Non-inferiority of cleavage-stage versus blastocyst-stage embryo transfer in poor prognosis IVF patients (PRECiSE trial): study protocol for a randomized controlled trial

Werner M Neuhausser, Denis A Vaughan, Denny Sakkas, Michele R Hacker, Tom Toth, Alan Penzias, Werner M Neuhausser, Denis A Vaughan, Denny Sakkas, Michele R Hacker, Tom Toth, Alan Penzias

Abstract

Background: With improvements in in vitro culture techniques there has been a steady shift in practice to transfer embryos at the blastocyst stage (post fertilization day (p.f.d.) 5-7), when embryos reach the endometrial cavity during natural conception. For patients with > 5 zygotes on day 1 of embryo development, fresh blastocyst embryo transfer (ET) increases live birth rates when compared to cleavage stage (p.f.d. 3) transfer. In poorer prognosis patients (≤ 5 zygotes) cleavage stage ET is commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst stage. However, there is a dearth of randomized controlled trial (RCT) data demonstrating improved live birth rates per cycle for cleavage vs blastocyst stage ET in this subgroup of patients. The hypothesis of the PRECiSE (PooR Embryo Yield Cleavage Stage Versus blaStocyst Embryo Transfer) trial is that blastocyst ET is not inferior to cleavage stage ET with regard to live birth rates per retrieval in poorer prognosis patients. The adoption of routine blastocyst culture for all patients would result in higher rates of single embryo transfers (SET), reduced incidence of multiple pregnancies and simplified laboratory protocols, thereby reducing costs.

Methods/design: Multicenter, non-inferiority randomized controlled trial (RCT) comparing blastocyst to cleavage stage embryo transfer in poorer prognosis patients with ≤5 zygotes on day 1 after fertilization. The primary outcome is live birth per retrieval. Secondary outcomes include: time to pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage and multiple pregnancy rate (per retrieval). This trial will enroll 658 women with ≤5 zygotes on day 1 at 6 IVF centers over the course of 22 months.

Discussion: If the hypothesis is proven true, the data from this trial may facilitate the adoption of uniform blastocyst culture in all IVF patients.

Trial registration: ClinicalTrials.gov Identifier: NCT03764865. Registered 5 December 2019, Protocol issue date: 4 December 2018, Original.

Keywords: Blastocyst transfer; Cleavage-stage transfer; In vitro fertilization; Non-inferiority randomized controlled trial.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study design flow diagram. First cycle IVF patients meeting inclusion criteria will be consented to participate in the study and undergo an autologous IVF cycle. Patients who consent to participate in the study may be determined ineligible prior to randomization depending on the number of available embryos on day 1 post fertilization. After allocation to cleavage-stage or blastocyst-stage fresh embryo transfer patients will receive standard care and any embryos not transferred will be cryopreserved at the blastocyst stage. If pregnancy is not achieved in the fresh transfer cycle any remaining frozen embryos will be transferred. All pregnant patients will be followed and pregnancy outcomes recorded. To investigate pregnancy outcomes per IVF retrieval we will follow participants until all cryopreserved embryos have been transferred or a transfer results in a live birth, whichever occurs first
Fig. 2
Fig. 2
Study protocol. IVF stimulation protocols, trigger agents (hCG) and fertilization (IVF or intracytoplasmic sperm injection) will follow standard clinical practice. Patients will be randomized to p.f.d. 3 or p.f.d. 5 ET on day 1 of embryo development if they have ≤5 embryos available. Selection of embryos will be based on morphology and the number of embryos transferred will be based on the current American Society of Reproductive Medicine (ASRM) guidelines. Following the embryo transfer, clinical care will follow standard practice. Participants will receive vaginal progesterone for luteal support starting the day after egg retrieval until 8 weeks gestation or until 10 days after fresh embryo transfer, if the serum pregnancy test is negative. Any unused embryos will be cultured to p.f.d. 5–7 and cryopreserved by vitrification per standard clinical protocols. A pregnancy test (serum hCG) will be performed on day 10 following embryo transfer. If negative, any cryopreserved embryos will be transferred in subsequent frozen embryo transfer cycles as per standard protocol. We will administer intra-muscular progesterone with or without vaginal progesterone for luteal support in thaw cycles after the endometrial lining reaches a minimal trilaminar endometrial thickness of 7 mm (=day 1) with embryo transfer in the afternoon of day 6
Fig. 3
Fig. 3
Possible outcomes of the PRECiSE non-inferiority RCT. The non-inferiority margin is set to a 10% absolute difference in live birth rate, which corresponds to a risk ratio (RR) of 0.6 for p.f.d 5 versus p.f.d.3 embryo transfer. a the lower bound of the confidence interval (CI) lies above the non-inferiority margin of 0.6: p.f.d. 5 is non-inferior to p.f.d. 3 embryo transfer (b) the lower bound of the CI lies above the non-inferiority margin and the CI includes the null value (RR = 1.0): p.f.d. 5 is non-inferior and equivalent to p.f.d. 3 embryo transfer (c) and (d) the CI includes the non-inferiority margin of 0.6: inconclusive (e) the upper bound of the CI lies below the non-inferiority margin of 0.6: p.f.d. 5 is inferior to p.f.d. 3 embryo transfer (f) the lower bound of the CI lies above the null value (RR = 1.0): p.f.d. 5 is superior to p.f.d. 3 embryo transfer

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