'Luckily, I don't believe in statistics': survey of women's understanding of chance of success with futile fertility treatments.

RESEARCH QUESTION: Why are women who face poor prognoses for success in assisted reproductive technology (ART) treatment choosing to pursue procedures using their own eggs, despite receiving information that their chances of success are very low. DESIGN: Cross-sectional study based on an anonymous questionnaire distributed to women aged between 43 and 45 years, undergoing ART using their own oocytes, at six public outpatient fertility clinics and three public in-hospital IVF units in Israel between 2015 and 2016. The main outcome measure was personal estimation of chance to achieve a live birth after the current ART treatment cycle and the cumulative estimated rate after all the treatment cycles the patient intended to undergo. RESULTS: Response rate was 70.0%, with 91 participants of mean age 43.8 ± 0.7 years. Participants estimated their delivery rates after the next ART treatment cycle at 49.0 ± 31.8% (response rate 93.4%) and their cumulative delivery rates after all the ART treatments they would undergo at 57.7 ± 36.3% (response rate 90.1%). This is significantly higher than the predicted success rates of 5% and 15%, respectively (both P < 0.001), which are based on national register data. Nearly one-half of patients rated themselves as having a better than average chance of conception (47.3%). CONCLUSION: Women do not pursue futile treatments because they lack information. Despite being informed of the low success rates of conception using ART treatments, many patients of advanced maternal age have unrealistically high expectations from ART, essentially ignoring their estimated prognosis when deciding on treatment continuation. Future work should examine the psychological reasons behind continuing futile fertility treatments.

Screening for blood born viruses in assisted reproduction: is annual testing necessary?

PURPOSE: Screening for blood born viruses is routinely performed before fertility treatment in assisted reproduction technology (ART) clinics worldwide. It involves testing for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), among others. Identifying patients with positive viral screening allows to refer them and their partners for appropriate counseling and treatment. The need for repeat viral screening and its required frequency have never been clearly established. In Israel, viral screening is mandatory and is repeated annually. Our aim was to determine the prevalence of HBV, HCV, and HIV seroconversion in patients with negative screening upon initiation of ART treatment. METHODS: A retrospective analysis of viral screening tests of all fertility patients in a single assisted conception unit between 1997 and 2015. RESULTS: During the study period, 2844 patients were treated at our clinic, out of whom 1945 patients met the inclusion criteria. The average length of treatment was 1.61 ± 0.81 years, during which female patients underwent screening tests 2.6 ± 0.9 times, and male patients 2.3 ± 1.2 times. No case of seroconversion to any of the three viruses was noted during the entire study period, resulting a seroconversion rate of 0%. CONCLUSIONS: Primary infection with HBV, HCV, or HIV is an extremely rare event among Israeli infertile patients, and the risk for seroconversion in this population is practically nil. Annual screening of both partners leads to substantial costs and appears to be futile. Our results question the current practice and support increasing the interval between screening tests in low-risk populations.

Endometrial nerve fibre density in patients undergoing IVF: a pilot study.

