Hananel Holzer

Obstetric outcomes and congenital abnormalities after in vitro maturation, in vitro fertilization, and intracytoplasmic sperm injection.

OBJECTIVE: To compare obstetric outcome and congenital abnormalities in pregnancies conceived after in vitro maturation (IVM), in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI) with those in spontaneously conceived controls. METHODS: Data were collected from the McGill Obstetrics and Neonatal Database (MOND). All children were examined and classified in a standard manner. Final data were reviewed 12 months after delivery. Pregnancies by IVM, IVF, and ICSI were compared with those of age- and parity-matched controls. Congenital abnormality, gestational age, birth weight, Apgar scores, cord pH, growth restriction, pregnancy complications, mode of delivery, and multiple pregnancy were compared. RESULTS: A total of 432 children were born from 344 pregnancies after assisted reproductive technology (ART) during the study period (IVM 55, IVF 217, ICSI 160). The observed odds ratios (ORs) for any congenital abnormality were 1.42 (95% confidence interval [CI] 0.52–3.91) for IVM, 1.21 (95% CI 0.63–2.62) for IVF, and 1.69 (95% CI 0.88–3.26) for ICSI. Twin pregnancy (IVM 21%, IVF 20%, ICSI 17%) and triplet pregnancy (IVM 5%, IVF 3%, ICSI 3%) were higher than those in controls (1.7% twins and 0% triplets) (P<.001). Cesarean delivery rates were higher after ART, even in singleton pregnancies (IVM 39%, IVF 36%, ICSI 36%; controls: 26.3%) (P<.05). Apgar scores, cord pH, growth restriction, and pregnancy complications were comparable in all groups. CONCLUSION: All ART pregnancies are associated with an increased risk of multiple pregnancy, cesarean delivery, and congenital abnormality. Compared with IVF and ICSI, IVM is not associated with any additional risk. LEVEL OF EVIDENCE: II

Obstetric outcomes following vitrification of in vitro and in vivo matured oocytes

OBJECTIVE To evaluate obstetric outcomes with oocyte vitrification after ovarian stimulation (OS) and in vitro maturation (IVM) of immature oocytes. DESIGN A prospective trial from October 2003 to April 2007. SETTING University-based medical center. PATIENT(S) OS group: 38 patients undergoing intrauterine insemination who overresponded to OS. IVM group: 20 patients who had previous unsuccessful intrauterine insemination. INTERVENTION(S) Mature oocyte retrieval following OS. Immature oocyte retrieval and IVM. Oocyte vitrification, thawing, insemination, and transfer of the resulting embryos. MAIN OUTCOME MEASURE(S) Live-birth rates and obstetric outcomes. RESULT(S) The OS group was superior to the IVM group in terms of oocyte survival (81.4 +/- 22.6% vs. 67.5 +/- 26.1%), fertilization rate (75.6 +/- 22.5% vs. 64.2 +/- 19.9%), and cumulative embryo score (38.4 +/- 22.3 vs. 20.0 +/- 13.8). However, the differences in the implantation rate per embryo (19.1 +/- 25.8% vs. 9.6 +/- 24.1%), clinical pregnancy rate per cycle started (44.7%, vs. 20.0%), and live-birth rate per cycle started (39.5% vs. 20.0%) were not statistically significant. Twenty healthy babies were born in the OS group and four in the IVM group. CONCLUSION(S) Pregnancies achieved with vitrification of oocytes after OS and IVM treatments do not appear to be associated with adverse pregnancy outcomes. Vitrification of IVM oocytes represents a novel option for fertility preservation.

Live birth after vitrification of in vitro matured human oocytes

OBJECTIVE To report the first healthy live birth from immature oocytes retrieved in a natural menstrual cycle, followed by in vitro maturation (IVM) and cryopreservation of the oocytes by vitrification. DESIGN Case report. SETTING University-based tertiary medical center. PATIENT(S) A 27-year-old woman with tubal disease and polycystic ovaries. INTERVENTION(S) Immature oocytes were retrieved by transvaginal ultrasound guided follicle aspiration on day 13 of her natural menstrual cycle, matured in vitro and vitrified. The oocytes were thawed in a subsequent menstrual cycle, inseminated by intracytoplasmic sperm injection, and the resulting embryos transferred. MAIN OUTCOME MEASURE(S) Oocyte maturation and survival rates, pregnancy, and live birth. RESULT(S) One metaphase II and 18 germinal vesicle stage oocytes were collected; 16 out of 18 germinal vesicle oocytes matured, and a total of 17 oocytes were vitrified. After thawing, four IVM oocytes survived; three embryos were transferred. The woman went on to deliver a single healthy live baby at term. CONCLUSION(S) We provide proof-of-principle evidence that the novel fertility preservation strategy of immature oocyte retrieval, IVM, and vitrification of oocytes can lead to successful pregnancy and healthy live birth.

