Maternal Embryo Interaction in Recurrent Miscarriages (MEER)

The Maternal-embryo Interaction and Its Role in the Etiology of Recurrent Miscarriages

Background of the study:

The etiology of recurrent miscarriage (RM, defined as three or more consecutive miscarriages without any proven maternal or fetal cause), remains undiagnosed in more than 50% of cases. In these cases it is generally considered that a disturbance in the normal mother-embryo interactions is a causal factor. This disturbance may be based on a dysregulation of embryo invasiveness and/or decidual acceptance (e.g. altered decidualization; endometrial changes in preparation for the acceptance of a putative pregnancy). Moreover, dysfunctional maternal immune regulatory natural killer (NK) cells, implicated in tolerance induction and trophoblast invasion,may also underlie the occurrence of RM. The Selection Failure hypothesis for RM suggests that super-receptive endometrium (possibly due to increased embryo invasiveness and/or decidual acceptance and/or dysregulated immune cell function) may allow 'poor quality' embryos to implant and present as a clinical pregnancy before miscarrying. Fundamental knowledge on mechanisms of embryo implantation, decidual function and maternal immune reactivity in successful pregnancies has accumulated over the past 5 years. This study aims to investigate whether dysregulation of (one of) these mechanisms may underlie RM.

Objective of the study:

To test The Selection Failure hypothesis by assessing A) the degree of embryo invasiveness and decidual acceptance (the quality of decidualization, endometrium-embryo communication and endometrial stromal cell (ESC) migration) and B) the angiogenic capacity of decidual NK (dNK) cells, in order to elucidate the pattern of the mother-embryo equilibrium in women with RM.

Study Overview

• Status: Completed
• Conditions: Recurrent Miscarriages

• Study Type: Observational
• Enrollment (Actual): 58

Contacts and Locations

Study Locations

• Netherlands
  • Utrecht, Netherlands
    • University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Recurrent miscarriage group: primary care clinic Control group: primary care clinic/community sample

Description

Inclusion Criteria:

1. Women with unexplained recurrent miscarriages (three or more first trimester miscarriages).
2. Proven fertile women (at least 1 successful pregnancy and no more than 1 miscarriage).
3. Age 18 - 40 years.
4. Willing and able to give informed consent.

Exclusion Criteria:

1. Any identifiable causes of recurrent miscarriages; antiphospholipid syndrome (lupus anticoagulant and/or anticardiolipin antibodies [IgG or IgM]), other recognised thrombophilic conditions (testing according to usual clinic practice), intrauterine abnormalities (as assessed by ultrasound, hysterosonography, hysterosalpingogram or hysteroscopy), submucous fibroids and tests initiated only if clinically indicated such as tests for diabetes, thyroid disease and SLE
2. Undergoing treatment (hormonal)
3. Women using oral contraception or having an intra uterine device.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Recurrent miscarriage group; Women with unexplained recurrent miscarriages (three or more first trimester miscarriages).
Control group; Proven fertile women (at least 1 successful pregnancy and no more than 1 miscarriage).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Embryo survival on decidualized ESCs of RM patients or fertile controls (Embryo survival as an indirect measure of embryo invasiveness)	Embryo survival as an indirect measure of embryo invasiveness	2 years

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Investigators: Principal Investigator: Cobi J Heijnen, Prof. dr., UMC Utrecht

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: April 1, 2010
• First Submitted That Met QC Criteria: May 15, 2017
• First Posted (Actual): May 17, 2017

Study Record Updates

• Last Update Posted (Actual): May 17, 2017
• Last Update Submitted That Met QC Criteria: May 15, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: recurrent miscarriages (RM); recurrent pregnancy loss (RPL); fetal-maternal interface; decidualization; co-culture; implantation; immune regulation
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pregnancy Complications; Recurrence; Abortion, Spontaneous; Abortion, Habitual
• Other Study ID Numbers: MEER-study; METC (Registry Identifier: 09-408/C); CCMO (Registry Identifier: NL30143.000.09)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No