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 angiogeneic…
ID
Source
Brief title
Condition
- Maternal complications of pregnancy
- Sexual function and fertility disorders
- Family issues
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
A) Embryo survival (indirect measure of embryo invasiveness) on decidualized
ESCs of RM patients or fertile controls, and B) the angiogeneic VEGF production
of dNK cells.
Secondary outcome
A) Embryo invasiveness and decidual acceptance
1. Embryo invasiveness:
- Three embryo invasion characteristics (time to start invasion, depth of
invasion, increase in embryo volume).
- The chromosomal composition of the embryo.
2. Decidual acceptance
- Decidualization (transcription factors, decidualization specific secretes and
their mRNA).
o Difference between cultures of dESCs of arrested vs. well
developing embryos
o Associated with invasiveness
- ESC migration towards the embryo.
B) Immune regulation
- NK cell phenotype (CD3, CD16, CD56, granzyme-B and perforin expresson) and
function (cytotoxicity, cytokines for angionenesis and
trophoblast invasion) into more detail.
- Immune regulatory capacity of ESCs.
Background summary
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.
Study objective
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 angiogeneic capacity of decidual NK (dNK) cells, in order to
elucidate the pattern of the mother-embryo equilibrium in women with RM.
Study design
This study is a prospective, observational study. We intend to employ an ex
vivo model of human implantation (i.e fresh surplus embryo in co-culture with a
monolayer of ESCs) to study embryo invasiveness, Matrigel invasion assays will
be employed to study decidual acceptance capacity and phenotyping and cytokine
profiling to study the angiogeneic NK cell function of RM patients and fertile
controls respectively.
Study burden and risks
Women with RM receive standard diagnostic care. The risks and burden of
participating in the trial are very limited. Endometrial tissue of RM patients
and controls will be obtained through an endometrial biopsy in the luteal phase
of the cycle. This is a minimally invasive procedure that is routinely
performed on an out-patient basis in the investigation of recurrent
miscarriage. Previous studies have demonstrated that this procedure can be
safely performed in the luteal phase of the previous cycle, without affecting
future pregnancy rates. Blood will be drawn by venapuncture, which is generally
accepted to be minimally invasive.
Lundlaan 6
3584 CX Utrecht
NL
Lundlaan 6
3584 CX Utrecht
NL
Listed location countries
Age
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.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL30143.000.09 |