Recurrent Implantation Failure RIF

What is RIF?

RIF is only applicable to patients undergoing Assisted Reproductive Techniques. There is as yet no universally accepted definition for RIF and the most accepted definition is failure to achieve a clinical pregnancy after transfer of at least four good quality embryos in a minimum of 3 fresh or frozen cycles in a woman under 40 years of age.

What are the risk factors for RIF?

Increased Maternal age (more than 35 years ), BMI  (>25 kg/m2), and Smoking are the risk factors for Recurrent Implantation Failure. Whether stress causes IVF failure or IVF failure causes stress is yet not very clear.

What are the Causes and Mechanisms of  Recurrent Implantation Failure?

Based on the definition proposed above, RIF is primarily due to uterine factors. However, there will inevitably be a proportion of cases due to gamete or embryo factors.

• Oocyte Factor The oocyte quality may be poor as in advanced maternal age, low AMH and high FSH, and Inappropriate or aggressive stimulation protocol.
• Sperm Factor– RoutineSemen analysis doesn’t reflect sperm quality.  Sperm DNA damage ( caused by cigarette smoking, genital tract infection, and previous chemotherapy or radiotherapy )is associated with poor embryo development.
• Genetics/ Parental chromosomes anomaly–There might be Chromosomal abnormalities like translocations, mosaicism, inversions, and deletions(translocation being most common) in one or both the parent which may lead to RIF though the overall prevalence is only about 2%. Parental karyotyping is recommended in cases of women suffering from RIF and in men with severe oligospermia.
• Thrombophilia-Whether hypercoagulable state leads to  RIF is still debatable however prothrombotic disorders are more prevalent in RIF patients than in controls. While patients with RIF who have prothrombotic disorder might benefit from heparin treatment, for those without this abnormality empiric treatment with heparin is not justifiable. Altogether, it is recommended that patients diagnosed with RIF be investigated for acquired as well as hereditary thrombophilia disorders, and be treated accordingly.
• Immunological Causes -There is much conflicting evidence in the literature on the role of immunological factors like peripheral and uterine natural killer cells, Th1/Th2 ratio, and TNF-α levels in women with RIF. There is no consensus on whether or not immunological investigations are useful and whether immunological treatment is of benefit.
• Anatomical abnormalities and endometrial thickness-Uterine pathologies like Septate Uterus, Bicornuate Uterus, Polyps, Myomas, Adenomyosis, and Adhesions can impact implantation rates in patients undergoing IVF. The anomalies can be congenital or acquired.

• Thin endometrium-Thin endometrium(<7 mm)  may occur following damage to the endometrium following intrauterine surgery or infection and may lead to RIF.  Hysteroscopy adhesiolysis is recommended by an experienced reproductive surgeon.

What are the investigations for RIF?

The investigations for the RIF need to be individualized after taking a detailed history and checking the previous records.  A broad Outline of the investigations is mentioned in the table below.

Flow Chart for Investigations

A multidisciplinary approach should be adopted in the management of a couple with RIF. Appropriate counseling and individualized treatment of the couple with RIF is of the utmost importance prior to proceeding with further treatment. A summary of the management is highlighted in the below-mentioned table.

Summary

Successful Implantation involves a synchronized cross-talk between an embryo capable of implanting, and an endometrium enabling implantation. The etiology of RIF can be attributed to the embryo itself, the mother, or, in some cases, both. Women with RIF should be offered appropriate investigations to rule out an underlying cause for the repeated failure. The main treatment strategy in couples with RIF is to improve the quality of the embryos transferred and the receptivity of the endometrium.