This document provides evidence-based recommendations for managing unexplained infertility. It discusses various treatment options including expectant management, oral agents with or without IUI, gonadotropins with IUI, and IVF. The key recommendations are that IUI in natural cycles or with oral agents is no more effective than expectant management. Gonadotropins with IUI can be offered but carries a higher risk of multiple pregnancy. IVF demonstrates superior pregnancy rates compared to other options and should be offered after failed ovarian stimulation cycles. Immediate IVF is recommended for women over 38 years old with unexplained infertility.

1. Dr . Akram H. Shalabi
Senior Consultant
ObGyn & Reproductive
Medicine
Amman 23/ 6/ 2021
drakram_ivf@yahoo.com
+962795553199
Managing Unexplained
Infertility : Evidence Based
Approach

2. UEI : Inability to conceive after 1 year of regular unprotected
intercourse without an identifiable cause after basic infertility
evaluation tests
Randolph 2000 , Zegers – Hochchild et al .2017 , J. Stewart 2019
Standard investigation protocol includes :
1- Normal ovulatory function and ovarian reserve
2- Adequate MFT ( WHO 2010 )
3- No visible uterine pathology
4- At least one patent tube ( HSG, SSG, Laparoscopy - debatable role )
Crosignani et al 1993, A.N. Kansouh 2018, J. Stewart
Diagnosis of UEI is primarily by exclusion after completely performed ,
correctly done and appropriately interpreted standard tests Moghissi et al.
2000
UEI leads to frustration, depression & sexual dysfunction Meller at al. 2002

3. Prevalence : 30-50 % of infertile couples meet the above criteria
Esteves et al 2015 , Collins & Crosignani 1992
10-20 % Balen 2003
NICE 2013 1 / 7 couples is infertile
 Male Factor 30%
Female Factor 45%
Combined 40%
UEI 25% In Jordan ?
 UEI is over diagnosed, misdiagnosed and over treated ( in 36% of couples)
–
Kersten et al, HR 2015 , Ben W. Mol et al. Clin Obstet Gynecol 2018
 UEI is on the decline with expanding diagnostic tests
Gleicher & Barad 2006

4. Abnormal folliculogenesis , LUF ,  PRL, LPD, genetic oocyte
defects , oocyte maturation arrest , poor quality embryos, POF
 Abnormal tubal cilial activity or immunological milieu, embryo
toxins
 Endometrial pathology :
Defective endometrial proteomics Altered production of integrins
Impropriate T & NK cell activity Abnormal uterine perfusion
Non-homogenous hyper - echogenic endometrial pattern
 Altered peritoneal immunity : minimal / mild endometriosis
 Impaired fertilizing capacity of sperm , abnormal acrosome reaction
, DNA fragmentation
Few causes are actually treatable Balen 2003

5. Role of Laparoscopy
Laparoscopy is not indicated in the absence of tubal / pelvic
pathology seen by HSG or pelvic ultrasound Level l
 However, laparoscopy is advisable in young women
with  3 yrs infertility in the absence of recognized
abnormalities ASRM guidelines 2015
 Parazzini reported LBR of 19.6 % after 12 months of
treating minimal / mild endometriosis laparoscopically

6. A.Kansouh et al. J. of Medicine in Scientific Research 2018
involving 250 UEI cases underwent laparoscopy reported that:
in 38 % Minimal /mild endometriosis
28 % Tubal / peritubal adhesions
4% PID
30% 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 saves resources

7. Evidence /
Recommendations
From guidelines of
 Canadian Fertility & Andrology Society By
William Buckett and Sony Sierra RBMO issue 4 /2019
• Canadian Task Force on Preventive Health Care
• ASRM recommendations 2020
• NICE guidelines 2013
• Cochrane reviews
• RCOG guidelines will be available this year

8. Evidence / Recommendations
 Level I : RCT Good Strong
 Level II non – randomized controlled Fair Moderate
Cohort Prospective
Case- controlled study from  1 centre or research group
 Level III Opinions of respected authorities :
based on experience
descriptive studies
reports of expert committees Good evidence against or
no enough evidence to make a recommendation
ASRM : Level A high confidence in evidence Strong recommendation
Level B moderate moderate strength
Level C low grade weak/ conditional
no recommendation