The presence of nerve fibres in the functional layer of the endometrium has been strongly associated with endometriosis. Presence of nerve fibres in the endometrium of women undergoing IVF has not been previously assessed. This prospective pilot study assessed the presence of nerve fibres in endometrium of women undergoing IVF due to various causes and examined the correlation between the presence of nerve fibres and IVF success. A total of 32 IVF patients underwent endometrial biopsy during days 21-23 of the menstrual cycle. Nerve fibres were identified by immunohistochemical staining. Correlations between the presence and density of nerve fibres and aetiology of infertility and IVF success were measured. Nerve fibres were identified in the endometrium of 10/31 (32.3%) women with a satisfactory biopsy. Presence of nerve fibres was not correlated with cause of infertility. Clinical pregnancy was achieved in 12/32 (37.5%) patients, without correlation to presence of nerve fibres in the endometrium. Nerve fibres were identified in a substantial percentage of women undergoing IVF, possibly reflecting underdiagnosis of endometriosis in this population. The presence of nerve fibres does not appear to interfere with implantation. The significance of nerve fibres in the endometrium of IVF patients warrants further research. The presence of nerve fibres in the functional layer of the endometrium has been strongly associated with endometriosis. The presence of nerve fibres in the endometrium of women undergoing IVF has not been previously assessed. Our aim was to assess the presence of nerve fibres in endometrium of women with various causes of infertility undergoing IVF and to examine the association between the presence of nerve fibres in the endometrium and IVF success. In a prospective study, 32 IVF patients underwent endometrial biopsy during days 21-23 of the menstrual cycle. Nerve fibres were identified by immunohistochemical staining. Associations between the presence and density of nerve fibres and the aetiology of infertility and IVF success were measured. Nerve fibres were identified in the endometrium of 10/31 (32.3%) women with a satisfactory biopsy. No association was found between the presence of nerve fibres and the cause of infertility. Clinical pregnancy was achieved in 12/32 (37.5%) patients, without association with the presence of nerve fibres in the endometrium. Nerve fibres can be identified in a substantial percentage of women undergoing IVF, possibly reflecting underdiagnosis of endometriosis in this population. Their presence does not interfere with embryo implantation. The significance of nerve fibres in the endometrium of IVF patients warrants further research.

Controlled ovarian stimulation using a long gonadotropin-releasing hormone antagonist protocol: a proof of concept and feasibility study.

BACKGROUND/AIMS: To evaluate the feasibility of a long protocol of controlled ovarian stimulation prior to in vitro fertilization (IVF) and embryo transfer with a gonadotropin-releasing hormone (GnRH) antagonist used for pituitary and ovarian suppression. METHODS: Thirty patients undergoing IVF/intracytoplasmic sperm injection were randomized into two groups. The control group (n = 16) received a standard flexible GnRH antagonist protocol. Ovarian stimulation consisted of 225 IU/day of recombinant follicle-stimulating hormone for 5 days, followed by 225 IU/day of human menopausal gonadotropin until human chorionic gonadotropin (hCG) administration. The study group (n = 14) received 0.25 mg of GnRH antagonist daily for 7 days, thereafter, upon confirmation of pituitary and ovarian suppression, ovarian stimulation was commenced with the same protocol as used in the control group. Hormone and follicle dynamics, as well as laboratory characteristics and cycle outcome, were compared for both groups. RESULTS: Both groups were comparable in baseline characteristics. Pituitary and ovarian suppression were effectively achieved in 12/14 patients in the study group. The duration of ovarian stimulation and gonadotropin consumption were similar in both groups, as was also the number and size of follicles on hCG day. CONCLUSION: The results of our study confirm the feasibility of a long GnRH antagonist protocol. This regimen could become another option to optimize GnRH antagonist protocols, and should thus be further explored.

Spontaneous ovulation versus HCG triggering for timing natural-cycle frozen-thawed embryo transfer: a randomized study.

In ovulatory patients, frozen-thawed embryo transfer (FET) is commonly performed during a natural cycle (NC). The objective was to compare serial monitoring until documentation of ovulation with human chorionic gonadotrophin (HCG) triggering, for timing NC-FET. Sixty women with regular menstrual cycles undergoing NC-FET were randomized into two groups: group A (n=30) had FET in a natural cycle after ovulation triggering with HCG; group B (n=30) had FET in a natural cycle after detection of spontaneous ovulation. The main outcome measure was the number of monitoring visits at the clinic per cycle. Secondary outcome measures included implantation rate, clinical pregnancy and live-birth rates. Both groups were similar in terms of demographic characteristics and reproductive history. Clinical and laboratory characteristics of fresh and frozen cycles and pregnancy and delivery rates were comparable for both groups. The number of monitoring visits in group A (3.2 ± 1.4) was significantly lower than in group B (4.7 ± 1.6) (P=0.002). In patients undergoing NC-FET, triggering ovulation by HCG can significantly reduce the number of visits necessary for cycle monitoring without an adverse effect on cycle outcome. Ovulation triggering can increase both patient convenience and cycle cost effectiveness.

