EARLY-PREG: A Preconception Cohort Study Based on Counterfactuals to Study Maternal-Embryonic Molecular Interactions (EARLY-PREG)

EARLY-PREG: A Preconception, Longitudinal, Bidirectional, and Counterfactual Cohort Study of Women Seeking Pregnancy, Designed to Investigate Maternal-Embryonic Molecular Interactions During the Peri-implantation Window

EARLY-PREG is an open-cohort clinical study with a preconception, longitudinal, bidirectional and counterfactual design. The aim of this cohort is to investigate the proteomic signatures of maternal-embryonic communication by interrogating a growing biorepository of maternal fluids and tissues collected during the first two weeks after fertilisation.

Participants in the EARLY-PREG cohort consist of healthy couples seeking pregnancy, as well as women who are not seeking to conceive. The three main outcomes in the cohort are defined according to menstrual cycles in which conception is achieved and those in which conception is not achieved. Their clinical definitions are as follows:

• Pregnancy with a full-term live birth refers to the cycle in which the ovum is fertilised, leading to pregnancy, with beta-hCG levels above the clinical threshold for a positive pregnancy test.
• Early pregnancy loss refers to a miscarriage up to 12 6/7 weeks.
• Non-pregnancy refers to a menstrual cycle in which conception does not occur, confirmed by a clinically negative beta-hCG test. When referring to the same individual, this is, by definition, considered the counterfactual to the corresponding conception cycle.

Study Overview

• Status: Recruiting
• Conditions: Healthy; Pregnancy; Early Pregnancy; Early Pregnancy Loss; Childbirth
• Intervention / Treatment: Other: EMBRYO EXPOSURE

Detailed Description

Successful pregnancy depends on a coordinated exchange of signals between the early embryo and the mother. This complex process begins immediately after fertilisation, during the pre-implantation period. Although it plays a critical role in preparing the maternal environment for pregnancy, the mechanisms behind this communication remain incompletely understood.

The unique 'dialogue' between the embryo and the mother is a bidirectional exchange known as embryo-maternal crosstalk. Evidence indicates that this interaction, mediated by molecular signals present in uterine fluid, supports appropriate embryo implantation and modulates the maternal immune system to facilitate tolerance of the developing embryo.

To date, the majority of knowledge in this field has been derived from animal models and in vitro studies, which may not fully represent the physiology of spontaneous human conception. The EARLY-PREG preconception open cohort has been established to address this gap by characterising embryo-maternal crosstalk in vivo. This study follows healthy women who are trying to become pregnant, following them from before conception through the first two weeks of a natural conception, with continued follow-up into pregnancy and childbirth.

Daily collection of a range of biological samples - including saliva, urine, blood, cervicovaginal fluid and cervicovaginal brushings - is undertaken during key phases of the menstrual cycle. These samples are processed, preserved and stored in a dedicated biorepository for subsequent analysis using omics-based approaches.

• Study Type: Observational
• Enrollment (Estimated): 223

Contacts and Locations

• Study Contact: Name: Elard S Koch; Phone Number: +56 41 246 7242; Email: ekoch@melisainstitute.org
• Study Contact Backup: Name: Patricio A Alcaino; Phone Number: +56 41 246 7242; Email: palcaino@melisainstitute.org

Study Locations

• Chile
  • Chiguayante, Chile
    • Recruiting
    • Clínica Sanatorio Alemán

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Women visiting gynaecologists, and midwives in private practices, public hospitals, and Family Health Centres (CESFAMs) in the Biobio region of Chile.

Description

Inclusion criteria:

• being between 18 and 40 years of age
• not being pregnant
• normal colposcopy
• body mass index (BMI) between 18 and 29
• regular menstrual cycles (21-35 days)
• absence of chronic diseases (hypertension, diabetes mellitus, cancer, depression, personality disorder, thyroid pathology, polycystic ovary syndrome, or hyperprolactinemia).
• If seeking pregnancy, they were included if their partners were males between 18 and 40 years old, without pathologies (diabetes mellitus, depression, personality disorder, or cancer), were not taking chronic medication, without erectile disorders, BMI between 18 and 29.9, moderate alcohol use, and with no recreational drug use.

