RECURRENT IMPLANTATION FALIURE

INCIDENCE

Due to variation in definition of implantation failure there is no accurate data available for Incidence or prevalence of RIF. RIF is unidentified and its sensitivity is analysed between 5-25%.

RISK FACTORS

1) MATERNAL AGE

Maternal age plays a crucial role in quality of embryos that are used in IVF cycle. With Increase in Maternal age frequency of aneuploidy also increases. Pregnancy rate also decreases with increased age.

2) BMI

BMI also impacts implantation so in obese patient there is high chance of implantation failure as compared with patient of normal weight.

3) SMOKING

Cigarette toxins play role in disrupting corpus lute formation and also affect embryo implantation.

4) STRESS

Stress leads to release of cortisol production in body which is called stress hormone and leads to greater chance of miscarriage.

INTRODUCTION

RIF is determined when transferred embryos fail to implant following several IVF cycles. For successful implantation we need a receptive endometrium and a normal healthy embryo (blastocyst) and a synchronized dialogue between embryo and endometrium.

The cross talk between endometrium and embryo finally leads to apposition, attachment and invasion of embryo that is required for successful pregnancy.

This process involves many hormones or mediators originating from embryo , endometrium and also maternal immunological system.

Any abnormality in endometrium, Embryo or Immunological system will result in failure.

CAUSES

I)GAMETE AND EMBRYO FACTOR

Embryo quality is very important for successful implantation. Quality of embryo depends upon oocyte and sperm quality.

OOCYTE

Oocyte quality is very important as it forms majority of volume for Embryo. Compromised oocyte quality can be seen when yield is in two extreme I.e. too high or too low.

Advanced maternal age, high FSH ,low AFC and low AMH is associated with poor response. Maternal age is related with increased chromosome non disjunction, aneuploidy, increased mitochondrial damage and decreased in mitochondrial membrane potential is noted.

Sperm

Sperm quality is equally important  to achieve fertilisation , good embryo quality and implantation. Sperm DNA Damage should be evaluated by DFI.

II) FACTORS AFFECTING ENDOMETRIAL RECEPTIVITY

1) ANATOMICAL FACTOR

UTERINE FACTORS can lead to RIF

Myomas

It can lead to distortion of endometrial lining and distorted uterine contractility. It leads to altered uterine vascular perfusion and increased uterine natural killer cells.

Polyps

Leads to mechanical interference with embryo transfer and implantation.

Adenomyosis

It leads to disturbed Endo Myometrial junction which leads to altered uterine vascular perfusion, progesterone resistance and alteration in PR-A and PR-B ratio.

Synechiae

This prevents embryo from attaching to luminal surface of endometrium and so it impairs endometriums receptivity by reducing progesterone receptors and increase risk of miscarriage.

2) THIN ENDOMETRIUM

Thin endometrium can be associated with low pregnancy rate. Uterine linning has two layers , functional layer which is shed with menstruation and basal layer which persists. Functional layer has plenty of small blood vessels and basal layer has large spiral arteries. When ovulation occurs there is constriction of spiral arteries with reduced blood flow to functional layer. This results in reduced oxygen tension  which is good for implantation of embryo.

When the endometrium is thin or less than 7mm it is the functional layer which is thin or absent and embryo will be closer to basal layer and spiral arteries and higher vascularity and oxygen concentration of basal endometrium, which affects implantation.

3) ALTERED EXPRESSION OF ADHESIVE MOLECULE

Various cytokines are involved in implantation . Local dysregulatin  of normal expression or action of cytokines can cause implantation failure.

Elevated natural killer cells , dysregulation of interleukins (IL) 12,15,18 and high IL-1Beta and low interferon and IL-10 were found in RIF.

There is also increase level of aromatase p450 mRNA , changes in pinopode expression and high matrix metalloproteinases are associated with RIF.

4) Contribution of Immunology and Thrombophillia towards alteration in Endometrial Receptivity

Three main player of immune system for implantation are

TH1-TH2 imbalance

Natural Killer Cells

Autoantibodies

TH1-TH2 Imbalance

There are two broad classes of T Helper lymphocytes TH1 and TH2.

TH1 cytokines which include interferon , tumor necrosis factor, interleukins IL 1,2,12,15,18

TH1 cytokines are counteracted by TH2 cytokines which are IL4,5,6,10,13 and granulocyte macrophage stimulating hormone.

