Maternal and embryonic determinants of recurrent embryo implantation failure after assisted reproductive techniques.

Despite advances in IVF procedures and the transfer of embryos of high
morphological quality, pregnancy rates from IVF remain around 30% per embryo
transfer procedure. Failure of transferred embryos to implant remains the most
important limiting factor determining in vitro fertilization (IVF) or intra
cytoplasmic sperm injection (ICSI) success rates.

If progress is to be made in improving implantation rates, a greater
understanding of the factors which determine succesful implantation is
required. Recurrent implantation failure after IVF may be due to an
endometrial, and embryo problem or both. All women entering our IVF program
undergo pre-conceptional counselling and a pre-treatment blood withdrawal for
hormonal investigation and investigation of uterine cavity by ultrasound
examination, hysteroscopy and endometrial biopsy (Pre-treatment Evaluation of
Periconceptional determinants of Successful Implantation: PEPSI screening).

The data generated by this pre-treatment screening potentially enables factors
predictive of implantation failure to be identified. In cases of recurrent
implantation failure (RIF), study of the further IVF cycle will increase our
knowledge of the factors of endometrial and embryo factors involved in
implantation and aid in the characterisation of the different causes of this
distressing clinical problem. On the basis of these data, rational
interventions designed to improve outcome can be designed and tested.

Primary Objective:

To identify maternal and embryonic factors associated with recurrent
implantation failure, by prospectively
• comparing embryo and endometrium secretion cytokine profiles of women with
recurrent implantation failure versus women who have achieved a pregnancy in
study 05/225-K.
• comparing uNK-cell expression in luteal pase biopsies among women with
recurrent implantation failure versus *normal* implanters (a reference group of
women who have delivered after achieving a pregnancy with ICSI treatment for
male indication).


Secondary Objective:

• To identify maternal phenotypes associated with recurrent implantation
failure by retrospectively comparing pre-treatment screening parameters (PEPSI
screening): lifestyle, endometrial markers of receptivity, occurrence of
deviations in the blood examination, of women with recurrent implantation
failure versus women who have achieved a pregnancy in the first/ second
treatment cycle.
• To assess how the pulsatility index of the a. uterina correlates with the
cytokine expression profiles of the endometrium secretion.

Mono-centre study, which consists of a
• retrospective component (analysis of PEPSI screening data in women who
subsequently present with recurrent implantation failure vs controls) and a
• prospective cohort study component (comparison of endometrial receptivity
markers and embryo cytokine expression vs controls).

Much of the data to be analysed will be collected from routine clinical work up
(pre-conceptional counselling and PEPSI screening). Women with recurrent
implantation failure then embarking on a further IVF cycle will be invited to
participate in this study and will undergo additional investigation. This will
include an endometrial biopsy prior to the treatment cycle and endometrial
secretion aspiration prior to embryo transfer in the subsequent treatment
cycle.

No negative effect on pregnancy rates from these interventions have been
reported. The theoretical risk associated with the aspiration of endometrial
secretion before embryo transfer might be disruption of embryo implantation.
However, our group has developed a technique which, as we have previously
shown, does not disrupt the process of implantation (van der Gaast et al.,
2003).

Two studies have performed endometrial biopsies on the day of oocyte retrieval
within the actual embryo transfer cycle. No deleterious effect of the
endometrial biopsy on clinical pregnancy was recorded (Kolibianakis et al.,
2002b; Ubaldi et al., 1997b). As we will perform an endometrial biopsy during
the preceding cycle, we do not expect a negative effect on pregnancy rates.