EmbryOx: Oxygen Tension on Human Embryonic Development

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Completed

CT.gov ID

NCT03964805

Collaborator

(none)

773

Enrollment

Arms

Actual Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Infertility Embryo Culture Hypoxia	Other: 20% oxygen Other: 5% oxygen Other: 20 % and 5 % oxygen	N/A

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 Design

Study Type:

Interventional

Actual Enrollment :

773 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 1, 2016

Actual Primary Completion Date :

Sep 6, 2018

Actual Study Completion Date :

Dec 1, 2018

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Embryo quality at Day 2 between groups A and B. [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.
Embryo quality at Day 3 between groups A and B. [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.
Embryo quality at blastocyst stage (Day 5) between groups A, B and C. [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.
Embryo quality at blastocyst stage (Day 6) between groups A, B and C. [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.

Secondary Outcome Measures

Fertilization rate [Days 1]
Percentage of oocytes fertilized per oocyte inseminated, assessed at Day 1
Early cleavage rate [25 hours after insemination]
Percentage of embryos at the 2-cell stage per oocyte fertilized, assessed 25 hours after insemination
Useable embryo rate [Days 2/3; 5/6]
Percentage of embryos transferred and/or frozen per embryo
Implantation rate [4-5 weeks after transfer]
Number of gestational sacs with fetal heart beat detected per embryo transferred
Clinical pregnancy rate [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
Miscarriage rate [4-5 weeks after transfer]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 39 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

Principal Investigator: Christophe Sifer, AP-HP_Hôpital Jean Verdier

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

Assistance Publique - Hôpitaux de Paris

ClinicalTrials.gov Identifier:

NCT03964805

Other Study ID Numbers:

2015-A02019-40

First Posted:

May 28, 2019

Last Update Posted:

May 28, 2019

Last Verified:

Apr 1, 2019

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Assistance Publique - Hôpitaux de Paris

Additional relevant MeSH terms:

Infertility

Hypoxia

Study Results

No Results Posted as of May 28, 2019