynecology at Brigham and Women's Hospital. I.G.I. works with Teladoc Health. A.L. has no disclosures. E.S.G. works as a consultant for Teladoc Health, and a writer and editor for UpToDate and BioMed Central. C.R. is a board member of the American Society for Reproductive Medicine and works with UpToDate. TRIAL REGISTRATION NUMBER:N/A.
Is it the egg or the endometrium? Elevated progesterone on day of trigger is not associated with embryo ploidy nor decreased success rates in subsequent embryo transfer cycles.
Kofinas Jason D,Mehr Holly,Ganguly Nandita,Biley Yelena,Bochkovsky Svetlana,McCulloh David,Grifo Jamie
Journal of assisted reproduction and genetics
PURPOSE:The purpose of our study was to determine if progesterone (P4) values on day of trigger affect certain cycle outcome parameters, ploidy status of embryos, as well as pregnancy outcomes in the subsequent first frozen embryo transfer cycle. METHODS:Two hundred thirty-eight patients undergoing pre-gestational screening and freeze all protocol at our fertility center from 2013 to 2014 were included. Excluded patients were those whom had cancelled cycles prior to egg retrieval as well as cycles utilizing donor eggs. Once patients were identified as eligible for this study, frozen serum from the day of trigger was identified and analyzed using the Siemens Immulite 2000. Number of eggs retrieved, number of available embryos for biopsy, and number of euploid/aneuploid embryos were analyzed. The first frozen embryo transfer cycle was linked to the initial egg retrieval and outcomes including pregnancy rates, and live birth/ongoing pregnancy rates were calculated and analyzed. A discriminatory P4 value of 1.5 ng/ml was set. Group A had P4 values of less than 1.5 ng/ml and group B had P4 values greater than or equal to 1.5 ng/ml. T tests and chi-squared tests were used for statistical analysis. RESULTS:Group A had an average trigger P4 value of 0.87 +/- 0.3 and group B had an average trigger P4 of 2.1 +/- 0.8. Table 1 shows the baseline characteristics of both group A and group B. The only significant difference between the two groups was total gonadotropin dosage (IU) with a p value of 0.02 and estradiol (pg/ml) at trigger, also with a p value of 0.02 (Table 1). Number of eggs retrieved, number of embryos biopsied, number euploid/aneuploid, and non-diagnosis embryos were all non-significant. Chi-square analysis was used to compare pregnancy rates between the two groups after the first frozen embryo transfer cycle. Group A had a pregnancy rate of 72 % and Group B had a pregnancy rate of 66.7 %, which was not significant. Ongoing pregnancy/live birth rates were 65.6 % in group A and 66.67 % in group B, also not significant (Table 2). CONCLUSIONS:P4 values on day of trigger do not affect number of eggs retrieved and number of chromosomally normal embryos available for transfer in a subsequent embryo transfer cycle. Elevated P4 values (≥1.5 ng/ml) also do not affect pregnancy rates or live birth/ongoing pregnancy rates in the first subsequent frozen embryo transfer cycle.
Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF/ICSI cycles.
Vanni V S,Somigliana E,Reschini M,Pagliardini L,Marotta E,Faulisi S,Paffoni A,Vigano' P,Vegetti W,Candiani M,Papaleo E
Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a "freeze-all" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p<0.01) and progesterone levels at ovulation triggering (p = 0.01) were the only two variables that significantly predicted top quality blastocyst formation rate after adjusting for relevant factors including female age, BMI, basal AMH and total dose of FSH used for COS. More specifically, progesterone levels at induction showed an inverse relation with top quality blastocyst formation (correlation coefficient B = -1.08, 95% CI -1.9 to -0.02) and ROC curve analysis identified P level >1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p<0.01). Our study is the first to investigate the top quality blastocyst formation rate in relation to progesterone levels in IVF/ICSI cycles, showing that increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are observed. This observation extends the results of two recent studies focused on day-3 embryos and deserves further research.
Female obesity increases the risk of miscarriage of euploid embryos.
Cozzolino Mauro,García-Velasco Juan Antonio,Meseguer Marcos,Pellicer Antonio,Bellver Jose
Fertility and sterility
OBJECTIVE:To determine whether female body mass index (BMI) is associated with an increased risk of miscarriage after euploid embryo transfer. DESIGN:A retrospective, observational, multicenter cohort study. SETTING:University-affiliated in vitro fertilization center. PATIENT(S):In this study, 3,480 cycles of in vitro fertilization with preimplantation genetic testing for aneuploidy (PGT-A) in the blastocyst stage and euploid embryo transfer were divided into four groups according to patient BMI. INTERVENTION(S):In vitro fertilization with PGT-A. MAIN OUTCOME MEASURE(S):The primary outcome was the miscarriage rate, which included both biochemical and clinical miscarriages. Secondary outcomes were implantation, pregnancy, clinical pregnancy, and live birth rates. RESULT(S):Cycles were divided into four groups according to BMI (kg/m): underweight (<18.5; n = 155), normal weight (18.5-24.9; n = 2,549), overweight (25-29.9; n = 591), and obese (≥30; n = 185). The number of PGT-A cycles per patient was similar in the four groups. Fertilization rate, day of embryo biopsy, technique of chromosomal analysis, number of euploid embryos, number of transferred embryos, and method of endometrial preparation for embryo transfer were similar in the four BMI groups. Miscarriage rates were significantly higher in women with obesity compared to women with normal weight, mainly due to a significant increase in the clinical miscarriage rates. Live birth rates also were lower in women with obesity. Obesity in women and day 6 trophectoderm biopsy were found to influence the reduced live birth rate. CONCLUSION(S):Women with obesity experience a higher rate of miscarriage after euploid embryo transfer than women with a normal weight, suggesting that other mechanisms than aneuploidy are responsible for this outcome.
Live birth rates after IVF are reduced by both low and high progesterone levels on the day of human chorionic gonadotrophin administration.