9. PR / month at 23-37 ys 30 % in first 2 months
8% after 6 months
4% after 9-12 months
Zinaman et al.
1996
Aim of treating UEI : increase the monthly PR above the
natural rate of 1.5- 3%
HOW? By increasing gamete number, improving gamete
quality and facilitating their interaction
When ? Depends on woman’s age, infertility duration , Rx
affordability and couple’s preferences

10. Typically empirical -as the specific & potentially treatable abnormality is
lacking Soules et el. 2000
Applying a step-wise approach from the least invasive & least expensive
option followed by a gradual progression to ART Ray et al,
2012
Recently a fast track towards ART has been advocated Reindollar et al.
2010
Options : Expectant ( Conservative ) Management
Surgical ( laparoscopy )
Intrauterine insemination IUI
Ovarian stimulation ( oral agents / Gns) + IUI or TSI

11. In good prognosis couples 35 yrs, 2-3 yrs infertility
Cumulative PR over 2 yrs 72% in young women
45% in  35 yrs
30 % with infertility  5 yrs
3yrs 60% Godon & Spirof 2002
5yrs 80% Randolph 2000
Bhattacharya et al. 2008
RCT 580 couples . 2.5yrs infertility
193 Expectant 194 CC 193 Un-stimulated IUI for 6 months
LBR Exp. 17% 32/193 vs 27% by Steures et al. 2006
14% 26/192 CC arm .
23% 43/191 IUI ( No Statistical sign. )

12. Expectant Management cont…
Deidre D et al. in a systematic review 2016 Fertility & Sterility
involving 3081 cases of UEI reached a conclusion that:
• Expectant Rx is comparable with CC + TSI or IUI
 CC may be more effective than letrozole
 Gns for OS are more effective than oral agents albeit significantly
higher risk of MPR
 IVF is no more effective than Gns +IUI

13. Expectant Management 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 , many oppose this strategy
 Expectant Rx can be combined with life style modification

14. Rationale: more eggs , correction of ovarian dysfunction & LPD
Oral Agents Cochrane review 2010 Hughes et al .
7 trials involved 11 59 participants : CC was not more effective than no Rx OR
0.79
Systematic Reiew Liu et al. 2014
Letrozole vs CC 1776 women from 3 studies
PR Letrozole 24.5 % vs 20.8% CC No statistical sign.
MPR : Letrozole 4.1% vs 8% CC No statistical sign.
Recommendation:
CC does not have any benefit over expectant Rx & should not be offered. Level 1
A
CC with TSI : not recommended as it is no more effective than expectant Rx
ASRM
2020

15. IUI resulted in 5 % chance of conception / natural cycle Guzick et al. 1999
Whereas after OS gives PR of 11.3 % / cycle K. George j Hum Rep Sci 2010
Any ovarian stimulation + IUI may succeed in 20-30 % over 3 cycles
Roy Homburg & Gulam Bahadur 2017
No significant difference in CLBR after 6 months in expectant group
16% vs 23 % in IUI alone Cochrane IUI review Veltman – Velhurst et al.
2016
Recommendatioin
Natural cycle IUI does not offer any benefit over expectant Rx. &
should not be offered Level 1 A CFAS Guidelines
2019
Double vs single IUI : No sign. difference PR 13.6% vs 14.4%
Polyzos et al .2010

16. Rationale: Correction of subtle defects in fol. development and / or LPD
Increase number of released oocytes Balen 2003
CC + IUI for 3 cycles vs 3 months expectant Rx.
RCT 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 2 RCTs
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
Multiple PR 13% 9% Diamond et al 2015a,b

17. Ovarian Stimulation with Oral
Agents & IUI cont.
Recommendation:
 IUI with oral agents is more effective than expectant Rx
Level 1 A
 Letrozole & CC are equally effective
Level 1A
 Letrozole can be an alternative to CC
ASRM
 Single IUI can be performed after 0-36hrs relative to hCG
after OS ASRM B/ moderate

18. Rationale: Increased number of eggs available for fertilization could
increase clinical PR & LBR
PR 8% Veltman-Vurhulst et al.2009
No RCTs comparing Gns for stimulation & expectant Rx
Gleicher et al . 2010 reported a possible benefit of Gns - stimulation
alone but on the expense of increased risk of multiple pregnancy, OHS
and cost .
Recommendation : There is insufficient evidence to recommend Gns
alone in managing UEI Level III
Cancel OS or convert to IVF if ≥ 3 fol . > 18mm or ≥ 5 fol. > 12mm
PR 1 fol 8.5 % 2 fol. 13.3% 3 fol. 21.4 %
K. George J Hum Rep Sci, 2010,2016

