Shevach Friedler

Outcome of assisted reproductive technology in women over the age of 41

OBJECTIVE To analyze the results of ongoing pregnancies and deliveries after assisted reproductive technology (ART) in women aged >/=41 years, stratified by year of age. DESIGN Retrospective study. SETTING University hospital, IVF unit. PATIENT(S) A total of 431 IVF and intracytoplasmic sperm injection (ICSI) cycles were initiated in women >/=41 years of age. INTERVENTION(S) Medical files of ART patients and pregnancy outcomes were reviewed. MAIN OUTCOME MEASURE(S) Oocytes retrieved, embryos developed, and clinical pregnancy and delivery rates. RESULT(S) Of the 431 started cycles, 376 (87%) reached the oocyte retrieval stage. The mean number of oocytes aspirated per patient was 5.4 +/- 0.9 and 6.7 +/- 1.2 in the IVF and ICSI cycles, respectively, and the number of embryos obtained was 2.3 +/- 1.3 and 2.8 +/- 1.6 in the IVF and ICSI cycles, respectively. The number of transferable embryos was 2.0 +/- 1.2 and 2.5 +/- 0.8. The pregnancy rate per oocyte pickup (OPU) was 12.4%; however, the delivery rate per OPU was 4.5%. The mean delivery rate per OPU among women aged 41-43 years was 2%-7%. There were no deliveries aged >/=44 years and no pregnancies at the age of 45 years. The pregnancy and delivery rates of the ICSI and IVF patients were similar after stratification by age. CONCLUSION(S) In our studies, ART performed with homologous oocytes, whether by IVF or ICSI, yielded no clinical pregnancies among women aged >/=45 years and no deliveries aged >/=44 years. The mean delivery rate per oocyte retrieval among women aged 41-43 years varied between 2% and 7%.

The Possible Association between IVF and Breast Cancer Incidence

BackgroundThe possible association between ovulation-inducing drugs and breast cancer development has been debated. Our aim was to evaluate the incidence of breast cancer in a cohort of women exposed to in vitro fertilization (IVF).MethodsA retrospective cohort analysis was performed by linkage of the computerized database of all women treated at the IVF Unit at Assaf Harofeh Medical Center between 1986 and 2003, and the Israeli National Cancer Registry. The standardized incidence ratio (SIR) was computed as the ratio between the observed number of breast cancer cases and the expected cases, adjusted for age and continent of birth, in the general population. Tumor characteristics of the IVF patients were studied by reviewing original medical records.Results35 breast carcinomas were diagnosed among 3,375 IVF-treated women, compared to 24.8 cases expected (SIR = 1.4; 95% CI 0.98–1.96). Age ≥40 years at IVF treatment (SIR = 1.9; 95% CI 0.97–3.30), hormonal infertility (SIR = 3.1; 95% CI 0.99–7.22), and ≥4 IVF cycles (SIR = 2.0; 95% CI 1.15–3.27) were found to be risk factors to develop breast cancer compared to the general population. Multivariate analysis revealed that women who underwent ≥4 IVF cycles compared to those with one to three cycles were at risk to develop breast cancer, although not significantly (SIR = 1.9; 95% CI 0.95–3.81). Of IVF-treated women 85% had ER(+) tumors and 29% had positive family history.ConclusionsA possible association between IVF therapy and breast cancer development was demonstrated, especially in women ≥40 years of age. These preliminary findings need to be replicated in other cohort studies.

Intracytoplasmic sperm injection outcome of ejaculated versus extracted testicular spermatozoa in cryptozoospermic men

OBJECTIVE To compare intracytoplasmic sperm injection (ICSI) outcome of patients with cryptozoospermia after use of ejaculated versus testicular sperm in different cycles of the same patients. DESIGN Retrospective cohort study. SETTING University-affiliated infertility center. PATIENT(S) A total of 17 patients with cryptozoospermia who underwent a total of 116 ICSI cycles. INTERVENTION(S) The patients initially underwent several ICSI cycles using ejaculated sperm (n = 68, 58.6%) that were followed by ICSI cycles using testicular sperm (n = 48, 41.4%). MAIN OUTCOME MEASURE(S) Fertilization rate, pregnancy rate (PR). RESULT(S) There were no significant differences in fertilization rates between the two subgroups. A comparison between testicular sperm extraction (TESE) versus ejaculated sperm cycles revealed significantly higher implantation rate (20.7% vs. 5.7%), higher PR (42.5% vs. 15.1%), and higher take home baby rate (27.5% vs. 9.4%). A multivariable logistic regression analysis showed three significant predictors for pregnancy, namely the use of testicular sperm (odds ratio [OR] 5.1, 95% confidence interval [95% CI] 1.8-14.8), use of motile sperm (OR 12.9, 95% CI 2.1-79.1), and female age (OR 0.83, 95% CI 0.7-0.9). CONCLUSION(S) Testicular sperm extraction is justified in patients with cryptozoospermia who fail to conceive by ICSI using ejaculated spermatozoa, as it offers higher PR.