In pregnancy there is a shift towards TH2 dominance which is required for maintenance of pregnancy.

In early pregnancy following changes are seen ,there is rise in levels of progesterone, there is increased secretion of TH2  cytokines like IL4 and 6 and there is decreased secretion go TH1 cytokines like IL 2,12 and interferon.

Sometimes its said that embryonic gestation & RPL are related to loss of TH2 dominance.

Natural Killer Cells

There are two type of natural killer cells peripheral and uterine. There are no such reports of evidence of association between NK cells and pregnancy outcome.

Autoantibodies

Another aspect of immune system altering endometrial receptivity is related to autoimmunity. At present association between autoimmunity and ART remains in conclusive.

5)Endometrial Microbiota

Before puberty vaginal flora is a mixture of both aerobic and anaerobic bacteria while after puberty vagina is colonised predominantly by lactobacilli species which is due to acidic environment created by rising glycogen.

There are studies which suggest that non lactobacilli dominant microbiota correlated with adverse reproductive outcome like RIF Miscarriage.

III) MULTIFACTORIAL EFFECTS

Various pathologies can cause RIF

1) Endometriosis

It causes Impaired Fertilisation and causes altered folliculogenesis.

It can also result in poor oocyte quality.

2) PCOS

It can result in altered folliculogenesis and defective ovulation. It can also lead to inadequate progesterone action , excessive androgen insulin action and sometimes poor oocyte quality.

3) Hydrosalphinx

Because of hydrosalphinx there is intermittent bathing of endometrium lining with hydrosalphinx fluid can cause interference  to apposition. There is Embryotoxic effect of inflammatory hydrosalphinx fluid.

INVESTIGATION

I) EVALUATING OF GAMETES AND EMBRYO FACTOR

 1) EVALUATING  THE OOCYTE

Assessment of oocyte quality and quantity through ovarian function test Patients with RIF are offered basal FSH. AFC and AMH to diagnose extremities of ovarian reserve which is generally associated with poor oocyte quality.

2) ASSESSMENT OF SPERM DNA DAMAGE

Studies have shown that DFI more than 27% is associated with pregnancy failure in ART.

3) PARENTRAL KARYOTYPE

Incidence of chromosomal Abnormality in couple with RIF is approximately 2.5%, which higher compared to general population. So karyotype should be considered in RIF.

4)EVALUATING EMBRYO

Time lapse Imaging

Comprehensive chromosome screening

OMICS

II) FACTORS AFFECTING ENDOMETRIAL RECEPTIVITY 

1) UTERINE FACTOR

Women with RIF should be investigated for uterine pathology which can be a cause for RIF.  Hysteroscopy and laparoscopy, sonohysterography and 3D USG are the investigation that can be used as diagnostic tool.

2) Investigating immunological and Thrombophilic condition in implantation failure

Testing TH1 & TH2 balance and imbalance are pregnancy is associated with TH2 dominance.

It is not known whether the the transition of TH2 dominance in poor pregnancy outcome is effect or cause.

So no screening tests can be done in advance to predict TH1/TH2 imbalance.

Testing of NK Cells can kill some cells in vitro but not directly. Routine testing of NK cells in women with RIF is not advised as there is no clear evidence of use. Testig for autoantibodies should be done.

3) Testing for ER

Success of IVF cycles is the collaboration between the embryo and the endometrium which decides success or failure.

There are two causes for RIF one is displaced WOI or pathologically disrupted WOI.

It is clearly seen that in natural process the endometrium becomes receptive after 8-10 days of ovulation.

ERA is customised microarray performed by next generation sequencing coupled with computation predictor which enables to identify the receptivity of endometrial sample i.e. whether the endometrium is within the time frame of WOI or not, thus providing personalised WOI of a given patient facilitating personalised embryo transfer.

A biopsy of endometrium tissue is taken at day LH + 7 days in a natural cycle and progesterone +5 in HRT Cycle.

A state of non receptivity proves that WOI is displaced.

Thus ERA can identify the patient will need personalised WOI or not especially in case of RIF.

MANAGEMENT

Multidisciplinary team should be there which should compromise of reproductive medicine specialist, embryologist, geneticist, immunological and endocrinologist.Couple with RIF should be evaluated by team.