Santos-Ribeiro S,Polyzos N P,Haentjens P,Smitz J,Camus M,Tournaye H,Blockeel C
Human reproduction (Oxford, England)
STUDY QUESTION:Are low serum progesterone levels on the day of human chorionic gonadotrophin (hCG) administration detrimental for live birth delivery rates during in vitro fertilization (IVF)? SUMMARY ANSWER:Progesterone levels ≤0.5 ng/ml on the day of hCG administration hinder live birth rates. WHAT IS KNOWN ALREADY:Fundamental research has shown that the presence of late follicular phase progesterone is essential for follicular development, ovulation and endometrial receptivity. However, previous studies in patients undergoing ovarian stimulation have only assessed if progesterone levels in the higher range are detrimental for pregnancy or not. That said, information on the effect of the full range of late follicular progesterone on IVF outcomes is still lacking. STUDY DESIGN, SIZE, DURATION:This was a retrospective, single-centre cohort study with 2723 cycles performed in patients aged between 19 and 36 and undergoing controlled ovarian stimulation between January 2006 and March 2012 for their first or second attempt of IVF followed by a fresh embryo transfer (ET). PARTICIPANTS/MATERIALS, SETTING, METHODS:All patients underwent ovarian stimulation using a gonadotrophin-releasing hormone (GnRH) antagonist for pituitary down-regulation. Final oocyte maturation was triggered with hCG 36 h before oocyte retrieval. On the day of hCG administration, serum progesterone evaluation was performed. Live birth delivery rates were compared amongst various ordinal and regular progesterone intervals (≤0.50, 0.50-0.75, 0.75-1.00, 1.00-1.25, 1.25-1.50, >1.50 ng/ml) using logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE:The average age of our sample was 30.5 years. Almost 82% of all embryo transfers were of a single embryo and 51.8% were performed with a Day 5 embryo. The average value (±standard deviation) of progesterone on the day of hCG administration was 1.02 ± 0.50 ng/ml and the live birth rate was 23.4%. The live birth rates (according to the above-described ordinal serum progesterone intervals) were 17.1, 25.1, 26.7, 25.5, 21.9 and 16.6%, respectively. The live birth rates were significantly lower in patients with both low (≤0.5 ng/ml) and high (>1.5 ng/ml) late follicular progesterone levels (P < 0.05). LIMITATIONS, REASONS FOR CAUTION:The main limitation of our study was its retrospective nature. Furthermore, our study was restricted to patients under GnRH antagonist pituitary suppression and requires confirmation in a GnRH agonist setting. WIDER IMPLICATIONS OF THE FINDINGS:This study comprehensively assessed the relationship between live birth delivery rates and progesterone levels on the day of hCG administration during ovarian stimulation for IVF. Clinically relevant lower (≤0.5 ng/ml) and higher (>1.5 ng/ml) progesterone level limits were determined. STUDY FUNDING/COMPETING INTERESTS:No funding was received for this study and the authors have no conflicts of interest to declare.
The role of progesterone elevation in IVF.
Drakopoulos Panagiotis,Racca Annalisa,Errázuriz Joaquín,De Vos Michel,Tournaye Herman,Blockeel Christophe,Pluchino Nicola,Santos-Ribeiro Samuel
Elevation of progesterone during the late follicular phase of stimulated in-vitro fertilization cycles is a frequent event, which negatively impacts the outcome. Over the years evidence has demonstrated a direct relationship between late-follicular elevated progesterone and endometrial receptivity. In this regard, elective cryopreservation of all good quality embryos and transfer in a subsequent frozen/thawed cycle is the most common strategy adopted by clinicians in case of elevated progesterone. Nonetheless, recent evidence suggests that elective cryopreservation might not entirely resolve the reduced pregnancy outcomes associated with the elevation of progesterone, considering that the increase may affect not only implantation, but also embryo quality.
Being on the side of old findings: progesterone elevation on the day of oocyte maturation induction does not affect embryological parameters throughout the blastocyst culture period.
Turgut Emre Niyazi,Ecemis Selen,Boynukalin Kubra Fazilet,Gultomruk Meral,Yarkiner Zalihe,Findikli Necati,Bahceci Mustafa
Archives of gynecology and obstetrics
PURPOSE:To investigate whether there is any detrimental effect of progesterone elevation (PE) on the day of oocyte maturation induction on embryological development potentials. METHODS:This retrospective single-center cohort study included a total of 1485 individual intracytoplasmic sperm injection (ICSI) cycles between January 2014 and December 2018. Serum progesterone (P) levels were measured on the day of oocyte maturation induction following the GnRH antagonist suppression protocol. Embryological parameters such as maturation, fertilization rate (FR), top-quality embryo (TQE) formation rate per 2PN on day 3, and excellent-quality blastocyst (EQB) formation rate per 2PN on day 5/6 were recorded. The inclusion criteria for women were an age ≤ 37 years, a BMI ≤ 30 kg/m, and access to a total sperm concentration ≥ 2 million. Groups were stratified according to the serum P levels using the cut-off levels of < 0.8 ng/ml; 0.8-1.49 ng/ml; and ≥ 1.5 ng/ml. RESULTS:Peak E2 level and total number of oocytes retrieved were significantly related to PE (p < 0.001). FR did not display a significance difference between groups (p = 0.108). The TQE and the blastulation rates were not affected by PE (p = 0.82 and p = 0.68, respectively). Chi square analysis revealed a significant relationship between PE and the EQB formation rate (p = 0.01). GEE analysis failed to present any statistical significance regarding the effect of PE on neither the TQE nor the EQB formation rates per 2PN [OR 1.07; 95% (0.98-1.16) p = 0.113 and OR 0.93; 95% (0.80-1.07) p = 0.32, respectively]. CONCLUSIONS:In accordance with previously published papers, our study could not find any detrimental effect of PE on embryological outcomes throughout the blastocyst culture period.
Late follicular phase progesterone elevation during ovarian stimulation is not associated with decreased implantation of chromosomally screened embryos in thaw cycles.
