Histologic characteristics of the endometrium predicts success when utilizing autologous endometrial coculture in patients with IVF failure

Purpose : To analyze the success of autologous endometrial coculture (AECC) in improving embryo quality and pregnancy outcome based on the histologic characteristic of the biopsy. Methods : Prospective study of 86 consecutive patients undergoing IVF utilizing AECC. Results : The patients were on average 37.4±4.0 years with a history of 2.6±1.8 failed previous attempts. An overall clinical pregnancy rate of 45.3% per ET was found. The embryos grown in AECC were of an improved quality in comparison to those grown in conventional media. 33.7% (29/86) of the biopsies were out of phase (>3 days). In-phase (IP) and OOP (out of phase) specimens both demonstrated an improvement in embryo quality. However, OOP endometrial biopsies that displayed significant retarded endometrial development (< cycle day 19) did not demonstrate an improvement in embryos grown on AECC as compared to IP endometrial biopsies or OOP endometrial biopsies that demonstrated at least an endometrial development of cycle day 19. Conclusions : We have demonstrated a significant improvement in embryo quality with AECC. We have also demonstrated that histologic dating of the endometrium is predictive of IVF outcome when utilizing AECC.     

Autologous endometrial coculture in patients with a previous history of poor quality embryos

Purpose : To evaluate the effect of autologous endometrial coculture in patients (less than 36 years old) with a history of a single IVF failed cycle associated with poor quality embryos. Methods : Design: Controlled clinical study. Setting: University-based in vitro fertilization center. Patients: Twenty-six patients with a history of a single prior failed IVF-ET with poor preembryo quality. Intervention(s): Autologous endometrial coculture. Main outcome measures: Preembryo blastomere numbers and cytoplasmic fragmentation rates were compared between the treatment and previous cycle. Clinical pregnancy rates were analyzed. Results : Twenty-six women with an average age of 32.8 ± 2.9 years underwent treatment. On Day 3 the overall mean number of blastomeres per preembryo on coculture compared to conventional medium in a previous cycle was 6.1 ± 1.8 vs. 5.1 ± 1.3 (P = 0.01; Wilcoxon test). The average percentage of cytoplasmic fragments on coculture compared to the conventional medium in a previous cycle was 14% ± 10 vs. 22% ± 13 (P = 0.003; Wilcoxon test). At transfer the mean number of blastomeres per preembryo on coculture was 7.4 ± 1.8 compared to 6.7 ± 1.5 on conventional medium in a previous cycle (P = 0.02; Wilcoxon test). The clinical pregnancy rate (positive fetal cardiac activity) per patient was 88.5%. The delivery rate was 73.1% (19/26). Conclusions : There was an improvement in the preembryo quality for preembryos on autologous endometrial coculture compared to noncocultured preembryos from the same patient in a previous cycle. An excellent delivery rate was subsequently found.     

Impact of preimplantation genetic diagnosis on IVF outcome in implantation failure patients

Implantation failure (IF) is defined as three or more failed IVF attempts, and preimplantation genetic diagnosis (PGD) is being used in these patients to improve IVF outcome. PGD was performed in 49 implantation failure patients with a mean number of 4.2 +/- 1.6 previous IVF failures, and in nine fertile controls. Fluorescence in-situ hybridization (FISH) on blastomeres from biopsied day 3 embryos was performed for chromosomes 13, 16, 18, 21, 22, X and Y. There was a significantly higher rate of chromosomal abnormalities (67.4%) compared with controls (36.3%). In 57 cycles, a pregnancy rate of 34.0% and an implantation rate of 19.8% was observed in implantation failure patients compared with controls (33.3 and 24.1% respectively), with all the pregnancies in the implantation failure group coming from the transfer of at least one chromosomally normal blastocyst on day 5. It is concluded that in IVF patients, use of PGD along with blastocyst transfer improves IVF outcome.     

