Placenta; ImplantationPROdENCT02372279
Prospective Randomized Study to Evaluate the Effect of Embryonic Observation on the Gestation (PROdE)
A study testing Embryo observation in people with Placenta; Implantation, run by Instituto Bernabeu at 1 site in Spain.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 years, women only
- Conditions the study is for
- Placenta; Implantation
- What is being tested?
- Embryo observation
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 193 participants
- Where
- 1 siteSpain
- Study dates
- Feb 2015to Mar 2021
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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).
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Prospective Randomized Study to Evaluate the Effect of Embryonic Observation on the Live Birth Rate (LBR)
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.
Read the 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.
- Conditions
- Placenta; Implantation
- Being tested
- Embryo observation
- Keywords
- Embryo development, Implantation, In vitro fertilization
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Embryo observationOther
In EO group, conventional observations will be made.
| Study group | Role | What they receive |
|---|---|---|
| No embryo observation (NEO) | No intervention | Study group. No embryonic observation from day one to day five of embryo development. |
| Embryo observation (EO) | Experimental | Control group. Conventional embryonic observations performed in day two, three and five of embryo development. Receives: Other: Embryo observation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Live Birth Rate
The number of deliveries that resulted in a live born neonate, expressed per 100 embryos
Measured: Nine months after treatment.
Secondary outcomes (8)
Positive hCG rate
Number of treatments with a level of BhCG >5 mUI/mL, assessed in serum.
Measured: 14 days after oocyte retrieval.
Implantation rate
Number of gestational sacs observed divided by the number of embryos transferred. expressed as a percentage, %.
Measured: 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.
Measured: 12 weeks after B-hCG positive test
Miscarriage rate
Loss of a pregnancy after 12 weeks of gestation.
Measured: From 12 weeks after gestation to delivery
Fertilization rate
Number of fertilized oocytes out of the total microinjected or inseminated.
Measured: 16-18 hours after microinjection or insemination
Blastocyst formation rate on day 5
Number of embryos that reach the blastocyst stage at day 5
Measured: 5 days after microinjection or insemination.
Blastocyst quality
The assessment of blastocyst morphology in several grades
Measured: 5 days after microinjection or insemination.
Number of usable blastocysts
Number of blastocysts transferred and frozen.
Measured: 5 days after microinjection or insemination.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Feb 2015 (estimated)
- Study startFeb 2015
- Primary completionMar 2021
- Study completionMar 2021
Why it stopped: The forecast regarding the number of patients that could enter the study were not met in the designated period
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Placenta; ImplantationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 193 participants (actual)
Sponsor and investigators
- Lead sponsor
- Instituto Bernabeu
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jorge Ten Morro, Instituto Bernabeu
- Investigators
- Jorge Ten Morro, Ph.D., Principal investigator, Instituto Bernabeu
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02372279
- Sponsor's protocol ID
- InstitutoBernabeu
- Acronym
- PROdE
- Status last verified
- Jun 2021
- First submitted
- 20 Feb 2015
- Last updated
- 23 Jun 2021
- Results posted
- No
- Data monitoring committee
- Yes
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.
PubMed 21502182Fujiwara 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. doi: 10.1007/s10815-006-9088-3. Epub 2006 Dec 13.
PubMed 17160731Gardner 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. doi: 10.1016/s0015-0282(00)00518-5.
PubMed 10856474Bernabeu R, Roca M, Torres A, Ten J. Indomethacin effect on implantation rates in oocyte recipients. Hum Reprod. 2006 Feb;21(2):364-9. doi: 10.1093/humrep/dei343. Epub 2005 Nov 10.
PubMed 16284067Herrero 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.
PubMed 24083877Zhang 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.
PubMed 20129824Kirkegaard K, Kesmodel US, Hindkjaer 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.
PubMed 23900207Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978 Aug 12;2(8085):366. doi: 10.1016/s0140-6736(78)92957-4. No abstract available.
PubMed 79723Bognar Z, Csabai TJ, Pallinger E, Balassa T, Farkas N, Schmidt J, Gorgey 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.
