Recurrent implantation

failure Prof. Aboubakr Elnashar Benha University Hospital, Egypt

elnashar53@hotmail.com

Aboubakr Elnashar

Contents 1. Introduction Definition, Incidence, Impact

2. Etiology

3. Investigations

4. Treatment

Conclusion

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1. Introduction Definition No universally accepted definition

Failure of implantation

After 3 consecutive IVF attempts,

after transfer of at least 4 good-quality embryos

in a woman under the age of 40 ys (Simon and Laufer, 2012; Coughlan et al, 2013).

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Failure of implantation

after 2 consecutive cycles

after transfer of at least 4 good-quality embryos

or 2 blastocysts (Polanski et al, 2014)

Not the same as R IVF F.

subgroup of R IVF F

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Incidence

10% of the cycles

(Margalioth et al, 2006).

Impact

Distress to couples

Frustration to doctor

Increases the cost of the procedure

Management

Major challenge to clinicians and embryologists.

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2. Etiology I. Endometrial

II. Gamete/embryo

III. Multifactorial

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I. Endometrial factors

1. Anatomic causes: Polyp, fibroid, adhesion, septum

2. Impaired function

Thin endometrium

Altered expression of adhesive molecules

3. Thrombophilia

4. Immunological factors

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II. Gamete/embryo factors 1. Parental chromosomal anomalies

2. Poor-quality oocyte

3. Poor-quality spermatozoa

4. Zona hardening

5. Suboptimal culture conditions

6. Suboptimal embryo quality

7. Suboptimal ET

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III. Multifactorial

1. Endometriosis

2. Hydrosalpinges

3. Suboptimal ovarian stimulation

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3. Investigations

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Investigations for endometrial causes: (Simon and Laufer, 2012)

1. Hysteroscopy: intra-uterine pathology

2. TVS/ MRI: Structural uterine anomalies

3. HSG: hydrosalpinges

4. Hormone profile: Endometrial defects secondary to

endocrine aberrations

5. Endometrial Biopsy: uNK cells

6. Blood tests for thrombophilia and antiphospholipid antibodies.

7. All tests: normal: test for HLA similarity Aboubakr Elnashar

Investigation of embriologic factors (Simon and Laufer, 2012, Coughlan et al, 2013)

1. Ovarian reserve tests

basal FSH, AMH, AFC

to exclude any significant compromise of ovarian

function: help in the counseling.

2. Sperm DNA fragmentation:

Sperm Chromatin Structure Assay (SCSA):

Sperm chromatin dispersion test (SCD)

DNA fragmentation index

>27%: RIF (Larson et al.,2000; Larson-Cook et al., 2003)

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Damaged DNA : no halo.

Intact DNA: chromatin dispersion halo

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3. Karyotype

to rule out structural anomalies of chromosomes.

2.5% (Stern et al., 1999)

4. If a structural anomaly:

preimplantation genetic diagnosis

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4. Treatment Individualized Multidisciplinary

Experienced fertility specialist

Senior embryologist

±Reproductive surgeon

Local protocol

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I. Endometrial 1. Correction of anatomic factors

Hysteroscopic correction of uterine cavity

pathology (Demirol and Gurgan, 2004).

Removal of fibroids

Distorting the uterine cavity

Intramural ≥5cm (Donnez and Jadoul, 2002).

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2. Improvement of endometrial function

a. Treatment of thin endometrium

To improve uterine blood

low-dose aspirin (Weckstein et al., 1997)

vaginal sildenafil (Sher and Fisch, 2002)

Freeze all embryos (when the endometrium <7

mm) and transfer them after stimulation with high-

dose estrogens

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Vaginal micronized estradiol (Tourgeman et al., 2001)

Antifibrotic: pentoxifylline (Trental) and

high-dose vitamin E (Ledee-Bataille et al., 2002)

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b. Endometrial sctatching

When:

cycle preceding the actual treatment cycle. (Friedler et al., 1993; Barash et al., 2003; Raziel et al., 2007; Zhou et

al., 2008). 7 days prior to the onset of menstruation,

immediately before the start of ovarian stimulation

for IVF tt.

