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RECURRENT IMPLANTATION FAILURE

Now-a days, IVF and ICSI are successful treatment options available for infertile couples. However, in spite of a number of transfers with apparently good embryos some cycles don’t end in successful implantation. Successful embryo implantation requires both asynchronous development and interaction between the embryo and the endometrium.

Recurrent implantation failure refers to a failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years. RIF  imposes a significant physical, emotional and financial burden on the infertile couples and is a problem for every IVF clinic as the responsibility falls on the treating physician to explain the possible reasons.

RIF may be a consequence of embryonic or uterine factors or both.

Broadly it may be divided into

• Maternal anatomic factors, like congenital uterine abnormalities, endometrial polyps, uterine fibroids, adhesions, hydrosalpinges, endometriosis, etc.
• Malefactors---like severe Oligoasthenozoospermia -spermatia with increased sperm DNA fragmentation which has an impact on the grading of the embryo.
• Aneuploidy in embryos
• Metabolic disorders like uncontrolled diabetes, variations in the thyroid or prolactin level, etc. in the couple
• Thrombophilias or antiphospholipid syndrome
• Immunological factors
• Impaired endometrium:  Implantation dysfunction is a very common cause of recurrent  IVF failure.  Where morphologically good embryos are transferred, the question arises as to whether the problem is due to incompetent egg/embryo or whether it is due to a defective endometrium. If the patient is young and there are morphologically high-grade embryos then there is a greater likelihood that the problem lies with endometrial dysfunction either in terms of thickness, character,  vascularity or immunology.
• Idiopathic RIF (impaired cross-talk between endometrium and embryo) --refers to unexplained unsuccessful attempts after the transfer of good quality embryos in a healthy uterus without any endometrial factor or any medical problem in the couple.

Investigations

Maternal blood tests

• Thrombophilia screen – Small clots in the blood have been identified as a possible cause for pregnancies failing to progress. Most of these patients can be treated with aspirin or low dose heparin.
• Immune screen – High levels of uterine natural killer cells and autoantibodies is also thought to be the cause for RIF.

Endometrial tests

Hysteroscopy or endometrial scratch/ injury  ---There is enough evidence to support that these procedures if done in the cycle before ovarian stimulation and IVF/ET increase the pregnancy rate in RIF patients.

Endometrial Receptivity Array –  The newly acquired capacity of the endometrium to welcome the embryo is termed “endometrial receptivity” and the short period of time in the menstrual cycle, when the endometrial receptivity is optimal and embryo implantation is possible, is called “window of implantation” (WOI). The result is the development and growth of a viable conceptus. An ERA is a reliable and reproducible test for determination of the exact time of the WOI for an individual and can make it possible to apply for a personalized embryo transfer in patients with RIF thus improving the chances of successful implantation. 

Paternal factors

DNA Fragmentation Index  – Assessing the degree of damage to sperm DNA by these special tests would help identify those couples that would benefit from ICSI treatment.

Embryo factors

• Genetic screening – Preimplantation Genetic Screening (PGS)  assesses for the presence of all the chromosomes of the embryo  (complete chromosomal karyotyping) and can help us to select the most “competent” embryos for transfer.
• Time-lapse imaging – allows assessing subtle changes seen during embryo development and identify the best embryos for transfer.
• Laser-assisted hatching – is a physical or chemical treatment carried out immediately before embryo transfer. The idea is to weaken an area of the zona pellucida with the aim of improving the chances of implantation.

Therapeutic approaches

The treatment offered should be aimed to improve the embryo quality and the endometrial receptivity. Several treatment strategies have been described to improve the endometrium receptivity and these include immunomodulatory agents, local endometrial injury, autologous derived stem cells, etc. For immunological factors immunomodulation, IVIG (intravenous immunoglobulin IgG) are widely used. Immunotherapy with IVIG or intralipids, when applied in patients with abnormal immunological risk factors, might increase the live birth rates.

 The couple should be offered gamete donation or surrogacy if there is no realistic chance of success with further IVF attempts.