Dehydroepiandrosterone supplementation increases baseline follicular phase progesterone levels.

The use of dehydroepiandrosterone (DHEA) supplementation in infertile patients with diminished ovarian reserve (DOR) has become increasingly popular. It has been our observation that serum progesterone levels during the follicular phase are often increased during controlled ovarian stimulation when DHEA is coadministered. Our aim was to compare progesterone levels during the follicular phase before and during DHEA supplementation in women with DOR undergoing in vitro fertilization (IVF). In a case-control study, we compared progesterone levels during the follicular phase in IVF cycles before and during DHEA supplementation in 15 women with DOR who received 75 mg of DHEA daily. Progesterone levels on stimulation day 5 (0.5 ± 0.29 ng/ml vs. 1.54 ± 0.49 ng/ml; p < 0.0001) and on the day of human chorionic gonadotropin administration (0.75 ± 0.31 ng/ml vs. 1.87 ± 0.49 ng/ml; p < 0.0001) were significantly higher during DHEA treatment. The number of retrieved and fertilized oocytes was similar in both the groups. DHEA administration during IVF cycles in women with DOR causes a significant elevation of progesterone levels without an apparent deleterious effect on cycle outcome.

What is the preferred method for timing natural cycle frozen-thawed embryo transfer?

Spontaneous ovulation during a natural menstrual cycle represents a simple and efficient method for synchronization between frozen embryos and the endometrium. The objective was to compare serial monitoring until documentation of ovulation, with human chorionic gonadotrophin (HCG) triggering, for timing frozen embryo transfer (FET) in natural cycles (NC). In a retrospective study, 112 women with regular menstrual cycles undergoing 132 NC-FET cycles were divided into two groups: group A (n = 61) patients had FET in an NC after ovulation triggering with HCG; group B (n = 71) patients had FET in an NC after spontaneous ovulation was detected. The main outcome measure was the number of monitoring visits at the clinic. Patients in both groups were similar in terms of demographic characteristics and reproductive history. Clinical and laboratory characteristics of fresh and frozen cycles were also found comparable for both groups, as were pregnancy and delivery rates. The number of monitoring visits in group A (3.46 +/- 1.8) was significantly lower than in group B (4.35 +/- 1.4) (P < 0.0001). In patients undergoing NC-FET, triggering ovulation by HCG can significantly reduce the number of visits necessary for cycle monitoring without an adverse effect on cycle outcome. Ovulation triggering can increase both patient convenience and cycle cost-effectiveness.

Pregnancies and live births following ICSI with testicular spermatozoa after repeated implantation failure using ejaculated spermatozoa.

The use of testicular spermatozoa for IVF/intracytoplasmic sperm injection (ICSI) is currently indicated exclusively for patients with azoospermia, since a favourable outcome is expected even when very few spermatozoa are present in the ejaculate. Here, a series of four couples with long-standing male factor infertility and multiple failed IVF/ICSI cycles are described. In all couples, the use of ejaculated spermatozoa for ICSI resulted in poor embryo quality and repeated implantation failure. Testicular sperm aspiration was performed in subsequent cycles, and testicular spermatozoa were used for ICSI. Embryo implantation and ongoing pregnancies/deliveries were achieved in all four couples. It is postulated that spermatozoa are subjected to post-testicular damage during sperm transport between the seminiferous tubules and epididymis, with the injection of damaged spermatozoa being the cause for repetitive IVF/ICSI failures. In selected patients, the use of testicular spermatozoa for IVF/ICSI should be considered, even when motile spermatozoa can be identified in the ejaculate.

A prospective randomized controlled trial of Wallace and Rocket embryo transfer catheters.

