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.
Conventional IVF insemination;
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;
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;
Parallel
NICS-AI
Other intervention1. 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, and sequencing. An AI-assisted model integrates sequencing results (including CNV resolution, mosaicism, euploidy/sex chromosome status, number of abnormal chromosomes), morphology grade, and day of blastulation to generate a composite implantation potential score (reported as \<10 or 10-66). 3. Frozen-thawed single blastocyst transfer: embryos are prioritized for transfer from highest to lowest composite score. If scores are identical, embryos are prioritized by cryopreservation order.
Morphology group
Other intervention1. 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 order: 6AA \> 6BA \> 6AB \> 5AA \> 5BA \> 5AB \> 4AA \> 4BA \> 4AB \> 6BB \> 5BB \> 4BB \> 6CA \> 5CA \> 6CB \> 5CB \> 4CA \> 4CB \> 6AC \> 5AC \> 6BC \> 5BC \> 4AC \> 4BC; iii) If both the day of blastulation and the morphological grade are identical, embryos are transferred according to the order of cryopreservation (e.g., based on the cryo-straw identification number). 3. For all enrolled patients, the study-designated (enrolled) blastocysts are prioritized for transfer.
Live birth rate of the first frozen embryo transfer
live birth: number of deliveries resulting in at least one live-born infant per embryo transfer cycle Live birth rate of the first frozen embryo transfer = (No. of deliveries with live-born infant(s) after the last embryo transfer / No. of randomized patients) × 100%
Clinical pregnancy rate of the first frozen embryo transfer
clinical pregnancy: ultrasonographic detection of one or more gestational sacs, including intrauterine pregnancy, ectopic pregnancy, and heterotopic pregnancy。 Clinical pregnancy rate of the first frozen embryo transfer = (No. of patients achieving clinical pregnancy of the first frozen embryo transfer / No. of randomized patients) × 100%
Early miscarriage rate of the first frozen embryo transfer
early miscarriage: spontaneous pregnancy loss before 12 completed gestational weeks, excluding biochemical pregnancy) Early spontaneous miscarriage rate of the first frozen embryo transfer = (No. of patients with early spontaneous miscarriage \<12 weeks of the first frozen embryo transfer / No. of patients with clinical pregnancy) × 100%
Ongoing pregnancy rate of the first frozen embryo transfer
Ongoing pregnancy rate at 12 gestational weeks after the first frozen embryo transfer, Ongoing pregnancy rate of the first frozen embryo transfer = (No. of participants with an ongoing pregnancy at 12 gestational weeks following the first FET / No. of randomized participants) × 100%
Cumulative clinical pregnancy rate
Cumulative clinical pregnancy rate: within a single oocyte-retrieval cycle; up to three single-blastocyst transfers within 1 year after randomization; meeting the definition of clinical pregnancy Cumulative clinical pregnancy rate = (No. of patients achieving clinical pregnancy during the transfer period / No. of randomized patients) × 100%
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