Accumulation of embryos over 3 natural modified IVF (ICSI) cycles followed by transfer to improve the outcome of poor responders.

BACKGROUND: Alternatives to improve treatment outcomes in poor responders are needed. For this we studied whether multiple (x3) Natural Modified (NM)-IVF(ICSI) cycles followed by an embryo transfer (ET) from the accumulated embryos can improve the treatment outcomes in poor responders. METHOD: A retrospective analysis was applied to a pool of participants qualifying as poor responders according to the Bologna criteria. This was performed over a 2-year IVF center database with a Study Group including women with a minimum of 3 cycles of NM-IVF (ICSI) and subsequent vitrified-thawed ET. As a control, 1 NM-IVF (ICSI) cycle with fresh ET was used. The primary outcome accounted was the livebirth rate (LBRs) following one ET; the secondary outcome was clinical pregnancy rates (CPRs), miscarriage and cycle cancellation rates. Comparisons were held over mean numbers by t-test, over median by Mann-Whitney, and categorical data were treated by Chi-square. RESULTS: The prognosis for livebirth in the study (n=125) and control (n=208) group was equally poor (mean age: 40.2 ± 3.0 vs 40.0 ± 3.3; median AMH: 2.1 vs 2.2 (pmol/L), AFC 4.0 vs 4.0). The LBR was significantly higher with the study protocol (30.6% vs 13.3%; p=0.002), particularly in women aged 35-39 years (31% vs 10.8%; p=0.05) and 40-44 years (26% vs 10.3%; p=0.02). Lower LBR in women aged ≥35 years in the control-group was mainly attributable to the higher miscarriage rate. With significantly more oocytes (mean: 6.5 ± 3.8 vs 2.0 ± 1.4; p <0.0001) and embryos available (mean: 3.6 ± 2.3 vs 0.9 ± 0.7; p<0.0001), only a minority ended up with no ET in the study-group (7.2% vs 35.6%; p<0.0001). None dropped-out while undergoing 3 cycles, whereas no patient opted for further attempts after one standalone cycle. CONCLUSION: Accumulation of embryos through 3 NM-IVF cycles before transfer improves livebirth rates and reduces the risk of lacking an embryo for transfer in poor responders aged ≥35 years.

Thaw, biopsy and refreeze strategy for PGT-A on previously cryopreserved embryos.

BACKGROUND: Preimplantation genetic testing for aneuploidy (PGT-A) with Next Generation Sequencing technology is a low-cost and powerful technology for the analysis of embryo quality. However, PGT-A requires freezing of embryos, suggesting that previously cryopreserved embryos cannot be tested. Here, we test whether use of the vitrification technique permits the refreezing of embryos, thus permitting PGT-A testing of cryopreserved embryos. METHODS: The results are a retrospective analysis of cases performed at Create fertility between 2016 and 2017. Results obtained after traditional PGT-A are compared with results after the thaw biopsy and refreeze (TBR) procedure. A total of 220 patients were treated with PGT-A and 54 patients with the TBR procedure. RESULTS: Maternal ages were not significantly different between the groups. The proportion of PGT-A normal embryos was not significantly different between the two groups. A clinical pregnancy rate of 61.5% was achieved with the PGT-A group and 52.4% with the TBR group. These results were not statistically significant. The efficiency of the thaw, biopsy and refreeze technique was not significantly different to that of fresh cycles for rates of survival, results obtained and aneuploidy incidence. Clinical pregnancy rates are not significantly different after the biopsy of fresh and previously cryopreserved embryos. CONCLUSION: The data shows that the TBR procedure has an equivalent success rate to that of classical PGT-A procedures.

Ovarian reserve may be compromised after adnexal surgery: Are we sufficiently fertility- focused in our surgical training?

There is a general trend towards delay in childbearing age amongst women. The ovarian reserve clearly falls with increasing age and the impact is greater with advancing age, particularly from late 30s. Presence of other risk factors can increase the risk of subfertility. A large number of women are exposed to pelvic surgery for various reasons, both elective and emergency. There is evidence that some of the pelvic surgery performed around ovaries and tubes has a negative impact on the ovarian reserve and in turn may cause a decline in woman's ability to conceive. A fertility-sparing focus on all pelvic surgery is likely to prevent further decline in ovarian reserve for women who are already at higher risk. Such focus seems to be currently lacking. It is proposed that integrating fertility-sparing focus to structured gynaecological surgical training will benefit women.

Why Fertility Education is needed in schools.

