Repeated implantation failure (RIF) is the repeated failure of the embryo to implant onto the side of the uterus wall following IVF treatment. Implantation happens at 6–7 days after conception and involves the embedding of the growing embryo into the mothers uterus and a connection being formed. A successful implantation can be determined by using an ultrasound to view the sac which the baby grows in, inside the uterus.
However, the exact definition of RIF is debated. Recently the most commonly accepted definition is when a woman under 40 has gone through three unsuccessful cycles of IVF, when in each cycle four good quality eggs have been transferred.
Repeated implantation failure should not be confused with recurrent IVF failure. Recurrent IVF failure is a much more broad term and includes all repeated failures to get pregnant from IVF. Repeated implantation failure specifically refers to those failures due to unsuccessful implanting to the uterus wall.
An unsuccessful implantation can result from problems with the mother or with the embryo. It is essential that the mother and embryo are able to communicate with each other during all stages of pregnancy, and an absence of this communication can lead to an unsuccessful implantation and a further unsuccessful pregnancy.
Contributing maternal factors
During implantation, the embryo must cross the epithelial layer of the maternal endometrium before invading and implanting in the stroma layer. Maternal factors, including congenital uterine abnormalities, fibroids, endometrial polyps, intrauterine adhesions, adenomyosis, thrombophilia and endometriosis, can reduce the chances of implantation and result in RIF.
Congenital uterine abnormalities
Congenital uterine abnormalities are irregularities in the uterus which occur during the mothers foetal development.
Hox genes
Two Hox genes have been identified to assist in the development and receptivity of the uterus and endometrium, Hoxa10 and Hoxa11. Hoxa10 has been shown to change the upper uterine segment into oviduct-like structures, creating a smaller uterus that appears normal. Embryo transfer into the lower uterine segment does not allow for implantation, so the Hoxa10 gene has multiple effects throughout the uterus. Hoxa11 mutations alter the endometrial gland development and reduce the secretion of Leukaemia-Inhibitory factor (LIF) which is required for implantation.
Fibroids
Fibroids are benign tumours found in the smooth muscle of the uterus, they are often asymptomatic but can cause pelvic pain. They effect implantation rates by altering the shape and cytokine composition of the uterus. Removal of submucosal fibroids has shown to increase implantation rates.
Endometrial polyps
Endometrial polyps are benign tumours found in the endometrium which factor into female infertility. There has been limited research into if their removal increases the chances of implantation and pregnancy.
Intrauterine adhesions
Intrauterine adhesions (Asherman's Syndrome) occur from scar tissue within the uterus which cause the closure of part or all of the uterus. The adhesions prevent embryos from implanting by reducing the surface area and decreasing the receptivity. Intrauterine adhesions normally occur after damage has been caused to the endometrium, either through removal of unwanted pregnancies, miscarriage, infection, and surgical damage.
Thrombophilia
Thrombophilia is a condition which makes the blood more likely to clot and this increases cardiovascular risk, meaning the individual is at higher risk of heart attacks, strokes or DVTs. In pregnancy it can lead to a disruption in the flow of blood to the placenta and the uterus wall. This can lead to a decreased receptivity of the uterus wall for a pregnancy and can lead to a miscarriage further on. However, how significantly this contributes to RIF is not fully known but each case should be assessed on a personal basis by a clinician
Embryonic factors
The successful implantation of an embryo not only relies on a receptive uterine environment in the mother but also on the quality of the embryo itself. Embryo quality and probability of implantation can be affected by maternal and paternal genetic abnormalities as well as zona pellucida dysfunction and poor embryo transfer technique.