In the follicular phase of the index cycle : no

benefit (Karimzade et al., 2010; Zhou et al., 2008).

Not on the day of OR:

significantly reduce CPR (Nastri et al, 2012)

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How

biopsy/scratch or hysteroscopy: CPR doubled. (Raziel et al., 2007 ; Narvekar et al, 2010)

CPR: twice as high with biopsy/scratch as

opposed to hysteroscopy (Potdar et al, 2012) (2 syst reviews: Potdar et al, 2012; El-Toukhy et al, 2013)

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(A) First, the pipelle sample is inserted until it reaches the fundus.

(B) The inner plunger is withdrawn to apply a suction force to the endometrial cavity.

(C) Endometrial scratch of the superficial layer of the endometrium is performed with

the use of a ‘hoovering’ movement, combining a rotational and in-and-out movement

of the pipelle sampler several times. Aboubakr Elnashar

Mechanisms:

1. Induce decidualization of the endometrium

2. Provoke wound healing, involving secretion

cytokines and growth factors (Li and Hao, 2009).

3. Recruit stem cells to the endometrium, creating a

partially new endometrium free of epigenetic defects (Taylor, 2004; Du and Taylor, 2007).

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3. Thrombophilia Thrombophilia: LMWH

Thrombophilic trait: prophylactic dose of LMWH:

improve IVF outcome (Bohlmann et al, 2011; Qublan et al, 2008).

Antiphospholipid antibody syndrome:

Empirical treatment:

LMWH, aspirin, or corticosteroids:

Not effective

Not advocated (Seshadri et al, 2011; Berker et al, 2011).

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4. Immunotherapy

IVIG

Although data showing some benefit on ART

outcome.

SR does not support

{paucity, or poor quality of, the evidence}. (SR: Polanski et al, 2014)

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Intralipid

Controlled, large-scale, confirmatory studies

are necessary to prove efficacy before it can be

recommended for routine use. (Shreeve; Sadek, 2011)

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Intrauterine administration of autologous

peripheral blood mononuclear cells (PBMC)

Freshly isolated from patients: effectively

improves embryo implantation (Yoshioka et al, 2006; Okitsu et al, 2011 Chen et al, 2011)

{1. Evoke favourable inflammatory reactions : producing cytokines 2. secrete proteases: regulate endometrial function}

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II. Treatment of the embryos

1. Chromosomal abnormality Preimplantation genetic screening

can clarify the reason for RIF. (Caglar et al. ,2005)

significantly lowered live birth rates in RIF (Meta-analysis of RCT, Mastenbroek et al,2011)

does not improve the live birth rates RIF

(ASRM, ESHRE, 2010).

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2. Sperm DNA fragmentation a. Oral antioxidant

reduce the incidence of sperm DNA fragmentation (Greco et al., 2005 ; Isidori et al., 2006).

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b. Select spermatozoa with low levels of DNA

damage from the ejaculated semen samples (Sakkas and Alvarez, 2010).

i. Annexin-V columns:

reduce the percentage of spermatozoa with DNA fragmentation as measured by the TUNEL test

ii. Sperm hyaluronic acid binding: (Jakab et al., 2005; Said et al., 2005, 2006).

iii. Onfocal light absorption scattering

spectroscopy (CLASS) technology

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iv. Intracytoplasmic morphologically selected

sperm injection (IMSI)

high-magnification microscope (6000x), to identify spermatozoa devoid of surface vacuoles (Bartoov et al., 2003).

