1. CLINICAL ALGORITHM UPDATE ON THE MANAGEMENT OF RECURRENT IMPLANTATION FAILURE
PROF MICHAEL E AZIKEN
MBBS(Ibadan), fwacs,fmcog,d.mas,d.art,d.sonology.
University of Benin/University of Benin teaching Hospital,
Benin City

2. Outline Introduction- Implantation Definition of RIF Causes of RIF
Investigations
Management

3. Implantation process Implantation is the most crucial event in ART
Embryo gets attached to the endometruim, invades it and finally gets embedded in the deeper layer.
Complex interaction between
Embryo, Endometrium and cumulus cells
Elaboration of biochemical substances(cytokines growth factors etc)
Benkhalifa et al 2012
Successful when USS confirms intrauterine GS

4. Introduction contd Implantation rates in IVF-ET cycles: TGS/TET
Day 2/3 ET = 25%
Day 5/6 ET = 40%
Successful Implantation is a function of embryo quality and endometrial receptivity
Despite advances in ART (medication and processes) majority of treatment cycles still fail
35.4% life birth in USA in Sunderam S et al
2009

5. What is Recurrent Implantation failure(RIF)
Defn.
Failure to achieve a clinical pregnancy after transfer of at least 4 good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years. Coughlan et al 2014
Other definitions
Failure-after 2-6 cycles during which at least 10 high grade embryos were transferred into the uterus.
Tan et al 2005.
Impacts on patient and physician

6. Causes RIF
By definition of RIF, causes should be limited to Uterine factors
Embryo grading is subjective. So ??? Embryo factor
Embryo quality : fn of oocyte and sperm quality and Lab environ:
Oocyte :
Age effect (both chronological and biological age)
AMA is assoc with mitochondrial damage = non-dysjunction and aneuploidy
*suspect poor oocyte in poor responders and women with reduced ovarian reserve(FSH, AMH, AFC values)

7. Causes cont Sperm quality Poor quality sperm= poor quality embryo
Conventional SFA may not be helpful
Sperm DNA damage: Smoking,
Genital tract infection
Chemo or radiotherapy

8. Causes cont Parental chromosomal anomalies -Balanced Translocation:
Recurrent miscarriage
Repeated IVF failure (2.5% chance of carrying
balanced chromosomal
translocation)

9. Causes cont Uterine factors
Congenital anomaly: defective mullarian development is genetically linked with defective pre-implantation endometrial development ( Hoxa 10 and Hoxa 11 gene)
eg: Septate uterus
disturbance of uterine cavity and poor blood supply to the septum
Untreated septum has high miscarriage rate(80 vs 30%

10. Causes cont Acquired intra-cavity conditions fibroids; sub-mucous+
Endometrial polyps + (Treatment doubled
Preg rate; Bosteel 2010)
Ashermans Syndrome (8.5% of pts with RIF)
Adenomyosis
Hydrosalpinges : fluid is embryotoxic and
reflux effect
Salpingectomy significantly improved CPR in several reports. (36.6% vs 23.9%; Strandel et al 1999……

11. Intracavity uterine lesions

12. Ashermans synd

13. Uterine fibroids in diff locations

14. Other Causes ? Immunological
Decidualized stromal cells regulate trophoblast invasion and also dampens local maternal immune response
? Relevance of immunological investigation and Rx in women with RIF(conflicting literature)
Thrombophilic conditions
Link between APS and miscarriage is well documented but not with RIF

15. Investigations Gamete and embryo factors
Ovarian reserve/ function test – assist in counseling
Sperm DNA integrity testing: Several lab test for this
but not widely in use for
now
Karyotyping : 2.5% of couples with RIF have abn Karyotype ( Stern et al 1999)

16. Investigations cont Uterine factors: -Ultra-sonography : fibroid
Hydrosalpinges
Uterine anomaly
Ashermans syndrome
-MRI
-HSG
- Sono-HSG
-Hysteroscopy
-Laparoscopy
- Combine Hysteroscopy and Laparoscopy- congenital
uterine anomaly