Variability of endometrial glandular opening count in infertile patients prior to first IVF treatment

The aim of the present study was to evaluate the number of endometrial glandular openings, using previously reported software that provides an objective count, and to assess the variability of this parameter during the luteal phase in a population of women who had no hormonal abnormalities presenting with tubal infertility or male factor infertility. A cross-sectional study was performed comprising 561 patients selected for a diagnostic hysteroscopy for the investigation of infertility. Hysteroscopy was performed during the mid-secretory phase prior to the first IVF treatment cycle. A total of 561 image frames from all patients were analysed. All images were automatically selected by the software, which also evaluated the number of endometrial glandular openings. The mean +/- SD glandular opening count was 53.2 +/- 30 (range 4-158). The analysis of variation showed a significant difference (P = 0.001) among all video frames. In conclusion, endometrial glandular opening count, as measured by the method described, can be used in investigations during the luteal phase. Although a lack of pattern was observed in endometrial maturation, this feature should be explored further in this subgroup of patients.     

Local endometrial injury and IVF outcome: a systematic review and meta-analysis

A systematic review was conducted of the influence of local endometrial injury (LEI) on the outcome of the subsequent IVF cycle. MEDLINE, EMBASE, the Cochrane Library, National Research Register, ISI Conference Proceedings, ISRCTN Register and Meta-register were searched for randomized controlled trials to October 2011. The review included all trials comparing the outcome of IVF treatment in patients who had LEI in the cycle preceding their IVF treatment with controls in which endometrial injury was not performed. The main outcome measures were clinical pregnancy and live birth rates. In total, 901 participants were included in two randomized (n = 193) and six non-randomized controlled studies (n = 708). The quality of the studies was variable. Meta-analysis showed that clinical pregnancy rate was significantly improved after LEI in both the randomized (relative risk, RR, 2.63, 95% CI 1.39–4.96, P = 0.003) and non-randomized studies (RR 1.95, 95% CI 1.61–2.35, P < 0.00001). The improvement did not reach statistical significance in the one randomized study which reported the live birth rate (RR 2.29, 95% CI 0.86–6.11). Robust randomized trials comparing a standardized protocol of LEI before IVF treatment with no intervention in a well-defined patient population are needed.The endometrium is the lining of the womb where the embryo implants. Endometrial surface injury is a simple office procedure. We reviewed the literature to find out if performing endometrial surface injury before an IVF treatment cycle improves its outcome. Our review found that when endometrial surface injury was performed before an IVF treatment cycle, there was a significant improvement in the outcome of that treatment cycle. We recommend this question is addressed in a well-conducted randomized study to confirm the findings of our review.     

The effect of endometrial thickness on the day of hCG administration on pregnancy outcome in the first fresh IVF/ICSI cycle

The aim of this study was to investigate the effect of endometrial thickness (EMT) on human chorionic gonadotropin (hCG) day on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcome. A retrospective study was conducted on the clinical data of 756 patients in their first fresh IVF/ICSI cycle at the Wuxi Maternity and Child Health Hospital. Compared with the pregnancy failure group, the clinical pregnancy group had more transferable embryos and good-quality embryos and had a thicker endometrium (p?<?0.05). The endometrial pattern was not significantly different between the two groups. EMT was found to be an independent prognostic factor for clinical pregnancy (adjusted OR?=?1.25, 95% CI: 1.15–1.36, p?<?0.01). Seven hundred and fifty-six cycles were categorized into three groups upon EMT on the hCG day: group 1 (EMT??14?mm). Group1 had significantly lower clinical pregnancy, embryo implantation and live birth rates compared with group 2 and 3 (p?<?0.01), while there was no significant difference in either spontaneous abortion or multiple-birth rate among these three groups. It was concluded that EMT on the hCG day was associated with pregnancy outcome in the first fresh IVF/ICSI cycle. A higher clinical pregnancy rate could be achieved when EMT?≥?8?mm, and no adverse pregnancy outcome was observed when EMT?>?14?mm.     