Hernandez-Nieto Carlos,Lee Joseph A,Alkon-Meadows Tamar,Luna-Rojas Martha,Mukherjee Tanmoy,Copperman Alan B,Sandler Benjamin
Human reproduction (Oxford, England)
STUDY QUESTION:What is the impact of a late follicular phase progesterone elevation (LFPE) during controlled ovarian hyperstimulation (COH) on embryonic competence and reproductive potential in thaw cycles of preimplantation genetic testing for aneuploidy (PGT-A) screened embryos? SUMMARY ANSWER:Our study findings suggest that LFPE, utilizing a progesterone cutoff value of 2.0 ng/ml, is neither associated with impaired embryonic development, increased rate of embryonic aneuploidy, nor compromised implantation and pregnancy outcomes following a euploid frozen embryo transfer (FET) cycle. WHAT IS KNOWN ALREADY:Premature progesterone elevation during COH has been associated with lower pregnancy rates due to altered endometrial receptivity in fresh IVF cycles. Also, increased levels of progesterone (P) have been suggested to be a marker for ovarian dysfunction, with some evidence to show an association between LFPE and suboptimal embryonic development. However, the effect of LFPE on embryonic competence is still controversial. STUDY DESIGN, SIZE, DURATION:Retrospective cohort analysis in a single, academic ART center from September 2016 to March 2020. In total, 5244 COH cycles for IVF/PGT-A were analyzed, of those 5141 were included in the analysis. A total of 23 991 blastocysts underwent trophectoderm biopsy and PGT analysis. Additionally, the clinical IVF outcomes of 5806 single euploid FET cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS:Cohorts were separated in two groups: Group 1: oocytes retrieved from cycles with normal P levels during ovulation trigger (P ≤ 2.0 ng/ml); Group 2: oocytes retrieved after cycles in which LFPE was noted (P > 2.0 ng/ml). Extended culture and PGT-A was performed. Secondly, IVF outcomes after a single euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE:Four thousand nine hundred and twenty-five cycles in Group 1 were compared with 216 cycles on Group 2. Oocyte maturity rates, fertilization rates and blastulation rates were comparable among groups. A 65.3% (n = 22 654) rate of utilizable blastocysts was found in patients with normal P levels and were comparable to the 62.4% (n = 1337) observed in those with LFPE (P = 0.19). The euploidy rates were 52.8% (n = 11 964) and 53.4% (n = 714), respectively, albeit this difference was not statistically significant (P = 0.81). Our multivariate analysis was fitted with a generalized estimating equation (GEE) and no association was found with LFPE and an increased odds of embryo aneuploidy (adjusted odds ratio 1.04 95% CI 0.86-1.27, P = 0.62). A sub-analysis of subsequent 5806 euploid FET cycles (normal P: n = 5617 cycles and elevated P: n = 189 cycles) showed no differences among groups in patient's BMI, Anti-Müllerian hormone (AMH), endometrial thickness at FET and number of prior IVF cycles. However, a significant difference was found in patient's age and oocyte age. The number of good quality embryos transferred, implantation rate, clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate and clinical pregnancy loss rates were comparable among groups. Of the registered live births (normal P group: n = 2198; elevated P group: n = 52), there were no significant differences in gestational age weeks (39.0 ± 1.89 versus 39.24 ± 1.53, P = 0.25) and birth weight (3317 ± 571.9 versus 3 266 ± 455.8 g, P = 0.26) at delivery, respectively. LIMITATIONS, REASONS FOR CAUTION:The retrospective nature of the study and probable variability in the study center's laboratory protocol(s), selected progesterone cutoff value and progesterone assay techniques compared to other ART centers may limit the external validity of our findings. WIDER IMPLICATIONS OF THE FINDINGS:Based on robust sequencing data from a large cohort of embryos, we conclude that premature P elevation during IVF stimulation does not predict embryonic competence. Our study results show that LFPE is neither associated with impaired embryonic development nor increased rates of aneuploidy. Embryos obtained from cycles with LFPE can be selected for transfer, and patients can be reassured that the odds of achieving a healthy pregnancy are similar to the embryos exposed during COH cycles to physiologically normal P levels. STUDY FUNDING/COMPETING INTEREST(S):No funding was received for the realization of this study. Dr A.B.C. is advisor and/or board member of Sema 4 (Stakeholder in data), Progyny and Celmatix. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:NA.
Low anti-Müllerian hormone concentration is associated with increased risk of embryonic aneuploidy in women of advanced age.
Jiang Xiao,Yan Junhao,Sheng Yan,Sun Mei,Cui Linlin,Chen Zi-Jiang
Reproductive biomedicine online
RESEARCH QUESTION:Does an association exist between serum anti-Müllerian hormone (AMH) level, the marker of biological ovarian age, and embryonic aneuploidy risk in recurrent spontaneous miscarriage (RSM) patients of reproductive age? DESIGN:This retrospective study included a total of 422 IVF cycles of 394 unexplained RSM patients undergoing preimplantation genetic testing for aneuploidy (PGT-A), enrolled from January 2014 to December 2016. Subjects were divided into three groups according to the 25th (1.50 ng/ml) and 75th (5.60 ng/ml) percentiles of AMH level (Group 1: low AMH <1.50 ng/ml [N = 107], Group 2: normal AMH 1.50- < 5.60 ng/ml [N = 210] and Group 3: high AMH ≥ 5.60 ng/ml [N = 105]). RESULTS:There was a significant difference in embryonic aneuploid rate between AMH groups (66.7% versus 42.9% versus 50.0%, Groups 1 to 3, respectively, P = 0.006). It was significantly higher in the low AMH group (Group 1) compared with that in the normal AMH group (Group 2, P = 0.002) and high AMH group (Group 3, P = 0.015). After age stratification, embryonic aneuploidy rate was still significantly different among AMH groups with a similar trend in women ≥35 years old (68.2% versus 54.4% versus 51.0%, P = 0.038, P = 0.025, P = 0.035), but not in young subjects. CONCLUSIONS:These findings indicate that low AMH level was associated with increased risk of embryo aneuploidy only in women of advanced age. Maternal diminished ovarian reserve along with oocyte ageing may contribute to impaired chromosomal competence of the embryo.
Which ovarian reserve marker relates to embryo quality on day 3 and blastocyst; age, AFC, AMH?
Scheffer Juliano Brum,Carvalho Rafaela Friche de,Aguiar Ana Paula de Souza,Machado Iole Joana Moreira,Franca Juliana Baumgratz,Lozano Daniel Mendez,Fanchin Renato
JBRA assisted reproduction
OBJECTIVE:The aim of the present prospective study was to evaluate which ovarian reserve marker would be more reliable as the quality of the A + B embryos (day 3 and blastocyst). METHODS:We ran a prospective study with 124 infertile women, aged 24-48 years, from 2017 to 2018. The patients were divided into 3 groups according to age and the subgroups were compared for AMH, AFC, number of A+B embryos. New division of the 3 groups was performed based on the AMH, and the subgroups were compared for age, AFC and number of A+B embryos. Finally, we divided the patients into 3 groups, based on the AFC, and we compared the subgroups for age, AMH and number of A+B embryos. P<0.05 was considered statistically significant. RESULTS:When the 124 patients were divided according to age, we found a significant fall in an A+B embryo quality (day3; blastocyst) after 35 years (p<0.038; p<0.035), and more severely after 37 years (p<0.032; p<0.027). When the 124 patients were divided according to AMH, there was a significant fall in A+B embryo quality (day 3; blastocyst), with AMH<1ng/ml (p<0.023; p<0.021). When the 124 patients were divided according to AFC, there was a significant fall in A+B embryo quality (day 3; blastocyst) with AFC<7 (p<0.025; p<0.023). These markers had significant associations with embryo quality (p<0.005). CONCLUSION:Age, AFC and AMH have significant associations with A +B embryo quality on day 3 and blastocyst.
