Unexplained infertility Amman 2024.pptx

Unexplained infertility:
ESHRE 2023 recommendations and more.
16th International congress of the Jordanian society of OBGYN, Amman 4-6th Sep 2024

1. Dr . Akram Shalabi Senior Consultant Infertility & IVF Senior Consultant ObGyn Amman September 2024 Unexplained Infertility : ESHRE Recommendations 2023 a nd More

2. Evidence and Recommendations Mainly from ESHRE 2023 GDG D. Romualdi et al. Hum.Reprod August 2023 For comparison I will sometimes refer to : RCOG guidelines 2021 ASRM recommendations 2020 Canadian Fertility & Andrology Society 2019 By William Buckett and Sony Sierra RBMO issue 4 /2019

3. Definition UI : Inability to conceive after 1 year of unprotected intercourse after normal basic infertility tests . Randolph 2000 , Zegers – Hochchild et al .2017 , J. Stewart 2019 ICMART & ESHRE GDG : Infertility ≥ 12 months in couples with apparently normal anatomy and function of female & male genital organs with adequate coital frequency and semen parameters 30 % of infertile couples have UI 30-50 % of infertile couples meet the above criteria Esteves et al. 2015

4. Diagnosis Standard investigations include : Regular ovulatory function and normal ovarian reserve Adequate MFT ( WHO 6 th edition 2021 ) No visible uterine pathology At least one patent tube ( HSG, HyCoSy , HyFoSy , Laparoscopy ) A.N. Kansouh 2018, J. Stewart 2019 Diagnosis depends on the available and used methodologies for testing Zegers Hoshchild et al 2017 Diagnosis is primarily by exclusion and it is on the decline Until now UI is over diagnosed and over treated Ben W. Mol et al. Clin O bstet Gynecol 2018

5. Diagnostic Tests For Males O ne normal MFT according to WHO criteria ( 6 th edition 2021 ) is needed without US evaluation of male genitalia ESHRE 2023 / Strong R Volume 1.3-1.5 ml Total sperm count 35 – 40 millions Count /ml ≥ 15 millions Progressive Motility ≥ 30% if less : vitality test is needed (N =50-55% ) Normal forms 4%

6. Diagnostic Tests For Males If the results of semen analysis are below the 5 th percentile reference limit a second SFA is needed 3 months later Testing for anti-sperm Abs & DNA integrity is not recommended if SFA is normal Strong R It is important to investigate the general, reproductive and sexual history of the male paying attention to ED

7. Testing For Females In Women with regular cycles , tests to confirm ovulation are not routinely recommended GPP Ovarian reserve tests are not required in pts with regular periods Strong R Tubal patency tests are valid compared to laparoscopy + dye Strong R Wang & Qiuain 2016, Alcazar et al. 2020 Visual demonstration of patency is necessary in p atients having high risk of tubal blockage GPP Patency tests can’t detect minor endometriosis , adhesions or subtle tubal lesions and hence laparoscopy is here beneficial as in young women with  3 years infertility . ASRM guidelines 2015

8. Testing For UI in Females Testing TSH is GPP , but testing thyroid antibodies or other immune conditions ( except celiac disease ) or thrombophilia are nor recommended ESHRE / Strong R Milenkovich et al. 2020 If TSH is normal no further thyroid tests or PRL are needed ESHRE 2023 /Strong R Rahman et al. 2020 , Qu et al. 2020 Orouji J et al. 2018, Duran et al. 2013

9. Subtle Causes of Infertility in Females Abnormal folliculogenesis : LUF ,  PRL, LPD, genetic / oocyte maturation defect Abnormal tubal ciliary activity : HS, primary ciliary dyskinesia L.Newman Hum.Reprod 2023 Endometrial pathology : Defective endometrial proteomics / integrins & cadherins Impropriate T & NK cell activity H yper - echogenic or thin endometrium ( TB ) Altered peritoneal immunity : endometriosis, autoimmune diseases

10. Imaging Techniques For Diagnosis 2D/3D US evaluation : if normal no further assessment is needed Bakes et el 2014, Yang et al 2019, ESHRE: Strong R Laparoscopy as a routine diagnostic procedure is not recommended ESHRE Strong R , ASRM 2015 Level 1 Pts at a higher risk for tubal pathology ( PID, previous ectopic or endometriosis should be counselled about benefits and risks of laparoscopy If endometriosis is accidentally found during laparoscopy this is not anymore considered a case of UI.