19. 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 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%
AMIGOS trial Diamond et al. F&S 2015 RCT n=900
PR 35.5% 28.3% CC 22,4% letrozole p = 0,003
CLBR 32.2 % 23.3% CC 187% Letrozole p = 0.001
Cancellation Rate : Higher with Gns ( over-response )

20. Gns + IUI vs Letrozole + IUI
 Recommendation :
 Gns /IUI can be offered to couples with UEI Level 1B
 Gns/IUI is associated with higher PR /cycle & higher 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 B/ moderate

21. IVF : Accepted , effective and recommended Rx. NICE 2004,
2013
Rationale: Higher number of eggs available for fertilization
Facilitates fertilization
To document fertilization & evaluate embryo quality
Can prevent TFF
Cost effective considering repeated IUI trials & FET
Cochrane review by Pandian et al. 2012
One IVF trial vs Expectant Rx for 90 days
LBR 45.8% vs 3.7% OR 12.4

22. IVF in UEI
 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

23. Summary :
There is a clear benefit in LBR following IVF over other Rx. options
IVF offers reduction of MPR with its adverse events
UK NICE guidelines 2004, 2013 advised against Gns /IUI moving towards IVF
adopting elective SET ( Canada also )
However
Gns +/- IUI vs IVF No difference Gunn and Bates F&S 2016 13 RCT n=
3081
Recommendations:
IVF can be offered as first line Rx Level 1B
IVF should be offered after 3 failed cycles of ovarian stimulation /IUI

24. During IVF in UEI total fertilization failure 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 should be the first treatment option in UEI Sertac et al 2000
ICSI should be the first option in women over 35yrs Balen 2003
LBR 46.7% IVF vs 50% ICSI Foong et al 2006

25. ICSI in UEI cont.
 Recent systemic review & MA : Suggested that routine ICSI
increases FR & decreases TFF Johnson et
al. 2013
• Rescue ICSI is advocated in case of TFF leading to PR ranging from
9.7% to 44% Beck- Frucher et al. 2014
 Recommendation :
No sufficient evidence to recommend routine ICSI to increase LBR ,
although it can reduce the rate of TFF Level 1B

26. Forty and Over Treatment Trial
FORT-T
 Reindollar et al, F&S 2014 RCT n=154
Female age : 38-42 Y with ≥ 6 months UEI
 CC+ IUI n=51 FSH+IUI X2 n=52 Immediate IVF n=51
 CPR 21.6% 17.3% 49%
 Conclusions : In IVF group
Remarkably higher PR 49%
IVF contributed in 84.2 % of all live births
36 % fewer treatment cycles
So, immediate IVF demonstrated superior PR with fewer Rx cycles

27. Age  35 yrs 35-39 yrs  40 yrs
Duration  2yrs  2yrs 1 yr Irrespective of
duration
Expectant Rx up to
2yrs
OS + IUI X3- 6 cycles OS + IUI X 2-3 OS+ IUI X1- 2
IVF IVF IVF IVF

28. 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 UEI are associated with a higher
incidence of PET, preterm labor & emergency CS

29. Most Relevant Recommendations to
Practice
 No place for IUI in NC : no more effective than expectant Rx A / strong
 No place for oral agents + TSI as above B / moderate
 No place for Gns + TSI Risk of multiple pregnancy B / moderate
 It is recommended to use CC or Letrozole + IUI A / strong
 It is not recommended to use low dose Gns +IUI as they are no more effective
than oral agents B / moderate
 Oral agents + conventional dose Gns for IUI are not recommended : MPR
B / moderate
 Gns in conventional doses for IUI are not recommended : MPR, expensive , as
effective as oral agents + IUI A / strong
 Couples should initially undergo 3-4 cycles of OS with oral agents + IUI
before embarking on IVF/ICSI attempt B / moderate

30.  Diagnosis of UEI should be made by exclusion after complete and correctly
interpreted standard fertility tests
 Therapeutic strategy should involve counseling with regard to prognosis,
adverse events and individually tailored treatment options based on:
age duration of infertility ovarian reserve
affordability couple’s preferences social circumstances
 Couples can be offered less invasive treatment options as expectant
management and IUI with ovarian stimulation
 There is a great deal of evidence emerging in favor of fast track management
towards IVF particularly in older females with  3 yrs infertility
What remains obliviously interesting is the gap between science and practice

31. Thank
You