Onit Sapir

High serum oestradiol concentrations in IVF cycles increase the risk of pregnancy complications related to abnormal placentation

The study was designed to evaluate the isolated effect of high serum oestradiol concentration on human chorionic gonadotrophin (HCG) day in IVF cycles on endometrial receptivity and placentation. A retrospective cohort included all women attending the IVF unit in 2006 and 2007, with the best prognosis to achieve pregnancy: age (<38 years), less than three IVF cycles, transfer of two highest grade embryos and no evidence of factors known to impair implantation or that are associated with increased risk of pregnancy complications. The total included 280 patients were categorized into three groups according to their serum oestradiol concentration on HCG day: group 1, oestradiol <5000 pmol/l, group 2, oestradiol in the range 5000-10,000 pmol/l and group 3, oestradiol in the range of 10,000-15,000 pmol/l. No significant differences were found between the groups in implantation, pregnancy and abortion rates. The high oestradiol group was characterized by high rate (20.8%) of pregnancy complications related to abnormal placentation--fetal growth restriction, pregnancy-induced hypertension and abnormal implantation of the placenta. Hence, the decision to perform embryo transfer in high-responder patients should take into consideration both possible risks of ovarian hyperstimulation syndrome and pregnancy complications related to abnormal placentation.

Cryopreservation of in vitro matured oocytes in addition to ovarian tissue freezing for fertility preservation in paediatric female cancer patients before and after cancer therapy

STUDY QUESTION Is a protocol that combines in vitro maturation of germinal vesicle-stage oocytes and their vitrification with freezing of cortical ovarian tissue feasible for use in fertility preservation for both chemotherapy-naive paediatric patients as well as patients after initiation of cancer therapy? SUMMARY ANSWER Follicle-containing ovarian tissue as well as oocytes that can undergo maturation in vitro can be obtained from paediatric patients (including prepubertal girls) both before and after cancer therapy. WHAT IS KNOWN ALREADY Anticancer therapy reduces the number of follicles/oocytes but this effect is less severe in young patients, particularly the paediatric age group. Autotransplantation of ovarian tissue has yielded to date 60 live births, including one from tissue that was cryostored in adolescence. However, it is assumed that autografting cryopreserved-thawed ovarian cortical tissue poses a risk of reseeding the malignancy. Immature oocytes can be collected from very young girls without hormonal stimulation and then matured in vitro and vitrified. We have previously shown that there is no difference in the number of ovarian cortical follicles between paediatric patients before and after chemotherapy. STUDY DESIGN, SIZE, DURATION A prospective study was conducted in a cohort of 42 paediatric females with cancer (before and after therapy initiation) who underwent fertility preservation procedures in 2007-2014 at a single tertiary medical centre. PARTICIPANTS/MATERIALS, SETTING, METHODS The study group included girls and adolescent females with cancer: 22 before and 20 after chemotherapy. Following partial or complete oophorectomy, immature oocytes were either aspirated manually ex vivo from visible small antral follicles or filtered from spent media. Oocytes were incubated in oocyte maturation medium, and those that matured at 24 or 48 h were vitrified. Ovarian cortical tissue was cut and prepared for slow-gradual cryopreservation. Anti-Mullerian hormone (AMH) levels were measured in serum before and after oophorectomy. MAIN RESULTS AND ROLE OF CHANCE Ovarian tissue was successfully collected from 78.7% of the 42 patients. Oocytes were obtained from 20 patients before chemotherapy and 13 after chemotherapy. The youngest patients from whom oocytes were retrieved were aged 2 years (two atretic follicles) and 3 years. Of the 395 oocytes collected, ∼30% were atretic (29.6% in the pre-chemotherapy group, 37% in the post-chemotherapy group). One hundred twenty-one oocytes (31%) were matured in vitro and vitrified: 67.8% from patients before chemotherapy, the rest after chemotherapy. Mature oocytes suitable for vitrification were obtained from 16/20 patients before chemotherapy and from 12/13 patients after chemotherapy (maturation rate, 32 and 26.4%, respectively). There were significant correlations of the number of vitrified oocytes with patient age (more matured oocytes with older age) (P = 0.001) and with pre-oophorectomy AMH levels (P = 0.038 pre-chemotherapy group, P = 0.029 post-chemotherapy group). Oocytes suitable for vitrification were obtained both by manual aspiration of antral follicles (45%) and from rinse solutions after dissection. There were significantly more matured oocytes in the pre-chemotherapy group from aspiration than in the post-chemotherapy group after both aspiration (P < 0.033) and retrieval from rinsing fluids (P < 0.044). The number of pre-antral follicles per histological section did not differ in the pre- versus post-chemotherapy. AMH levels dropped by approximately 50% after ovarian removal in both groups, with a significant correlation between pre- and post-oophorectomy levels (P = 0.002 pre-chemotherapy group, P = 0.001 post-chemotherapy group). LIMITATIONS, REASONS FOR CAUTION There were no patients between 5 years and 10 years old in the post-chemotherapy group, which might have affected some results and correlations. Oocytes from patients soon after chemotherapy might be damaged, and caution is advised when using them for fertility-restoration purposes. The viability, development capability and fertilization potential of oocytes from paediatric patients, especially prepubertal and after chemotherapy, are unknown, in particular oocytes recovered from the media after the tissue dissection step. WIDER IMPLICATIONS OF THE FINDINGS Although more oocytes were collected and matured from chemotherapy-naïve paediatric patients, ovarian tissue and immature oocytes were also retrieved from young girls in whom cancer therapy has already been initiated. Our centre has established a protocol for potential maximal fertility preservation in paediatric female patients with cancer. Vitrified-in vitro-matured oocytes may serve as an important gamete source in paediatric female patients with cancer because the risk of reseeding the disease is avoided. Further studies are needed on the fertility-restoring potential of oocytes from paediatric and prepubertal patients, especially after exposure to chemotherapy. STUDY FUNDING/COMPETING INTERESTS The study was conducted as part of the routine procedures for fertility preservation at our IVF unit. No funding outside of the IVF laboratory was received. Funding for the AMH measurements was obtained by a research grant from the Israel Science Foundation (to B.-A.I., ISF 13-1873). None of the authors have competing interests. TRIAL REGISTRATION NUMBER N/A.