The aim of this study was to compare the efficacy of two embryo transfer catheters: Wallace and Rocket Embryon in an IVF programme of a tertiary referral university centre. A total of 308 patients undergoing embryo transfer were prospectively randomized to either a transfer with the Wallace catheter or a transfer with the Rocket catheter. The main outcome measure in this study was the clinical pregnancy rate, and secondary outcome measures included implantation rate, visibility of the catheter under ultrasound, number of retained embryos post transfer, and whether change of catheter was required. In addition, patient discomfort during the procedure was recorded. Pregnancy and implantation rates were similar when Wallace or Rocket catheters were used. However, for the Rocket catheter, the tip was more often clearly seen on ultrasound and it had a lower rate of retained embryos in the catheter after transfer (P < 0.05). Experience with different transfer catheters is recommended for difficult cases.

[Transfer of single embryo as a method to reduce twins pregnancy rate in in-vitro fertilization treatment].

INTRODUCTION: The high success rate in IVF treatments is followed by a high rate of multiple pregnancies. Over 30% of IVF pregnancies are multiples and carrying higher risk to the neonates compared with singleton pregnancy. Twin pregnancy is less dangerous then high order multiple pregnancy but it has a significantly higher risk factor compared with singleton pregnancy. Therefore, it is crucial to find methods to reduce twin pregnancy rate. The goal of this review is to present the peril of twin pregnancy and to evaluate the alternative of selective single embryo transfer (SET) in order to reduce the rate of multiple pregnancies in IVF. METHODS: Survey of the literature on SET. RESULTS: Patients with high pregnancy rate bear higher risk for multiple pregnancy. In these cases transfer of single high quality embryo can result in a pregnancy rate of over 30% without the risk of multiple pregnancies. Selective SET may lead to a significant decrease in multiple pregnancies rate with only a slight drop in the general pregnancy rate. CONCLUSIONS: Selective SET in patients with elevated chance to conceive may result in good pregnancy rate without the risk of multiple pregnancy.

Zygote intrafallopian transfer among patients with repeated implantation failure.

OBJECTIVE: To summarize the experience of a single center with laparoscopic zygote intrafallopian transfer (ZIFT) performed exclusively among patients with high-order repeated implantation failure (RIF) following in vitro fertilization-embryo transfer (IVF-ET). METHODS: A retrospective cohort study was performed at the Edith Wolfson Medical Center, a tertiary referral university hospital located in Holon, Israel. A group of 176 patients with 8.15±3.9 previously failed IVF-ET cycles underwent 280 ZIFT procedures between 1995 and 2010. The main outcome measure was the live birth rate per patient treated. RESULTS: In all, there were 274 fresh and 6 frozen ZIFT cycles recorded in the study cohort, resulting in 96 clinical pregnancies per attempt (34.3%) and 72 live births (25.7%). The live birth rate per patient was 39.8%. CONCLUSION: The use of ZIFT remains a powerful tool in the clinical management of selected patients with high-order RIF. This procedure should be kept in mind when all other measures fail among patients with at least 1 unobstructed fallopian tube.

The effect of delayed initiation of gonadotropin-releasing hormone antagonist in a flexible protocol on in vitro fertilization outcome.

OBJECTIVE: To determine the proportion of patients stimulated on a flexible GnRH antagonist regimen who meet the criteria for antagonist administration after stimulation day 6 (S6) and to compare their clinical characteristics and cycle outcome with those patients who start the antagonist on S6 or earlier. DESIGN: Retrospective study. SETTING: Tertiary university hospital. PATIENT(S): Patients undergoing IVF (n = 442) using a flexible GnRH antagonist protocol. INTERVENTION(S): Ovarian stimulation was performed using gonadotropins and GnRH antagonists. Group A (n = 323) patients met the criteria for antagonist administration (follicle size >12 mm, E2 >300 pg/mL) on S6 or earlier. Group B patients (n = 119) started the antagonist later. MAIN OUTCOME MEASURE(S): Implantation rate. RESULT(S): Comparable implantation (30.4% vs. 33.7%), clinical (47.4% vs. 52.9%), and ongoing pregnancy rates (41.2% vs. 47.9%) were observed in groups A and B, respectively. Group B patients had a significantly higher body mass index, longer stimulation, increased gonadotropins dosage, fewer oocytes and two pronuclei oocytes, fewer frozen embryos, and fewer cycles with embryo freezing. Patients with polycystic ovary syndrome were more likely to be in group B. CONCLUSION(S): A considerable proportion of patients on a flexible regimen begin GnRH antagonist administration later than S6. Despite different stimulation and laboratory characteristics, their reproductive outcome is not compromised as compared with patients with an earlier antagonist start.

