A Multicenter Prospective Randomized Controlled Clinical Trial Comparing Constant (5%) Versus Sequential (5%-2%) Oxygen Concentration Embryo Culture Protocols in Assisted Reproductive Technology

Official title

A Multicenter Prospective Randomized Controlled Clinical Trial Comparing Constant (5%) Versus Sequential (5%-2%) Oxygen Concentration Embryo Culture Protocols in Assisted Reproductive Technology: Evaluating Term Live Birth and Offspring Health Outcomes

Overview

To evaluate whether there were significant differences in the effects of constant (5%) versus sequential (5%-2%) oxygen concentration protocols in embryo culture on term live birth rates. This study will be conducted in five centers including the Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical Universit. 980 women who wish to undergo blastocyst transplantation will be included in the study. The study data will be analyzed statistically.

Detailed description

While blastocyst transfer has been shown to improve live birth rates, concerns exist regarding potential telomere shortening in offspring, which is associated with premature aging and various health issues. Our previous study further explores the role of oxygen tension in telomere length regulation, identifying hypoxia-inducible factor 1α (Hif1α) degradation as a key factor. Based on these findings, the study proposes a prospective, randomized controlled clinical trial comparing constant (5%) versus sequential (5%-2%) oxygen concentration protocols in embryo culture to assess their impact on term live birth rates and offspring telomere length.

This study will be conducted in five centers including the Clinical Center of Reproductive Medicine, First Affiliated Hospital of Nanjing Medical Universit. 980 women who wish to undergo blastocyst transplantation will be included in the study.

Female infertile patients who consent to blastocyst transfer will be considered for inclusion in the study. Patients will be randomly assigned to a constant (5%) or sequential (5%-2%) oxygen concentration protocols in embryo culture. This study will record live birth rates, perinatal and perinatal complications, and offspring health status of women in both groups of embryo culture regimens to assess the effects of different embryo culture regimens on term live birth rates and offspring health.

Interventions

• Procedure Constant oxygen concentration protocols in embryo culture
  Participants were randomly assigned to constant (5%) oxygen concentration group and received different blastocyst culture protocols.
• Procedure Sequential oxygen concentration protocols in embryo culture
  Participants were randomly assigned to sequential (5%-2%) oxygen concentration group and received different blastocyst culture protocols.

Primary outcome measures

• Term live births [Time frame: 3 years]

Secondary outcome measures (5)

• Offspring health (Peripheral blood telomere length) [Time frame: 3 years]
• Clinical pregnancy rate [Time frame: 3 years]
• Ectopic pregnancy rate [Time frame: 3 years]
• Implantation rate [Time frame: 3 years]
• Miscarriage rate [Time frame: 3 years]

Eligibility criteria

Inclusion criteria

• Female: age ≥20 and ≤40 years, male: age ≥20 and ≤50 years;
• Proposed 1st or 2nd cycle of IVF or ICSI fertilization;
• ≥ 4 transferable embryos at oocyte stage.

Exclusion criteria

• Diagnosis of abnormal uterine cavity morphology (confirmed by 3D ultrasound or hysteroscopy), including uterine malformations (mediastinal uterus, unicornuate uterus, bicornuate uterus), submucosal uterine fibroids, or uterine adhesions;
• Patients who are proposed to undergo IVM;
• Patients who are proposed to undergo PGD/ PGS;
• Patients with untreated severe hydrosalpinx (confirmed by ultrasound or HSG);
• Patients with a history of recurrent miscarriage (2 or more previous pregnancy losses, excluding biochemical pregnancies);
• Patients who plan to freeze whole embryos and are unable to complete a single embryo transfer within six months;
• Patients with contraindications to assisted reproductive technology and pregnancy, or suffering from diseases that have a definite effect on pregnancy: including uncontrolled hypertension, heart disease with definite symptoms, uncontrolled diabetes, undefined diagnosis of liver or kidney disease or liver or kidney insufficiency, severe anemia, history of previous venous thrombosis, pulmonary embolism or cerebrovascular events, history of malignant tumors, suspected malignant tumors, and undiagnosed abnormal uterine bleeding.

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 · 6 centers

• The Third Affiliated Hospital of Zhengzhou University — Zhengzhou
• Changzhou Maternal And Child Health Care Hospital — Changzhou
• Nanjing Women and Children's Healthcare Hospital — Nanjing
• Reproductive Medicine of First Affiliated Hospital with Nanjing Medical University — Nanjing
• Suzhou Municipal Hospital — Suzhou
• Northwest Women's and Children's Hospital — Xi’an

Publications

• De Munck N, Janssens R, Segers I, Tournaye H, Van de Velde H, Verheyen G. Influence of ultra-low oxygen (2%) tension on in-vitro human embryo development. Hum Reprod. 2019 Feb 1;34(2):228-234. doi: 10.1093/humrep/dey370. PMID 30576441
• Kaser DJ, Bogale B, Sarda V, Farland LV, Williams PL, Racowsky C. Randomized controlled trial of low (5%) versus ultralow (2%) oxygen for extended culture using bipronucleate and tripronucleate human preimplantation embryos. Fertil Steril. 2018 Jun;109(6):1030-1037.e2. doi: 10.1016/j.fertnstert.2018.02.119. PMID 29935641
• Brouillet S, Baron C, Barry F, Andreeva A, Haouzi D, Gala A, Ferrieres-Hoa A, Loup V, Anahory T, Ranisavljevic N, Gaspari L, Hamamah S. Biphasic (5-2%) oxygen concentration strategy significantly improves the usable blastocyst and cumulative live birth rates in in vitro fertilization. Sci Rep. 2021 Nov 17;11(1):22461. doi: 10.1038/s41598-021-01782-6. PMID 34789773
• Chakravarti D, LaBella KA, DePinho RA. Telomeres: history, health, and hallmarks of aging. Cell. 2021 Jan 21;184(2):306-322. doi: 10.1016/j.cell.2020.12.028. Epub 2021 Jan 14. PMID 33450206
• Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID 36599349
• Wang C, Gu Y, Zhou J, Zang J, Ling X, Li H, Hu L, Xu B, Zhang B, Qin N, Lv H, Duan W, Jiang Y, He Y, Jiang T, Chen C, Han X, Zhou K, Xu B, Liu X, Tao S, Jiang Y, Du J, Dai J, Diao F, Lu C, Guo X, Huo R, Liu J, Lin Y, Xia Y, Jin G, Ma H, Shen H, Hu Z. Leukocyte telomere length in children born following blastocyst-stage embryo transfer. Nat Med. 2022 Dec;28(12):2646-2653. doi: 10.1038/s41591-022-02 PMID 36522605

Identifiers

NCT: NCT07050537 · RCT-ECP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