Male factor infertility, low fertilisation rate following ICSI and low number of high-quality embryos are associated with high order recurrent implantation failure in young IVF patients

Background. The aim of this study was to characterise the clinical and laboratory parameters in young in vitro fertilisation (IVF) patients with high order recurrent implantation failure (RIF). Methods: The first 3 cycles (n = 141 cycles) of 47 consecutive (age <35 years) couples with RIF (≥6 IVF cycles) were compared with 252 consecutive cycles of 152 couples, treated during the same period, who conceived within the first 3 IVF cycles. Results. The incidence of male factor infertility or of combined male and female factors was significantly higher in the study group than the control group (male factor: 78.7 versus 42.5%, p = 0.002, OR =3.2 (95% CI: 1.5–6.8)). Lower fertilisation rates were noted for the intracytoplasmic sperm injection (ICSI)‐treated oocytes of the study group compared with the control group. The availability of high quality embryos for transfer was significantly lower in the RIF group. On multivariate logistic regression analysis, the significantly different variables between the groups were cause of infertility (male factor or combined male and female factors) (p = 0.03), fertilisation rate (p = 0.038), and semen concentration (p = 0.05). Conclusions. Young IVF patients with high order RIF are characterised by male factor infertility, lower fertilisation rate with ICSI, and fewer high quality embryos available for transfer.

The effect of oral contraceptive pill for cycle scheduling prior to GnRH-antagonist protocol on IVF cycle parameters and pregnancy outcome

