Assumed etiologies for repeated implantation failure [RIF] :-
Decreased endometrial receptivity :
Uterine cavity abnormalities
Altered expression of adhesive molecules
18-27% women reveal uterine abnormalities, mainly hyperplasia polyps, endometritis, synechiae and leiomyomata
Effect of leiomyomata on implantation is uncertain
Impact of intramural lesions or myomas < 4 cm on implantation failure remain controversial
Presence of thin or hyperechogenic endometrium or persistent endometrial fluid impaired the outcome in tubal factor
Local dysregulation of the normal expression or action of various cytokines are related to implantation failure
Elevated endometrial NK cells
Dys regulation of interleukin [IL] 12,15 & 18
High IL –Iβ and low interferon –γ & IL-10 are associated with implantation failure
Failure of appearance of a specific integrin – α V β 3 in endometrium at the time of implantation can cause implantation failure.
High levels of aromatase p450 mRNA
Changes in pinopodes expression
High matrix metalloproteinases are associated with implantation failure
Role of immunological causes and thrombophilia in implantation failure
18 specific antiphospholipid antibodies
β 2- glycoprotein – I antibodies are related to IVF failure
Antibodies to annexin –V, which acts as an inhibitor of phospholipid –dependant coagulation and also necessary for trophoblast differentiation lead to implantation failure.
T-helper 1 & 2 [Th1,Th2] intracellular cytokine expression was increased in peripheral lymphocytes.
Presence of natural killer cells also leads to implantation failure.
Couples sharing HLA alleles are at high risk of recurrent implantation failure & biochemical pregnancies.
Prevalence of PAT-1 mutation & multiple thrombophilic gene mutations higher in implantation failure group.
Significantly decreased expression of specific endometrial molecules suggested that functional, not only morphological endometrial defects may be associated with unexplained infertility.
Suggested methods for investigation and treatment of Recurrent implantation failure
Improving endometrial receptivity
Hysteroscopic correction of cavity pathology
Treatment of intrauterine pathologies found by hysteroscopic evaluation improved the pregnancy outcome.
PR significantly higher in treatment group following
Normal hysteroscopy – 30.4%
Post hysteroscopic operation – 32.5%
Control – 21.6%
Hysteroscopic removal of submucous fibroids and myomas distorting the uterine cavity increases the pregnancy rate and live birth rates
Treatment of thin endometrium
Improving uterine blood flow boosts endometrial development Low-dose aspirin and vaginal sildenafil are effective.
Embryo freezing and transfer in next cycle
Vaginal administration of micronized estradiol and progesterone
Antifibrotic treatment with pentoxifylline and high dose vitamin E will increase pregnancy rates.
Endometrial stimulation [biopsy]
Endometrial injury or stimulation may cause pseudo-decidual reaction that enhances implantation
Combination of hysteroscopy, curettage, triple antibiotic and estrogen treatment enhances pregnancy rates to 43%
Pregnancy rates and live birth rates double following endometrial biopsy
Local injury to endometrium enhances implantation.
Immunotherapy [intravenous immunoglobulins steroids , aspirin and heparin]
Immunotherapy with intravenous immunoglobulin [IVIG] bas been introduced empirically in IVF programmes.
Out come is controversial
Combined treatment of glucocorticosteriods and aspirin improve PR in autoantibody seropositive patients
Aspirin and heparin treatment may improve PR and implantation rates
Immunotherapy using partners leukocytes remains controversial to improve implantation rate.
Heparin is involved in the adhesion of blastocyst to the endometrial epithelium and the subsequent invasion
Prolonged heparin treatment increases PR
Administration of leukocyte ultrafiltrate significantly improved treatment results.
Growth factors and cytokines secreted by leukocytes have an important influence on embryonic implantation and growth.