I) IMPROVING GAMETE AND EMBRYO QUALITY

1) TREATMENT OF POOR OOCYTE QUALITY

In few patients RIF might be because of compremised oocyte quality and this could be because  of inherent problems in oocyte quality or because of suboptimal ovarian stimulation which can be corrected.

2) TREATMENT OF HIGH DNA FRAGMENTATION

1) Oral antioxidant

It reduces oxidative stress on sperm

2) USE of hyaluronic acid

Reduces number of sperms with increased DFI

3)IMSI

Morphologically selected sperms may improve reproductive outcome

4)Testicular sperm retrieval

Sperm DNA damage is lower in seminiferous tubules as compared with caudal epididymis and ejaculated sperms

3)TREATMENT OF POOR EMBRYO QUALITY

-Blastocyst transfer

-laser assisted hatching

-preimplantation genetic testing for aneuploidy

-time lapse imaging &Metabolomics

4)IMPROVING EMBRYO TRANSFER

-Ultrasound guided transfer should be done

-use of embryo glue and adherent compound

-Freeze all strategy should be done

II) IMPROVING ENDOMETRIAL RECEPTIVITY

1) TREATMENT OF UTERINE ABNORMALITY

UTERINE SEPTUM

Operative Hysteroscopy and septal resection . It causes increased implantation rate and decreased miscarriage rate and increased term delivery rate.

POLYPS

Hysteroscopic polypectomy as it improves pregnancy rate

SUBMUCOSAL & IMTRAMURAL FIBROID PROTRUDING IN ENDOMETRIAL CAVITY

Myomectomy ca be done as it improves implantation rate and decreases miscarriage rate ,CPR,LBR.

ADENOMYOSIS

Depot Gnrha alone or in combination with cytoreduction surgery. Gnrha causes regression of Adenomyoma by hypogonadotropin status as it acts on type 1 and 2 receptors on endometrioum.

Cytoreduction surgery reduces hypertrophy and subsequently improves function by bringing uterine layer closer . It also enhances blood supply.

SYNECHIAE

Hysteroscopic Adhesiolysis

Repair the impaired linking ,restoring normal uterine cavity and fertility. Adhesiolysis permits endomterium to establish its anatomy and fuction.

2) TREATMENT OF THIN ENDOMETRIUM

A) ENDOCRINE STRATEGY

-High dose estradiol

-IM/Vaginal estradiol

-Gnrh antagonist

-G-CSF can be used

-Autologus PRP

B) VITAMIN &SUPPLEMENTS

-Asprin

-Vitamin E plus pentoxifyline

-sidenafil

-L-arginine

3) SURGICAL STRATEGY

-Hysteroscopy

-Endometrial scratching

-Stem cells

III)TREATMENT OF THROMBOPHILLIA AND IMMUNOLOGICAL FACTOR

1) GLUCOCORTICOIDS

It mends the intrauterine envoirnment by acting as immunomodulator and reduces uterine natural killer cells count and stabilises cytokine expression in endometrium and decreases Endometrium inflammation.

2) ASPIRIN

Reduction of inflammation in uterine cavity and improvement of uterine and ovarian perfusion which improves endometrial receptivity and and ovarian responsiveness.

3) HEPARIN

It enables invasive phenotype of thromboblast. It also increases insulin like growth factor which increases trophoblast invasion.

4) INTRAVENOUS IMMUNOGLOBULIN

It reduces cytotoxic natural killer cells and enhancement of regulatory T cells and downregulation of antibody producing cells.

5) INTRALIPID

It decreases peripheral natural killer cells actively and suppression of pro inflammatory cytokines.

IV) TREATMENT OF MULTIFACTORIAL EFFECTS

1) ENDOMETRIOSIS

Administration of Gnrh antagonist for 3-6 months before ART in women with endometriosis significantly improves pregnancy rate. Surgery can also be done but it does affect ovarian reserve upto some extent.

2) TREATMENT OF HYDROSALPHINX

-Salphingectomy

-Laproscopic proximal tubal occlusion

-USG guided drainage of hydrosalphinx fluid can be done(but there is risk re accumulation and also risk of introducing infections higher)

V) GAMETE DONATION AND SURROGACY

If implantation fails to occur in spite of repeated treatment attempts or prognosis is poor alternative treatment option should be given.

If problem lies with embryo gamete donation is recommended.

If problem lies in uterus surrogacy must be discussed.

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