Arie Raziel

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%.

Pregnancy rate and ovarian hyperstimulation after luteal human chorionic gonadotropin in in vitro fertilization stimulated with gonadotropin-releasing hormone analog and menotropins.

The value of luteal phase supplementation with human chorionic gonadotropin (hCG) was assessed after a combined protocol of ovarian stimulation, using a long acting gonadotropin releasing hormone analog (GnRH-a) and human menopausal gonadotropins (hMG), in a randomized prospective study of 36 consecutive cycles in an in vitro fertilization (IVF) program. The patients were allocated on the transfer day to either luteal phase supplementation with hCG (Group A, n = 18) or none (Group B, n = 18). Nine patients of Group A conceived as compared with 3 in Group B. Five patients, all in Group A, developed ovarian hyperstimulation syndrome (OHSS) (3 moderate and 2 severe forms). Analysis of the hormonal profiles disclosed similar progesterone (P), estradiol (E2), and E2/P ratio up to the 6th post ovum pick-up day. Then, E2 and mainly P levels decreased only in Group B resulting in a rising E2/P ratio. These findings stress the importance of luteal support in IVF cycles treated with GnRH-a. In light of the increased risk of OHSS among hCG treated patients, further studies are needed to assess the optimal preparation needed.

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.

The effect of chronic gonadotropin-releasing hormone analog (D-Trp-6) treatment on elevated and normal serum prolactin levels

A long-acting GnRHa (D-Trp-6 microcapsules) proved capable of lowering serum PRL levels in a young hyperprolactinemic patient treated for a large myomatous uterus. No similar inhibitory effect was found in normoprolactinemia. Chronic GnRHa therapy may constitute an alternative to the existing forms of treatment for hyperprolactinemia and pituitary adenomas.

Reproductive outcome after conservative surgery for unruptured tubal pregnancy—a 15-year experience

The fertility outcome is presented in 118 patients after conservative surgery for unruptured tubal pregnancies. This patient group experienced 142 pregnancies, 127 of which were intrauterine (89.4%). The intrauterine pregnancies (IUPs) occurred in 83 patients (70.3%) and 63.5% (75/118) had live births. The recurrence rate of tubal pregnancy was 12.7%. Of the 65 patients with a normal contralateral tube 53 (81.5%) followed surgery with an IUP, 76.1% a live birth, and 7.7% a recurrent tubal pregnancy. Fifty-seven percent of the patients with a single tube followed with an IUP, and 47.6% had a live birth. The recurrence of tubal pregnancy in this group was 28.5%. Of the patients who underwent expression of tubal gestation, 60.6% followed with an IUP, and 57.5% with a live birth with no recurrence of tubal pregnancy.

Follicle cyst formation following long-acting gonadotropin-releasing hormone analog administration

The incidence of follicular cyst formation is 13.6% in cycles treated with GnRH-a. A conservative mode of treatment is suggested, leading to the disappearance or regression of the cysts. Doing so, the number and quality of the oocytes and embryos, the pregnancy and abortion rates are not significantly different between the groups with and without follicular cysts.

Current management of ruptured corpus luteum

The objectives of the study are to assess current management of the rather frequent event of ruptured corpus luteum. Special emphasis is made on the value of ultrasonography, laparoscopy and culdocentesis in deciding appropriate treatment. A series of 70 patients with ruptured corpus luteum diagnosed and treated during a period of 6 years in one institution in Israel is reported. Eighteen patients with concurrent ruptured corpus luteum and ectopic pregnancy are included. Abdominal pain, the most prevalent presenting symptom, has no typical characteristics. The correlation between large amount of fluid as observed by ultrasound and the finding of > 250 ml of blood at laparotomy is very high. Culdocentesis was performed in only 21 patients. Surgical intervention (laparoscopy, laparotomy following laparoscopy or direct laparotomy) was carried out in 58 patients (83%). The remaining 12 cases were handled by observation only. Forty patients required laparotomy in whom 17 underwent wedge resection. We conclude that observation is sufficient treatment in hemodynamically stable patients, without severe abdominal pain and in the presence of a small amount of pelvic fluid demonstrated by ultrasound. When a large amount of fluid is observed and/or in the presence of severe abdominal pain laparoscopy should be performed on admission. Direct laparotomy is mandatory in case of circulatory collapse.

CLINICAL ASSISTED REPRODUCTION: Improvement of IVF Outcome in Poor Responders by Discontinuation of GnRH Analogue During the Gonadotropin Stimulation Phase—A Function of Improved Embryo Quality

Purpose: To assess the efficacy of a protocol involving the discontinuation of the GnRH analogue at the mid-phase of ovarian stimulation for IVF in patients with a previous poor response.Methods: Prospective case-control evaluation compared with same patients previous performance. Thirty-six patients enrolled in an IVF program were treated in two consecutive cycles. The first with a standardized protocol utilizing mid-luteal administration of Nafarelin (N) 600 mcg/d continued throughout the stimulation phase with human menopausal gonadotropin (hMG) until follicles of 20 mm were identified by transvaginal ultrasound (Standard group). Patients with a poor response in the Standard cycle were treated in the subsequent cycle with N and hMG initially in a similar manner, then N was stopped after 5 days of hMG stimulation (N-stop group). All clinical and laboratory aspects of treatment were done in a similar fashion in both cycles, each patient acting as her own control.Results: Results were analyzed by paired t test. The change in each parameter in the N-stop cycle was expressed as the percent change as compared with the standard protocol cycle for each patient. Peak estradiol (E2) and number of aspirated oocytes were increased in the N-stop cycle (+16.9% and +28%, respectively), but insignificantly so. The percent of cleaving embryos was significantly increased by 27.9% (p = 0.03) in the N-stop cycle, as embryo morphology was improved by 22% (p = 0.02). The efficacy of gonadotropin treatment was enhanced in the N-stop cycle, as expressed by a 32.5% increase in oocytes retrieved per hMG ampoule administered (p = 0.04). Three cycles of 36 were cancelled during the N-stop cycle, whereas only one was cancelled in the standard protocol cycle. Of the 36 patients, 7 conceived in the N-stop protocol and 5 are ongoing pregnancies.Conclusion: Discontinuation of GnRH-a during ovarian stimulation for IVF has a beneficial, but not statistically significant, effect on both E2 and oocyte production. Embryo cleavage rates and morphology were significantly improved, this may be due to improved oocyte quality, which may have been responsible for achieving pregnancies. The efficacy of gonadotropin treatment was enhanced when GnRH-a was discontinued. These results hint that GnRH-a may have a direct negative effect on folliculogenesis and oocytes, which is apparent especially in poor responder 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.

Midluteal gonadotropin-releasing hormone analog administration in early pregnancy

The incidence of GnRH-analog administration in the presence of undiagnosed pregnancy is discussed. Immediate hormonal supplementation avoids luteolysis. The report includes two cases, one without hormonal replacement, in which preclinical pregnancy occurred, and the second, where P was supplemented immediately upon diagnosis of pregnancy.