Delivery of a healthy singleton live birth is the target outcome for all infertility treatment. Although elective SET has emerged as the best answer to reduce the multiple gestation rate in IVF, uncertainty about the technique itself, low patient awareness of the process, lack of a favorable reimbursement system, and inferior cryopreservation success rates have hindered the uptake of this approach [38
]. The value of promoting SET was recently underscored by a population-based cohort study of IVF outcomes where cerebral palsy (CP) incidence was noted among 1042 IVF singletons born after SET in Denmark [39
]. Only one of those children received a CP diagnosis, compared with 21 CP diagnoses among IVF singletons born after two or more embryo transfers [39
]. In Canada, efforts to mandate SET gained support from a multi-year review showing how this change in IVF practice would prevent infant deaths and reduce serious complications associated with multiple gestations [40
]. Researchers found 17% of all NICU admissions—82 infants from 44 multiple gestations—resulted from assisted fertility treatments, and most NICU admissions (75 of 82 infants) were twins or triplets whose mothers used IVF to become pregnant. Among those 75 babies there were 6 deaths, and 5 more developed severe intraventricular hemorrhage [40
Given this background, IVF patients should be encouraged to consider elective SET during pre-treatment counseling. Except for Sweden and Belgium [41
], all other jurisdictions allow the decision for number of embryos for transfer to be made by doctor and patient, so the role of the reproductive endocrinologist in this process is vital [38
]. How the choice to have elective SET is communicated has been shown to be an important influencing factor as this choice is made [43
]. Yet in many clinics, if SET is offered at all, it is the patient herself who requests this option. Confidence in chance of success after SET, younger patient age, and first IVF treatment appear to favor a patient asking for SET [44
]. We support the basic criteria for elective SET as proposed by others [45
], including age <37
yrs, at least two good quality embryos available (3–5 cells on d2 or 6–9 cells on d3; <20% fragmentation and no multinucleate blastomeres), and no more than one previous failed treatment cycle. Among Australian IVF patients, preference for a healthy singleton pregnancy was predictive for elective SET, but perception of risk of multiple gestation was not [44
]. Reporting on IVF patients in Ireland, Walsh et al.
] investigated pre-treatment anxiety about twins and no association with patient age was observed. When presented with the option of SET, good prognosis IVF patients in Ireland agreed with this approach [47
So why hasn’t elective SET found wider application in clinical IVF practice? Low pregnancy rates after fresh SET [48
] have limited its acceptance, but this criticism of elective SET may be offset when cumulative outcome with subsequent frozen embryo transfer (FET) cycles is considered [52
]. To be sure, more IVF patients would request elective SET if the success rate approached that following a two embryo transfer [56
]. It is therefore understandable for both patients and clinicians to view elective SET with skepticism unless significant refinements in fresh embryo assessment come forward to facilitate the selection of competent embryos.
The current study extends prior research where aCGH was used for IVF patients with a known chromosomal rearrangement [29
], and is the first to apply this technology to embryos from young, good prognosis patients undertaking IVF for the first time. Because SET is more frequently requested by IVF patients with a favorable prognosis [47
], and since in this setting the clinical urgency to identify the best single embryo for transfer is maximal, our hypothesis developed this clinical problem into a therapeutic solution where aCGH figured prominently. Incorporating aCGH within an IVF clinic not only promises improved reproductive competency of each embryo at fresh transfer, it also offers important ploidy information regarding any supernumary (non-transferred) embryos which may be cryopreserved for later use. At our center, integrating aCGH with the clinical IVF program was associated with the same extra cost typically charged for the more limited genetic assessment gained from 5-probe FISH—less than $3000. These considerations should be particularly welcome among patients and clinicians contemplating elective SET, but who hesitate to make decisions without the advantage of comprehensive chromosomal screening. Moreover, an integrated testing approach also removed the a priori requirement for material to be frozen and shipped off-site for testing, followed by arranging subsequent FET based on findings from aCGH performed remotely. We believe that patient stress was reduced by eliminating FET medications entirely, while also reducing overall IVF treatment time. How patients quantify the distinctions between fresh transfer and FET treatment regimes is the target of ongoing study.
Our research contributes new aCGH data on embryos from good-prognosis IVF patients, placing the limitations of standard embryo morphology in sharp relief. The extent of aneuploidy in early human embryos can be extensive [11
] although this rate is typically lower in blastocysts [25
]. Yet, the current study provides further evidence of substantial genetic abnormality in apparently normal blastocysts, including monosomy and complex aneuploidy [7
]. Our data show conventional morphological criteria alone to be insufficiently accurate even for young, low-risk IVF patients (see Figure ). Recent research on thawed blastocysts after SNP-based comprehensive chromosomal screening and vitrification has yielded similar results [60
Figure 2 Representative aCGH data obtained from human blastocysts via trophectoderm biopsy performed on post-fertilization day 5. While standard microscopy confirmed good morphology (Grade 5AA) for both blastocysts, ploidy status was not uniform. Using aCGH to (more ...)
Several limitations of our investigation should be acknowledged. First, although elective SET brings distinct advantages for many IVF patients, the approach is not for everyone. Indiscriminate use of elective SET for patients with multiple failed cycles has been criticized as inferior to a two-embryo strategy [61
], and the improved pregnancy rate noted here may not fully generalize to all IVF patients. Additionally, this pilot study was designed to use aCGH for selection of a single blastocyst for fresh transfer. It is possible that embryo assessment by conventional morphology inappropriately excludes euploid embryos from transfer although this question was outside the scope of our study. Hence, the relation between chromosomal integrity and morphological grades based on developmental stage, ICM and TE appearance, requires further investigation with a larger sample.