AMH as a Prognostic Factor for Blastocyst Development.
De Conto Emily,Genro Vanessa Krebs,da Silva Daniela Scherer,Chapon Rita de Cassia Borges,Cunha-Filho João Sabino Lahorgue
JBRA assisted reproduction
OBJECTIVE:To investigate the relationship between AMH blood levels and the likelihood of blastocyst formation. METHODS:Two hundred ninety-two patients, 22-44 years of age, undergoing routine explorations during spontaneous cycles that preceded assisted reproductive technologies at our Center, were studied. As the present study did not require previous submission to our Institutional Review Board. Serum AMH and FSH levels were measured and laboratory data was obtained after ovulation induction with an antagonist protocol. Participants were sorted into two different groups paired by age. The first group (No Blasto; n=219) involved women having no blastocyst formation; the second group (Yes Blasto group; n=73) was made up of those women who were considered eligible to undergo 5 days of embryo culture. Furthermore, we analyzed blastulation rate. Patients were divided according to the rate of blastocyst formation <0.43 (n=36) and ≥ 0.43 (n=37). The Statistical analysis was performed using SPSS version 20.0. We ran Student's t-test for independent samples and Pearson's correlation. A P < 0.05 was considered significant. RESULTS:AMH levels were statistically different (P=0.002) between the YES and NO blasto groups. Number of oocytes, MII oocytes and embryos were higher in Yes Blasto group. FSH levels were similar between the groups (P=0.149). Pearson correlation coefficient shows that the rate of blastocyst formation is inversely correlated to AMH levels. CONCLUSIONS:We conclude that patients that were considered eligible to undergo blastocyst formation have higher levels of serum AMH, however too high concentration of this hormone can be harmful to blastocyst development.
Female age, serum antimüllerian hormone level, and number of oocytes affect the rate and number of euploid blastocysts in in vitro fertilization/intracytoplasmic sperm injection cycles.
La Marca Antonio,Minasi Maria Giulia,Sighinolfi Giovanna,Greco Pierfrancesco,Argento Cindy,Grisendi Valentina,Fiorentino Francesco,Greco Ermanno
Fertility and sterility
OBJECTIVE:To study the relative role of female age and ovarian reserve, measured through serum antimüllerian hormone (AMH) in determining the rate and number of euploid blastocysts in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. DESIGN:Retrospective analysis of cycles performed in 2014-2015. SETTING:Tertiary referral IVF center. PATIENT(S):A total of 578 infertile couples undergoing IVF/ICSI and preimplantation genetic screening (PGS) analysis. INTERVENTIONS(S):All embryos were cultured and biopsied at the blastocyst stage. The method involved whole-genome amplification followed by array comparative genome hybridization. Serum AMH was measured by means of the modified Beckman Coulter AMH Gen II assay. MAIN OUTCOME MEASURES:The rate and number of euploid blastocysts and their correlation with ovarian reserve and response to stimulation. RESULT(S):The mean (±SD) age of patients was 37.6 ± 4.1 years, and the mean number of blastocysts per patient was 3.1 ± 2. The total number of blastocysts available to the analysis was 1,814, and 36% of them were euploid after PGS. Age and serum AMH were significantly and independently related to the rate of euploid blastocysts available for patients. As an effect of the cohort size, the number of mature oocytes positively affected the total number of euploid blastocysts per patient. CONCLUSION(S):A strong positive age-independent relationship between AMH level and the rate of euploid blastocysts was found. This confirms that the measurement of ovarian reserve by means of AMH has high relevance when counseling infertile patients.
Follicular-fluid anti-Mullerian hormone (FF AMH) is a plausible biochemical indicator of functional viability of oocyte in conventional in vitro fertilization (IVF) cycles.
Mehta Bindu N,Chimote Meena N,Chimote Nishad N,Nath Nirmalendu M,Chimote Natachandra M
Journal of human reproductive sciences
CONTEXT:Oocyte quality may be a governing factor in influencing in vitro fertilization (IVF) outcomes. However, morphological evaluation of oocyte quality is difficult in conventional IVF cycles. Follicular-fluid (FF), the site for oocyte growth and development, has not yet been sufficiently explored to obtain a marker indicative of oocyte quality. Anti-Mullerian hormone (AMH) is produced by granulosa cells of preantral and early-antral follicles and is released in FF. AIM:To investigate AMH as a biochemical indicator of functional viability/quality of oocyte produced in the FF micro-environmental milieu. SETTINGS AND DESIGN:Prospective study involving 132 cycles of conventional IVF-embryo transfer (ET) in infertile women. SUBJECTS AND METHODS:AMH concentration was estimated in pooled FF on day of oocyte pickup. Cycles were sorted into low and high groups according to median (50 (th) centile) values of measurement. Main outcome measure was oocyte viability, which included morphological assessment of oocyte quality, fertilization rate, clinical pregnancy, and implantation rates. STATISTICAL ANALYSIS:Graph-pad Prism 5 statistical package. RESULTS:Low FF AMH group shows significantly higher percentage of top-quality oocytes (65.08 ± 24.88 vs. 50.18 ± 25.01%, P =0.0126), fertilization (83.65 ± 18.38 vs. 75.78 ± 21.02%, P =0.0171), clinical pregnancy (57.57 vs. 16.67%, P >0.0001), and embryo implantation rates (29.79 vs. 7.69%, P >0.0001) compared to high FF AMH group. FF AMH shares an inverse correlation with FF E2 (Pearson r = -0.43, r(2) = 0.18) and clinical pregnancy (Pearson r = -0.46, r(2) = 0.21). Threshold value of FF AMH for pregnancy is >1.750 ng/mg protein. CONCLUSION:FF AMH is a plausible biochemical indicator of functional viability of oocyte in conventional IVF cycles.
The predictive value of anti-Mullerian hormone on embryo quality, blastocyst development, and pregnancy rate following in vitro fertilization-embryo transfer (IVF-ET).
