Prof Aboubakr Mohamed Elnashar

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MANAGEMENT OF
RECURRENT
IMPLANTATION
FAILURE
British Fertility Society
Guidelines, 2020
Prof. Aboubakr
Elnashar
Benha university , EgyptABOUBAKR ELNASHAR
8/19/2020
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IMPLANTATION
 The classical model of implantation where the embryo
undergoes rolling, apposition, adhesion& invasion
into the endometrium (Genbacev et al., 2003) is being
challenged by
 New evidence suggesting mutual attraction between
the embryo & decidualised endometrial stromal cells
(Teklenburg et al., 2010).
 An active interplay between the embryo& receptive
endometrium
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Apposition
Adhesion
InvasionEmbryo
Endometrial stroma
Invading trophoblast
Uterine
epithelium
 Starts 5 to 7 days after fertilization of the oocyte:
formation of a gestation sac (Hochschild et al., 2017).
 Continue up to 22 w gestation
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 Implantation rates/ET: 20-30%
(Voullaire et al., 2002).
 Cumulative LBR: after
 3 cycles of IVF: 42-57%
 6 cycles: 44-75%
(IVF cycles in UK between 1999 and 2017; McLernon et al., 2016).
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RIF
 Definition:
 Failure to conceive after repeated attempts of IVF
(Coughlan et al., 2014).
 The number of failed treatments has not been
universally agreed.
 Distinct from Recurrent failure of ART due to
 Patient characteristics or
 Treatment protocol failure
 ±include scenarios where no embryos are
transferred (Ferraretti et al., 2011).
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 After 3 consecutive ET of
 at least 4 good-quality embryos
 in a woman under the age of 40 ys
(Simon and Laufer, 2012; Coughlan et al, 2013).
 After 2 consecutive ET (fresh or frozen) of
 at least 4 good-quality clevage stage embryos or
 2 good quality blastocysts
(Polanski et al, 2014)
 Absence of a positive pregnancy test after 3
consecutive ET of good quality embryos
(BFS,2020)
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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 & embryologists.
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 Causes:
I. Endometrial factors
I. Gamete/Embryo: ± of male or female origin
II. Other= multifactorial
III. Combination of these.
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I. ENDOMETRIAL FACTORS
1. Anatomic causes:
 Polyp
 Fibroid
 Adhesion
 Septum
2. Infection
 Chronic endometritis
 Vag/ut. Microbiome
 Low abundance of endometrial Lactobacillus
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3. Impaired function
 Thin endometrium
 Altered expression of adhesive molecules
4. Thrombophilia
5. 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
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III. OTHER= MULTIFACTORIAL
1. Suboptimal ovarian stimulation
2. Suboptimal ET
3. Hydrosalpinges
4. Endocrine
5. Endometriosis
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INVESTIGATIONS
I. ENDOMETRIAL
 Anatomical
 Immunological Disorders & Thrombophilia
II. GAMETE/EMBRYO
 Sperm Quality Tests
 Oocyte Tests
 Parental Karyotype
III. OTHER
 Adnexal Factors
 Endocrine Investigations
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I. ENDOMETRIAL
1. Anatomical:
1. An evaluation of the pelvic anatomy for detection
of Mullerian abnormalities using 3D US. Good Practice
Point
2. No evidence to support the use of hysteroscopy
in the absence of suspected uterine pathology in
first cycle of IVF. Grade A evidence
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3. ERA test with individualised ET time is not
recommended. Grade B evidence
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2. Testing For infection Disorders:
 Insufficient evidence to recommend Microbiome
testing Grade D evidence
 If infection such as tuberculosis is diagnosed, a
course of antibiotics would be recommended as
per NICE guidelines. Good practice point
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3. Testing For Immunological Disorders:
 Insufficient evidence to recommend
 uNK or pNK cell testing Grade B, C evidence
 endometrial& peripheral blood cytokine testing
Grade C evidence
 HLA incompatibility testing. Grade C evidence
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4. Testing for thrombophylia
 Current evidence does not support testing for
congenital thrombophilia
 Further research is needed to establish whether
or not APLA testing is indicated. Grade C evidence
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II. GAMETE/EMBRYO
1 Sperm Quality Tests
 There is insufficient evidence to support
 Sperm aneuploidy testing
 Epigenetic testing or
 CASA for Sperm motility
characteristics. Grade C evidence
 Sperm DNA fragmentation testing.
Grade C evidence
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2. Oocyte Tests:
 AMH
 weak predictor for clinical pregnancy.