Increased frequency of female partner chromosomal abnormalities in patients with high-order implantation failure after in vitro fertilization

OBJECTIVE To find the type and frequency of chromosomal abnormalities in a selected group of high-order implantation failure (> or =6 IVF trials and > or =15 transferred embryos) and to evaluate its impact on pregnancy outcome. DESIGN A retrospective study. SETTING In vitro fertilization (IVF) unit in a university affiliated hospital. PATIENT(S) Sixty-five couples with high-order implantation failure in IVF and embryo transfer. INTERVENTION(S) In vitro fertilization/embryo transfer (ET), work-up for implantation failure, cytogenetic analysis of the couple. MAIN OUTCOME MEASURE(S) We studied the type and frequency of chromosomal changes, quality of embryos, cumulative pregnancy rates, and pregnancy outcome. RESULT(S) The mean number of treatment cycles per patient, before karyotyping was 7.8 +/- 2.4 (range: 6 to 16 cycles). The mean cumulative number of all transferred embryos per patient was 25.7 +/- 10.3 (range: 9 to 65 embryos). Chromosomal abnormalities were found in 10 of 65 (15.4%) cases: translocations in six, mosaicism in two, and inversion or deletion in another two. The morphologic characteristics of the transferred embryos and the cumulative pregnancy rates were similar in patients with implantation failure with and without chromosomal changes. Three of the 16 patients with abnormal karyotype delivered and three miscarried within a follow-up period of 1 year. CONCLUSION(S) A high frequency of chromosomal aberrations was found in a selected group of high-order implantation failures, a similar frequency to recurrent miscarriages. Karyotyping is recommended as part of the work-up for repeated implantation failure in assisted reproduction. Treatment options include further IVF trials, preimplantation genetic diagnosis, or oocyte donation, tailored according to the type of chromosomal change. An international registry should be considered to assist in counseling these patients.

The effect of medical clowning on pregnancy rates after in vitro fertilization and embryo transfer

This experimental prospective quasi-randomized study examining the impact of a medical clowning encounter after embryo transfer (ET) after in vitro fertilization (IVF) found that the pregnancy rate in the intervention group was 36.4%, compared with 20.2% in the control group (adjusted odds ratio, 2.67; 95% confidence interval, 1.36-5.24). Medical clowning as an adjunct to IVF-ET may have a beneficial effect on pregnancy rates and deserves further investigation.

Luteal phase characteristics following GnRH antagonist or agonist treatment - a comparative study

Due to inherent differences between gonadotrophin-releasing hormone (GnRH) antagonists and agonists, their late effect on ovarian steroidal production during the luteal phase of IVF cycles may differ. The aim of this study was to characterize and compare the luteal phase hormonal profile after the use of GnRH antagonists or agonists in ovarian stimulation protocols for IVF, in non-conception cycles, to avoid the effect of human chorionic gonadotrophin (HCG) during the luteal phase in conception cycles. Seventy-eight normo-ovulatory patients <35 years old, undergoing IVF due to male or tubal infertility were randomly allocated either to a GnRH antagonist (study group) or GnRH agonist treatment (control group). Similar standard luteal support was given to all patients, using vaginal micronized progesterone. In non-conception cycles, no statistically significant differences were found comparing luteal phase. oestradiol or progesterone levels in the study and control groups. No statistically significant differences were found comparing the hormonal profile dynamics, the mid-luteal (HCG day +8) oestradiol/progesterone ratio and the percentage of mid-luteal oestradiol decline between the study and control groups. In conclusion, similar characteristics and dynamics of luteal phase oestradiol and progesterone were demonstrated comparing ovarian stimulation for IVF using GnRH agonist or antagonists, under similar luteal support.

The cytogenetic constitution of embryos derived from immature (metaphase I) oocytes obtained after ovarian hyperstimulation

OBJECTIVE To examine the chromosomal content of embryos resulting from metaphase I (MI) oocytes obtained after ovarian hyperstimulation for IVF. DESIGN Prospective cohort study. SETTING University-based IVF Center, Assaf Harofeh Medical Center, Tel Aviv University, Israel. PATIENT(S) One hundred fifty women undergoing assisted reproduction technique (ART). INTERVENTION(S) Intracytoplasmic sperm injection (ICSI) was performed in MI oocytes that were retrieved after ovarian stimulation. A portion of these oocytes extruded their polar body (rescued in vitro-matured metaphase II [IVM-MII]) after different incubation periods and the remainder did not (arrested MI oocytes). Fluorescence in situ hybridization was performed using probes for chromosomes X, Y, 18. MAIN OUTCOME MEASURE(S) Fertilization rate, number of blastomeres, and embryo euploidy. RESULT(S) Embryos from rescued IVM-MII oocytes showed significantly higher fertilization rates and more blastomeres per embryo compared with those from arrested MI oocytes (58.5% vs. 43.9% and 5.7 vs. 5.0, respectively). The chromosomal analysis of these embryos revealed a high rate of aberrations (80.6%), mainly complex mosaics. This rate was elevated in embryos from arrested IVM oocytes (97.2%), and after longer incubation periods. No chromosomally normal embryos were found after 24 hours of incubation of their corresponding oocytes. CONCLUSION(S) Embryos originating from MI oocytes have a high rate of chromosomal aneuploidy, and their replacement should be reconsidered.

