Abstract
Study question
Is double stimulation in the same ovarian cycle (DuoStim) a valuable strategy to rescue advanced-maternal-age patients obtaining ≤ 3 blastocysts for chromosomal-testing after conventional stimulation?
Summary answer
DuoStim is effective to prevent treatment discontinuation thereby increasing the 1-year cumulative-live-birth-rate among advanced-maternal-age patients obtaining 0–3 blastocysts after a first conventional stimulation.
What is known already
Folliculogenesis is characterized by continuous waves of follicular growth. DuoStim approach exploits these dynamics to conduct two stimulations in a single ovarian cycle and improve the prognosis of advanced-maternal-age and/or reduced-ovarian-reserve women. Independent groups worldwide successfully adopted DuoStim with various regimens reporting similar oocyte/embryo competence after both stimulations. Recently, we have demonstrated the fruitful adoption of DuoStim in patients fulfilling the Bologna criteria, especially because of the prevention of treatment discontinuation. Here we aimed at investigating whether DuoStim can be adopted to rescue poor prognosis patients obtaining 0–3 blastocysts after the conventional approach.
Study design, size, duration
Proof-of-concept matched case-control study. All patients obtaining 0–3 blastocysts after conventional-stimulation between 2015–2018 were proposed DuoStim. The 143 couples who accepted were matched for maternal age, sperm factor, cumulus-oocyte-complexes and blastocysts obtained after the first stimulation to 143 couples who did not. The primary outcome was the 1-year cumulative-live-birth-rate. If not delivering, the control group had 1 year to undergo a second attempt with conventional-stimulation. All treatments were concluded (live-birth achieved or no euploid left).
Participants/materials, setting, methods
Only GnRH-antagonist with recombinant-gonadotrophins and agonist trigger stimulation protocols were adopted. All cycles entailed ICSI with ejaculated sperm, blastocyst culture, trophectoderm biopsy, comprehensive-chromosome-testing and vitrified-warmed euploid single-embryo-transfer(s). Cumulative-live-birth-rate was calculated per patient considering both stimulations in the same ovarian cycle (DuoStim group) or up to two stimulations in 1 year (control group). Treatment discontinuation rate in the control group was calculated as patients who did not return for a second stimulation among non-pregnant ones.
Main results and the role of chance
Among the 286 couples included (41.0±2.9yr;4.9±3.1 cumulus-oocytes-complexes and 0.8±0.9 blastocysts), 126 (63 per group), 98 (49 per group), 52 (26 per group) and 10 (5 per group) obtained 0,1,2 and 3 blastocysts after the first stimulation, respectively. The cumulative-live-birth-rate was 9% in the control group after the first attempt (N = 13/143). Among the 130 non-pregnant patients, only 12 returned within 1-year (165±95days later;discontinuation rate=118/130,91%), and 3 delivered. Thus, the cumulative-live-birth-rate from two stimulations in 1-year was 11% (N = 16/143). In the DuoStim group, the cumulative-live-birth-rate was 24% (N = 35/143; Fisher’s-exact-test< 0.01,power=80%). The odds-ratio of delivering in the DuoStim versus the control group adjusted for all matching criteria was 3.3,95%CI:1.6–7.0,p<0.01. This difference (0%,22%,15% and 20% in the control versus 10%,31%,46% and 40% in the DuoStim group among patients obtaining 0,1,2 and 3 blastocysts at the first stimulation, respectively) is mainly due to treatment discontinuation in the control group (98%,65%,77% and 80% among patients obtaining 0,1,2 and 3 blastocysts at the first stimulation, respectively) and the further increased maternal age at the time of second retrieval (∼6 months). Notably, 2 patients delivered 2 live-births after DuoStim (none in the control) and 14 patients with a live-birth have euploid blastocysts left (2 in the control).
Limitations, reasons for caution
Randomized-controlled-trials and cost-effectiveness analyses are desirable to confirm these data. Moreover, 75% of the patients included were >39yr and 44% obtained no blastocyst after the first stimulation. Therefore future studies among younger women and/or more women obtaining ≥1 blastocyst are advisable to set reasonable cut-off values to apply this strategy.
Wider implications of the findings: A second stimulation in the same ovarian cycle might be envisioned as a rescue strategy for poor IVF outcomes after a first stimulation, so to prevent treatment discontinuation and increase the cumulative-live-birth-rate. This is feasible since 6–7 days span the first and the second stimulation in the DuoStim protocol.
Trial registration number
none
Does preimplantation genetic testing for aneuploidy really improve IVF outcomes in advanced maternal age patients without compromising cumulative live-birth rate?