PubMed 30852462Barberet 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.
PubMed 29175066Armstrong 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(5):CD011320. doi: 10.1002/14651858.CD011320.pub4.
PubMed 31140578Kalleas 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.
PubMed 32098536
Study at a glance
From the registry record, last updated by the sponsor on 23 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Randomized Study to Evaluate the Effect of Embryonic Observation on the Live Birth Rate (LBR)
- ClinicalTrials.gov ID
- NCT02372279
- Acronym / sponsor ID
- PROdE / InstitutoBernabeu
- Conditions
- Placenta; Implantation
- Keywords
- Embryo development, Implantation, In vitro fertilization
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The forecast regarding the number of patients that could enter the study were not met in the designated period
- Enrolment
- 193 participants (actual)
- Lead sponsor
- Instituto BernabeuUniversity, hospital or other
- Study start
- Feb 2015 (actual)
- Primary completion
- Mar 2021 (actual)
- Study completion
- Mar 2021 (actual)
- First posted
- 26 Feb 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| No embryo observation (NEO) | No intervention | –Study group. No embryonic observation from day one to day five of embryo development. |
| Embryo observation (EO) | Experimental | Other: Embryo observationControl group. Conventional embryonic observations performed in day two, three and five of embryo development. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (4 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Embryo observationIn EO group, conventional observations will be made. | Other | Embryo observation (EO) |
Primary outcome
Live Birth Rate
Time frame: Nine months after treatment.
The number of deliveries that resulted in a live born neonate, expressed per 100 embryos
8 secondary outcomes
Positive hCG rate
Time frame: 14 days after oocyte retrieval.
Implantation rate
Time frame: 6-7 weeks after oocyte retrieval.
Ongoing pregnancy rate
Time frame: 12 weeks after B-hCG positive test
Miscarriage rate
Time frame: From 12 weeks after gestation to delivery
Fertilization rate
Time frame: 16-18 hours after microinjection or insemination
Blastocyst formation rate on day 5
Time frame: 5 days after microinjection or insemination.
Blastocyst quality
Time frame: 5 days after microinjection or insemination.
Number of usable blastocysts
Time frame: 5 days after microinjection or insemination.
Results and safety
The study was stopped early (reason given: The forecast regarding the number of patients that could enter the study were not met in the designated period). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jun 2021.
- Background: PubMed 21502182Alpha 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.
- Background: PubMed 17160731Fujiwara 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. doi: 10.1007/s10815-006-9088-3. Epub 2006 Dec 13.
- Background: PubMed 10856474Gardner 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. doi: 10.1016/s0015-0282(00)00518-5.
- Background: PubMed 16284067Bernabeu R, Roca M, Torres A, Ten J. Indomethacin effect on implantation rates in oocyte recipients. Hum Reprod. 2006 Feb;21(2):364-9. doi: 10.1093/humrep/dei343. Epub 2005 Nov 10.
- Background: PubMed 24083877Herrero 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.
- Background: PubMed 20129824Zhang 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.
- Background: PubMed 23900207Kirkegaard K, Kesmodel US, Hindkjaer 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.
- Background: PubMed 79723Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978 Aug 12;2(8085):366. doi: 10.1016/s0140-6736(78)92957-4. No abstract available.
- Background: PubMed 30852462Bognar Z, Csabai TJ, Pallinger E, Balassa T, Farkas N, Schmidt J, Gorgey 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.
- Background: PubMed 29175066Barberet 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.
- Background: PubMed 31140578Armstrong 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(5):CD011320. doi: 10.1002/14651858.CD011320.pub4.
- Background: PubMed 32098536Kalleas 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jorge Ten Morro, Ph.D. principal investigator
Instituto Bernabeu
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Embryo observation in people with Placenta; Implantation, run by Instituto Bernabeu at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 23 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: The forecast regarding the number of patients that could enter the study were not met in the designated period). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Live Birth Rate (time frame: Nine months after treatment.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02372279, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2021; AzTrials last refreshed its copy on 30 Oct 2026.