The only confirmed indication for IMSI is RIF. (MA: Boitrelle et al, 2014)

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c. Use of testicular spermatozoa

{sperm DNA damage is lower in the seminiferous tubules as compared with the cauda epididymis and ejaculated spermatozoa} (Greco et al., 2005; Steele et al., 1999; Suganuma et al., 2005)

Significant increase in PR (Greco et al., 2005b; Weissman et al., 2008)

reduction of miscarriage rate (Borini et al., 2006)

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3. Assisted hatching

Significant increases CPR in RIF (Three RCTs: Chao et al., 1997; Magli et al., 1998; Nakayama et al.,

1999; Metaanalysis, Martins et al, 2011)

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4. Suboptimal culture a. Co-culture

Homologous endometrial cells (Jayot et al., 1995; Eyheremendy et al, 2010)

49% PR in RIF. (Spandorfer et al. ,2004)

Most IVF units do not have facilities and experience

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b. Blastocyst transfer

Significantly higher CPR (Guerif et al., 2004; Levitas et al., 2004).

{Improved embryo selection and uterine receptivity}

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5. Improving ET

Essential in each cycle and must be reconsidered

in RIF.

Atraumatic, US guided

Embryos deposited in the mid uterine cavity (Sallam, 2005)

Avoidance of blood, mucus, bacterial

contamination, touching the fundus, and excessive

uterine contractions

Trial transfer, filled bladder, soft catheters (Schoolcraft et al, 2001)

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Fibrin glue

doubled CPR in RIF (Bar-Hava et al. ,1999).

Transfer large number of embryos

significant increase in CPR in RIF (Azem et al.1995)

No comparative study.

Sequential embryo transfer

Interval double ET (on days 2 and 4 or 5):

improves CPR in RIF (Loutradis et al, 2004; Almog et al., 2008)

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Personalized embryo transfer (pET)

ERA test to determine endometrium is receptive

or not)

pET performed on the day designated by the

ERA: 50.0% PR and 38.5% IR (Ruiz-Alonso et al, 2013).

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III. Multifactorial treatment options Lifestyle changes Smoking

Alcohol consumption

BMI

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1. Salpingectomy of hydrosalpinges

CPR and live birth rates: doubled (Strandell et al., 1999; Cochrane sys rev Johnson et al., 2004).

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2. Treating endometriosis

GnRHa for 3–6 months before ART: significantly

increases CPR (Surrey et al., 2002).

increased CPR by 4-fold (Sallam et al., 2006).

Endometrioma:

No benefit of removal before IVF (Garcia-Velasco et al., 2004; Wong et al., 2004),

Surgery ± deleterious for ov reserve.

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3. Danazol

significantly increased CPR (40 vs 19.5%) (Tei et al., 2003).

{Immunosuppressive effects

increase receptivity of the endometrium

upgrade the endometrial αVβ3 integrin.} (Hill et al., 1987).

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4. Tailoring the stimulation protocols GnRHan protocols:

improved blastocyst quality and pregnancy

outcome after RIF with GnRHa protocols (Takahashi et al. ;2004).

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Addition of LH

1. Poor responders to FSH stimulation in down-

regulated cycles (Phelps et al., 1999; Surrey and Schoolcraft, 2000).

2. Above 35 ys (Balasch et al., 2001; Marrs et al.,2004; Phelps et al., 1999).

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Natural cycle

particularly with high uNK cell count (Kadoch, 2003, Ledee-Bataille et al., 2004).

No RCT to prove that changing any stimulation

protocol can improve treatment outcome.

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Conclusions Many known and unknown reasons for RIF, and

we do not have the tools to diagnose in each case

the exact cause.

After failure of 2 or 3 transfers of good-quality

embryos in a unit with CPR of at least 30%, one

should take some special measures.

The management of RIF should be

individualized

multidisciplinary

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RCT: beneficial

Hysteroscopy procedures

Endometrial injury

IU administration of autologous PBMC

Blastocyst transfer

Assisted hatching

Salpingectomy for tubal disease

Aspirin, heparin, IVIG, intralipid does not have a

clear impact on tt outcome.

Co cultures, sildenafil, transfer of six embryos,

natural IVF, and PGS await further clinical

assessment.

Aboubakr Elnashar

Thank you Aboubakr Elnashar

Benha university Hospital, Egypt elnashar53@hotmail.com

Aboubakr Elnashar