Lin Wen-Qin,Yao Ling-Nv,Zhang Dong-Xue,Zhang Wei,Yang Xiao-Jing,Yu Rong
Journal of assisted reproduction and genetics
PURPOSE:The objective of this study was to investigate the predictive value of anti-Mullerian hormone (AMH) on fertilization rate (FR), blastocyst development, embryo quality, the outcome of the pregnancy and the live birth rate (LBR) following in vitro fertilization-embryo transfer (IVF-ET)/intracytoplasmic sperm injection (ICSI). METHOD:In this prospective study outcomes were followed in 83 women undergoing cycles of IVF/ICSI within a university hospital. Basal serum AMH, follicle stimulating hormone (FSH), luteinizing hormone (LH) and antral follicle count (AFC) were measured on Day 3. Serum AMH (Gn6 AMH ) level was measured on Day 6 after the administration of gonadotrophin (Gn). AMH was measured in follicle fluid (FF AMH) on the day of ovum pick-up (dOPU). The numbers of retrieved and fertilized oocytes, good quality embryos and blastocysts were counted. Secondary outcome variables included clinical pregnancy rate (CPR) and LBR. RESULTS:Spearman correlation analysis indicated that the numbers of oocytes, good quality embryos and blastocysts were associated with AMH (P < 0.05) and that LBR was correlated with FF AMH (r = 0.495, P < 0.05). No associations were found between FR and AMH (P > 0.05). Receiver operating characteristic analysis showed that the sensitivity of FF AMH at predicting CPR was 91.2%; the specificity was 86.5% and ROC(AUC) was 0.893 (P < 0.0001). CONCLUSION:AMH parameters were correlated with good quality embryos and blastocysts, but only FF AMH showed a significant correlation with LBR and CPR.
Serum anti-Müllerian hormone is associated with oocyte dysmorphisms and ICSI outcomes.
Azizi Elham,Naji Mohammad,Nazari Leila,Salehpour Saghar,Karimi Maryam,Borumandnia Nasrin,Shams Mofarahe Zahra
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics
OBJECTIVE:To evaluate the association between serum levels of anti-Müllerian hormone (AMH) and oocyte dysmorphisms in intracytoplasmic sperm injection (ICSI) cycles. METHODS:A retrospective study of data from 628 ICSI cycles with successful oocyte retrieval carried out at a single center in Tehran from November 2015 to July 2018. Cycles were divided into six groups by serum AMH level. Various oocyte dysmorphisms, quantity of retrieved oocytes, fertilization rates, cleavage-stage embryos, and pregnancy rates were compared among the groups. RESULTS:Serum AMH was associated with cytoplasm granulation, abnormally amorphous oocytes (P˂0.01), extended perivitelline space (P˂0.001), granulated perivitelline space (P˂0.05), fragmented polar body (P˂0.001), and average of oocyte quality index (AOQI) (P˂0.01). The total number of aspirated and metaphase ΙΙ oocytes increased with increasing AMH levels (P<0.001). There was no difference in the rate of fertilization or cleavage-stage embryos among the study groups; however, the pregnancy rate differed significantly (P<0.05). CONCLUSIONS:Serum levels of AMH were associated with specific oocyte dysmorphisms and AOQI. Serum AMH levels might influence both qualitative and quantitative aspects of the ovarian response to stimulation and also the pregnancy rate in ICSI cycles.
Anti-Müllerian hormone is an independent marker for oocyte survival after vitrification.
Melado Laura,Arnanz Ana,Bayram Asina,Elkhatib Ibrahim,De Munck Neelke,Navarro Alfredo Tomás,Coughlan Carol,Lawrenz Barbara,Fatemi Human Mousavi
Reproductive biomedicine online
RESEARCH QUESTION:This study explored the relationship between anti-Müllerian hormone (AMH) and oocyte survival after vitrification. The association between AMH and blastocyst formation after oocyte vitrification was also assessed. DESIGN:A retrospective observational analysis was performed in a private IVF centre. A total of 4507 metaphase-II warmed oocytes were included from 450 couples, predominantly of Arab ethnicity. Between August 2015 and August 2018, couples underwent 484 intracytoplasmic sperm injection (ICSI) treatments using vitrified-warmed oocytes. RESULTS:Patients' median age ± SD was 36.2 ± 6.1 years, AMH concentration 2.6 ± 3.4 ng/ml and body mass index (BMI) 26.5 ± 4.6 kg/m. The oocyte survival rate after vitrification was 87.37 ± 20.42%. AMH concentration showed a significant correlation (Kendall's tau 0.087, P = 0.0079) with oocyte survival rate independent of oocyte yield. Correlation was significant (odds ratio 1.041, 95% confidence interval 1.007-1.077, P = 0.018) when a multivariant model was applied that included AMH, age and BMI. The receiver operating characteristic curve showed an AMH cut-off value of 1.09 ng/ml that could obtain at least a 70% survival rate, with an area under the curve of 0.669. Regarding embryo development in ICSI cycles including fresh and warmed oocytes for the same patient, blastocyst formation rate was higher in fresh compared with warmed oocytes (P < 0.001). In this subgroup no significant correlation was seen between fertilization or blastocyst rate and AMH concentration. CONCLUSIONS:AMH concentration showed a significant correlation with oocyte survival. Blastocyst formation was significantly lower after oocyte vitrification, but no correlation was found with AMH. Clinicians should carefully evaluate oocyte vitrification for patients with AMH below 1.09 ng/ml and consider embryo accumulation for these patients in preference to oocyte accumulation.
AMH has no role in predicting oocyte quality in women with advanced age undergoing IVF/ICSI cycles.
Dai Xiuliang,Wang Yufeng,Yang Haiyan,Gao Tingting,Yu Chunmei,Cao Fang,Xia Xiyang,Wu Jun,Zhou Xianju,Chen Li
It has been widely acknowledged that anti-Müllerian hormone (AMH) is a golden marker of ovarian reserve. Declined ovarian reserve (DOR), based on experience from reproductive-aged women, refers to both the quantitative and qualitative reduction in oocytes. This view is challenged by a recent study clearly showing that the quality of oocytes is similar in young women undergoing IVF cycles irrespective of the level of AMH. However, it remains elusive whether AMH indicates oocyte quality in women with advanced age (WAA). The aim of this study was to investigate this issue. In the present study, we retrospectively analysed the data generated from a total of 492 IVF/ICSI cycles (from January 2017 to July 2020), and these IVF/ICSI cycles contributed 292 embryo transfer (ET) cycles (from June 2017 to September 2019, data of day 3 ET were included for analysis) in our reproductive centre. Based on the level of AMH, all patients (= > 37 years old) were divided into 2 groups: the AMH high (H) group and the AMH low (L) group. The parameters of in vitro embryo development and clinical outcomes were compared between the two groups. The results showed that women in the L group experienced severe DOR, as demonstrated by a higher rate of primary diagnosis of DOR, lower antral follicle count (AFC), higher level of basal follicle stimulating hormone (FSH) and cancelation cycles, lower level of E2 production on the day of surge, and fewer oocytes and MII oocytes retrieved. Compared with women in the H group, women in the L group showed slightly reduced top embryo formation rate but a similar normal fertilization rate and blastocyst formation rate. More importantly, we found that the rates of implantation, spontaneous miscarriage and livebirth were similar between the two groups, while the pregnancy rate was significantly reduced in the L group compared with the H group. Further analysis indicated that the higher pregnancy rate of women in the H group may be due to more top embryos transferred per cycle. Due to an extremely low implantation potential for transfer of non-top embryos from WAA (= > 37 years old) in our reproductive centre, we assumed that all the embryos that implanted may result from the transfer of top embryos. Based on this observation, we found that the ratio of embryos that successfully implanted or eventually led to a livebirth to top embryos transferred was similar between the H and the L groups. Furthermore, women with clinical pregnancy or livebirth in the H or L group did not show a higher level of serum AMH but were younger than women with non-pregnancy or non-livebirth. Taken together, this study showed that AMH had a limited role in predicting in vitro embryo developmental potential and had no role in predicting the in vivo embryo developmental potential, suggesting that in WAA, AMH should not be used as a marker of oocyte quality. This study supports the view that the accumulation of top embryos via multiple oocyte retrieval times is a good strategy for the treatment of WAA.