Immature oocyte retrieval in the luteal phase to preserve fertility in cancer patients

As cancer treatment outcomes improve, the number of women with cancer seeking fertility preservation increases. Currently, embryo/oocyte cryopreservation appears to provide the best fertility preservation option. However, patients may not have sufficient time to undergo ovarian stimulation prior to chemotherapy and/or the hormones used in ovarian stimulation are contraindicated for certain tumours. In-vitro maturation has been suggested as an effective treatment for these patients. This report presents three women aged 21, 30 and 40 years, without male partners, seeking fertility preservation prior to chemotherapy. They were first seen during the luteal phase of their menstrual cycle and were to undergo gonadotoxic treatment imminently. They underwent immature oocyte retrieval in the luteal phase and seven, five and seven immature oocytes were recovered, respectively. After in-vitro maturation, five, three and five metaphase II (MII) oocytes were vitrified. Two patients later underwent one and two more retrievals, respectively, in the follicular phase of the next cycle(s) and additional oocytes were cryopreserved. These results suggest that immature oocytes recovered in the luteal phase can successfully be matured in vitro; therefore, if there is not sufficient time for conventional follicular-phase oocyte retrieval in a stimulated/unstimulated cycle prior to chemotherapy, a retrieval in the luteal phase could be considered.

Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study

OBJECTIVE To produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO). DESIGN Retrospective cohort analysis. SETTING Fifteen academic reproductive centers. PATIENT(S) A total of 3,871 infertile women. INTERVENTION(S) Blood sampling for AMH level. MAIN OUTCOME MEASURE(S) Serum AMH levels and correlation between age and different percentiles of AMH. RESULT(S) Age-related normograms for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles of AMH were produced. We found that the curves of AMH by age for the 3rd to 50th percentiles fit the model and appearance of linear relation, whereas the curves of >75th percentiles fit cubic relation. There were significant differences in AMH and FSH levels and in antral follicle count (AFC) among women aged 24-33 years, 34-38 years, and ≥39 years. Multivariate stepwise linear regression analysis of FSH, age, AFC, and the type of AMH kit as predictors of AMH level shows that all variables are independently associated with AMH level, in the following order: AFC, FSH, type of AMH kit, and age. CONCLUSION(S) Age-related normograms in non-PCO infertile women for the 3rd to 97th percentiles were produced. These normograms could provide a reference guide for the clinician to consult women with infertility. However, future validation with longitudinal data is still needed.

Young Low Responders Protected from Untoward Effects of Reduced Ovarian Response

OBJECTIVE(S) To correlate fertilization and clinical pregnancy rates (PRs) in low responders with their E2 levels (<500, 500-800, >800-1,000 pg/mL), age (20-30, 31-40, >40 years), number of follicles, and number of oocytes retrieved. DESIGN A retrospective study. SETTING The IVF unit of an academic hospital. PATIENT(S) One hundred forty-three women who failed to attain E2 levels of 1,000 pg/mL on the day of hCG administration. INTERVENTION(S) Controlled ovarian hyperstimulation, blood E2 and progesterone measurements, ultrasonographic scanning of ovarian follicles, oocyte retrieval after hCG administration, and ET. MAIN OUTCOME MEASURE Clinical PR. RESULT(S) Although E2 levels, fertilization rates, age, and number of oocytes did not differ significantly between the three age groups, the PR achieved in the youngest group was approximately three times as high (19.3%) as that achieved in the two older groups. CONCLUSION Young low responders represent a unique subset in that their age protects them from the deleterious effects of poor ovarian response.

Working to eliminate multiple pregnancies: a success story in Québec

In August 2010, the provincial government of Québec, Canada introduced funding of assisted reproduction treatment through the provincial health programme. Alongside this benefit, legislation was introduced to control assisted reproduction treatment activities in the province, including restrictions on the number of embryos that could be transferred in any one cycle. The aim of the programme was to transfer a single embryo in every cycle; multiple embryos could be transferred under suboptimal conditions but required physician justification. In the first 3 months of this programme, 1353 cycles of IVF were performed in five Québec assisted reproduction centres, with an overall clinical pregnancy rate of 32% per embryo transfer and 50% of transfers used elective single-embryo transfer (eSET). The multiple-pregnancy rate was only 3.7% per clinical pregnancy. In 2009, prior to the introduction of the programme, eSET was used in only 1.6% of embryo transfers, resulting in a multiple-pregnancy rate of 25.6%. These data demonstrate that providing provincially funded assisted reproduction treatment created an environment in which the aggressive use of eSET was not only possible, but also rapidly implemented. The result was a dramatic drop in multiple-pregnancy rates, approaching those for natural pregnancies.

