Early Pregnancy Cohort and Preimplantation Factor (PEP-cohort)

Prospective Early Pregnancy Cohort and Preimplantation Factor: Factors Related to Successful Implantation, Risk of Miscarriage and Recurrent Pregnancy Loss in the First Trimester

Miscarriage is a common event associated with severe psychological and social morbidity, further tormenting in women suffering recurrent pregnancy loss (RPL) by at least three consecutive losses.

Ultrasonography and biomarkers have yet to precisely predict viability in pregnancies with symptoms of threatening miscarriage.

A novel biomarker Preimplantation Factor (PIF) derived by the developing embryo might be the key factor for this prediction ameliorating the implantation process by promoting a favorable local immune system in the uterus.

The investigators aim to establish a prospective early pregnancy cohort (PEP-cohort) that includes women throughout the first trimester by both assisted reproductive technology (ART) and spontaneous conceptions. By a combination of consecutive ultrasonographys and blood samples of known predictors of implantation PIF as a predictor of viability will be evaluated.

These data are finally compared to the same data in a retrospective cohort of RPL patients emphasizing the role of PIF.

All collected data will be stored in a Research Biobank for the current studies outlined as well as potential future studies of reproductive medicine in the first trimester.

Study Overview

• Status: Completed
• Conditions: Pregnancy; Biomarkers; Abortion, Habitual; Abortion, Spontaneous; Luteal Phase

Detailed Description

The investigators aim to evaluate Preimplantation Factor (PIF) throughout the first trimester we need to employ two settings of recruitment.

Early part:

The PEP in ART (PEP-A) will enroll participants referred for fertility treatment at Rigshospitalet and North Zealand Hospital. Participants all have cryopreserved embryos suitable for frozen embryo transfer in a natural menstrual cycle. No type of ovulation trigger will be employed, as the LH peak is monitored via home urine-LH test.

For a thorough examination of the luteal phase, participants are recalled for blood samples on day 7, 11, 14 and 16 after positive urine-LH test. Hereafter positive serum human chorionic gonadotropin (hCG) denotes a pregnancy and these participants are offered to continue in the later part of the PEP-cohort.

Late part:

PEP in Spontaneous conceptions (PEP-S) represents the sampling of expected normal pregnancies from the local community. Enrolled at the time of the first positive pregnancy test, participants are expected to be included from approximately 5 weeks of gestation. Hereafter participants are recalled every two weeks for blood sampling and transvaginal ultrasonographys of endometrial thickness until a gestational sac and yolk sac are visible for mean sac diameter measuring and eventually the crown-rump-length.

Research biobank All collected data: questionnaires of medical history before enrollment, ultrasonographys and blood samples of progesterone, 17-OH-progesterone, estradiol, alpha-feto-protein (AFP), pregnancy associated placental protein A (PAPP-A), hCG and PIF are stored in a research biobank.

• Study Type: Observational
• Enrollment (Actual): 210

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

PEP-A: Women in ART treatment by natural cycles of frozen embryo transfer at North Zealand Hospital and Rigshospitalet.

PEP-S: Women with a positive pregnancy test by spontaneous conception, prior to eight weeks of gestation.

Description

PEP-A

Inclusion Criteria:

1. Women in ART treatment by natural cycle frozen embryo transfer only monitored by urine LH.
2. Age above 18 years.
3. Ability to understand read and write Danish for the informed consent.
4. Planned delivery at the hospitals involved in the project.

Exclusion Criteria:

1. Abnormal uterine anatomy or function already known or estimated at first transvaginal ultrasonography.
2. History of recurrent pregnancy loss.
3. Ongoing or former (at least 12 months of no use) narcotics or alcohol abuse (above 14 units of alcohol per week).
4. Contraindication for pregnancy.

PEP-S

Inclusion Criteria:

1. Spontaneous pregnancy in women above 18 years of age.
2. Gestational age of singleton pregnancy below full eight weeks by first transvaginal ultrasound.
3. Ability to understand read and write Danish for the informed consent.
4. Planned delivery at the hospitals involved in the project.

Exclusion Criteria:

1. All types of ART treatment in the actual pregnancy.
2. Abnormal uterine anatomy or function already known or estimated at first transvaginal ultrasonography.
3. History of recurrent pregnancy loss.
4. Ongoing or former (at least 12 months of no use) narcotics or alcohol abuse (above 14 units of alcohol per week).
5. Contraindication for pregnancy.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
PEP-A; See detailed description
PEP-S; See detailed description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PIF in PEP-A	Serum PIF by gestational age in the luteal phase	During 2018
Prediction model for the risk of spontaneous abortion	The ability of serum PIF to predict viability of natural pregnancies with and without other biomarkers, ultrasonographys and medical history data.	During 2018
PIF and recurrent pregnancy loss (RPL)	Serum PIF levels in a unique retrospective cohort of RPL patients	Late 2018

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hormonal development in the luteal phase	Descriptive overview of natural hormones in the luteal phase and their ability to predict pregnancy and live birth rates	During 2018

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Research biobank for future use	Establishment of a robust research biobank for future studies in blood derived conditions in the first trimester of pregnancy	During 2017

Collaborators and Investigators

• Sponsor: Nordsjaellands Hospital
• Collaborators: Yale University; Rigshospitalet, Denmark; BioIncept LLC
• Investigators: Principal Investigator: Jesper F Petersen, M. D., Nordsjaellands Hospital

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): September 1, 2017
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: May 2, 2016
• First Submitted That Met QC Criteria: May 3, 2016
• First Posted (Estimate): May 4, 2016

Study Record Updates

• Last Update Posted (Actual): March 27, 2019
• Last Update Submitted That Met QC Criteria: March 25, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Preimplantation Factor
• Additional Relevant MeSH Terms: Pregnancy Complications; Abortion, Spontaneous; Abortion, Habitual
• Other Study ID Numbers: PEP-PIF-2016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Following collection, data are planned to be shared within a global archive.