 Normal & good response to previous COS
 favourable prognostic indicators for women
with RIF planning on further IVF treatment.
Grade C evidence
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3. Parental Karyotype:
 No evidence to support parental karyotype testing.
 Some evidence that parental karyotype testing
±appropriate in the presence of additional risk
factors such as:
 Personal or family history of RM or
 Higher-order RIF(≥6 consecutive failed ET) with
no previous live-births Grade C evidence& Good practice
point
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III. OTHER
1. An evaluation of the pelvic anatomy for detection of
hydrosalpinges using TV US. Good Practice Point
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2. Endocrine Investigations:
 TSH testing can be offered. Grade B evidence
 Vit D should be assessed in high risk groups, with
treatment provided if deficiency is identified. Good
practice point.
 Insufficient evidence to recommend
 Thyroid autoimmunity testing. Grade C evidence
 Prolactin
 Free androgen index. Grade C evidence
 Diabetic screening for men or women Grade C
evidence
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TREATMENT
I. ENDOMETRIAL
1. Anatomical
2. Treatment for immunological dysfunction
II. GAMETE/EMBRYO
1. Sperm
2. Genetic Counselling
3. Embryo quality and selection
III. OTHERS
1. Lifestyle Changes
2. Ovarian stimulation strategies
3. Strategies to improve Embryo Transfer Technique
4. adnexal factors
5. endocrine conditions
6. Empirical treatment:
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I. EDOMETRIAL
1. Anatomical causes
 Endometrial polyps& submucosal fibroids
should be removed. Grade A evidence
 Insufficient evidence to support the removal of
fibroids not distorting uterine cavity. Grade B evidence
 An individualised approach to myomectomy after
careful counselling for large intramural fibroids not
distorting endometrial cavity. Good practice point
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 Insufficient evidence to recommend hysteroscopic
septal resection. Grade B evidence
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2. Improving endometrial function
 Insufficient evidence to recommend
 Endometrial scratch. Grade B evidence
 LMWH Grade B evidence
 G-CSF
 PRP
 Sildenafil Grade C evidence
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3. Treatment for immunological dysfunction
 IVIg is not recommended. Grade C evidence
 Insufficient evidence to support the use of Steroid
for women with a history of RIF, even in the
presence of high pNK or high uNK cell levels. Grade
C evidence
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II. GAMETE
1. Sperm
 No specific oral antioxidants recommended for the
male partner.
 Further study is required to identify individual
antioxidant supplements that could improve sperm
quality, implantation & LBR. Grade C evidence
 No evidence to support the hyaluronic acid binding
sperm selection technique for improving outcome
Grade D evidence
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 Insufficient data to support Intracytoplasmic
morphologically selected sperm injection (IMSI). Grade
B evidence
 Surgical sperm retrival (SSR) should not be
recommended unless indicated by azoospermia. Grade
D evidence
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2. Embryo quality& selection
 There is some evidence to support
blastocyst transfer. Grade B evidence
 Assisted hatching
 May improve CPR with RIF but in
the absence of data on LBR
 In combination with an association with
multiple pregnancies, assisted hatching
is not recommended. Grade B evidence
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 Insufficient evidence to support the use of
 TLI technology for embryo selection. Grade D evidence
 PGT-A . Grade C evidence
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3. Gamete Donation & Surrogacy
 Insufficient evidence to recommend the use of
donor gametes or surrogacy in unexplained RIF.
Grade B evidence
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4. Counselling including genetic counselling:
 {Failed IVF cycles can be associated with both
short-term& long-term adverse psychological
sequelae}. Grade B evidence
 Counselling should be made available to all
couples who have had a failed IVF cycle. Good
practice point
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III. OTHER
1. Lifestyle Changes
 Men& women undergoing IVF should be advised
 stop smoking
 optimise their weight. Good practice point.
 Women undergoing fertility treatment should be
advised to take 400 IU of supplemental vit D daily.
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2.Strategies to improve Embryo Transfer Technique
 Good quality evidence for all ET to be performed
under ultrasound guidance. Grade A evidence
 Insufficient evidence identifying the ideal
intrauterine location for transferring an embryo
 Most studies agree that catheter tip should be >15
mm from the fundus
 No data specific to women with RIF.
Grade C evidence
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 Good quality evidence for a full bladder at ET, in
order to achieve ‘passive’ straightening of the
uterocervical angle
 Insufficient evidence for or against
use of tenaculum. Grade C evidence
 Insufficient evidence to recommend cervical dilatation
in settings of previous ‘difficult’ ET.
