Prospective Randomized Study to Evaluate the Effect of Embryonic Observation on the Gestation (PROdE)

Study Overview
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Brief Summary
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In a conventional in vitro fertilization (IVF) cycle, daily microscopic observation of embryos outside the incubator to assess their morphology and establish a selection process is performed. In this way it is possible to know which embryo or embryos have greater implantantion capacity and will be transferred to the uterus to obtain a viable pregnancy. However, these observations can produce deleterious effects on embryo development due to changes in temperature, pH and osmolarity of the culture media, as well as a negative effect of direct light microscope for observation. This project aims to test the hypothesis that non-embryonic observation produces a beneficial effect on embryo quality until day 5 of development (blastocyst stage) and, therefore, on rates of implantation and ongoing gestation, compared with the conventional protocol of observations under the inverted microscope on days two, three and five of development.

Detailed Description
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The present study is a prospective double-blind randomised controlled trial (RCT) approved by a local Ethics Committe. Summarily, in the control group we did three embryo observations outside the incubator as we usually do in our conventional protocol: day 2, day 3 and day 5, just before ET; in the study group we performed a unique embryo observation on day 5 before ET. All the subjects that participated in the study were informed and gave us their consent to take part on it. The inclusion criteria of the study were: first cycle of ART treatment with conventional IVF or ICSI with donated eggs, normal uterine cavity and a single or double embryo transfer, always performed on day 5 at blastocyst stage. The exclusion criteria were the following: patients above 50 years old, patients that were diagnosed with recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL) or uterine pathologies, body mass index >30 kg/m2, the use of seminal samples coming from donors or testicular origin and cycles that included preimplantational genetic testing (PGT). LBR was the main outcome of our study, defined as the number of deliveries that resulted in a live born neonate, expressed per 100 embryo transfers (Zegers- Hochschild et al., 2009). Secondary efficacy endpoints were positive hCG rate (>5 mUI/mL, assessed in serum 14 days after oocyte retrieval), implantation rate (number of gestational sacs observed divided by the number of embryos transferred, expressed as a percentage, %), ongoing pregnancy rate, defined as a pregnancy with a detectable heart rate at 12 weeks of gestation or beyond and miscarriage (loss of a pregnancy after 12 weeks of gestation). In addition, we assessed the next IVF laboratory parameters: fertilization rate, blastocyst formation rate on day 5, blastocyst quality, number of transferred embryos and number of usable blastocysts (number of blastocysts transferred and frozen). The sample size calculation was based on the primary outcome. We assumed a live birth rate of 40% in the control group, compared to 50% in the non-observational group deduced from previous studies. By applicating the sample size calculation program, 776 patients (388 per group) were required in order to detect a risk difference (RD) of 10% between the two groups in the final analysis, with a power of 80% at a two-sided, adjusted alpha-level of 0.05. A follow-up loss rate of 10% was estimated.

Official Title
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Prospective Randomized Study to Evaluate the Effect of Embryonic Observation on the Live Birth Rate (LBR)

Conditions
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Placenta; Implantation

Intervention / Treatment
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* Other: Embryo observation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First cycle of ART treatment with conventional IVF or ICSI with donated eggs. Normal uterine cavity and a single or double embryo transfer, always performed on day 5 at blastocyst stage. Exclusion Criteria: Patients above 50 years old, patients that were diagnosed with recurrent implantation failure (RIF) and/or recurrent pregnancy loss (RPL) or uterine pathologies, Body mass index >30 kg/m2. The use of seminal samples coming from donors or testicular origin. Cycles that included preimplantational genetic testing (PGT).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: No embryo observation (NEO)<br>Study group. No embryonic observation from day one to day five of embryo development. | |
| Experimental: Embryo observation (EO)<br>Control group. Conventional embryonic observations performed in day two, three and five of embryo development. | Other: Embryo observation<br>* In EO group, conventional observations will be made.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Live Birth Rate | The number of deliveries that resulted in a live born neonate, expressed per 100 embryos | Nine months after treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive hCG rate | Number of treatments with a level of BhCG >5 mUI/mL, assessed in serum. | 14 days after oocyte retrieval. | 
| Implantation rate | Number of gestational sacs observed divided by the number of embryos transferred. expressed as a percentage, %. | 6-7 weeks after oocyte retrieval. | 
| Ongoing pregnancy rate | Defined as a pregnancy with a detectable heart rate at 12 weeks of gestation or beyond. | 12 weeks after B-hCG positive test | 
| Miscarriage rate | Loss of a pregnancy after 12 weeks of gestation. | From 12 weeks after gestation to delivery | 
| Fertilization rate | Number of fertilized oocytes out of the total microinjected or inseminated. | 16-18 hours after microinjection or insemination | 
| Blastocyst formation rate on day 5 | Number of embryos that reach the blastocyst stage at day 5 | 5 days after microinjection or insemination. | 
| Blastocyst quality | The assessment of blastocyst morphology in several grades | 5 days after microinjection or insemination. | 
| Number of usable blastocysts | Number of blastocysts transferred and frozen. | 5 days after microinjection or insemination. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Embryo development, Implantation, In vitro fertilization