Exclusion criteria:

• pregnant women
• history of alcoholism
• infertility treatment
• endometriosis
• pelvic inflammatory disease
• pelvic surgery
• allergy to latex or silicone
• If seeking pregnancy, they were excluded if their partners were working in contact with pesticides, or with history of erectile dysfunction, or history of mumps in adulthood, or with chronic diseases, or with psychological problems.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
CONCEPTION CYCLE; Conception cycle refers to the menstrual cycle in which the ovum is fertilised, leading to pregnancy. Confirmation of a conception cycle requires beta-hCG levels above the clinical threshold for a positive pregnancy test, which is determined in peripheral venous blood on the 14th day post-ovulation.	Other: EMBRYO EXPOSURE; The counterfactual design of EARLY-PREG enables the comparison of the systemic and localised physiological effects associated with embryo appearance and implantation in an individual (the factual) against the physiological state of the same individual without experiencing pregnancy (the counterfactual).
NON-CONCEPTION CYCLE; Non-conception cycle refers to a menstrual cycle in which pregnancy does not occur. When referring to the same individual, it is, by definition, considered the counterfactual to the conception cycle described above. Confirmation of a non-conception cycle requires a clinically negative beta-hCG test, determined in peripheral venous blood on the 14th day post-ovulation. This cycle is characterised by the absence of a clinical pregnancy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of menstrual cycles leading to full-term pregnancies	This outcome refers to the menstrual cycle in which the ovum is fertilised, leading to pregnancy with a full term live birth. The conception cycle requires beta-hCG levels above the clinical threshold for a positive pregnancy test, which is determined in peripheral venous blood on the 14th day post-ovulation.	From enrollment for up to six menstrual cycles (each cycle ranges from 21-35 days) or until pregnancy resulting in live birth, whichever occurs first.
Number of menstrual cycles not leading to pregnancy	This outcome refers to a menstrual cycle in which pregnancy does not occur. When referring to the same individual, it is, by definition, considered the counterfactual to the conception cycle described above. A non-conception cycle is confirmed by a clinically negative beta-hCG test, which is determined in peripheral venous blood on the 14th day post-ovulation. This cycle is characterised by the absence of a clinical pregnancy.	From enrollment for up to six menstrual cycles (each cycle ranges from 21-35 days) or until pregnancy occurs, whichever occurs first.
Number of menstrual cycles leading to early pregnancy loss	This outcome refers to the menstrual cycle in which the ovum is fertilised, leading to a miscarriage until 12 6/7 weeks. The conception cycle requires beta-hCG levels above the clinical threshold for a positive pregnancy test, which is determined in peripheral venous blood on the 14th day post-ovulation.	From the time beta-hCG levels rise above the clinical threshold for a positive pregnancy test until a miscarriage occurring up to 12 6/7 weeks.

Collaborators and Investigators

• Sponsor: MELISA Institute Genomics & Proteomics Research SpA
• Investigators: Study Director: Elard S Koch, MELISA Institute Genomics & Proteomics Research SpA

Publications and helpful links

Helpful Links

• MELISA Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2017
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: January 8, 2026
• First Submitted That Met QC Criteria: January 21, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: menstrual cycle; longitudinal study; biorepository; counterfactual design; embryo-mother crosstalk; maternal fluids; preconception open cohort
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pregnancy Complications; Abortion, Spontaneous
• Other Study ID Numbers: 17-03-06; MEL109112011, MEL109112011R4 (Other Grant/Funding Number: Fundacion de investigacion san Ramon (FISAR)); MEL109112011R5, MEL131032017R1 (Other Grant/Funding Number: Fundacion de investigacion san Ramon (FISAR)); MEL205062018, REH042024-01 (Other Grant/Funding Number: Fundacion de investigacion san Ramon (FISAR))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD information underlying the results of a publication will be shared with the sole exception of sensitive information that could reveal a person's identity.
• IPD Sharing Time Frame: January 2027 - December 2028
• IPD Sharing Access Criteria: The protocol data and results will be deposited in appropriate public repositories.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No