Clinical background affecting pregnancy outcome following local endometrial injury in infertile patients with repeated implantation failure

Local endometrial injury (LEI) has been performed as a promising medical intervention to improve the pregnancy outcome in infertile women suffering from repeated implantation failure (RIF) in in vitro fertilization-embryo transfer cycles. The effect of LEI, however, remains controversial. The aim of this retrospective study was to identify the subgroups of patients with RIF who benefit from LEI. We compared the clinical parameters between the patients who had had a clinical pregnancy in the subsequent embryo transfer cycle following the LEI cycle (LEI-CP group, n?=?94) and those who had resulted in negative pregnancy test (LEI-NP group, n?=?114). The female age, basal follicle stimulating hormone concentration, number of past oocyte pickup cycles, and embryos/blastocysts transferred in the past three RIF cycles were significantly (p?p?=?0.0059) higher in the LEI-CP group than in the LEI-NP group. These findings suggest that LEI is most effective to improve the pregnancy outcome in patients undergoing RIF with uncompromised ovarian reserve, particularly in those with polycystic ovarian syndrome.     

Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development

OBJECTIVE: To evaluate the effects of vaginally administered sildenafil on endometrial thickness and IVF outcome in a large cohort of infertile women with poor endometrial development. DESIGN: Retrospective cohort analysis. SETTING: Private practice setting. PATIENT(S): A cohort of 105 infertile women aged <40 years, with normal ovarian reserve and at least two consecutive prior IVF failures attributed to inadequate endometrial development. INTERVENTION(S): Patients underwent IVF using a long GnRH-a protocol with the addition of sildenafil vaginal suppositories (25 mg, 4 times per day) for 3-10 days. MAIN OUTCOME MEASURE(S): Peak endometrial development, pregnancy, and implantation rates. RESULT(S): Of 105 patients, 73 (70%; Group A), attained an endometrial thickness of >/=9 mm, whereas 32 (30%; Group B) did not. Implantation and ongoing pregnancy rates were significantly higher for Group A (29% and 45%) than for Group B (2% and 0). Of 11 women in Group B who had embryos transferred in that cycle, only one conception occurred, which resulted in a miscarriage. In Group B, 59% of women had a history of endometritis, compared with 44% in Group A. CONCLUSION(S): Vaginal administration of sildenafil enhanced endometrial development in 70% of patients studied. High implantation and ongoing pregnancy rates were achieved in a cohort with a poor prognosis for success. Previous endometritis may decrease the response to sildenafil.     

Importance of endometrial quality in women with tubal infertility during a natural menstrual cycle for the outcome of IVF treatment

Purpose: The importance of endometrial maturation at estimated time of implantation for the outcome of IVF treatment in regularly menstruating women with tubal infertility was evaluated. Methods: FSH was measured on cycle day 3, on days 10–15 urine and blood were collected to estimate the day of the LH peak, and E₂ and P₄ were measured during the luteal phase, on cycle days 19–26. An endometrial biopsy was obtained on days LH + 3 to LH + 6. Results: The number of subjects with delayed endometrial maturation was larger in the group of infertile women who did not become pregnant compared to pregnant women and controls. Those infertile women who did not become pregnant after IVF treatment also presented with a higher basal FSH on cycle day 3 and lower E₂ and P₄ AUC in the luteal phase. Six infertile women and two controls presented with mid- and late-proliferative endometrium in the luteal phase on cycle days LH + 3 to LH + 6, in the presence of adequate E₂ and P₄ secretion. Six morphological characteristics were compared in the three groups: (1) 17 infertile women who became pregnant, (2) 18 who did not become pregnant, and (3) 28 controls. The pregnant infertile women did not differ from the controls. The numbers of glandular and stromal mitoses were significantly higher in those women who did not become pregnant (P<0.01) compared with those who became pregnant. Endometrial biopsies obtained on cycle days LH + 5 and LH + 6 showed significant differences in glandular epithelial height (P<0.05) and number of vacuolated cells among the nonpregnant women (P<0.01), the pregnant women (P<0.05), and controls. Conclusions: A higher frequency of retarded endometrial development in women who did not become pregnant following IVF treatment was found. In some cases, endometrial insensitivity could most likely cause retarded endometrial development and failure of implantation after IVF treatment, which could not be overcome by routine luteal-phase support. However, our results do not allow conclusions concerning its relative importance compared to preembryo quality; this has to be investigated further.     

