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Implantation failure

It is defined as the embryo’s failure to implant during the IVF cycle. Implantation failure is a part of the in vitro fertilization procedure that is not very well understood because patients succeed to produce healthy embryos but at the implantation phase things go wrong for inexplicable reasons.
Failure to achieve a pregnancy following 2-3 IVF cycles in which reasonably good [ high embryos] embryos were transferred is termed as implantation failure.
Embryonic loss which occurs repeatedly after Assisted Reproduction may be attributed to many factors.
There are three main causes of IVF implantation failure:

1. Decreased endometrial receptivity

   Studies show that the toxins coming into the uterus from infections (current or previous) have a high impact on embryo implantation. It is very difficult to determine the cause of the infection. Some doctors take a sample from the uterine cavity using a catheter inserted through the vagina and the cervix but this is not a very efficient way because the catheter could collect bacteria from the cervix and the vagina not only from the uterine cavity. Other specialists treat the uterine infection with antibiotics when the correct antibiotic can be precisely identified.

   Decreased endometrial receptivity

   • Uterine cavity abnormalities
   • Thin endometrium
   • Altered expression of adhesive molecules
   • Immunological factors
   • Thrombophilas

   Causes

   • 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
2. Embryonic defect

   For several years it was believed that the best time for embryo transfer was in the third day after the egg retrieval. There are embryos that look very good in the third day, but they might lead to implantation failure afterwards. On the other hand some embryos might look poorly in the third day but they can develop very well by the fifth day. That is the reason for which blastocyst transfer appeared.
   
   Another issue is the embryo’s hatching. Before the implantation can start the embryos has to get out of its shell and afterwards make contact with the uterus cells. It is believed that implantation failure can be caused by the fact that the embryo is not able to hatch from its shell. That’s why the concept of assisted hatching was introduced. The assisted hatching “helps” the embryo by creating a small opening in its shell. However the risk of identical twins appears along with this technique due to the fact that the embryo can divide easily when its shell is removed. So the assisted hatching remains at the stage of experiment in treating IVF implantation failure.

   Defective Embryonic development

   • Genetic abnormalities [Male / Female / gametes/ embryos]
   • Zona hardening
   • Suboptimal culture conditions

   Causes

   • Chromosomal abnormalities of the male or female partner, the gametes or the developing embryo may burden embryogenesis.
   • Increased frequency of female chromosomal abnormalities such as translocations, mosaics, inversion, deletion and chromosomal breakages, particularly at the centromere region in young women with implantation failure have been found.
   • Increased incidence of sperm chromosomal abnormalities in patients with normal karyotype & Recurrent implantation failure was also observed.
   • FISH for chromosomes 13,16,18,21,22, X & Y on blastomeres from biopsied embryos → showed % of embryonic aneuploidy higher in implantation failure group.
   • 60% of the blastomere biopsies showed abnormalities in implantation failure groups.
   • Disruption of chromosomal replication & segregation caused by maternal cytoplasmic factors or mutations in cell cycle control genes can be common causes for Recurrent implantation failure.
   • Despite good morphology and development rate, chromosomally abnormal embryos fail to implant.
   • Zona pellucia which surrounds the mammalian oocyte, hardens naturally after fertilization to prevent polyspermic fertilization and to protect the integrity of the pre-implantation embryo.
   • Increased zona thickness was associated with lower implantation rates.
   • Zona hardening induced by invitro culture or invivo aging affect hatching [failure of the zona to rupture] causing implantation failure.
3. Factors with combined effect

   Multifactorial effectors

   • Endometriosis
   • Hydrosalpinges
   • Suboptimal ovarian stimulation

   Multifactorial causes

   • Endoemtriosis leads to implantation failure
   • All markers of reproductive process, including ovarian response, embryo quality, implantation and Pregnancy rates are decreased in endometriosis and the decrease is directly proportional .

   Psychological assistance

   • Stress can interfere with infertility treatments
   • Psychotherapy [individual or group] reduces anxiety and depression and possibly enhances conception success.
   • We recommend psychological interventions and various relaxation techniques, but proof of their efficacy is lacking.

   Our experience

   There are many reasons for implantation failure.
   • We believe that we do not have the tools to diagnose in each and every case the exact cause for the repeated failure. After failure of three transfers of good quality embryos in a unit with a PR of atleast 30% one should take some special measures .
   • Each individual case should be analyzed specially to see the reason and the treatment tailored according to the needs to enhance the pregnancy outcome.
   • Everyone agrees that taking a different approach achieves a pregnancy in many cases that failed repeatedly.
   • After three failures repeated hysteroscopy and atry of blastocyst transfer are highly recommended
   • Change in the stimulaton protocol has a place.
   • AH, PGS and co-culture are probably beneficial in experienced hands.
   • Long –term use of danazol or GnRH agonists probably has a place in repeated failures with endometriosis
   • Frozen embryo transfer can also be considered.
   • Use of IVIG is controversial but may be justified after many failures in specific cases
   • Steroids might have place in patients with any sign of autoimmunity, and ZIFT has a place in cases of difficult embryo transfers.