ObjectiveTo evaluate the effect of oral contraceptive pills (OCP) pretreatment on IVF cycle outcome in GnRH-antagonist protocol.DesignRetrospective cohort study.SettingMajor tertiary university-affiliated center.PatientsAll patients treated with GnRH antagonist in our IVF unit during the last 3 years were included in the study. Overall 1,799 IVF cycles were performed. Of these, in 604 cycles OCP pretreatment was used prior to GnRH-antagonist for cycle scheduling. Patients were divided into two age groups—young group aged ≤35 years and older group aged ≥36 years.InterventionsThe young group underwent 927 cycles, 281 cycles with OCP pretreatment and 646 cycles without. The older group underwent 872 cycles, 323 cycles with OCP pretreatment and 549 cycles without. Data was analyzed within each age group.Main outcome measuresTreatment duration and total dose of FSH IU used for stimulation, number of oocytes retrieved, implantation and pregnancy rates.ResultsAll OCP-pretreated cycles required significantly longer stimulation than non-pretreated cycles (young: 10.76 vs. 9.21 days; older: 10.48 vs. 8.73 days, respectively) and higher total dose of FSH IU (young: 3,210 IU vs. 2,565 IU; older: 4,973 IU vs. 3,983 IU, respectively). There were no other differences in cycle characteristics between groups. Implantation and pregnancy rates were not affected by OCP pretreatment.ConclusionsOCP pretreatment can be offered as a mode for cycle scheduling prior to GnRH-antagonist protocol, though it may be associated with longer stimulation and higher gonadotropin consumption.

Correlations between antral follicle count and ultrasonographic ovarian parameters and clinical variables and outcomes in IVF cycles

Aims: To assess the correlation between the antral follicle count (AFC) and other ultrasonographic parameters and clinical variables in in vitro fertilization (IVF) cycles. Methods: Pretreatment ultrasonographic evaluation included AFC (total), large (5–10 mm) and small (2–4 mm) antral follicles, ovarian volume, and ovarian Doppler indices. Data were prospectively uploaded and subsequently analysed in relation to IVF cycle results. Results: The study included 128 women (128 cycles). Analysis of body mass index (BMI) yielded a weak significant correlation with large (5–10 mm) AFC but not with other sonographic variables. AFC was significantly correlated with patient age, ovarian volume, number of retrieved oocytes, total dose of used gonadotropins, peak estradiol, number of top-quality embryos, and number of frozen embryos and marginally correlated with number of aspirated immature oocytes. Lower large (5–10 mm) AFC was the only ovarian parameter associated with oral contraception pretreatment compared to nontreatment, even after adjustment for age and BMI. There was no difference in any of the parameters between short and long IVF cycles. Conclusions: BMI is only weakly correlated with AFC. Pretreatment with oral contraceptives may be associated with lower AFC. Pretreatment with gonadotropin-releasing hormone agonist (long protocol) does not alter the ultrasonographic ovarian parameters.

In vitro fertilization cycle outcome after coasting in gonadotropin-releasing hormone (GnRH) agonist versus GnRH antagonist protocols

OBJECTIVES To compare the results of IVF cycles after coasting in patients treated with a GnRH antagonist or GnRH agonist protocol. DESIGN A retrospective case-control study. SETTING Infertility unit in a university-affiliated tertiary medical center. PATIENT(S) The study group included all women less than 38 years old attending the IVF unit from 2000 to 2006 in whom coasting was used. Data on E(2) levels before and after coasting, duration of coasting, number of oocytes retrieved and fertilized, embryo quality, moderate-severe ovarian hyperstimulation syndrome (OHSS), and pregnancy were collected from the files and compared between GnRH agonist (n = 329) and GnRH antagonist (n = 45) cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Number of retrieved oocytes and pregnancy rates. RESULT(S) There were no between-group differences in cycle parameters. In the antagonist group, there was no need for more than 2 days of coasting. There was a significant decrease in the number of retrieved oocytes even in short periods of coasting in the antagonist group but not in the agonist group. On the day of hCG administration, E(2) levels dropped to a lower level in the antagonist cycles. The OHSS rate after coasting was 4.6% in the agonist group and 4.4% in the antagonist group. Corresponding pregnancy rates after coasting were 27.4% and 24.4%. CONCLUSION(S) The same criteria for coasting can be applied in GnRH agonist as in GnRH antagonist cycles, with a similar IVF result.