Female obesity does not impact live birth rate after frozen-thawed blastocyst transfer.
Prost E,Reignier A,Leperlier F,Caillet P,Barrière P,Fréour T,Lefebvre T
Human reproduction (Oxford, England)
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.
Anti-Müllerian hormone (AMH): a reliable biomarker of oocyte quality in IVF.
Lehmann Pierre,Vélez Maria P,Saumet Julio,Lapensée Louise,Jamal Wael,Bissonnette François,Phillips Simon,Kadoch Isaac-Jacques
Journal of assisted reproduction and genetics
PURPOSE:To evaluate the impact of serum AMH levels on stimulated IVF implantation and clinical pregnancy rates. METHODS:• DESIGN:Retrospective study with multivariate analysis. • SETTING:Clinique ovo (Montreal University affiliated Center). • PATIENT(S):Six hundred and thirty seven patients undergoing a stimulated IVF protocol were included. Only non-polycystic ovary patients at their first IVF attempt were considered for the analysis. • INTERVENTION(S):None. • MAIN OUTCOME MEASURES(S):Implantation and ongoing pregnancy rates. RESULT(S):Cycle outcomes were analysed according to AMH percentiles based on the AMH normogram per patient's age of our infertile population. Multivariate analyses were done to adjust for potential confounding factors such as age, total exogenous FSH dosage and number of eggs retrieved. Compared to the reference population, a significant lower mean implantation rate (0.26 vs 0.45) was observed in patients under 35 years of age with AMH < 1 ng/ml. Women with AMH < 25th percentile had less chances of having an embryo transferred, lower chances of having an ongoing pregnancy per started IVF cycle and a lower embryo freezing rate compared to the reference population. CONCLUSION(S):Patients with AMH < 0.47 ng/ml should be advised before starting a stimulated IVF cycle of the poorer prognosis compared to our reference population independently of their age, total exogenous FSH dosage and number of eggs retrieved. Therefore, AMH could enable a more individualized number of embryo transfer policy based on oocyte quality.
Menstrual cycle length in reproductive age women is an indicator of oocyte quality and a candidate marker of ovarian reserve.
Vassena Rita,Vidal Ricard,Coll Oriol,Vernaeve Valérie
European journal of obstetrics, gynecology, and reproductive biology
OBJECTIVE:The menstrual cycle is a finely tuned biological process comprising a precisely orchestrated sequence of events: follicular growth, selection and ovulation, extensive endometrial changes, corpus luteum (CL) growth and maturation, and luteolysis. Differences in the length of the menstrual cycle (MCL) have been associated with variable female fecundity. However, the reason for these differences is so far unknown. The donor-recipient model, separating uterine from ovarian factors, allows clarifying the origin of MCL-associated fecundity variations. STUDY DESIGN:We analyzed retrospectively 2015 oocyte donation cycles, resulting in 3427 embryo transfers (ET) and pregnancy follow-up. RESULTS:Surprisingly, we found that oocyte donors MCL of 34-35 days were strongly associated with significantly higher biochemical, clinical and ongoing pregnancy rates in woman who received the embryos, compared to the reference group of MCL of 27-29 days. Moreover, donors with longer MCL presented higher ovarian response to stimulation and lower amount of hormonal stimulation needed to achieve multifollicular growth. Conversely, MCL of <25 days were associated with a poorer ovarian response to stimulation, less cumulus oocyte complexes (COCs) and less mature oocytes (MII) retrieved; however, the quality of oocytes in these women is not associated to their ovarian response, as evidenced by the pregnancy rates obtained when transferred into an adequately prepared endometrium. CONCLUSIONS:We conclude that oocyte quality, rather than natural endometrial preparation, is the main reason for the reported higher fecundity of women with longer MCL. This result is further confirmed by our data on bleeding length in the donor pool. Response to ovarian stimulation is the definitive test of ovarian reserve; moreover, since different MCLs result from varying length of the follicular phase, longer MCL should be associated with a higher number of follicular recruitment events. We hypothesize that MCL is associated with - and a marker of - ovarian reserve in healthy reproductive age women.
A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy.
Tiegs Ashley W,Tao Xin,Zhan Yiping,Whitehead Christine,Kim Julia,Hanson Brent,Osman Emily,Kim Thomas J,Patounakis George,Gutmann Jacqueline,Castelbaum Arthur,Seli Emre,Jalas Chaim,Scott Richard T
Fertility and sterility
OBJECTIVE:To determine the predictive value of an aneuploid diagnosis with a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy (PGT-A) assay in prognosticating the failure of a successful delivery. DESIGN:Prospective, blinded, multicenter, nonselection study. All usable blastocysts were biopsied, and the single best morphologic blastocyst was transferred before genetic analysis. Preimplantation genetic testing for aneuploidy was performed after clinical outcome was determined. Clinical outcomes were compared to PGT-A results to calculate the predictive value of a PGT-A aneuploid diagnosis. SETTING:Fertility centers. PATIENT(S):Couples undergoing their first in vitro fertilization cycle without recurrent pregnancy loss, antral follicle count < 8, or body mass index ≥ 35 kg/m. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):The primary outcome was the ability of the analytical result of aneuploid to predict failure to deliver (clinical result). A secondary outcome was the impact of the trophectoderm biopsy on sustained implantation. RESULT(S):Four hundred two patients underwent 484 single, frozen, blastocyst transfers. The PGT-A aneuploid diagnosis clinical error rate was 0%. There was no difference in sustained implantation between the study group and an age-matched control group, where biopsy was not performed (47.9% vs. 45.8). CONCLUSION(S):The PGT-A assay evaluated was highly prognostic of failure to deliver when an aneuploid result was obtained. Additionally, the trophectoderm biopsy had no detectable adverse impact on sustained implantation. CLINICAL TRIAL REGISTRATION NUMBERS:NCT02032264 and NCT03604107.