Oral administration of l-carnitine improves the clinical outcome of fertility in patients with IVF treatment

Age-dependent decline of mitochondrial function has been proposed to be a main cause of decline of embryo quality. Then, l-carnitine plays important roles in reducing the membranous toxicity of free-fatty acids by forming acyl-carnitine and promoting β-oxidation, preventing cell damage. Recent research revealed that l-carnitine played important roles in vitro in oocyte growth, oocyte maturation and embryo development. However, such beneficial effects of l-carnitine in vivo have yet to be verified. The effect of oral l-carnitine supplementation on embryo quality and implantation potential was examined. A total of 214 patients were included in this study. They all previously received in vitro fertilization-embryo transfer (IVF-ET) and failed to conceive. Then they were administered l-carnitine for 82 days on average and underwent IVF-ET again. There were no significant differences in the total number of retrieved oocytes, and their maturation and fertilization rates between before and after l-carnitine administration. The quality of embryos on Days 3 and 5 after insemination was improved following l-carnitine administration (p?l-carnitine administration compared with previous cycles. Healthy neonates were born after IVF-ET following l-carnitine administration. Our data suggested that oral administration of l-carnitine to fertility patients improved the developmental competence of their oocytes after insemination.     

Sperm chromosome analysis and outcome of IVF in patients with non-mosaic Klinefelter's syndrome

OBJECTIVE: The aim of the study was to determine the potential risk for fetal chromosomal anomalies in non-mosaic Klinefelter's syndrome patients undergoing IVF and intracytoplasmic sperm injection. DESIGN: Individually collected spermatozoa were isolated from wet testicular tissue preparations and fixed on glass slides using micromanipulation. Their nuclei were analyzed for chromosomes X, Y, and 18 by fluorescent in situ hybridization. SETTING: Assisted reproductive technology program. PATIENT(S): Consenting patients with non-mosaic Klinefelter's syndrome undergoing testicular biopsy and IVF (fresh specimens) or following such treatment (cryopreserved specimens). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The rates of numerical chromosome abnormalities for chromosomes X, Y, and 18 among spare testicular sperm and the pregnancy outcome following treatment. RESULT(S): Testicular sperm were found in 8 of 20 patients. Four couples became pregnant following embryo replacement. Sperm chromosomes were analyzed in five patients. One hundred and five sperm of 112 analyzed (93.7%) were normal with X to Y ratio of 50:55 (NS) respectively. Among the 112 sperm tested, seven (6.3%) demonstrated chromosomal abnormalities, of which five were related to the sex chromosomes and two to chromosome 18. One set of triplets, one set of twins, and two singletons (four males and three females) with normal karyotypes were born. CONCLUSION(S): Most of the testicular sperm retrieved from Klinefelter's syndrome patients demonstrates a normal pattern of sex chromosome segregation. Therefore, the risk of transmitting numerical sex chromosome abnormalities is relatively low and probably comparable with the rates found in other severe male factor infertility patient groups.     

Impact of luteal phase hysteroscopy and concurrent endometrial biopsy on subsequent IVF cycle outcome

Purpose

Endometrial biopsy preceding implantation in in vitro fertilization (IVF) treatment causes a type of injury which facilitates implantation. Pre-treatment hysteroscopic evaluation of uterine cavity also raises the success in IVF. This study investigates whether office hysteroscopy and concurrent endometrial biopsy performed in the luteal phase, on the day of GnRH agonist initiation for long protocol, improves subsequent IVF outcome.

Methods

A prospective, nonrandomized, controlled study of 128 normoresponder women was performed: In 70 women (study group), office hysteroscopy and concurrent endometrial biopsy were performed on the day of GnRH agonist initiation preceding ET cycle and in 58 women (control group), GnRH agonist was initiated without any intervention. However, uterine cavity was shown to be normal with hysteroscopy within the previous 6 months in those women. Implantation and pregnancy rates were compared between the groups.