 If performed, it should be in the cycle prior to ET&
not on the day of ET.
 There is no evidence that relates specifically to
management of RIF. Grade. C evidenceABOUBAKR ELNASHAR

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 Bed rest
 Good quality evidence that bed rest after ET does
not significantly affect LBR
 Some evidence that bed rest may be detrimental
to embryo implantation rates. Grade B evidence
 Insufficient evidence to recommend the use of
 Fibrin sealants or
 Antibiotics after ET.
 There is no evidence that relates specifically to
management of RIF. Grade C evidence
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 Evidence for the use of hyaluronan-enriched culture
media to improve LBR in unselected populations
 No clear evidence specifically for women with RIF.
Grade B evidence
 Insufficient evidence to recommend routine elective
FET for women with RIF. Grade D evidence
 Additional data on multiple pregnancy rates are
required to understand the role of sequential ET for
women with RIF. Grade B evidence
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3. Ovarian stimulation strategies
 No evidence to indicate recommendation of a
specific strategy for COS. Grade B evidence
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4. Laparoscopic salpingectomy
recommended for women undergoing IVF with a
history of RIF& ultrasound-visible hydrosalpinges.
Grade A evidence
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5.Optimise endocrine conditions
 Some evidence for women who are already
receiving thyroxine for subclinical hypothyroidism
 Dose should be titrated for a preconceptual TSH
level 0.4 - 2.5 mU/L Grade B evidence
 Euthyroid women with thyroid autoimmunity should
not be provided thyroxine. Grade C evidence
 Insufficient evidence to recommend treatment for
hyperprolactinemia for women with a history of RIF
solely to improve pregnancy outcome. Grade B
evidence
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CONCLUSIONS
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INVESTIGATIONS
I. ENDOMETRIAL
1. Anatomical:
1. 3 DUS: Green
2. Screening hysteroscopy: Red
3. ERA: Red
2. Immunological
1. uNK cells: Amber
2. pNK cells: Red
3. uCytokines: Red
4. pCytokines: Red
5. Genital micobiome: Red
6. HLA incompatability: Red
3. Thombophilia:
1. APA: Amber
2. Congenital thrombophilia: Red
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II. GAMETE/EMBRYO
1. Sperm:
1. Sperm aneuplody: Amber
2. DNF: Amber
3. Sperm epigenetis: Red
4. CASA: Red
2. Oocyte:
AMH: Amber
3. Genetic testing:
Karyotype: Red
Amber: High order RIF or additionalABOUBAKR ELNASHAR

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III. OTHER
1. Hydrosalpinx: US: Green
2. Endocrine:
1. TSH: Green
2. Tab: Amber
3. PRL: Red
4. FAI: Red
5. HbA1c: Red
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TREATMENT
I. Endometrial
1. Anatomical
1. Polymectomy: Green
2. Myomectomy of Submucous F: Green
3. Septoplasty: Amber
4. Improve endometrial function:
1.Heparin: Red
2.Sildenafil: Red
3.GCSF: Red
4.PRP: Red ABOUBAKR ELNASHAR

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3. Immunological:
1. Endometrial scratching: Amber
2. Corticosteroids: Amber
3. IVIg: Red
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II. GAMETE/ Embryo
1. Counseling including genetic counseling: Green
2. Sperm:
1. Antioxidants: Red
2. Hyaluronic ac binding for sperm selection: Red
3. IMSI: Red
4. Surgical sperm retrival in absence of
azospermia: Red
3. Embryo:
1. Blastocyst transfer: Amber
2. Assissted H: Red
3. TL imaging: Red
4. PGT-A: Red
4. Donor gametes/Surrogacy: Red
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III. OTHER
1. Life style:
1. Smoking cessation: Green
2. Optimizing wt: Green
3. Vit D supplementation: Green
2. Ovarian stimulation particular protocol: Amber
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3. Embryo transfer:
1. US guided: Green
2. Full bladder: Green
3. Catheter tip >15mm from fundus: Amber
4. Cervical dilatation: Amber
5. Hyaluronic ac ET medium: Amber
6. Cervical mucous removal: Red
7. Bed Rest: Red
8. Fibrin sealant: Red
9. Antibiotics: Red
10. FET: Red
11. Sequential ET: Red
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4. Endocrine:
1.Treatment of Subclinical hypothyroidism: Green
2.Treatment of hyperprolactinaemia when indicated:
Green
5. Hydrosaplinx: salpingectomy: Green
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