Recurrent Implantation Failure
Repeated implantation failure (RIF) is a condition in which the woman is not able to get clinically pregnant after 2 or 3 attempts of embryo transfer. Multiple failed cycles can leave couples frustrated and desperate for answers.
What is Implantation?
What is successful implantation?
What is RIF ?
Where does the problem lie?
Successful implantation involves two main components, a healthy embryo that should have the potential to implant and a receptive endometrium that should enable implantation. The “cross-talk” between them is essential. These processes involve many mediators and the maternal immunologic system. Any abnormality attributed to the embryo, the endometrium or the immune system will result in implantation failure.
The cause can be with :
1) The seed (embryo)
2) The soil (uterine lining- endometrium)
3) The environment
The Embryo (seed): RIF is primarily due to uterine factors but embryonic causes are also responsible for 1/3rd of RIF cases. The current methods used to assess embryo quality are subjective and not always accurate. Morphologically normal looking embryos can be Genetically abnormal. Thick embryonic zona (covering) can be there which prevents the embryo from hatching. Abnormalities may be due to the egg or the sperm or may arise de novo during development of the embryo. GoodQuality gametes are essential to generate a healthy embryo.
The Egg Reduced quality or quantity of eggs can be due to Advanced maternal age, Genetic problems, Polycystic Ovarian Syndrome (PCOD), Low ovarian reserve, Endometriosis, ovarian surgery
The Sperm- Reduced quality and quantity of sperm are due to advanced age, Lifestyle (Alcoholism, smoking, obesity, certain drugs etc), Diabetes. These can lead to sperm DNA fragmentation and affect the fertilization potential of the sperm.
Both male and female partners may produce genetically aneuploid gametes if they are carriers of balanced translocation. Thus, two thirds of the generated embryos following fertilization will be genetically abnormal and either fail to implant or be aborted. Increased incidence of chromosomal translocations, mosaics, inversions and deletions of genetic material were reported in patients with RIF
Endometrial factors ( soil ) : Endometrial receptivity can be adversely affected due to the presence ofanatomic abnormalities of uterus (congenital or acquired ) like Uterine septae , Submucous or intramural fibroids ,Endometrial polyps ,Intrauterine adhesions. Function could be impaired due to thin endometrium, Adenomyosis , endometritis. There can be problems of maternal Immune system, PCOS, Thrombophilia (which disturbs the blood supply in the uterus).
Multifactorial: Environment which the gametes and embryo get in body of the woman and the lab may be affected due to Advanced age, Diabetes, Obesity, Hydrosalpinx, Endometriosis, Suboptimal ovarian stimulation, Suboptimal culture conditions in lab. The Technique of embryo transfer is also important.
The Management of RIF Embryonic / gamete factors:
Egg and sperm quality & quantity
For ovarian reserve, anti-Mullerian hormone (AMH) and antral follicle counts AFC, Basal FSH can be done. PCOD & endometriosis can be managed before starting the process A good controlled ovarian stimulation protocol helps. Karyotyping of the couple to identify any genetic abnormality. A healthy lifestyle and use of antioxidants to enhance quality of the gametes. If maternal age is above 40 years then donor egg could be a preferred option. DNA fragmentation index can be done to identify sperm damage. High magnification IMSI or surgical sperm retrieval (TESA) can be done to select the best quality sperm for ICSI. Donor sperm can be used in cases of azoospermia.
Embryo
Preimplantation genetic tests such as PGT/PGD can be done before implantation to select good quality normal embryos, This is the testing of the genetic composition of embryos. It helps to identify chromosomally normal embryos
Assisted hatching - which helps release the embryos from its thick covering –zona
Blastocyst culture and transfer to increase the chances of implantation
Better embryo selection with Time lapse imaging (embryoscope), metabolomics
Endometrial factors
Hysteroscopy:
This is a minimally invasive surgical technique used in viewing and assessing the inside of the uterus (uterine cavity) to diagnose or treat fertility. It allows for removal of polyps,submucousfibroid,adhsions and correct other uterine cavity abnormalities and has shown to increase the chances of women becoming pregnant.
Laparoscopy:
This is also a minimally invasive surgical procedure used to examine the organs inside the abdomen, such as ovaries, uterus and fallopian tubes. Laparoscopy may be needed to block the fallopian tubes or remove them (salpingectomy) in case of gross hydrosalpinges, and to also clear endometriosis and cysts if any.
Endometrial Receptivity Assay (ERA):
This is the most recent test of endometrial receptivity, whichanalyzes the expression levels of the 236 genes to assess the optimal time to place an embryo into the uterus to promote a successful implantation and pregnancy . It is reproducible and very accurate at determining when the window of implantation is open so it tells us if the endometrium is receptive or not. Some women might have a receptive uterus at an earlier time than expected and some might be receptive at a later time. Infertility specialists can then use this information to change the time that embryos are placed into the uterus so that it matches up better with the window of implantation.Medications and Therapies
have been tried for certain conditions. While some of these have proven therapeutic value, others still lack definite clinical evidence.Thrombophilia - Heparin, Aspirin, Steroids
Immunological causes - IVIG, Intralipid, Immunotherapy
Others - GCSF, PRP (Platelet rich plasma), PBMC (peripheral blood mononuclear cells-stem cells)
Donor eggs and Surrogacy:
A woman who is too old or has premature ageing of her ovaries might not have a successful in vitro fertilization (IVF) cycle. Such patients may opt to use donor eggs. If the uterine problem cannot be resolved then surrogacy is the option.The trauma of repeated failures , combined with the lack of a clear explanation about the cause of the failures leads to continued stress in patients. Please don’t lose hope as RIF can be diagnosed and can be managed increasing the chances of conceiving by IVF.