Results

Intrauterine pathologies were observed in 28 % of women in the study group. Implantation rate (38 vs. 25 %; p = 0.04) and pregnancy rate per ET (67 vs. 45 %; p = 0.01) were found to be significantly higher in the study group compared to the control group.

Conclusion

Office hysteroscopy and concurrent endometrial biopsy performed in the luteal phase, on the day of GnRH agonist initiation for long protocol, provide direct evaluation of the uterine cavity immediately before ET cycle and also significantly improve the implantation and IVF outcome.     

The effect of anti-thyroid antibodies on endometrial volume,embryo grade and IVF outcome

Thyroid auto-immunity (TAI) has been implicated as the most common cause of hypothyroidism in general population, especially in women. Many studies revealed that increased infertility incidences with TAI. The aim of the present article was to evaluate the effect of thyroid auto-antibody (TAA) positivity on embryological parameters, IVF-outcome and endometrial volume (EnV) in infertile patients who were applied for routine artificial reproductive technologies (ART) programme. This study included prospective, sequential, cross-sectional analyses of parameters obtained from 69 patients with unexplained infertility. It was the first ART application of patients. Patients were homogenous for age, body mass index, basal hormone measurements and underwent same ovulation induction protocol. They were evaluated for thyroid hormone profile and TAAs and divided into three groups; TAA negative group (n = 31), TAA positive group (n = 23) and TAA positive and euthyroid with medication group (n = 15). There were no differences among groups for the number of Grade-1 and Grade-2 embryos, distribution of embryo-grades, number of oocytes retrieved and fertilised, biochemical pregnancy ratios (PR), EnV and miscarriage ratio. However, the clinical PR was significantly lower in the TAA positive group (p = 0.024). In conclusion, the embryo grades and EnV did not differ among groups. But the clinical PR differs and the anti-thyroid peroxides positivity, above the cut-off point, affects the clinical PR.     

Serum oxytocin profiles in patients with repeated implantation failure during IVF cycles

Abstract

Objective: The objective of this study is to investigate the association between oxytocin (OT) levels and repeated implantation failure (RIF) during in vitro fertilization-embryo transfer (IVF-ET) cycles.

Methods: Blood samples were collected from 108 women undergoing IVF-ET treatment at the following time points: gonadotrophin (Gn) administration day (Gn Day 0), hCG administration day (hCG Day 0), ET administration day (ET Day 0), and 5?d after ET (ET Day 5). Serum OT and steroid profiles were measured and compared among three groups: Group A included 38 women with a history of RIF, Group B included 41 women who became pregnant following the first fresh ET, and Group C included 29 women who did not become pregnant following the first fresh ET.

Results: The OT levels of the three groups at different time points were not significantly different. Serum OT levels were significantly higher on hCG Day 0, ET Day 0, and ET Day 5 than on Gn Day 0, and they were significantly correlated with the estradiol concentration on ET Day 0.

Conclusions: RIF patients do not have elevated serum OT levels during IVF-ET cycles.     

Negative effect of P72 polymorphism on p53 gene in IVF outcome in patients with repeated implantation failure and pregnancy loss

Purpose

Investigate whether R72P on p53 gene polymorphism has a higher prevalence among women with a history of recurrent implantation failure (RIF) and pregnancy loss (RPL) and its influence in their IVF cycle outcome.

Material and methods

p53 polymorphism R72P has been studied in 181 women. The control group included 83 oocyte donors. In the study group 98 women were included: 44 with RIF and 54 with RPL. From the study group, 76 patients underwent IVF-cycles (55 RPL and 21 RIF).

