M.H. Dahan

The role of intracytoplasmic sperm injection in non-male factor infertility in advanced maternal age

STUDY QUESTION Does ICSI improve reproductive outcomes compared with conventional IVF when used for non-male factor infertility in women aged 40 years and over? SUMMARY ANSWER There is no advantage of ICSI over conventional IVF in women aged 40 years and over when used for non-male factor infertility. WHAT IS KNOWN ALREADY The use of ICSI has increased dramatically in recent years and is being applied for indications other than male factor infertility. Currently, ICSI is used in 65% of IVF cycles in Europe and in 76% of cycles in the USA. Despite its increase use, there is no clear evidence of a benefit in using ICSI over conventional IVF. Older women undergoing infertility treatments are at an increased risk of having diminished ovarian reserve and lower oocyte quality, which could make ICSI the preferred insemination method in this group. However, studies that have examined the benefits of ICSI in this age group are lacking. STUDY DESIGN, SIZE, DURATION A retrospective, single center study included women, aged 40–43 years, who underwent IVF treatments for non-male factor infertility between January 2012 until June 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 745 women were included in the study. Of these, 490 women underwent ICSI and 255 women underwent conventional IVF. In order to be included in the study, women had to be at least 40 years of age at the beginning of ovarian stimulation and their male partner had to have normal sperm parameters according to World Health Organisation (WHO) fifth edition. Exclusion criteria included: more than three previous IVF cycles, a history of fertilization failure or low fertilization (<50%), the use of donor or frozen oocytes and the use of donor or frozen sperm samples. The primary outcome was the live birth rate. Secondary outcomes included fertilization rates, fertilization failure and embryo quality. MAIN RESULTS AND THE ROLE OF CHANCE Baseline characteristics were similar between the two groups, except for the number of previous IVF cycles, which was higher in the ICSI group (1.0 vs. 0.6, P = 0.0001). Despite similar numbers of oocytes retrieved (7.2 vs. 6.5), when examining oocytes maturity (performed 2 h after oocyte retrieval in the ICSI group and after 18 h in the conventional IVF group), the conventional IVF group had a higher number of Metaphase II (MII) oocytes (6.1 vs. 4.7, P < 0.0001). The conventional IVF group also had higher numbers of zygotes formed (4.48 vs. 3.66, P = 0.001), more cycles with embryos transferred at the blastocyst stage (36 vs. 26%, P = 0.005) and more cycles where embryos were available for cryopreservation (26.4 vs. 19.7%, P = 0.048), compared with the ICSI group. The fertilization rates (64 vs. 67%) and fertilization failure (9.0 vs. 9.7%) were similar. After logistic regression analysis controlling for confounders, the live birth rates were similar between the groups (11.9 vs. 9.6%). Subgroup analyses of women undergoing their first IVF cycle and women with ⩽3 oocytes retrieved did not show an advantage of ICSI over conventional IVF. LIMITATIONS, REASONS FOR CAUTION The retrospective nature of this study was a major limitation. The ICSI group had a higher number of previous IVF cycles, which could mean that ICSI was performed in poorer prognosis patients. Moreover, although this study is one of the largest studies to examine the question of whether ICSI is of value for older women with non-male factor infertility, based on a post hoc power analysis, it was still underpowered to detect differences in live birth rates, which can limit the conclusions of the study. Prospective studies are needed to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS The decision regarding performing ICSI should be based on sperm parameters and previous history. The use of ICSI for the sole indication of advanced maternal age shows no benefit over conventional IVF. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER N/A.

Issues related to human oocyte vitrification: a consideration of the facts

Dear Editor, The advent of human oocyte vitrification has resulted in improved oocyte survival and reproductive potential that are equivalent to those of fresh retrieved oocytes. This has led the American Society for Reproductive Medicine (ASRM) in 2013 to change its position and classify oocyte cryopreservation as a non-experimental technique [1]. However, this change in position relied mainly on small-scale trials that came from the most experienced reproductive centers. Indeed, the ASRM had emphasized this fact and questioned whether the results of these trials can be generalized and reproduced in other fertility centers. However, since this change in committee position, there has been an increase in cycles that utilize vitrified oocytes, for the purpose of generating commercial banks of donor oocytes and for fertility preservation [2]. Although limited data is available on the outcomes of these cycles, the recent results show a persistently worse outcomes when using vitrified compared to fresh oocytes [3]. These worrisome results are particularly relevant to women who cryopreserve oocytes for social or medical reasons, for whom, this maybe their only hope to have their biologic offspring. This highlights the need of reproductive centers offering fertility preservation for continuous surveillance of the laboratory techniques to ensure consistent results. The following case can be an example of this issue. A 36-year-old healthy woman underwent three consecutive fertility preservation cycles which yielded a total of 43 MII oocytes that were vitrified. The oocytes from the first and second cycles (14 and 12 oocytes respectively) were vitrified by two senior embryologists and the oocytes from the third cycle (17 oocytes) were vitrified by a junior embryologist. Seven years later, at the age of 43, the patient returned for fresh IVF cycle with a partner. The patient opted also for oocytes thawing and fertilization. All the oocytes were thawed on the same day by the same embryologist. There was a significant difference in the oocyte survival rate between the three groups of oocytes: 71.4% (10/14) and 70.5% (12/17) for the first and third cycle, and 16.7% (2/12) for the second cycle (p = 0.04). These resulted in the formation of 18 embryos; of these, 8 were found to be euploid when tested by comparative genomic hybridization (CGH). Furthermore, four embryos were obtained from the fresh cycle; however, all were aneuploid when tested by CGH. Two embryos were transferred on day 5; however, pregnancy was not achieved. Three important points can be drawn from this case. First, as expected, oocyte vitrification for social fertility preservation is a way to obtain euploid embryos for use at an advanced age, when oocyte aneuploidy rate is high. This is not surprising, but has been minimally demonstrated. Secondly, oocytes can be vitrified for long periods (7 years in this case) and yet can survive, fertilize, and result in the formation of euploid embryos. The third point is that slight intra-laboratory variations in vitrification technique can result in different oocyte survival rates, even when performed under the same laboratory protocol. A recent study that analyzed the outcomes of oocyte donation cycles in the USA showed that between the years 2013 and 2015, there was a 44% increase in the utilization of vitrified oocytes along with a 33% decrease in the use of fresh oocytes [4]. However, cycle cancelation rates in vitrifiedthawed oocytes cycles increased from 8.5 to 15% compared to a decrease from 11.7 to 9.1% in cycles that used fresh oocytes between these years. This increase in cycle cancelation among vitrified oocyte cycles is likely related to lower oocyte survival rate and a lack of viable embryos to transfer. Furthermore, the live birth rate per recipient cycle start was * Samer Tannus sr.tannus@gmail.com