17. MANAGEMENT Multidisciplinary- experienced fertility specialist
- Snr Embryologist
-Reproductive surgeon and
-Counselor
Agreed local protocol on how RIF should be
managed including what investigations to do.
Appropriate counseling through out the period of treatment

18. General Intervention Life style changes: Smoking BMI
Alcohol consumption

19. Specific Interventions
Improve Egg quality
Review stimulation protocol
May increase gonadotrophin dose in poor responders
Antagonist vs Agonist protocol
Poor responders to FSH in DR cycle may benefit from addition of LH(phelps et al 1999, Surrey et al 2000
Ultra long protocol for cases with endometriosis and Adenomyosis

20. Improving sperm Quality
Antioxidants
Select sperm with least DNA damage from ejaculated sperm; several techniques can be used
Intra-cytoplasmic morphologically-selected sperm injection(IMSI). Recent meta-analysis has confirmed the superiority of IMSI over ICSI

21. IMPROVING EMBRYO QUALITY
Need to improve embryo quality.
-Embryo grading methods not reliable
Need careful review of ORT, response to stimulation, oocyte yield, fertilisation rate and proportion of good quality embryo transferred should be noted
Blastocyst transfer better ( Papanikolaou et al 2008) Only 55% of embryo will blast. Majority of the remaining 45% have chromosomal abnormality. Several meta-analysis recommend this.
56% vs 40% (Graceland clinic Benin City 2017)

22. Improving embryo quality contd.
Coculture with autologous cells
Improved: embryo morphology
Blastocyst development
Hatching
Synchronizes embryo development with the
uterine environment
Hu Y, Maxson WS, Hoffman DI et al, 1997

23. Assisted Hatching Artificial thinning or beaching of the ZP
-Thick Zona P. ˃ 15μm – older women, RIF
Some meta-analysis Recommend it for the older women and RIF pts
More recent study: beneficial if limited to pt with RIF less than 38 years. (Ghobara 2006, ASRM 2008a)
? Risk of infection and monozygotic twinning.

24. PGD, Metabolomics and Proteomic studies.
Embryonic aneuploidy in older women and women with RIF is high
*63% of embryos from women older than 35 years are aneuploid
* 57% of embryos of patients with RIF are aneuploid
Mosaicism is a source of Misdiagnosis
With advances in methods of cytogenetics study, PGD may be more useful in the nearest future in pts with RIF
Metabolomic and Proteomic studies.
*Mantoudis et al 2001

25. Embryo transfer
Review previous transfer and note any difficulty encountered: cervical stenosis or acute ante-flexion or retroflexion
USS guided transfer
Irrigation and aspiration of cervical mucus
Sequential ET : controversial
ZIFT: no longer attractive for several reasons

26. Treatment of Uterine Lesions
Hysteroscopic: myomectomy, Polypectomy
Adhesiolysis
Resection of Ut septum
All are associated with improved implantation, pregnancy and delivery rates
Removal of Hydrosalpinges: salpingectomy
salpingostomy
Discourage: ligation without excision
USS guided aspiration

27. Improving the Endometrium
Thin endometrium ( less than 7mm)– Not responding to E2
- Turners synd
-Radiotherapy
-Prev Uterine surgery (Ashermans)
- Infection
Evaluate with hysteroscopy.

28. Thin and Trilaminar endometrium

29. Improving the Endometrium
Modified Long protocol with exogenous E2
Sidenafil/Low dose aspirin/Heparin
Luteal support with GnRHa to usual regimen
Granulocyte colony-stimulating factor
Endometrial scratching
Exercise/Fertility Yoga

30. Other options
Gamete Donation
Surrogacy
Adoption

31. SUMMARY RIF impacts on both patient and physician
Need to reevaluate the patient with the aim of:
Making a diagnosis of possible causes
Cytogenetic studies
Radiological evaluation of the female genital track
Laparoscopy
Hysteroscopy
Treat identified causes with approaches with clear benefit.
Know when to think Gamete donation and Surogacy.

32. Appreciation
THANK YOU FOR LISTENING