11. Laparoscopy in UI A.M.Kansouh / J. of Medicine in Scientific Research 2018 250 UI cases underwent laparoscopy reported that: 38 % Minimal /mild endometriosis 4 % PID 28 % T ubal / peri-tubal adhesions 30% (n=50 ) abnormal hysteroscopic findings Conclusion : Laparoscopy is the final diagnostic procedure of female fertility exploration ( WHO guidelines ) It may be therapeutic at the same settings It can avoid direct shift to IVF and save resources

12. Hysteroscopy in UI Hysteroscopy : is not recommended i f US imaging showed no abnormalities Endom . scratch is not recommended ESHRE: Strong R Yildiz et al 2021. Wang et al 2022 Ghuman et al 2020, Jafarabadi et al 2020

13. Treatment of UI Aim of RX : increase the monthly odds of getting pregnant close the natural rate of ≈ 20% HOW? By increasing gamete number, improving gamete quality and facilitating their interaction , development and implantation . When ? Depends on woman’s age, infertility duration, previous reproductive history & couple’s preference ( prognostic model criteria )

14. Treatment cont. Rx. is typically empirical - as the specific & potentially treatable abnormality is lacking Soules et el. 2000 Options : Expectant m anagement IUI + OS IVF ICSI

15. Expectant Policy In good prognosis couples ( 35 yrs, 2-3 yrs infertility ) wait 6 months LBR after 6 months 17% Bhattacharya et al. 2008 27% Steures et al. 2006 OPR 21% SR n= 3081 Deidre D et al. Fertility & Sterility 2016 Cumulative PR over 2 yrs 72% in young women 45% in  35 y 30 % with infertility  5 y

16. Expectant Rx cont . Recommendation : In good prognosis couples ( based on age & infertility duration ) expectant management can be offered Level IA NICE guidelines 2013 recommended : Expectant Rx for 2yrs before proceeding to IVF , blatantly ruling out IUI as an intermediate treatment Anti-oxidants ( couple), inositol and acupuncture ( female ) during expectant Rx : not recommended ESHRE 2023 Expectant Rx can be combined with life style modification (Psychological support , balanced diet, exercise , behavioral therapy & BMI reduction) GPP/ ESHRE 2023

17. IUI with OS Rationale: more eggs , correction of ovarian dysfunction & LPD IUI+ OS is recommended as a first- line treatment in UI Strong R Pandian et al 2015, Harira et al 2018, Ayeleke et al. 2020 Aromatase inhibitors do not show any benefit over CC & should not be offered . ASRM 2021 Level 1 A To avoid MP & OHSS Gns should be used in low doses for OS with adequate monitoring GPP /ESHRE Any ovarian stimulation + IUI may succeed in 20-30 % over 3 cycles Roy Homburg & Gulam Bahadur 2017 Natural cycle IUI does not offer any benefit over expectant Rx. & should not be offered ASRM Level 1 A CFAS Guidelines 2019

18. Oral Agents + IUI vs Expectant CC + IUI for 3 cycles vs 3 months expectant Rx. R CT n= 101 Mean age 34yrs 3.6 yrs infertility CLBR in CC + IUI 31% vs 9% in expectant group Farquhar et al 2018 CC / IUI vs Letrozole / IUI Clinical PR 18 % letrozole /IUI vs 11% CC / IUI n=214 Fouda and Sayed 2011 37% 36% n= 412 Badawy et al. 2009 18.7 % 23.3 % n=900 Diamond et al 2015 a,b 24.5 % 20.8% CC SR Liu et al. 2014 Multiple PR 9% 13% Diamond et al 2015a,b 4.1 % 8% SR Liu et al. 2014

19. Oral Agents & IUI cont . Recommendation: IUI with oral agents is more effective than expectant Rx ASRM 2021 Level 1 A Letrozole & CC are equally effective , apart from a higher MPR with CC ASRM 2021 Level 1A Single IUI can be performed after 0 - 36hrs relative to hCG trigger after OS ( more convenient for the pts ) ASRM B / ESHRE moderate

20. Ovarian Stimulation: Gns + IUI Cochrane review 2016 Veltman - Verlhurst et al . Gns + IUI 231 couples 246 Gns only Higher PR /couple with Gns +IUI OR 1.69 Multiple PR ranged 5%-12% in both arms 2 small RCTs Gns +IUI vs CC+IUI Ongoing PR 18% 11.6 % Baker et al. 2011 CLBR 31.4% 30.3% Dankert et al 2007 MPR 4.3% 7.4% Cancellation Rate :Higher ( over-response ) CLBR 32.2 % 23.3% AMIGOS trial Diamond et al. F&S 2015

21. Gns + IUI vs Letrozole +IUI Gns +IUI Letrozole +IUI Clinical PR 15.7% 18.4% Baysoy et al 2006 CLBR 36 % 24 % Gregorio et al 2008 LBR 32.2% 18.7% MPR 31.8% 9.4% ( 8 twins ) ( 24 twins, 10 triplets)