Results

The frequency of PP genotypes on p53 among RIF was 11.4 % compared with 18.5 % for RPL and 6 % in controls (p < 0.01). There were no significant differences with respect to patient characteristics. Significant differences were reported in pregnancy rate (69.4 % for RR/RP and 33.3 % for PP; p < 0.05), embryo implantation rate (33.3 % for RR/RP and 7.3 % for PP; p < 0.05) and ongoing pregnancy rate (53.1 % for RR/RP and 14.3 % for PP; p < 0.05) among RIF and RPL.

Conclusions

This investigation reveals that in RIF and RPL patients R72P on p53 gene is more prevalent than fertile population. Moreover, patients carrying a PP genotype on p53 codon 72 will have less chance to achieve an ongoing pregnancy. This information together with some additional markers will allow development of diagnostic tests for detects risk for RIF and RPL before infertility treatment is initiated.     

HP-hMG在卵巢次高反应患者体外受精周期中的临床应用效果

目的:探讨卵巢次高反应患者体外受精-胚胎移植(in vitro fertilization-embryo transfer,IVF-ET)周期应用高纯度尿促性素(HP-hMG,贺美奇)与重组人卵泡刺激素(r-FSH,果纳芬)促排卵的临床结局。方法:选择IVF-ET助孕的卵巢次高反应患者310例,随机分为A组和B组,分别给予r-FSH+HP-hMG(A组,n=124)和r-FSH(B组,n=186)促排卵,统计促性腺激素(Gn)总用量、Gn使用天数、获卵数、受精率、卵裂率、优质胚胎率、临床妊娠率以及因卵巢过度刺激综合征(OHSS)周期取消率及ET后OHSS发生率。结果:患者的基本情况组间无统计学差异(P0.05),B组Gn使用天数明显多于A组(P0.05),Gn总用量明显多于A组(P0.05),hCG注射日E_2、LH组间无统计学差异(P0.05),B组hCG注射日孕酮(P)值显著高于A组(P0.05);获卵数B组显著多于A组(P0.05),受精率、卵裂率、移植胚胎数组间无统计学差异(P0.05),但优质胚胎率B组却显著低于A组(P0.05),移植患者临床妊娠率组间差异无统计学意义(P0.05),A组仅稍高于B组。A组预防OHSS周期取消率较B组明显下降(P0.05),B组移植患者OHSS发生率略高于A组(P0.05)。结论:在卵巢次高反应患者人群中从启动日添加HP-hMG能改善胚胎质量,增加子宫内膜容受性,降低OHSS发生率。     

Autologous platelet-rich plasma improves the endometrial thickness and live birth rate in patients with recurrent implantation failure and thin endometrium

PurposeThe aim of this study was to evaluate the effects of intrauterine platelet-rich plasma (PRP) infusion on endometrial thickness and pregnancy outcomes in a population of patients with either recurrent implantation failure (RIF), thin endometrium (TE), or both (RIF + TE)MethodsThis retrospective study included patients attending the CReATe Fertility Centre between October 2018 and July 2021 who received intrauterine PRP infusion to prepare the endometrium for frozen embryo transfer. PRP was prepared from 21 cc of whole blood using the 2-step centrifugation method to yield 0.5–0.75 cc of concentrated platelets. Endometrial thickness was measured before infusion and within 72 h after infusion. All embryos transferred were tested for genetic abnormalities using next-generation sequencing.ResultsA total of 85 patients, 133 cycles, and 211 infusions were included. The majority of patients (56.5%) were diagnosed with RIF, some with TE (27.0%), and the remainder with both RIF and TE (16.5%). The majority of patients received one PRP infusion per cycle (55%). The endometrial thickness significantly increased across all diagnoses with a significant increase of 1.0 mm (0.5–1.7), which was also significantly greater than in previous cycles. The clinical pregnancy rate per embryo transfer after intrauterine PRP infusion was significantly greater compared to previous cycles (37% vs 20%, odds ratio 2.2) as was the live birth rate (19% vs 2%, odds ratio 11.6).ConclusionOur study suggests that PRP should be considered a noninvasive front-line therapy for improving endometrial thickness and implantation in patients with RIF, a TE, or both.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10815-022-02505-0.