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د�ير5 ع�ل�يم5 ق�د�ق� الله� الع�ظ�يم ص�

القرآن الكريم - سورة الشورى

UNEXPLAINED ICSI FAILURE

By

Dr/ Ahmed Ali M. NasrAssistant professor of obstetrics and gynecology

Faculty of Medicine-Al-Azhar University- Assiut

2014

ICSI is the method of choice to achieve

pregnancy when other forms of assisted reproduction fail.

Fe r t i l i z a t i on r a te

70 - 80%.

Implanta t ion r a te

30 % and has not improved significantly over the past 5

years of reporting (Miller et al. 2012)

Despite the improvements

in ICSI technology many

couples experience

multiple failures. (Javed & Michael 2012)

Intended learning outcomes

Extracting the possible causes for unexplained ICSI failure and suggesting a systemic approach for diagnosis and treatment.

Highlighting the recent advances in ICSI technologies which may help to overcome unexplained failure in near future.

ICSI FAILURES

FERTILIZATION FAILURE

Explained

IMPLANTATION FAILURE

Explained

Explained ICSI failure

Fertilization

failure Oocyte related factorsPoor response to COH

Poor Morphology

Poor Maturity

Sperm related factorsMotility & viability

Origin

Maturity

Poor ICSI Technique

Implantation failure

Uterine anomalies

Thin endometr

ium

Pelvic pathology

Unexplained ICSI failure

Unexplained ICSI failure is a difficult unresolved

challenge in reproductive medicine and a source of

endless patient frustration and despair

(Machtinger et al. 2013)

According to the current review

several investigative measures and therapeutic interventions were found

to be useful in this complex condition

Possible causes for unexplained ICSI failures

Fertilization failure

Implantation failure

A). Unexplained fertilization failure

Some patients may face TFF in spite of

good ovarian response ,

normal sperm parameters and experienced practitioners

performing ICSI. (Machtinger et al. 2013)

Unexplained fertilization failure

Oocyte related factors

Activation

failure

Dysfunction

Sperm related factors

Structural defect

Chromosomal

condensatio

n

DNA dama

ge

Oocyte activation is a complex process starts with intracellular calcium oscillation and ends with the extrusion of the second polar body and formation of male and female pronuclei. For unexplained causes this process of oocyte activation fails

(Vanden Meerschaut et al. 2012)

1. Failure of oocyte activation

Management

Assisted oocyte activation through:

• Calcium ionophores

• Treatment with strontium chloride

• Piezoelectric stimulation of oocyte

(Nasr-Esfahani et al. 2010)

The cytoplasmic maturation of oocyte is difficult to be evaluated and may be a cause for RFF.

The mitochondrion plays a vital role in the oocyte cytoplasm and can be used as an indicator for cytoplasmic maturation as it can provide ATP and acts as a stores of intracellular calcium.

(Steffann & Fallet 2010)

2. Oocyte dysfunction

•Allomitochondrial transfer

•Self-mitochondrial transfer

•anti-oxidant drugs

(Steffann & Fallet 2010)

Management

Sperm related factors1. Sperm structural defects 2. Chromosomal condensation3. Sperm DNA damage

ManagementA. Selective isolation of relatively

undamaged spermatozoa.B. Antioxidant treatment.

(Aitken & De Iuliis 2010)

B). Unexplained Implantation Failure

Maternal FactorsDefective

Endometrial Receptivity

Hyper Coagulability

ImmunologicFactors

Embryonic FactorsGenetic

Abnormality

Suboptimal Embryo Growth

In Culture

Zone Hardening

Maternal Factors

1). Defective endometrial receptivity

It accounts for > 2/3 of causes of implantation failures .

The endometrium i s normally a non receptive environment for embryo except during the implantation window.

(Miller et al. 2012)

Implantation window

is a period

during which the endometrium is

optimally receptive

to implanting blastocyst

I m p l a n t a t i o n w i n d o w

(Miller et al. 2012)

A). Biochemical Markers:1. Endometrial adhesion molecules

2. Endometrial anti adhesion molecules

3. Endometrial cytokines

4. Endometrial growth factors

5. Endometrial immune markers

B). Histological Markers:6. Pinopodes

7. Epithelial tight junction changes

(Ganesh et al. 2014)

Markers of Endometrial Receptivity

Assessment of endometrial receptivity

Invasive assessment• Biochemical assessments of markers.• Histological study of Pinopodes.