High-quality embryos maintain high pregnancy rates in passive smokers but not in active smokers

This study assesses the effect of passive and active smoking on pregnancy rates after IVF with transfer of high-quality embryos. In a cohort study, women attending the IVF unit in 2006–2007 with favourable parameters for pregnancy (<38 years; less than three IVF cycles, transfer of two highest-grade embryos) grouped by smoking status were included. The cohort included 237 patients/cycles: 42 smokers, 195 non-smokers. The clinical pregnancy rate was significantly lower in smokers (35.7% versus 55.4%,P = 0.021, OR = 0.44 (95% CI 0.22–0.89)), even after conditional stratification on covariates (passive smoker, passive or partner smoker, age group). The live-birth rate was lower in smokers (28.6% versus 42.6%), but the difference was not statistically significant(OR = 0.54 (0.26–1.11)). Among non-smokers, there was no difference in pregnancy rate by passive or partner smoking. On logistic regression, variables predicting pregnancy were age <35 years (P = 0.008, OR = 2.58 (1.2–5.2)) and non-smoking (P = 0.003,OR = 3.47 (1.51–7.98)). In conclusion, transfer of high-quality embryos does not overcome the negative effect of active smoking on pregnancy rate in IVF treatment. The endometrium is apparently involved in the mechanism underlying IVF failure in smokers.

Pregnancy outcome after ICSI with thawed testicular sperm from men with non-obstructive azoospermia compared to ICSI with ejaculated sperm from men with severe oligoasthenoteratozoospermia and IVF with normal ejaculated sperm

Abstract The aim of the study was to evaluate the clinical pregnancy outcomes, fetal complications and malformation rate of intracytoplasmic injection of thawed cryopreseverd sperm extracted by testicular aspiration from men with non-obstructive azoospermia (NOA) compared with intracytoplasmic injection of fresh ejaculated sperm from men with severe oligoteratoasthenozoospermia (OTA) and standard in vitro fertilization using ejaculated sperm from normospermic men. The mean oocyte fertilization rate was significantly lowest for ICSI with testicular aspirated sperm (NOA group). However, there was no significant difference among the three groups in pregnancy outcomes, namely rates of spontaneous abortion, biochemical pregnancy, extrauterine pregnancy, singleton multifetal pregnancy, preterm delivery before 36 weeks’ gestation, maternal complications, transfer to the neonatal intensive care unit, intrauterine growth restriction or fetal malformations. These results suggest that despite some earlier findings that intracytoplasmic injection of aspirated sperm from men with NOA is associated with lower fertilization rates and embryo quality, the pregnancy and immediate neonatal outcomes may be unaffected.

Small antral follicle count (2–5 mm) and ovarian volume for prediction of pregnancy in in vitro fertilization cycles

Aims. To assess the value of antral follicle count (AFC) and other parameters as predictors of pregnancy in in vitro fertilization (IVF). Methods. In a cohort study, unselected consecutive women in IVF treatment were evaluated. Pretreatment parameters included AFC (subpopulations of small (2–5 mm) and large (5–10 mm) AFC), ovarian volume, and ovarian stroma Doppler indices. Results. The study included 115 women of whom 38 (33%) were pregnant. Total AFC was significantly higher in the pregnant than in the non-pregnant group (13.7 ± 5.8 vs. 11.3 ± 5.3, p = 0.034). On receiver operator characteristic (ROC) curve analysis, the pretreatment variables that were significantly associated with pregnancy were small AFC (2–5 mm), total AFC, and ovarian volume/AFC ratio. Women with a positive score (total AFC >15; small AFC (2–5 mm) >10; ovarian volume in mm3/AFC, <1400), had a significantly higher number of retrieved oocytes and a higher pregnancy rate than women with a negative score (12.1 ± 5.1 vs. 8.7 ± 5.0, p = 0.027 and 58.3% vs. 30.1%, p = 0.049, respectively). On multivariate logistic regression analysis, total AFC was the only significant and independent predictor of pregnancy (p = 0.034). Conclusion. Pretreatment small AFC and ovarian volume may identify women with a higher probability to achieve pregnancy in IVF.

Aspiration of immature oocytes during cesarean section for fertility preservation and future surrogacy

A 38-year-old pregnant patient with a history of renal transplantation sought embryo freezing for fertility preservation and future surrogacy. A cesarean section was performed with direct aspiration of small ovarian follicles. Thirteen identified oocyte-cumulus complexes were cultured. Intracytoplasmatic sperm injection was performed on all mature oocytes and the resulting 4 zygotes were cryopreserved.