A comparison of the incidence, presentation, and management of ovarian pregnancies between two periods of time

STUDY OBJECTIVE To compare the prevalence, presentation diagnostic modalities, and management of 37 ovarian pregnancies in one institution during two time periods. DESIGN A retrospective study (Canadian Task Force classification II-2). SETTING Department of Gynecology in a university-affiliated hospital. PATIENTS Twenty patients with ovarian pregnancy between 1971-1989 compared with 17 patients with ovarian pregnancy between 1990-2000. MEASUREMENTS AND MAIN RESULTS Seventeen ovarian pregnancies, diagnosed between 1990-2000, comprised 2.6% (17/634) of all ectopic pregnancies, 1:3500 of all live births leading to a mean ovarian pregnancy rate per year of 1.5, as opposed to 3.1% (20/647) of all ectopic pregnancies, 1:3600 of all live births, and a mean ovarian pregnancy rate per year of 1.1 in the previous period. Circulatory collapse was present in 4/17 (23%) patients in the 1990-2000 time period and in 6/20 (30%) in the previous period. Culdocentesis for diagnostic purposes was practically abandoned in the recent decade. Wedge resection by laparotomy was the treatment of choice in the past, and after 1997, it was performed exclusively by laparoscopy. When an ovarian pregnancy was diagnosed, an intrauterine device (IUD) was present in 65% of all patients and in 73% of women who had previously conceived in the 1999-2000 time period, compared with higher rates in the previous period (90% and 100%, respectively). CONCLUSION The absolute number of ovarian pregnancies in the last 11 years increased when compared with the previous 19 years; however, the prevalence rate per delivery was stable. Patients still experienced circulatory collapse despite modern diagnostic modalities. Culdocentesis for diagnostic purposes has become an unnecessary procedure. Laparoscopic wedge resection was the treatment of choice. The relationship between IUD use and ovarian pregnancies was still strong.

Influence of a short or long abstinence period on semen parameters in the ejaculate of patients with nonobstructive azoospermia

OBJECTIVE To compare the effect of a short (4 days) or a long (14 days) abstinence period on sperm retrieval by extended sperm preparation in patients with nonobstructive azoospermia scheduled for testicular biopsy and intracytoplasmic sperm injection (ICSI). DESIGN A prospective case control study. SETTING Male infertility clinic in a university hospital. PATIENT(S) Fifty male patients with nonobstructive azoospermia, scheduled for testicular biopsy for ICSI. INTERVENTION(S) Diagnosis of nonobstructive azoospermia and a thorough microscopic search for sperm cells (extended sperm preparation). MAIN OUTCOME MEASURE(S) The number of sperm cells collected, sperm motility, and total motile sperm count after short and long abstinence periods. RESULT(S) There was a significant difference between long and short abstinence with an increase in sperm count (log-to-log transformed analysis of variance P<.025) and total motile sperm (P<.025 analysis of variance, P<.02 paired Students t-test) in the former group, but no significant change in sperm motility (Wilcoxon and paired Students t-test). In 18 patients, sperm concentration and sperm motility were similar in a second collection, done after the same abstinence period, compared with the same parameters in the first sample. When at least 10 motile sperm were defined as the cutoff number, allowing ICSI without testicular biopsy, no significant differences were found between the two abstinence periods. No clinical or laboratory male characteristic could predict the detection of 10 motile sperm by extended sperm preparation either after a short or a long abstinence period. CONCLUSION(S) Sperm count and total motile sperm were increased after a long abstinence period, with no change in sperm motility. No additional advantages were conferred by long abstinence as opposed to short abstinence when 10 motile sperm were defined as the cutoff number for ICSI. The recommended period of abstinence for extended sperm preparation and ICSI, whether short or long, should be individualized for each patient.

Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium

Pigment epithelium-derived factor (PEDF) is highly expressed in the female reproductive system and is subjected to regulation by steroid hormones in the ovary. As the uterine endometrium exhibits morphological and functional changes in response to estrogen (E2) and progesterone (P4), we aimed at characterizing the expression of PEDF in this component of the female reproductive tract and further at exploring the hormonal regulation of its expression. We found that PEDF is expressed in human and mouse endometrium. We further showed that this expression is subjected to regulation by steroid hormones, both in vivo and in vitro, as follows: E2 decreased PEDF expression and P4 increased its levels. In human endometrial samples, PEDF levels were dynamically altered along the menstrual cycle; they were low at the proliferative and early secretory phases and significantly higher at the late secretory phase. The expression levels of PEDF were inversely correlated to that of vascular endothelial growth factor (VEGF). We also showed that PEDF receptor was expressed in the endometrium and that its stimulation reduced VEGF expression. Illustrating the pattern of PEDF expression during the menstrual cycle may contribute to our understanding of the endometrial complexity.