Noninvasive Implantation Potential vs Morphology-Based Selection in IVF Single Blastocyst Transfer

Official title

Clinical Outcomes of Non-invasive Embryo Implantation Potential Assessment Versus Conventional Morphological Selection for Single Blastocyst Transfer Following Conventional IVF: A Multicenter Randomized Controlled Trial

Overview

Background: Morphology-based embryo selection cannot detect aneuploidy, which is common in advanced maternal age and recurrent pregnancy loss. NICS-AI combines non-invasive chromosome screening (NICS) of cell-free DNA from spent blastocyst culture medium with AI integration of developmental day and morphology to improve embryo ranking. Methods: This multicenter, single-blind, parallel randomized controlled trial will include 520 participants. Participants undergoing conventional IVF will be eligible if they meet either (i) female age 35-43 years or (ii) recurrent miscarriage (≥2 losses \<28 gestational weeks, including biochemical pregnancy with serum hCG \>25 IU/L). They must consent to blastocyst culture/vitrification and frozen-thawed single blastocyst transfer (SBT), and have ≥2 Day-5/Day-6, 2PN-derived blastocysts with morphology grade ≥4BC/4CB at randomization. Key exclusions include any ICSI-based fertilization or PGT-related procedures, known genetic disease meeting PGT indications, donor oocytes, untreated uterine anomalies/hydrosalpinx, or contraindications to pregnancy/ART. Randomization/interventions: Participants will be randomized 1:1 to NICS-AI-guided selection or morphology-based selection. In the NICS-AI arm, culture-medium DNA is tested and an AI-derived composite implantation score ranks embryos; controls use morphology alone (tie-break by cryopreservation order). Outcomes/analysis: The primary endpoint is live birth after the first SBT (delivery with ≥1 live-born infant per transfer cycle, per randomized participant). Secondary endpoints include first clinical pregnancy, early miscarriage (\<12 weeks, excluding biochemical pregnancy), ongoing pregnancy to 12 weeks, and cumulative pregnancy/live birth outcomes within 1 year (≤3 SBTs from one retrieval). Safety includes fetal malformations and neonatal outcomes through 1 year postpartum.

Interventions

• Other NICS-AI
  1. Collection of spent blastocyst culture medium and embryo cryopreservation: after thorough removal of granulosa cells from the zona pellucida, Day-4 embryos are washed and the medium is refreshed. When the embryo reaches an expanded stage-4 blastocyst (about 180 um), pre-freeze collapse is performed and the culture medium is collected. Samples are stored at -20 ℃ pending testing; blastocysts are vitrified. 2. Testing and scoring: samples undergo whole-genome amplification, library preparation,
• Other Morphology group
  1. When the embryo reaches an expanded stage-4 blastocyst (about 180 um), pre-freeze collapse is performed and the culture medium is collected. Samples are stored at -20 C pending testing; blastocysts are vitrified. 2. Single-blastocyst transfer in frozen-thawed cycles, determined solely by the day of blastulation and morphological grading: i) Day 5 blastocysts are prioritized over Day 6 blastocysts (Day 5 \> Day 6); ii) For blastocysts formed on the same day, prioritization follows this ord

Primary outcome measures

• Live birth rate of the first frozen embryo transfer [Time frame: At delivery (following the first frozen embryo transfer)]

Secondary outcome measures (7)

• Clinical pregnancy rate of the first frozen embryo transfer [Time frame: 4 weeks after the first frozen embryo transfer]
• Early miscarriage rate of the first frozen embryo transfer [Time frame: From clinical pregnancy confirmation to 12 gestational weeks (following the first frozen embryo transfer)]
• Ongoing pregnancy rate of the first frozen embryo transfer [Time frame: At 12 gestational weeks (following the first frozen embryo transfer)]
• Cumulative clinical pregnancy rate [Time frame: From the first single-blastocyst transfer; clinical pregnancy assessed at 4 weeks after each transfer; up to three transfers within 12 months after randomization.]
• Cumulative early miscarriage rate [Time frame: From the first single-blastocyst transfer; follow-up through 12 gestational weeks for each pregnancy achieved (max 3 transfers within 12 months after randomization).]
• Cumulative ongoing pregnancy rate [Time frame: From the first single-blastocyst transfer; follow-up through 12 gestational weeks for each pregnancy achieved (max 3 transfers within 12 months after randomization).]
• Cumulative live birth rate [Time frame: From the first single-blastocyst transfer; assessed at delivery for pregnancies achieved within 12 months after randomization (max 3 transfers).]

Eligibility criteria

Inclusion criteria

• Conventional IVF insemination;
• Meeting either of the following:

• Advanced maternal age: female age 35-43 years;
• Recurrent miscarriage: ≥2 spontaneous pregnancy losses (<28 gestational weeks), including biochemical pregnancy (hCG >25 IU/L) ;
• Willingness to culture all Day 3 embryos to the blastocyst stage in the fresh cycle, or to culture ≥6 embryos (with at least one embryo ≥7 cells), and to cryopreserve all blastocysts as single-blastocyst vitrification;
• Willingness to undergo frozen-thawed single-blastocyst transfer;
• At least two blastocysts formed on Day 5/Day 6 from 2PN fertilization, with morphological grading ≥4BC/4CB;
• Provision of written informed consent.

Exclusion criteria

• Any use of intracytoplasmic sperm injection-based fertilization, including but not limited to ICSI, TESA, and PGT-related cycles;
• Known monogenic disorders or chromosomal abnormalities at enrollment;
• Patients who use donated eggs to achieve pregnancy;
• Definite conditions affecting uterine cavity anatomy or endometrial receptivity, such as untreated uterine malformations (e.g., septate uterus, unicornuate uterus, didelphys uterus) or untreated hydrosalpinx;
• Contraindications to pregnancy or to assisted reproductive technology;
• Any other condition deemed by the investigators to make the participant unsuitable for this study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University — Guangzhou

Identifiers

NCT: NCT07461077 · SYS-5010-202609

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