Prospective Randomized Study to Evaluate the Effect of Embryonic Observation on the Gestation (PROdE)
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| No Intervention: No embryo observation (NEO) Study group. No embryonic observation from day one to day five of embryo development. |
|
| Experimental: Embryo observation (EO) Control group. Conventional embryonic observations performed in day two, three and five of embryo development. |
Other: Embryo observation
In EO group, conventional observations will be made.
|
Outcome Measures
Primary Outcome Measures
- Live Birth Rate [Nine months after treatment.]
The number of deliveries that resulted in a live born neonate, expressed per 100 embryos
Secondary Outcome Measures
- Positive hCG rate [14 days after oocyte retrieval.]
Number of treatments with a level of BhCG >5 mUI/mL, assessed in serum.
- Implantation rate [6-7 weeks after oocyte retrieval.]
Number of gestational sacs observed divided by the number of embryos transferred. expressed as a percentage, %.
- Ongoing pregnancy rate [12 weeks after B-hCG positive test]
Defined as a pregnancy with a detectable heart rate at 12 weeks of gestation or beyond.
- Miscarriage rate [From 12 weeks after gestation to delivery]
Loss of a pregnancy after 12 weeks of gestation.
- Fertilization rate [16-18 hours after microinjection or insemination]
Number of fertilized oocytes out of the total microinjected or inseminated.
- Blastocyst formation rate on day 5 [5 days after microinjection or insemination.]
Number of embryos that reach the blastocyst stage at day 5
- Blastocyst quality [5 days after microinjection or insemination.]
The assessment of blastocyst morphology in several grades
- Number of usable blastocysts [5 days after microinjection or insemination.]
Number of blastocysts transferred and frozen.
Eligibility Criteria
Criteria
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).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Instituto Bernabeu | Alicante | Spain | 03016 |
Sponsors and Collaborators
- Instituto Bernabeu
Investigators
- Principal Investigator: Jorge Ten Morro, Ph.D., Instituto Bernabeu
Study Documents (Full-Text)
None provided.More Information
Publications
- Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18.
- Armstrong S, Bhide P, Jordan V, Pacey A, Marjoribanks J, Farquhar C. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database Syst Rev. 2019 May 29;5:CD011320. doi: 10.1002/14651858.CD011320.pub4.
- Barberet J, Chammas J, Bruno C, Valot E, Vuillemin C, Jonval L, Choux C, Sagot P, Soudry A, Fauque P. Randomized controlled trial comparing embryo culture in two incubator systems: G185 K-System versus EmbryoScope. Fertil Steril. 2018 Feb;109(2):302-309.e1. doi: 10.1016/j.fertnstert.2017.10.008. Epub 2017 Nov 23.
- Bernabeu R, Roca M, Torres A, Ten J. Indomethacin effect on implantation rates in oocyte recipients. Hum Reprod. 2006 Feb;21(2):364-9. Epub 2005 Nov 10.
- Bognar Z, Csabai TJ, Pallinger E, Balassa T, Farkas N, Schmidt J, Görgey E, Berta G, Szekeres-Bartho J, Bodis J. The effect of light exposure on the cleavage rate and implantation capacity of preimplantation murine embryos. J Reprod Immunol. 2019 Apr;132:21-28. doi: 10.1016/j.jri.2019.02.003. Epub 2019 Mar 4.
- Fujiwara M, Takahashi K, Izuno M, Duan YR, Kazono M, Kimura F, Noda Y. Effect of micro-environment maintenance on embryo culture after in-vitro fertilization: comparison of top-load mini incubator and conventional front-load incubator. J Assist Reprod Genet. 2007 Jan;24(1):5-9. Epub 2006 Dec 13.
- Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril. 2000 Jun;73(6):1155-8.
- Herrero J, Tejera A, Albert C, Vidal C, de los Santos MJ, Meseguer M. A time to look back: analysis of morphokinetic characteristics of human embryo development. Fertil Steril. 2013 Dec;100(6):1602-9.e1-4. doi: 10.1016/j.fertnstert.2013.08.033. Epub 2013 Sep 29.
- Kalleas D, McEvoy K, Horne G, Roberts SA, Brison DR. Live birth rate following undisturbed embryo culture at low oxygen in a time-lapse incubator compared to a high-quality benchtop incubator. Hum Fertil (Camb). 2022 Feb;25(1):147-153. doi: 10.1080/14647273.2020.1729423. Epub 2020 Feb 26.
- Kirkegaard K, Kesmodel US, Hindkjær JJ, Ingerslev HJ. Time-lapse parameters as predictors of blastocyst development and pregnancy outcome in embryos from good prognosis patients: a prospective cohort study. Hum Reprod. 2013 Oct;28(10):2643-51. doi: 10.1093/humrep/det300. Epub 2013 Jul 30.
- Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978 Aug 12;2(8085):366.
- Zhang JQ, Li XL, Peng Y, Guo X, Heng BC, Tong GQ. Reduction in exposure of human embryos outside the incubator enhances embryo quality and blastulation rate. Reprod Biomed Online. 2010 Apr;20(4):510-5. doi: 10.1016/j.rbmo.2009.12.027. Epub 2009 Dec 28.
- InstitutoBernabeu