ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12619000824167

Ethics application status

Approved

Date submitted

30/05/2019

Date registered

7/06/2019

Date last updated

7/06/2019

Date data sharing statement initially provided

7/06/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Evaluation of progesterone levels at oocyte retrieval and impact on pregnancy outcomes: a retrospective cohort study.

Scientific title

Evaluation of progesterone levels at oocyte retrieval and impact on pregnancy outcomes in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI): a retrospective cohort study

Secondary ID [1]

Nil Known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Infertility

Condition category

Condition code

Reproductive Health and Childbirth

Fertility including in vitro fertilisation

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

Blood samples are routinely tested for hormonal changes during controlled ovarian stimulation for IVF/ICSI cycles. Progesterone levels at the time of oocyte retrieval, 36-38 hours after trigger, were assessed routinely. IVF/ICSI cycle outcomes were recorded and serum progesterone concentration used to determine the probability of ongoing pregnancy in women undergoing IVF/ICSI cycles. Observation duration is from oocyte retrieval to second trimester of pregnancy.

Intervention code [1]

Not applicable

Comparator / control treatment

No Control Group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Clinical Pregnancy, The ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy.

Timepoint [1]

Approximately 12 weeks during pregnancy cycle

Secondary outcome [1]

Biochemical pregnancy assessed using beta hCG in maternal serum.

Timepoint [1]

At time of the detection of beta hCG in maternal serum, 11-15 days after embryo transfer.

Eligibility

Key inclusion criteria

Females aged 18 years or older
Undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle using fresh or frozen ejaculated sperm from a male partner or sperm donor.
Have serum progesterone recorded at the time of oocyte retrieval from the Fertility SA pathology laboratory.

Minimum age

18 Years

Maximum age

53 Years

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

Oocyte Donors
Women undergoing ovarian preservation for fertility preservation.

Study design

Purpose

Screening

Duration

Longitudinal

Selection

Defined population

Timing

Retrospective

Statistical methods / analysis

Due to the exploratory retrospective nature of the study it has been determined that all eligible cycles within the last 2 years would be utilised. Uncertainty around the effect estimates produced by this study will be communicated using 95% confidence intervals.

All continuous variables will be expressed as mean (standard deviation-SD) or as median (interquartile range-IQR) depending on the normality of their distribution, which will be evaluated by inspection of distribution plots and the Kolmogorov-Smirnov test. Categorical variables will be expressed as proportions or percentages.
Regarding the research question of interest and in accordance with the exploratory nature of the study, the following approaches will be undertaken:
a) Firstly, the association will be explored by using the variable “Progesterone at the time of OPU” as a continuous one. For this purpose, fractional polynomial regression models will be constructed which can account for non-linear associations of the continuous predictors.
b) Subsequently, the variable “Progesterone at the time of OPU will also be divided and quartiles and their association with ongoing pregnancy rates will also be explored.
c) Receiver operating characteristics analyses will also be undertaken and the area under the curve will be estimated. Similarly, for any predictive regression model, the c-statistic will be calculated.
Due to the clustered nature of data (some patients contributed more than one cycles) the analysis of the data will be performed with the use of generalized estimating equations (GEE), which is an extension of the generalised linear model framework and accounts for any auto-correlation (cluster effect) between the data. Depending on the continuous or binary nature of the dependent variable, linear and logit regression models will be used to extract results regarding potential associations. Potential confounders will be identified through bivariate regression analyses. These confounders will subsequently be entered as covariates in the multivariable regression models which will be constructed aiming to evaluate the association of interest.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

30/06/2019

Actual

Date of last participant enrolment

Anticipated

31/07/2019

Actual

Date of last data collection

Anticipated

31/07/2019

Actual

Sample size

Target

800

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

St Andrew's Hospital Inc - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Ferring Pharmaceuticals Pty Ltd

Address [1]

Suite 2, Level 1, Building 1
Pymble Corporate Centre
20 Bridge Street
Pymble NSW 2073
Australia

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Fertility SA

Address

Fertility SA,
Level 9, 431 King William Street,
Adelaide SA 5000

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Andrews Human Research Ethics Committee

Ethics committee address [1]

St Andrews Hospital,
350 South Terrace,
Adelaide, SA, 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

17/08/2018

Ethics approval number [1]

Project Number #106

Summary

Brief summary

Elevated progesterone on the day of hCG administration has been associated with significantly lower pregnancy rates when a fresh embryo transfer occurs. Although evidence is available to support this notion, numerous contradictory studies also exist . Presently, many clinics practice minimal stimulation and/or “minimal intervention” cycles, where patients are managed externally, and therefore patient’s progesterone levels at the time of hCG are not monitored.
In 2014 Nayak et al demonstrated that elevated progesterone on the day of oocyte retrieval is associated with significantly lower implantaton and ongoing pregnancy rates. Implantation and pregnancy rates were significantly higher when the progesterone level was less than 12 ng/mL on the day of oocyte retrieval. Furthermore, miscarriage rates were higher when the P level was greater than or equal to 12 ng/mL, although this did not reach statistical significance. 
Premature progesterone elevation is believed to negatively impact endometrial receptivity however, premature progesterone rise has also been shown to have no effect on oocyte/embryo quality.  Peripheral progesterone in the late follicular phase is likely to influence endometrial maturation. Endometrial samples exposed to low and high concentrations progesterone on the day of HCG administration had significantly different gene expression. These observations could explain the impairment of endometrial receptivity in the presence of elevated progesterone.  Some reports discuss measures to prevent a premature progesterone rise, however once the progesterone rise has occurred then the optimal solution is to vitrify all embryos and transfer in a natural cycle. This method is supported by the fact that embryos obtained from cycles with an elevated progesterone and transferred into endometrium unaffected by elevated progesterone do not result in impaired pregnancy rates in either frozen-thawed or donor/recipients.
Therefore, by evaluating progesterone levels at a time more proximal to embryo transfer, when patients must be in attendance with fertility staff, premature progesterone elevation could be identified so patient treatment could be modified to improve the chances of a successful pregnancy.
Primary Objective: To determine the impact of serum progesterone concentration on the day of OPU on the probability of ongoing pregnancy in women undergoing IVF/ICSI. 
Secondary Objectives: To determine a progesterone cut-off value at oocyte retrieval that has the best capacity to discriminate between cycles that do and those that do not result in an ongoing pregnancy.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Ryan Rose

Address

Fertility SA,
St Andrews Hospital,
350 South Terrace,
Adelaide, SA, 5000

Country

Australia

Phone

+61 08 8100 2916

Fax

rrose@fertilitysa.com.au

Contact person for public queries

Name

Ryan Rose

Address

Fertility SA,
St Andrews Hospital,
350 South Terrace,
Adelaide, SA, 5000

Country

Australia

Phone

+61 08 8100 2916

Fax

rrose@fertilitysa.com.au

Contact person for scientific queries

Name

Ryan Rose

Address

Fertility SA,
St Andrews Hospital,
350 South Terrace,
Adelaide, SA, 5000

Country

Australia

Phone

+61 08 8100 2916

Fax

rrose@fertilitysa.com.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

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