Low vs. Air Oxygen Concentration CAPA-IVM Culture of Cumulus-oocyte Complexes

Effect of Low Versus Air Oxygen Concentration in In-vitro Maturation With Biphasic Capacitation-IVM (CAPA-IVM) Culture of Human Cumulus-oocyte Complexes in PCOS Patients: a Sibling Oocyte Pilot Study

IVM with a pre-maturation step, known as capacitation IVM (CAPA-IVM), has demonstrated enhanced maturation of human oocytes in vitro and successful live births. However, CAPA-IVM has shown lower rates of embryo formation when compared to conventional in vitro fertilization/ intra cytoplasmic sperm injection (IVF/ICSI) cycles. To optimize the CAPA-IVM culture system, this pilot study aims to evaluate the impact of low oxygen versus air oxygen concentrations on embryological outcomes in PCOS patients.

Study Overview

• Status: Recruiting
• Conditions: IVM; PCOS (Polycystic Ovary Syndrome)
• Intervention / Treatment: Other: The way of Cumulus-oocyte complexes (COC) CAPA-IVM culture condition

Detailed Description

Oocyte in vitro maturation (IVM) is an alternative approach to assisted reproductive technology (ART) that has the advantage of minimal stimulation, resulting in reduced hormone-related side effects and risks, especially in women with polycystic ovary syndrome (PCOS). Oocytes retrieved for IVM procedures are derived from a diverse pool of follicles with an average diameter of between 2 and 10mm and are characterized by variable cellular and molecular attributes that indicate their immature status. Therefore, the development of an IVM culture system that could enable and enhance the acquisition and synchronization of meiotic and developmental competence prior to the meiotic resumption is essential for optimizing human IVM protocols.

IVM with a pre-maturation step, known as capacitation IVM (CAPA-IVM), has been shown to improve the competence of human oocytes matured in vitro and result in live births. The pre-maturation culture of CAPA-IVM utilizes C-type natriuretic peptide (CNP), and maturation takes place in the presence of amphiregulin (AREG), both of which are physiological compounds that have been shown to prevent spontaneous meiotic resumption of oocytes (CNP) and enhance oocyte competence (AREG) during IVM.

To date, the results of pilot studies have shown that CAPA-IVM increases the rates of oocyte maturation, good-quality embryos on day 3 and good-quality blastocysts, resulting in a result, a higher embryo yield was obtained compared with standard IVM. Additionally, the reported cumulative live birth rate after use of CAPA-IVM, and its non-inferiority to the cumulative live birth rate with standard in vitro fertilization highlight the clinical utility and potential of this approach. Improvements in the culture system could make CAPA-IVM more effective, but these need to be investigated.

The oxygen concentration during the IVM process plays a crucial role in oocyte maturation. The use of oxygen concentrations higher than physiological levels can lead to cell damage and affect embryo development. Recent studies in mice have suggested using lower oxygen concentrations to improve IVM outcomes. However, the effectiveness of using lower oxygen concentrations in human IVM remains unproven. Therefore, this pilot study aims to compare the effectiveness of lower oxygen concentration conditions versus air oxygen in CAPA-IVM on embryology outcomes in PCOS women.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Huy H Pham; Phone Number: +84 966145510; Email: huy.ph@myduchospital.vn
• Study Contact Backup: Name: Anh TL Vu; Phone Number: +84 389565849; Email: anh.vtl@myduchospital.vn

Study Locations

• Vietnam
  • Ho Chi Minh City, Vietnam, 70000
    • Recruiting
    • My Duc Hospital
    • Contact: Tuong M Ho, MSc, MD; Phone Number: +84 90 3633377; Email: tuongho.ivfmd@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ≤38 years
• Having polycystic ovarian morphology: at least 25 follicles (2-9 mm) throughout the whole ovary and/or increased ovarian volume (>10ml)
• Having at least 20 follicles on the Oocyte Pick-up day
• Patients consent to culture embryos to the blastocyst

Exclusion Criteria:

• Cases with severe male factor (concentration <5 million/ml, cryptozoospermia, azoospermia)
• Oocyte donation
• Pre-implantation genetic testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Oxygen Concentration CAPA-IVM culture; Half of COCs were cultured in the CAPA step and IVM step in a low oxygen concentration (5%) and 6% carbon dioxide at 37 degree	Other: The way of Cumulus-oocyte complexes (COC) CAPA-IVM culture condition; Cumulus-oocyte complexes (COC) will be cultured in CAPA-IVM 24 hrs capacitation followed by 30h maturation. The first group will be cultured in low oxygen concentration (5%Oxygen), 6% carbon dioxide at 37 degree. The second group will be cultured in air oxygen concentration (20%Oxygen), 6% carbon dioxide at 37 degree.
Experimental: Air Oxygen Concentration CAPA-IVM culture; Half of COCs were cultured in the CAPA step and IVM step in a air oxygen concentration (20%) and 6% carbon dioxide at 37 degree	Other: The way of Cumulus-oocyte complexes (COC) CAPA-IVM culture condition; Cumulus-oocyte complexes (COC) will be cultured in CAPA-IVM 24 hrs capacitation followed by 30h maturation. The first group will be cultured in low oxygen concentration (5%Oxygen), 6% carbon dioxide at 37 degree. The second group will be cultured in air oxygen concentration (20%Oxygen), 6% carbon dioxide at 37 degree.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of blastocyst	Number of blastocyst obtained	At least 5 days after intra-cytoplasmic sperm injection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multiple pregnancy	Defined as presence of more than one sac at early pregnancy ultrasound (6-8 weeks gestation)	5 weeks after embryo placement after the completion of the first transfer
Number of matured oocytes	Number of oocytes which have a polar body after maturation	Two days after oocytes pick-up
Number of normal fertilized oocytes	Number of oocytes which have 2 pronuclear	16-18 hours after intra-cytoplasmic sperm injection
Number of day-3 embryos	Number of day-3 embryos obtained	At least 3 days after intra-cytoplasmic sperm injection
Number of good-quality day-3 embryos	Number of good quality Day 3 embryos obtained	At least 3 days after intra-cytoplasmic sperm injection
Number of good-quality blastocyst	Number of good quality blastocyst obtained	At least 5 days after intra-cytoplasmic sperm injection
Number of vitrified blastocyst	Number of vitrified blastocyst obtained	At least 5 days after intra-cytoplasmic sperm injection
Positive pregnancy test	Serum human chorionic gonadotropin level greater than 25 mIU/mL	At 2 weeks after the completion of the first frozen embryo transfer
Clinical pregnancy	At least one gestational sac on ultrasound at 7 weeks' gestation with the detection of heart beat activity	5 weeks after embryo placement after the completion of the first transfer
Ongoing pregnancy	Defined as pregnancy with detectable heart rate at 12 weeks' gestation or beyond, after the completion of the first transfer	At 12 weeks' gestation
Implantation rate	Defined as the number of gestational sacs per number of embryos transferred	3 weeks after embryo transferred after the completion of the first transfer
Miscarriage	pregnancy loss at <12 weeks	at 12 weeks of gestation after the completion of the first transfer

Collaborators and Investigators

• Sponsor: Mỹ Đức Hospital
• Investigators: Principal Investigator: Tuong M Ho, Mỹ Đức Hospital

Publications and helpful links

General Publications

• Sanchez F, Le AH, Ho VNA, Romero S, Van Ranst H, De Vos M, Gilchrist RB, Ho TM, Vuong LN, Smitz J. Biphasic in vitro maturation (CAPA-IVM) specifically improves the developmental capacity of oocytes from small antral follicles. J Assist Reprod Genet. 2019 Oct;36(10):2135-2144. doi: 10.1007/s10815-019-01551-5. Epub 2019 Aug 9.
• Vuong LN, Le AH, Ho VNA, Pham TD, Sanchez F, Romero S, De Vos M, Ho TM, Gilchrist RB, Smitz J. Live births after oocyte in vitro maturation with a prematuration step in women with polycystic ovary syndrome. J Assist Reprod Genet. 2020 Feb;37(2):347-357. doi: 10.1007/s10815-019-01677-6. Epub 2020 Jan 4.
• Vuong LN, Ho VNA, Ho TM, Dang VQ, Phung TH, Giang NH, Le AH, Pham TD, Wang R, Smitz J, Gilchrist RB, Norman RJ, Mol BW. In-vitro maturation of oocytes versus conventional IVF in women with infertility and a high antral follicle count: a randomized non-inferiority controlled trial. Hum Reprod. 2020 Nov 1;35(11):2537-2547. doi: 10.1093/humrep/deaa240.
• Preis KA, Seidel GE Jr, Gardner DK. Reduced oxygen concentration improves the developmental competence of mouse oocytes following in vitro maturation. Mol Reprod Dev. 2007 Jul;74(7):893-903. doi: 10.1002/mrd.20655.
• Akin N, Ates G, von Mengden L, Herta AC, Meriggioli C, Billooye K, Stocker WA, Ghesquiere B, Harrison CA, Cools W, Klamt F, Massie A, Smitz J, Anckaert E. Effects of lactate, super-GDF9, and low oxygen tension during bi-phasic in vitro maturation on the bioenergetic profiles of mouse cumulus-oocyte complexdagger. Biol Reprod. 2023 Oct 13;109(4):432-449. doi: 10.1093/biolre/ioad085.

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2023
• Primary Completion (Estimated): February 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: October 12, 2023
• First Submitted That Met QC Criteria: October 12, 2023
• First Posted (Actual): October 17, 2023

Study Record Updates

• Last Update Posted (Estimated): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: CAPA-IVM; Low oxygen; Cumulus-oocyte complexes
• Additional Relevant MeSH Terms: Neoplasms; Endocrine System Diseases; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome
• Other Study ID Numbers: 11/23/DD-BVMD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No