Follicular growth and development under continuous gonadotropin-releasing hormone antagonist administration.

OBJECTIVE: Ovarian follicle and cyst formation have been recognized as an advance phenomenon associated with GnRH agonist administration. With the use of GnRH antagonists, pituitary suppression is immediate and no flare effect and follicle growth are expected. We describe two patients who developed a dominant follicle and presumably ovulated in response to hCG triggering under continuous sole administration of a GnRH antagonist. DESIGN: Case report. SETTING: An IVF unit at a university hospital. PATIENT(S): Two young healthy female patients undergoing IVF because of male-factor infertility. INTERVENTION(S): Continuous daily administration of a GnRH antagonist from menstruation with the aim of achieving ovarian suppression. MAIN OUTCOME MEASURE(S): Endocrine and ultrasound characteristics of follicular growth. RESULT(S): Both patients developed a dominant follicle under sole administration of a GnRH antagonist, accompanied by a gradual rise in serum estradiol and endometrial thickness which culminated in a spontaneous LH surge. Ovulation was triggered by hCG and mid-luteal progesterone levels were suggestive of ovulation. CONCLUSION(S): We describe for the first time the development of a dominant follicle and presumable ovulation under continuous administration of a GnRH antagonist. Serum gonadotropin concentrations indicate that the pituitary failed to suppress in both patients. The exact mechanism of this phenomenon remains to be elucidated.

Timing intra-Fallopian transfer procedures.

With the gradual decline in the use of zygote intra-Fallopian transfer (ZIFT), current practice is to offer ZIFT almost exclusively to patients with repeated implantation failure (RIF). For practical reasons, the procedure is sometimes deferred by 1 day and embryo intra-Fallopian transfer (EIFT) is performed. The aim of the present study was to compare the reproductive outcome of ZIFT versus EIFT. In a retrospective analysis, 176 patients who failed in 7.65 +/- 3.7 previous IVF cycles underwent 200 ZIFT and 73 EIFT procedures. Implantation and live birth rates were compared for both groups. Patients in both groups were found comparable for demographic and clinical parameters. Similar numbers of oocytes were retrieved and fertilized in both groups, and 5.2 +/- 1.2 zygotes/embryos were transferred. Implantation and live birth rates (10.5 and 26.5% versus 10.9 and 24.7% for ZIFT and EIFT respectively) were comparable. It is concluded that tubal transfer of zygotes and day-2 cleavage stage embryos are equally effective.

Expression and regulation of Sprouty-2 in the granulosa-lutein cells of the corpus luteum.

Growth factor signalling has important modulatory roles in the process of human follicular growth, oocyte maturation and corpus luteum (CL) formation. Recently, Sprouty-2, an inhibitor of receptor tyrosine kinase (RTK) signalling pathway was advocated as a marker of oocyte competence in the bovine ovary. We sought to study Sprouty-2 expression and regulation in the human ovary. RT-PCR was used to detect Sprouty-2 mRNA in human granulosa-lutein cells (GLC) collected from follicular aspiration of IVF patients. The effect of epidermal and fibroblast growth factors (EGF and FGF) on Sprouty-2 mRNA expression in GLC was studied using quantitative real-time PCR. Immunohistochemistry was performed on cultured GLC, human CL and stimulated rat ovary sections. Sprouty-2 mRNA was expressed in human GLC. EGF and basic FGF, but not FGF4 and FGF10, increased Sprouty-2 mRNA expression in GLC. The Sprouty protein was localized to GLC of early and late human CL but not to the theca cell layer. Immunostaining of developing rat CL confirmed the temporal and spatial expression of Sprouty in humans. The detection of Sprouty-2 mRNA and protein in human GLC may suggest a role for Sprouty-2 during the final stages of follicle maturation and CL formation.