Oxygen Tension on Human Embryonic Development (EmbryOx)

May 24, 2019 updated by: Assistance Publique - Hôpitaux de Paris

Impact of Low Versus Atmospheric Oxygen Tension on Human Embryo Development : A Prospective Randomized Study

In mammals, uterine environment is at low oxygen concentration (2-8% O2). Thus, human embryo culture under low O2 tension (5%) is now recommended by European Society of Human Reproduction and Embryology (ESHRE) revised guidelines for good practices in in vitro fertilization (IVF) labs. Indeed, hypoxia seems to improve embryo quality at cleavage and blastocyst stages, presumably by reducing damages of oxidative stress (OS). Nevertheless, recent meta-analyses concluded only with a low evidence to a superiority of hypoxia on IVF/ICSI outcomes. Furthermore, a study on mouse embryos suggested a negative impact of OS only at cleavage stage. The aim of the present prospective randomized study was to investigate this hypothesis for the first time in human embryos.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In mammals, uterine environment is at low oxygen tension, between 2 and 8% O2 . However, most IVF labs perform embryo culture at atmospheric tension (around 20% O2). Several randomized studies in human embryos have reported the superiority of hypoxia (5%) in terms of embryo quality and blastulation rates. This fact might be explained by a more physiological environment, probably inducing a decrease in oxidative stress (OS), which has a harmful impact on embryo development. Other studies have also suggested that before compaction, OS damages might be irreversible.

Wale et Gardner have investigated this impact of oxygen tension on mouse embryo development, by comparing four culture conditions: (i) group 1: culture exclusively at 5% O2 ; (ii) group 2: culture at 5% from Day 0 to Day 2, then at 20% from Day 2 to Day 4; (iii) group 3: at 20% then at 5% from Day 2; (iv) and group 4: culture exclusively at 20% Interestingly, no difference in terms of blastulation had been reported between groups 1 and 2, suggesting the OS might impact only at cleavage stage, and that switching culture under atmospheric conditions from Day 2/3 might not influence embryo development thereafter.

Hence, all those investigations suggest that embryo culture using trigas incubators (5% O2, 6% CO2 and 89% N2) would be preferable. However, this system is very expensive, notably due to a high N2 consumption, and requires a more complicated logistics (e.g. N2 levels monitoring). Yet, Wale and Gardner's results imply that sequential culture conditions (trigas from Day 0 to Day 2/3, then conventional incubator at 20% O2 until blastocyst stage) could be an valuable option, reducing the costs and, essentially, without any detrimental impact on embryo development.

The present study has two main objectives: (i) to confirm the improvement in embryo quality under low oxygen tension and (ii) to demonstrate the negative impact of OS only at cleavage stage in human embryos, as assumed by Wale and Gardner. For that purpose, we designed an original prospective randomized study comparing three culture conditions: (i) culture excusively at 20% O2 (Day 0 to Day 6) (Group A); (ii) culture exclusively at 5% O2 (Day 0 to Day 6) (Group B); (iii) culture at 5% from Day 0 to Day 3, then at 20% from Day 3 to Day 6) (Group C). Inclusion criteria and outcome measures are detailed in the following sections.

Study Type

Interventional

Enrollment (Actual)

773

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 39 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age: 18 - 39 years
  • IVF / ICSI Attempt with Ejaculated Sperm Sperm (Fresh or Frozen)
  • At least 8 oocytes retrieved in total
  • Good understanding of the protocol by the patient
  • Informed and consentment signed of the couple

Exclusion Criteria:

  • - Hydrosalpinx

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: group A
Embryo culture at 20% O2
Other: 20% oxygen
culture excusively at 20% O2 (Day 0 to Day 6)
Other Names:
  • culture at 20% O2
Active Comparator: group B
Embryo culture at 5% O2
Other: 5% oxygen
culture excusively at 5% O2 (Day 0 to Day 6)
Other Names:
  • culture at 5% O2
Active Comparator: group C
Embryo culture at 5% O2 and at 20% O2
Other: 20 % and 5 % oxygen
culture at 5% from Day 0 to Day 3, then at 20% from Day 3 to Day 6)
Other Names:
  • culture at 20 % and at 5%O2

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Embryo quality at Day 2 between groups A and B.
Time Frame: Day 2
Embryo morphology is qualified as the number of blastomeres, degree of cytoplasmic fragmentation, regularity of the cells and presence/absence of multinucleated blastomeres. Day 2 top-quality embryos are defined as 4 regular blastomeres, <20% cytoplasmic fragmentation, no multinucleations.mbryos are defined as 4/8 regular blastomeres, <20% cytoplasmic fragmentation, no multinucleations.
Day 2
Embryo quality at Day 3 between groups A and B.
Time Frame: Day 3
Embryo morphology is qualified as the number of blastomeres, degree of cytoplasmic fragmentation, regularity of the cells and presence/absence of multinucleated blastomeres. Day 3 top-quality embryos are defined as 8 regular blastomeres, <20% cytoplasmic fragmentation, no multinucleations.
Day 3
Embryo quality at blastocyst stage (Day 5) between groups A, B and C.
Time Frame: Day 5
Blastocyst morphology is assessed according to Gardner and Schoolcraft's classification: degree of blastocele expansion (graded from B1 to B6), inner cell mass and trophectoderm morphology (both graded A, B or C). Day 5 top quality blastocyst are defined as ≥B4AA/AB/BA.
Day 5
Embryo quality at blastocyst stage (Day 6) between groups A, B and C.
Time Frame: Day 6
Blastocyst morphology is assessed according to Gardner and Schoolcraft's classification: degree of blastocele expansion (graded from B1 to B6), inner cell mass and trophectoderm morphology (both graded A, B or C). Day 5 top quality blastocyst are defined as ≥B4AA/AB/BA.
Day 6

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fertilization rate
Time Frame: Days 1
Percentage of oocytes fertilized per oocyte inseminated, assessed at Day 1
Days 1
Early cleavage rate
Time Frame: 25 hours after insemination
Percentage of embryos at the 2-cell stage per oocyte fertilized, assessed 25 hours after insemination
25 hours after insemination
Useable embryo rate
Time Frame: Days 2/3; 5/6
Percentage of embryos transferred and/or frozen per embryo
Days 2/3; 5/6
Implantation rate
Time Frame: 4-5 weeks after transfer
Number of gestational sacs with fetal heart beat detected per embryo transferred
4-5 weeks after transfer
Clinical pregnancy rate
Time Frame: 4-5 weeks after transfer
Percentage of pregnancies diagnosed by ultrasonographic visualization of at least one gestational sac with fetal heart beat per embryo transfer
4-5 weeks after transfer
Miscarriage rate
Time Frame: 4-5 weeks after transfer
4-5 weeks after transfer

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Assistance Publique - Hôpitaux de Paris

Investigators

  • Principal Investigator: Christophe Sifer, AP-HP_Hôpital Jean Verdier

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2016

Primary Completion (Actual)

September 6, 2018

Study Completion (Actual)

December 1, 2018

Study Registration Dates

First Submitted

May 14, 2019

First Submitted That Met QC Criteria

May 24, 2019

First Posted (Actual)

May 28, 2019

Study Record Updates

Last Update Posted (Actual)

May 28, 2019

Last Update Submitted That Met QC Criteria

May 24, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2015-A02019-40

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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