Fertility education needs to be at the top of the agenda if we want to make a major impact in preventing infertility. We have been successful in reducing teenage pregnancies through Sex and Relationship education (SRE) and education on contraception. Sex and relationship education is for now and fertility education is for the future. Conception and contraception are two sides of the same coin. We need to empower our young people with education on fertility so that they can stand a better chance of falling pregnant when they choose to. Education empowers.

Add-ons in IVF programme - Hype or Hope?

A series of new technologies and adjuvant therapies have been advocated in order to improve the success of IVF treatment. Dehydro-epiandrostenedione, growth hormones, Coenzyme Q 10, calcium ionosphores, immune therapy, heparin, low-dose aspirin, and vasodilators are among commonly prescribed pharmacological adjuvants. New technologies that are proposed to improve IVF outcomes include advanced sperm selection procedures, time- lapse embryo monitoring, preimplantation genetic screening, assisted hatching endometrial injury or embryo-glue. This review looked into current evidence to justify the use of these co-interventions and whether some of them can still be offered while awaiting more robust evidence to con rm or refute their role.

The (t)WE lab Simplified IVF Procedure: First Births after freezing/thawing.

BACKGROUND: Infertility care is one of the most neglected health care issues in developing countries (DC), affecting more than 50 million couples. The social stigma of childlessness still leads to isolation and abandonment. Bilateral tubal occlusion due to sexually transmitted diseases and pregnancy-related infections is the most common cause of infertility in DC. Consequently most cases of infertility are only treatable by using assisted reproductive technologies which are either unavailable or too costly. Lowering the laboratory costs associated with IVF is a crucial step to make IVF affordable for a larger part of the world population. We recently developed and described a new simplified method of IVF culturing, called the (t)WE lab method. Our initial results in fresh IVF cycles showed that IVF methodology can be significantly simplified and result in successful outcomes at levels that compare favourably to those obtained in high resource programs. CASE-REPORTS: We report three pregnancies and four live births as a result of transferring five cryo/thawing embryos which were developed after using the simplified (t)WE lab system. The two singleton babies delivered vaginally, for the twin pregnancy a caesarean section was performed. All babies were healthy, the perinatal outcome was uneventful in all cases. CONCLUSION: We provide proof-of-principle evidence that transferring cryopreserved/thawed embryos obtained with our (t)WE lab simplified culture system can lead to successful pregnancies and healthy live births.

A successful pregnancy following 'double rescue' egg retrieval in a woman with Natural cycle IVF.

A case is reported of a patient with critically low anti-mullerian hormone (AMH) having successful 'rescue' oocyte retrieval in natural in vitro fertilization (IVF) cycle 24 hours after the initial procedure had resulted in no oocyte being collected. Following administration of 10,000 units human chorionic hormone (hCG) a second retrieval was performed 24 hours after the first, producing one Metaphase-I oocyte. After in vitro maturation (IVM) over 4 hours in oocyte maturation medium, introcytoplasmic sperm injection (ICSI) was performed. A subsequent transfer of a 2-cell embryo proceeded on day 2. A positive hCG was recorded 15 days after embryo transfer (ET), and a viable clinical pregnancy has been confirmed. We believe this is the first reported case of a successful egg collection following a prior failed follicle aspiration in Natural IVF cycle. Factors such as good peri-follicular flow and initial follicular fluid cell content are probably essential before attempting a repeat procedure. This report highlights the importance of rescue IVM when an immature oocyte is collected.

ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.

The definition presented here represents the first realistic attempt by the scientific community to standardize the definition of poor ovarian response (POR) in a simple and reproducible manner. POR to ovarian stimulation usually indicates a reduction in follicular response, resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to define the poor response in IVF, at least two of the following three features must be present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and (iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore, one stimulated cycle is considered essential for the diagnosis of POR. However, patients of advanced age with an abnormal ORT may be classified as poor responders since both advanced age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of ovarian stimulation cycle outcome. In this case, the patients should be more properly defined as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal' criteria needed to select patients for future clinical trials, more homogeneous populations will be tested for any new protocols. Finally, by reducing bias caused by spurious POR definitions, it will be possible to compare results and to draw reliable conclusions.

Mild ovarian stimulation for IVF.