Does ovarian stimulation benefit ovulatory women undergoing therapeutic donor insemination?
Carpinello Olivia J,Jahandideh Samad,Yamasaki Meghan,Hill Micah J,DeCherney Alan H,Stentz Natalie,Moon Kimberly S,Devine Kate
Fertility and sterility
OBJECTIVE:To compare clinical and ongoing pregnancy after natural cycle (NC) intrauterine insemination (IUI) versus ovarian stimulation (OS) IUI in ovulatory women undergoing therapeutic donor insemination (TDI). DESIGN:Retrospective cohort. SETTING:Single infertility center. PATIENT(S):A total of 76,643 IUI cycles in patients treated with intrauterine insemination were examined. Women undergoing TDI in the absence of diagnosed female factor infertility were included. INTERVENTION(S):NC TDI or OS TDI with either clomiphene citrate or letrozole. MAIN OUTCOME MEASURE(S):Clinical and ongoing pregnancies were analyzed by generalized estimating equations adjusting for age, body mass index, total motile sperm at time of insemination and cycle number. Ongoing multiple gestations were examined as a secondary outcome. RESULT(S):Six thousand one hundred ninety-two TDI cycles from 2,343 patients (711 patients without repeated IUI cycles) met inclusion criteria and were available for analysis (3,837 NC and 2,355 OS). There was no difference in mean age between the two groups (NC, 34.2 years vs. OS, 34.3 years). Probability of clinical and ongoing pregnancy was higher in the OS cohort compared with the NC cohort (OS, 22.4% vs. NC, 18.7% and OS, 15.4% vs. NC, 14.9%, respectively). However, OS significantly increased ongoing multiple gestations (OS, 10.8% vs. NC, 2.4%). CONCLUSION(S):Ovarian stimulation in TDI cycles resulted in a <4% increase in clinical and <1% increase in ongoing pregnancy, and more than fourfold increase in ongoing multiple gestations. Natural cycle IUI should be considered as a first-line treatment for ovulatory women who need donor insemination.
Impact of multiple blastocyst biopsy and vitrification-warming procedures on pregnancy outcomes.
Bradley Cara K,Livingstone Mark,Traversa Maria V,McArthur Steven J
Fertility and sterility
OBJECTIVE:To assess the impact of multiple blastocyst biopsy and vitrification-warming procedures on clinical outcomes. DESIGN:Retrospective study. SETTING:Private fertility clinic. PATIENT(S):Preimplantation genetic diagnosis (PGD) patients undergoing comprehensive chromosome screening, including monogenic disorder and chromosome rearrangement cases. INTERVENTION(S):Warming and transfer of euploid blastocysts biopsied and vitrified-warmed once (group 1 [G1, control]; n = 2,130), biopsied once but vitrified-warmed twice (group 2 [G2]; n = 34), or biopsied and vitrified-warmed twice (group 3 [G3]; n = 29). MAIN OUTCOME MEASURE(S):Thaw (for transfer) survival rate and clinical pregnancy rate (CPR). RESULT(S):The thaw survival rates were 98.4% for G1, 97.3% for G2, and 93.3% for G3, with once biopsied and vitrified-warmed embryos being significantly higher than twice biopsied and vitrified-warmed embryos (G1 vs. G3; P=.032). There was a slight reduction in CPR with an additional vitrification-warming (G1 54.3% vs. G2 47.1%) and larger reduction with an additional embryo biopsy (G2 47.1% vs. G3 31.0%), but neither difference was statistically significant. However, the combined effect of both additional biopsy and vitrification-warming resulted in a significantly reduced CPR (G1 54.3% vs. G3 31.0%; P=.013). CONCLUSION(S):This study indicates that blastocysts biopsied and vitrified-warmed twice have reduced clinical outcomes compared with blastocysts biopsied and vitrified-warmed once. PGD patients should be advised that performing a second biopsy and vitrification-warming in cases of failure to obtain a result from initial biopsy will reduce the chance of pregnancy. Patients with inherited disorders may elect to proceed with the second biopsy and vitrification to avoid transfer of embryos with the genetic condition.
Association between women's age and stage, morphology, and implantation of the competent blastocyst: a multicenter cohort study.
Borgstrøm Maria Buhl,Grøndahl Marie Louise,Klausen Tobias Wirenfeldt,Danielsen Anne Kjærgaard,Thomsen Thordis,Gabrielsen Anette,Zedeler Anne,Povlsen Betina Boel,Hnida Christina,Almind Gitte Juul,Fedder Jens,Kirk John,Hindkjær Johnny,Lemmen Josephine G,Petersen Karsten,Haahr Katrine,Petersen Morten Rønn,Laursen Steen,Hansen Thomas Høst,Knudsen Ulla Breth,Bentin-Ley Ursula,Larsen Thomas,Kesmodel Ulrik Schiøler
Fertility and sterility
OBJECTIVE:To study if the age of women undergoing assisted reproductive technology treatment associates with stage, morphology, and implantation of the competent blastocyst. DESIGN:Multicenter historical cohort study based on exposure (age) and outcome data (blastocyst stage and morphology and initial human chorionic gonadotrophin [hCG] rise) from women undergoing single blastocyst transfer resulting in singleton pregnancy/birth. SETTING:Sixteen private and university-based facilities. PATIENT(S):In this study, 7,246 women who, between 2014 and 2018, underwent controlled ovarian stimulation (COS) or frozen-thawed embryo transfer (FET) with a single blastocyst transfer resulting in singleton pregnancy were identified. Linking data to the Danish Medical Birth Registry resulted in a total of 4,842 women with a live birth being included. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):The competent blastocyst development stage (1-6), inner cell mass (A, B, C), trophectoderm (A, B, C), and initial serum hCG value. RESULT(S):Adjusted analysis of age and stage in COS treatments showed that for every 1-year increase in age there was a 5% reduced probability of the competent blastocyst assessed as being in a high stage at transfer. Comparison between hCG values in women 18-24 years and 25-29 years in both COS and FET showed significantly lower levels in the youngest women. CONCLUSION(S):The initial hCG rise was influenced by the age of the woman, with an identical pattern for hCG values in COS and FET treatments. In COS, the competent blastocyst had a reduced stage with increasing women's age.
