Consecutive ovarian stimulation is beneficial in patients with a poor response to high-dose follicle-stimulating hormone.

OBJECTIVE: To investigate if an immediate additional IVF-ET cycle bear an advantage to patients with poor ovarian response in comparison to a cycle performed at some delay. METHODS: A cohort study including 632 patients who underwent a fresh IVF-ET cycle with high-dose (≥300 IU/d) FSH stimulation that yielded ≤4 oocytes and did not achieve a clinical pregnancy. All underwent a second stimulation and oocyte pick-up (OPU), either consecutively or separately within 180 days (nonconsecutive OPU). The oocyte yield, number of embryos available for transfer, pregnancy live birth rates of the second OPU were compared between patients who had consecutive and nonconsecutive cycles. RESULTS: Consecutive OPU was associated with more mature follicles in the second cycle compared to nonconsecutive OPU (p = .03) in addition to higher peak estradiol level (p < .0001), and more aspirated oocytes (p = .03) and available embryos (p = .023). There was no between-group difference in ongoing pregnancy and live birth rates. In a multivariate analysis of variance controlling for potential confounders, the difference in the number of aspirated oocytes and available embryos was associated significantly only with consecutive performance of the second cycle. CONCLUSION: Immediate sequential stimulation (without an intervening menstrual cycle) in poor responders is advantageous over delayed stimulation in terms of number of aspirated oocytes and available embryos. The administration of high-dose FSH in the first cycle may benefit follicular recruitment also in the subsequent cycle. Although the effect is modest, given that each additional oocyte aspirated contributes to the outcome, it might be of significance especially in younger patients.

The entire range of trigger-day endometrial thickness in fresh IVF cycles is independently correlated with live birth rate.

RESEARCH QUESTION: What is the association of the entire range of trigger-day endometrial thickness (EMT) with live birth rate (LBR) after IVF and fresh embryo transfer? Although EMT is amenable to convenient non-invasive routine measurement, studies of the association between pre-trigger EMT and assisted reproductive technology outcome have yielded equivocal results. DESIGN: A cohort of IVF fresh day-3 embryo transfers in patients aged 42 years and younger in a single centre between 2009 and 2017. The LBR was calculated for all trigger-day EMT values, stratified into five groups overall and within subgroups of patient age and ovarian response. Univariate analysis and multivariate logistic regression models were used to compare the LBRs at different EMT measurements adjusting for various independent variables. RESULTS: A total of 5133 cycles were included. The LBRs were as follows: 11.22% (35/312) in cycles with EMT 6 mm or less, 17.98% (380/2114) in cycles with EMT 7-9 mm, 23.44% (476/2031) in cycles with EMT 10-12 mm, 25.62% (144/562) in cycles with EMT 13-15 mm and 34.21% (39/114) in cycles with EMT 16 mm or more (P < 0.001). Similar findings were observed by patient age and ovarian response. The observation was confirmed by multivariate logistic regression analysis in which the EMT was found to be a significant independent predictor of LBR even after controlling for various confounders (OR 0.935, 95% CI 0.908 to 0.962; P < 0.001). CONCLUSIONS: Pre-trigger EMT is in significant independent correlation with LBR, even after adjusting for age and ovarian response. Maximal endometrial proliferation is beneficial, and fresh embryo transfer can be carried out at high EMT values without endangering the outcome of the cycle.

Use of Aromatase Inhibitors in IVF for Fertility Preservation of Non-Breast Cancer Patients: A Case Series.

BACKGROUND: Controlled ovarian hyperstimulation (COH) followed by oocyte retrieval is a leading option for fertility preservation before chemotherapy, yet this procedure causes excessive serum levels of estradiol (E2), which are often detrimental for cancer patients. Aromatase inhibitors are often used in breast cancer patients during COH to prevent elevated levels of E2. OBJECTIVES: To describe our experience with COH for oocyte cryopreservation in non-breast cancer patients using aromatase inhibitors. METHODS: Of the five patients treated, two had an aggressive abdominal desmoid tumor, one had endometrial carcinoma, one had uterine sarcoma, and one patient had a brain oligodendroglioma. In all cases the treating oncologist suggested an association between estrogen and possible tumor progression. All patients were treated with a standard in vitro fertilization antagonist protocol combined with aromatase inhibitors, similar to the protocol used for breast cancer patients. RESULTS: The average duration of treatment was 10.5 days, mean peak E2 was 2348 pmol/L, mean number of oocytes aspirated was 17.3, and a mean of 14.6 embryos/oocytes were cryopreserved. CONCLUSIONS: COH with aromatase inhibitors is apparently effective in non-breast cancer patients and spares exposure to high E2 levels.

Short-term exposure of human ovarian follicles to cyclophosphamide metabolites seems to promote follicular activation in vitro.