22. Gns vs Letrezole + IUI Recommendation : Gns +IUI can be offered to couples with UI Level 1B Gns + IUI is associated with higher PR & MPR/cycle than IUI with oral agents Level 1A Letrozole + low dose Gns +IUI is comparable with CC + low dose Gns + IUI in terms of PR & LBR ASRM 2020 Oral stimulation & standard dose Gns + IUI carries a higher risk of multiple gestation ASRM 2021 B / ESHRE moderate

23. IVF in UI IVF : Accepted , effective and recommended Rx. NICE 2013 IVF has to be individualized based on prognosis model criteria Age D uration of infertility Previous Rx Previous pregnancy Couple’s preference Pandian et al 2015,Nandi et al 2022 , ESHRE GPP Rationale of IVF : Facilitates and documents fertilization / embryo development Can prevent TFF Cost effective considering FET IVF LBR ranges 33.1% ( 35y ) to 12.5% ( 40- 42 y) HFEA 2011

24. IVF in UI vs Gns +IUI 6 RCTs Pandian et al. 2012 n= CPR ( Gns /IUI) CPR( IVF ) Goverde et al. 2000 172 7.80% /cycle 12.2 % /cycle Reidollar et al. 2010 503 21.4 % after 3cycles 52 % after 3 trials van Rumste et al.2014 116 17.2 % after 3cycles 22.4 % /cycle Bensdorp et al. 2015 602 56% after 6cycles 58.7% after 3trials Goldman et al 2014  154 17.3 % after 2cycles 49% after 2cycles Nandi et al. 2017 207 28.7 % after 3 cycles 33.1 % / cycle  Womens ’ age 38-42yrs Cochrane Review 2012

25. IVF in UI Summary : There is a clear increase in LBR following IVF over other treatment options despite its cost . IVF offers reduction of MPR by adopting SET UK / NICE guidelines 2013 advised against Gns +IUI moving towards IVF as first line Rx in poor prognosis couples Level 1B, GPP and Particularly after 3 failed cycles of OS + IUI Level 1A

26. ICSI in UI Total fertilization failure with c lassic IVF occurs in 5-10% of cases Bungum et al 2004, Jaroudi et al. 2003 Tournaye et al .2002 ICSI has no benefit over standard IVF in non-male factor infertility Bhattacharya et al . 2001, Bukulmez et al. 2000 ICSI is not recommended over classic IVF Dand et al. 2021 ESHRE/ strong R Unless there is a history of TFF

27. Pregnancy Rates in UI Cochrane Review & MA 2019 LBR Exp. Rx 17 % OS 9% -28% IUI 11% -33 % OS + IUI 25%-37 % IVF 14 % - 47 %

28. Management Flowchart By Laxmi S. 2024 /Based on ESHRE 2023 Consider prognostic factors after investigations Good Prognosis Poor Prognosis IVF Expectant Management OS + IUI for 6 months 3-6 cycles Additional Care Healthy diet, exercise Behavioral therapy when IVF Psychological support needed Laxmi Sh. 2024

29. Prognosis Woman’s age, duration of infertility and the chosen treatment modality are the most crucial prognostic factors OS + IUI and IVF give satisfactory long term outcome in terms of LBR Pregnancies after UI are associated with obliviously higher incidence of PET, preterm labor & emergency CS

30. Summery of the Evidence No place for IUI in NC : results as in expectant Rx A / strong * No place for OS ( oral agents or Gns )+ TSI B / moderate It is recommended to use CC or Letrozole + IUI A / strong * L ow dose Gns +IUI are no more effective than oral agents B / moderate Gns in conventional doses + IUI are not recommended :  MPR, expensive , as effective as oral agents + IUI A / strong * Couples should initially undergo 3-4 cycles of OS + IUI before embarking on IVF/ICSI attempt B / moderate

31. Most Relevant ESHRE 2023 Recommendations in Practice Ovarian reserve testing is not required in women with regular periods Ultrasound ( preferably 3D ) is the imaging method of choice to exclude uterine anomalies in women with UI , if findings are normal: no further evaluation ( hysteroscopy +/- scratching ) Tubal patency tests are valid compared to laparoscopy + dye test Laparoscopy is not recommended as a routine diagnostic procedure IUI with o varian stimulation is the first line Rx , keeping in mind multiple pregnancy & OHSS IVF should be individualized according to prognosis criteria ICSI is not s uperior to conventional IVF except in cases with history of TFF

32. Conclusions Diagnosis of UI should be made by exclusion after complete standard infertility tests Therapeutic approach should be individually tailored based on prognosis ( prediction ) model established by the caring team , giving priority to OS+IUI as a first line of active management before IVF Couples can be offered less invasive treatment options as expectant management based on prognosis and couple’s preference There is a great deal of evidence emerging in favor of fast track management towards IVF particularly in older females with  3 ys infertility or failed 3 IUI with OS

33. No matter how successful you’ve been , there’s always more to do, more to learn and more to achieve. Thank You