DisadvantagesInvasive

Expensive

Sophisticated

Cannot Be Repeated Many Times

(Von Grothusen et al. 2014)

1. Transvaginal U/S:

•Endometrial thickness >8 mm

•Triple line endometrial

pattern

(Simon & Laufer 2012)

Non invasive assessment

2. Three Dimensional Volumetry Of The Endometrium: >2mL

3. Doppler U/S Studies Of Endometrial blood flow & Uterine Artery

4. Magnetic Resonance Imaging.

(Achache & Revel 2006)

Strategies to improve endometrial receptivity

1. Development of stimulation protocols with minimum effect on endometrium.

2. Improve uterine blood flow by aspirin, NO donors & Sildenafil

3. Avoidance of endometrium during stimulated cycles by cryopreservation of embryos to the next cycle

(Von Grothusen et al. 2014)

4. Treatment of pathological conditions as LPD (progesterone) and auto immune conditions (pridnisone)

5. Stimulation of endometrial proliferation by Endometrial samplings in the antecedent cycle for ET. (Granot et al. 2012)

Thrombophilia and APS may cause RIF.

Management: LMWH

(Polanski et al. 2014)

2) Hypercoagulability

3) Immunological Factors

Couples who share unusual number of HLA alleles may experience RIF.

Management paternal leukocytes immunization High dose IVIg administration Infusion of 20 % intralipid to

suppress NK cell activity

(Simon & Laufer 2012).

Embryonic Factors

1). Genetic AbnormalitiesManagement

Preimplantation genetic screening.

Determination of Parental karyotype.

(Hardarson et al. 2012)

2). Suboptimal embryo growth in Culture media

Even embryos that are described as good quality may cease to progress into a blastocyst stage due to either suboptimal local conditions or intrinsic factors within the embryos

(Simon & Laufer 2012)

Management1.Selection of a suitable Culture

media.2.Co-culture of embryos with

endometrial cells.3.Extended embryo culture to the

blastocyst stage before ET.4.ZIFT.5. Proper ET technique

(Simon & Laufer 2012).

3). Zona Hardening Increased ZP thickness and hardness

may be a cause for RIF.

Management

Assisted hatching through different mechanical, chemical and optical techniques to regionally weaken the ZP or even create an opening in it

(Cohen & Alikani 2013)

Recent advances

in manageme

nts of

unexplained

ICSI failure

A PICSI dish is a dish similar to ICSI dish, contains 3 microdots of hyaluronan hydrogel

Its idea depends on the fact that only mature, biochemically competent sperm will bind to the micro dots where they can be isolated by the embryologist and used for ICSI (Worrilow et al. 2013)

1). Use Of PICSI Dishes For Sperm Selection

It includes examination of unstained spermatozoa at 6000 or higher magnification to select sperm with best morphology.

It requires two embryologists working together (1-3 hrs.) on the same sample at the same time to minimize the subjective nature of sperm evaluation

(Kim et al. 2014)

2). Intra Cytoplasmic Morphologically Selected Sperm Injection (IMSI)

It is a digital polarized light microscope designed to image the oocyte spindle non invasively based on its optical property to protect it from damage during ICSI.

(Omidi et al. 2014)

3). Use of Polscope

POLSCOPE (LEFT) AND MEIOTIC SPINDLE (RIGHT) AS SEEN BY POLSCOPE

Computer assisted Time-lapse imaging

Imaging of the fertilized egg and the embryo at a predefined time points and neglecting the periods in between.

Computer processing of images on the day of ET help selection of embryos with the highest potentials for implantation (Hashimoto et al. 2014)

Clinical Approach to a

Case of Unexplained ICSI Failure

1. Repeated ICSI treatment because there is a high possibility of achieving normal fertilization.

2. Morphologic analysis of the sperm.

3. Use of PICSI dish for sperm selection

4. IMSI should be considered as a mean of improving fertilization.

(Javed & Michael 2012)33

IF FAILURE IS DUE TO FERTILIZATION FAILURE

If failure is due to implantation failure

1. Hysteroscopy , 3D U/S & HSG should be performed, Once an abnormality is recognized, treatment options should be considered

2. Stimulate endometrium growth by high dose estrogen, aspirin, and endometrial stimulation by biopsy sampling.

3. Screening for thrombophilia and APS. Once detected, LMWH is recommended.

4. Testing the couple similarity of HLA alleles. If positive, high dose IV immunoglobulin should be offered.

5. Using intralipid infusion at time of ET.

6. Using the computer assisted time-lapse imaging technology to select the embryo with the highest potential for implantation (Simon & Laufer 2012)

Options for patients after repeated unexplained ICSI failure

Couple may need to accept that they may not achieve a pregnancy and be infertile.

Adoption is encouraged in Islam provided that the child must be able to identify its biological father by keeping his name (Husain 2000)

53

Thank you