Oocyte ability to repair sperm DNA fragmentation: the impact of maternal age on intracytoplasmic sperm injection outcomes.
Setti Amanda Souza,Braga Daniela Paes de Almeida Ferreira,Provenza Rodrigo Rosa,Iaconelli Assumpto,Borges Edson
Fertility and sterility
OBJECTIVE:To study the impact of sperm DNA fragmentation (SDF) on clinical outcomes of assisted reproductive technology in women with different age ranges. DESIGN:Historical cohort study. SETTING:Private university-affiliated in vitro fertilization center. PATIENT(S):Five hundred forty couples undergoing intracytoplasmic sperm injection cycles. INTERVENTION(S):Cycles were split into three groups according to maternal age: ≤36 years old (n = 285), 37-40 years old (n = 147), and >40 years old (n = 108). Semen samples were evaluated for SDF using the Sperm Chromatin Dispersion test and, for each age group, the cycles were subdivided according to SDF index: low fragmentation index (<30% SDF) and high fragmentation index (≥30% SDF). MAIN OUTCOME MEASURE(S):Implantation, pregnancy, and miscarriage rates. RESULT(S):For younger patients (≤36 years old) and those between 37 and 40 years of age, no significant differences were noted in laboratory and clinical outcomes for cycles with <30% SDF or ≥30% SDF. When maternal age was >40 years of age, significantly lower high-quality day-3 embryos (54.4% vs. 33.1% and blastocyst development rates (49.6% vs. 30.2%), lower pregnancy (20.0% vs. 7.7%) and implantation rates (19.7% vs. 11.9%), and increased miscarriage rate (12.5% vs. 100.0%) were observed for cycles with ≥30% SDF compared with <30% SDF, respectively. CONCLUSION(S):Older oocytes, when injected with sperm derived from samples with high SDF index, develop into embryos of poor quality that lead consequently to lower implantation and pregnancy rates and higher miscarriage rates, in intracytoplasmic sperm injection cycles from women with advanced maternal age.
Clarifying the relationship between total motile sperm counts and intrauterine insemination pregnancy rates.
Muthigi Akhil,Jahandideh Samad,Bishop Lauren A,Naeemi Firoozeh K,Shipley Sharon K,O'Brien Jeanne E,Shin Paul R,Devine Kate,Tanrikut Cigdem
Fertility and sterility
OBJECTIVE:To study the relationship between postwash total motile sperm count (TMSC) and intrauterine insemination (IUI) outcomes. DESIGN:Retrospective review SETTING: Large fertility clinic PATIENT(S): A total of 92,471 insemination cycles from 37,553 patients were included in this study. INTERVENTION(S):All stimulated clomiphene citrate, letrozole, and/or injectable gonadotropin IUI cycles performed at a single institution from 2002 through 2018 were reviewed. Generalized estimating equations (GEE) analysis was used to account for multiple cycles by individual patients and to adjust for female partner age, body mass index, and stimulation protocol. MAIN OUTCOME MEASURE(S):Successful clinical pregnancy was defined as ultrasound confirmation of an intrauterine gestational sac with fetal cardiac activity. RESULT(S):A total of 92,471 insemination cycles were available to evaluate the relationship between postwash TMSC and clinical pregnancy. Pregnancy rates were highest with TMSC of ≥9 × 10 and declined gradually as TMSC decreased. Complete data for the adjusted GEE analysis were available for 62,758 cycles. Adjusted GEE analysis among cycles with TMSC of ≥9 × 10 (n = 46,557) confirmed that TMSC in this range was unrelated to pregnancy. Conversely, TMSC was highly predictive of pregnancy (Wald χ = 39.85) in adjusted GEE analysis among cycles with TMSC of <9 × 10 (n = 16,201), with a statistically significant decline. CONCLUSIONS:IUI pregnancy is optimized with TMSC of ≥9 × 10, below which the rates gradually decline. Although rare, pregnancies were achieved with TMSC of <0.25 × 10. Since the decline in pregnancy is gradual and continuous, there is no specific threshold above which IUI should be recommended. Rather, these more specific quantitative predictions can be used to provide personalized counseling and guide clinical decision making.
Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use.
Viotti Manuel,Victor Andrea R,Barnes Frank L,Zouves Christo G,Besser Andria G,Grifo James A,Cheng En-Hui,Lee Maw-Sheng,Horcajadas Jose A,Corti Laura,Fiorentino Francesco,Spinella Francesca,Minasi Maria Giulia,Greco Ermanno,Munné Santiago
Fertility and sterility
OBJECTIVE:To study how the attributes of mosaicism identified during preimplantation genetic testing for aneuploidy relate to clinical outcomes, in order to formulate a ranking system of mosaic embryos for intrauterine transfer. DESIGN:Compiled analysis. SETTING:Multi-center. PATIENT(S):A total of 5,561 euploid blastocysts and 1,000 mosaic blastocysts used in clinical transfers in patients undergoing fertility treatment. INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Implantation (gestational sac), ongoing pregnancy, birth, and spontaneous abortion (miscarriage before 20 weeks of gestation). RESULT(S):The euploid group had significantly more favorable rates of implantation and ongoing pregnancy/birth (OP/B) compared with the combined mosaic group or the mosaic group affecting only whole chromosomes (implantation: 57.2% vs. 46.5% vs. 41.8%; OP/B: 52.3% vs. 37.0% vs. 31.3%), as well as lower likelihood of spontaneous abortion (8.6% vs. 20.4% vs. 25%). Whole-chromosome mosaic embryos with level (percent aneuploid cells) <50% had significantly more favorable outcomes than the ≥50% group (implantation: 44.5% vs. 30.4%; OP/B: 36.1% vs. 19.3%). Mosaic type (nature of the aneuploidy implicated in mosaicism) affected outcomes, with a significant correlation between number of affected chromosomes and unfavorable outcomes. This ranged from mosaicism involving segmental abnormalities to complex aneuploidies affecting three or more chromosomes (implantation: 51.6% vs. 30.4%; OP/B: 43.1% vs. 20.8%). Combining mosaic level, type, and embryo morphology revealed the order of subcategories regarding likelihood of positive outcome. CONCLUSION(S):This compiled analysis revealed traits of mosaicism identified with preimplantation genetic testing for aneuploidy that affected outcomes in a statistically significant manner, enabling the formulation of an evidence-based prioritization scheme for mosaic embryos in the clinic.