BACKGROUND: Mild ovarian stimulation for in vitro fertilization (IVF) aims to achieve cost-effective, patient-friendly regimens which optimize the balance between outcomes and risks of treatment. METHODS: Pubmed and Medline were searched up to end of January 2008 for papers on ovarian stimulation protocols for IVF. Additionally, references to related studies were selected wherever possible. RESULTS: Studies show that mild interference with the decrease in follicle-stimulating hormone levels in the mid-follicular phase was sufficient to override the selection of a single dominant follicle. Gonadotrophin-releasing hormone antagonists compared with agonists reduce length and dosage of gonadotrophin treatment without a significant reduction in the probability of live birth (OR 0.86, 95% CI 0.72-1.02). Mild ovarian stimulation may be achieved with limited gonadotrophins or with alternatives such as anti-estrogens or aromatase inhibitors. Another option is luteinizing hormone or human chorionic gonadotrophin administration during the late follicular phase. Studies regarding these approaches are discussed individually; small sample size of single studies along with heterogeneity in patient inclusion criteria as well as outcomes analysed does not allow a meta-analysis to be performed. Additionally, the implications of mild ovarian stimulation for embryo quality, endometrial receptivity, cost and the psychological impact of IVF treatment are discussed. CONCLUSIONS: Evidence in favour of mild ovarian stimulation for IVF is accumulating in recent literature. However, further, sufficiently powered prospective studies applying novel mild treatment regimens are required and structured reporting of the incidence and severity of complications, the number of treatment days, medication used, cost, patient discomfort and number of patient drop-outs in studies on IVF is encouraged.

The ISMAAR proposal on terminology for ovarian stimulation for IVF.

IVF is performed with oocytes collected in natural and stimulated cycles. Different approaches to ovarian stimulation have been employed worldwide. Following the introduction of GnRH antagonists and strategies to reduce multiple births such as single embryo transfer, there is a genuine scientific interest in the revival of natural cycle and mild approaches to ovarian stimulation in IVF. Recent evidence suggests that application of natural and mild IVF is patient-centred, aimed at reducing the cost of treatment, patient discomfort and multiple pregnancies. However, there seems to be no consistency in the terminology used for definitions and protocols for ovarian stimulation in IVF cycles. Following the recent International Society for Mild Approaches in Assisted Reproduction (ISMAAR) meeting and communication with interested international experts, this article has recommended revised definitions and terminology for natural cycle IVF and different protocols used in ovarian stimulation for IVF. It is proposed that these terms are adopted internationally in order to achieve a consistency in clinical practice, research publications and communication with patients.

Evaluation of endometrial receptivity during in-vitro fertilization using three-dimensional power Doppler ultrasound.

OBJECTIVE: To compare sonographic endometrial characteristics in in-vitro fertilization (IVF) cycles between women who conceive and those who do not. METHODS: Thirty-five women undergoing IVF treatment participated in the study. Using three-dimensional (3D) power Doppler ultrasound, we assessed endometrial patterns, volume and vascularization, after follicle stimulating hormone (FSH) stimulation but before human chorionic gonadotropin (hCG) administration (referred to hereafter as 'after FSH stimulation') and again on the day of oocyte retrieval. RESULTS: The pregnancy rate was 37% (13/35). After FSH stimulation, 29 of the 35 women had a triple-line endometrial pattern, compared with five out of 35 on the day of oocyte retrieval. In those who had a triple-line pattern after FSH stimulation the pregnancy rate was 44.8% (13/29) and it was 0% (0/6) in those with a homogeneous pattern (chi-square test, P = 0.039). If a triple-line pattern was present on the day of oocyte retrieval the pregnancy rate was 80.0% (4/5), whereas if the pattern was homogeneous the pregnancy rate was 30.0% (9/30) (P = 0.032). There were no differences between those who conceived and those who did not in endometrial thickness, volume or vascularization on either day examined. Endometrial volume decreased significantly after hCG injection in women who conceived, but not in those who did not conceive. In both groups endometrial and subendometrial vascularization decreased after hCG injection, while the endometrial thickness remained unchanged. CONCLUSIONS: The existence of a homogeneous endometrial pattern after FSH stimulation seems to be a prognostic sign of an adverse outcome in IVF, while a triple-line pattern after FSH stimulation and a decrease in endometrial volume appear to be associated with conception.

Intraobserver and interobserver variability of ovarian volume, gray-scale and color flow indices obtained using transvaginal three-dimensional power Doppler ultrasonography.

