Clinical trial NCT03964805: Oxygen Tension on Human Embryonic Development
Official title: Impact of Low Versus Atmospheric Oxygen Tension on Human Embryo Development : A Prospective Randomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Infertility
Embryo Culture
Hypoxia
Keywords: Embryo culture
oxygen tension,
embryo quality,
extended culture
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-05-28
Enrollment: 773
Sex: ALL
Minimum age (years): 18
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Embryo quality at Day 2 between groups A and B.
timeFrame: Day 2
measure: Embryo quality at Day 3 between groups A and B.
timeFrame: Day 3
measure: Embryo quality at blastocyst stage (Day 5) between groups A, B and C.
timeFrame: Day 5
measure: Embryo quality at blastocyst stage (Day 6) between groups A, B and C.
timeFrame: Day 6
Secondary outcomes:
measure: Fertilization rate
timeFrame: Days 1
measure: Early cleavage rate
timeFrame: 25 hours after insemination
measure: Useable embryo rate
timeFrame: Days 2/3; 5/6
measure: Implantation rate
timeFrame: 4-5 weeks after transfer
measure: Clinical pregnancy rate
timeFrame: 4-5 weeks after transfer
measure: Miscarriage rate
timeFrame: 4-5 weeks after transfer
Other outcomes:
Locations:
Study officials:
affiliation: AP-HP_Hôpital Jean Verdier
name: Christophe Sifer
role: PRINCIPAL_INVESTIGATOR
References:
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