Comparison of in-vitro maturation cycles with and without in-vivo matured oocytes retrieved

This study compared the embryological characteristics and clinical outcome of in-vitro maturation (IVM) treatment cycles with and without in-vivo matured oocytes collected following human chorionic gonadotrophin (HCG) priming. The patients were administered 10,000 IU of HCG subcutaneously when endometrial thickness reached > or =6 mm and oocyte collection was performed 35-36 h after HCG administration. The clinical outcome and embryological aspects were analysed between IVM cycles with (group 1) and without (group 2) in-vivo matured oocytes. In group 1, three (range 1-12) in-vivo matured oocytes per patient were retrieved on average. The number of good quality embryos derived from in-vivo matured oocytes in group 1 was significantly higher than those derived from in-vitro matured oocytes in group 1 and group 2 (P < 0.05). However, there was no difference between the number of good quality embryos produced from in-vitro matured oocytes in the two groups. There were 12 clinical pregnancies (40.0%) in group 1, and seven pregnancies (23.3%) in group 2. These results suggest that IVM cycles with in-vivo matured oocytes resulted in a good clinical pregnancy rate, which could be explained by the superior quality of embryos derived from the in-vivo matured oocytes.

Selection of the optimal day for oocyte retrieval based on the diameter of the dominant follicle in hCG-primed in vitro maturation cycles

BACKGROUND The efficiency of in vitro maturation (IVM) techniques is suboptimal compared with controlled ovarian stimulation combined with IVF cycles, and studies are needed to identify factors that predispose IVM cycles to success or failure. We compared the outcome of IVM cycles with different dominant follicle (DF) size at oocyte retrieval following hCG priming. METHODS IVM was performed in 160 patients with polycystic ovaries (171 cycles). We administered 10,000 IU hCG s.c. 35-38 h before oocyte collection when endometrial thickness reached at least 6 mm. IVM cycles were retrospectively analyzed according to DF diameter as follows; Group 1: DF diameter <or=10 mm, Group 2: between 10 and 14 mm, Group 3: >14 mm. RESULTS A positive correlation was observed between DF size and number of in vivo matured oocytes collected (Group 1, 2 and 3 = 6.9, 10.6 and 15.1%, respectively). The rates of IVM, fertilization and embryo development were similar among the sibling immature oocytes collected from the three groups. However, clinical pregnancy rate in Group 2 (40.3%) was higher than Group 3 (17.1%) (P < 0.05). Moreover, implantation rates in Groups 1 (13.6%) and 2 (14.3%) were higher than Group 3 (4.9%) (P < 0.01). CONCLUSIONS Our results suggest that oocyte collection in IVM cycles should be performed when the DF is 14 mm diameter or less. Sibling immature oocytes may be affected detrimentally if a DF >14 mm is present at oocyte collection.

Fertility preservation for breast-cancer patients using IVM followed by oocyte or embryo vitrification.

Unstimulated in-vitro maturation (IVM) cycles are considered for fertility preservation in breast cancer due to avoidance of ovarian stimulation and shortened time to oocyte retrieval. This study evaluated the efficacy of this approach in a retrospective cohort analysis of 66 patients with breast cancer. Immature oocytes were collected and matured in vitro and then either vitrified or fertilized and preserved as vitrified embryos. In group 1 (vitrified oocytes, n=35), the average number of oocytes retrieved was 11.4 ± 8.8, the maturation rate was 64.2% and an average of 7.9 ± 6.6 oocytes were vitrified per patient treated. The median duration from the first evaluation to oocyte retrieval was 8 days. In group 2 (vitrified embryos, n=31) the average number of oocytes retrieved was 9.7 ± 6.4, the maturation rate was 53.2% and an average of 5.8 ± 2.7 mature oocytes were available for fertilization/patient. The fertilization rate was 77.8%, resulting in 4.5 ± 2.7 vitrified embryos/patient. The median duration from the first evaluation to oocyte retrieval was 13 days. Calculated pregnancy rates per vitrified oocyte and embryo were 3.8% and 8.1%, respectively. IVM can be considered a useful option for fertility preservation in breast-cancer patients.