How chemotherapy affects dormant ovarian primordial follicles is unclear. The 'burnout' theory, studied only in mice, suggests cyclophosphamide enhances primordial follicle activation. Using 4-hydroperoxycyclophosphamide (4hc) and phosphoramide mustard (PM), this study assessed how the active cyclophosphamide metabolites 4-hydroxycyclophosphamide (4-OHC) and PM, affect human primordial follicles. Frozen-thawed human ovarian samples were sliced and cultured with basic culture medium (cultured controls) or with 4hc/PM (3 µmol/l/10 µmol/l) (treated samples) for 24-48 h. Follicular counts and classification, Ki67 and anti-Müllerian hormone (AMH) immunohistochemistry and an apoptosis assay were used for evaluation, and 17ß-oestradiol and AMH were measured in spent media samples. Generally, there was primordial follicle decrease and elevated developing follicle rates in treated samples compared with cultured (P = 0.04 to P < 0.0005) and uncultured controls (P < 0.05 to P < 0.0001). No traces of apoptosis were found. There were almost twicethe levels of AMH and 17ß-oestradiol in treated compared with untreated samples (AMH with 4hc 3 µmol/l; P = 0.04). All follicles stained positively for AMHincluded treated samples. Ki67 positive staining was noted in all samples. Cyclophosphamide metabolites seem to enhance human primordial follicle activation to developing follicles, in vitro. Study findings support the 'burnout' theory as the mechanism of chemotherapy-induced ovarian toxicity.

Why do couples discontinue unlimited free IVF treatments?

Worldwide, IVF is often discontinued before a live birth is achieved due to high costs. Even when partial financial coverage is provided, often medical providers advise treatment discontinuation. In Israel, unlimited IVF is offered free of charge for a couples' first two children. Our objective was to assess the reasons couples discontinue IVF treatments before achieving two children in a completely unlimited cost-free environment. This cohort study included all primary infertile women, <35 years, referred for their first IVF cycle to Sheba IVF unit between 2001 and 2002. Patients were followed until February 2012. Those who ceased treatments for 12 months were interviewed to assess the main reason they ceased treatments. Of the 134 couples included, only 46 ceased IVF treatments without achieving two children, after performing an average of 6.2 IVF cycles to achieve their first birth. The reasons given were: lost hope of success (13), psychological burden (18), divorce (6), medical staff recommendation (5), bureaucratic difficulties (3) and general medical condition (1). The main reasons for "drop out" in our cost-free environment were as follows: psychological burden and lost hope of success. Due to high availability of treatments, medical staff recommendation was a less significant factor in our study.

Spontaneous conceptions following successful ART are not associated with premature referral.

STUDY QUESTION: What is the rate of spontaneous live births after successful IVF treatment in a cost-free environment, and were couples who achieved a spontaneous live birth referred prematurely? SUMMARY ANSWER: Despite unlimited IVF treatments offered free of charge, the spontaneous live birth rate following successful IVF remained unchanged compared with that cited in previous literature. Couples were not referred prematurely to IVF before fully utilizing other less invasive treatments. WHAT IS KNOWN ALREADY: A significant number of infertile couples, who achieve their first live birth through assisted reproductive technology (ART), subsequently achieve a second live birth spontaneously. As IVF has become more widely available, it is used in less severe cases of infertility, perhaps explaining a rise in the subsequent spontaneous live birth rate after successful treatments. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study was performed at a university-based tertiary medical center. The study population included women aged <35 years, with primary infertility, referred for their first IVF treatment to the Sheba Medical Center IVF unit between 2001 and 2002 and followed up for 7 years. The primary outcome was spontaneous live birth rate following successful ART. Relevant data were obtained from the patient files and supplemented by a standardized telephone questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 171 couples who met the study inclusion criteria, 6 refused to participate in the questionnaire and 31 couples were lost to follow-up. Of the 134 couples who participated, 109 achieved a first live birth with ART. After achieving their first live birth with ART, seven couples who began using contraception or separated or divorced were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: Of 102 couples who continued unprotected intercourse after successful ART, 22 subsequently achieved their second live birth spontaneously (21.6%). The women who achieved a second birth spontaneously were not referred earlier to IVF, and actually performed a higher number of ovulation induction cycles before initiating IVF, compared with women who did not conceive spontaneously. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective cohort study, and findings should be reaffirmed with a larger prospective randomized study comparing retreatment to achieve a second pregnancy with attempting to conceive spontaneously. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggests that young patients (<35 years), who previously conceived with IVF, without utilizing ICSI and with no known tubal pathology, should consider attempting to conceive spontaneously. STUDY FUNDING AND COMPETING INTEREST(S): No funding was obtained for this study and the authors have no competing interests.

Couples offered free assisted reproduction treatment have a very high chance of achieving a live birth within 4 years.

OBJECTIVE: To assess the long-term success rate among couples with primary infertility offered unrestricted, free in vitro fertilization (IVF) treatments. DESIGN: Historical prospective cohort study. SETTING: University-based tertiary medical center with unlimited coverage of IVF for couples' first two children. PATIENT(S): Women aged <35 years, with primary infertility, referred for their first IVF treatment to the Sheba Medical Center IVF unit between 2001 and 2002. INTERVENTION(S): Relevant data were obtained from patient files and supplemented by a standardized telephone questionnaire. MAIN OUTCOME MEASURE(S): Pregnancies, live births, adoptions, divorces, and discontinuations of further treatment. RESULT(S): During the 5- to 7-year follow-up period, 95.5% of couples conceived, and 89.6% of couples gave birth to a live infant. Of these couples, 81.3% achieved a live birth within the first 4 years of the follow-up period, and 85.1% within eight treatment cycles. Of the 14 couples (10.4%) who did not give birth to a live infant, five adopted, two divorced, four are still undergoing IVF treatments, and three (1.8%) decided not to become parents. CONCLUSION(S): Young couples beginning IVF treatment in an environment free of economic hurdles can be reassured that they have an excellent chance (∼ 90%) of achieving a live birth within 4 years. When IVF is provided free of cost, very few couples discontinue treatment before a live birth is achieved.