OBJECTIVE: To assess intraobserver and interobserver variability in ovarian volume and gray-scale and color flow index measurements using transvaginal, three-dimensional, power Doppler ultrasonography. METHODS: Eleven women (22 ovaries) were examined on day 8 of controlled ovarian hyperstimulation therapy, which was part of their in vitro fertilization treatment protocol. The patients were examined twice by the first observer and once by the second observer. The acquired volume datasets were analyzed using the VOCAL imaging program, enabling the assessment of ovarian volume, vascularization index (VI), flow index (FI), vascularization flow index (VFI) and mean grayness (MG). For these parameters the intraclass (intra-CC) and interclass (inter-CC) correlation coefficients, within-observer and between-observers repeatability coefficient (r) and limits of agreement were calculated. RESULTS: Both intraobserver and interobserver repeatability of ovarian volume measurements were considered very good with an intra-CC value of 1.00 and inter-CC value of 0.99, respectively. Also VI, FI, VFI and MG measurements were repeatable by a single observer, the intra-CC ranging from 0.82 to 0.91. The interobserver reproducibility was also good for VI, VFI and MG measurements (inter-CC values 0.73, 0.70 and 0.81, respectively), but for FI measurements the reproducibility was poor (inter-CC = 0.29, r = 7.87). CONCLUSIONS: In general, the intraobserver reproducibility was better than interobserver reproducibility for all parameters. The volume assessments were reproducible both by one observer and by two separate observers. The intraobserver and interobserver variabilities were acceptable for VI, VFI and MG, whereas for FI the interobserver reproducibility was poor. Our results suggest that measurement of gray-scale and color Doppler flow indices is reproducible thus allowing them to be used in clinical practice and research.

Characterization of normal and polycystic ovaries using three-dimensional power Doppler ultrasonography.

PURPOSE: To evaluate the characteristics of polycystic compared to normal ovaries using three-dimensional (3-D) power Doppler ultrasonography. METHODS: We recruited 42 volunteers, all of whom were commencing IVF treatment. Each patient was examined in the cycle preceeding the start of drug therapy during the late follicular phase. If eight or more subcapsular follicles of 2-8 mm in diameter in one two-dimensional (2-D) plane were detected in either of the ovaries, the patient was categorized as having polycystic ovaries (PCO); otherwise the ovaries were considered normal. The parameters examined were volume of the ovary, vascularization index (VI), flow index (FI), vascularization flow index (VFI), and mean greyness (MG). In addition, the ovary was arbitrarily divided into cortex and stroma, and thereafter volume, VI, FI, VFI, and MG were calculated for these two regions. RESULTS: Twenty-eight women had normal ovaries and 14 had PCO. The comparison between normal and PCO showed that as a group the PCO were larger, without any differences in VI, Fl, VFI, or MG. In patients with PCO, the right ovary was larger than the left one. In patients with normal ovaries, Fl was higher on the left side. Division into cortex and stroma revealed that there were no differences in cortical or stromal VI, FI, VFI, or MG between normal and PCO on either side. CONCLUSIONS: The ovaries defined as polycystic were larger than normal ovaries, but there was no difference in the echogenicity of the stroma between polycystic and normal ovaries. We were also unable to demonstrate that the polycystic ovarian stroma was more vascularized than the stroma in the normal ovaries.

Three-dimensional sonographic and power Doppler characterization of ovaries in late follicular phase.

OBJECTIVE: To determine ovarian blood flow characteristics using three-dimensional power Doppler ultrasound. METHODS: We examined 30 patients (30 cycles) prior to the start of their in vitro fertilization treatment in the late follicular phase using three-dimensional power Doppler ultrasound. The volume, vascularization index, flow index, vascularization flow index, mean grayness and the presence of the dominant follicle were determined for each ovary separately. RESULTS: The dominant follicle could be detected in 24 out of 30 cycles (80.0%). The volume of the dominant ovary was 9.9 (standard deviation, 4.0) cm3 and the volume of the non-dominant ovary 6.8 (standard deviation, 2.8) cm3 (P < 0.001). Mean grayness in the dominant ovary was 43.3 (standard deviation, 5.0) and in the non-dominant 47.2 (standard deviation, 4.0) (P < 0.001), but no other differences could be observed between dominant and non-dominant ovaries. The shell with a diameter of 2 mm surrounding the dominant follicle had a higher vascularization index (mean, 9.0; standard deviation, 5.9) and vascularization flow index (mean, 4.2; standard deviation, 2.8) than the whole dominant ovary (mean, 5.5; standard deviation, 2.5 and mean, 2.5; standard deviation, 1.3, respectively) (P = 0.003 and 0.002, respectively). In the cycles without a dominant follicle (n = 6), flow index (mean, 50.0; standard deviation, 5.9) and vascularization flow index (mean, 7.3; standard deviation, 6.2) on the left side were higher than on the right side (mean, 40.2; standard deviation, 3.1; mean, 1.5; standard deviation, 1.4; P-values 0.013 and 0.046, respectively). CONCLUSION: In the dominant ovary, the volume was higher and mean grayness lower than in the non-dominant ovary. The vascularization index in the shell surrounding the dominant follicle was higher than the average vascularization index in the whole dominant ovary. In addition, there were differences in the vascularization and flow indices between right and left ovaries, which may be related to the anatomical difference in the venous drainage between right and left ovaries.