415% to 30% of infertile couples DefinitionUnexplained infertility means that ,couple does not conceived after 1 year of unprotected vaginal sexual intercourse, with basic infertility evaluation shows no obvious abnormality(RCOG guidelines,1998; Randolph,2000; ASRM,2006).Incidence15% to 30% of infertile couples(ASRM,2006)
5Basic investigations for diagnosis of Unexplained infertility Normal basic semen analysis according to WHO criteria (WHO ,2010).Patent fallopian tube confirmed by HSG.Ovulation confirmed by mid-luteal serum progesterone level.
6Expectant Encourage Advice Inform In unexplained infertility: the cause is not defined ,so the treatment is empirical (ASRM, 2006).ExpectantEncourageAdviceInformActiveIUIOral stimulating agents (CC / letrozole)CC+ IUIGonadotropin injections with or without IUIIVF/ICSIAlternatives:Bromocriptine, Danazol, Tubal flushing.
7Treatment Dependent on: The standard protocol is to: Availability of resources ,Patients’ age ,Duration of infertility.The standard protocol is to:Progress from simple to complex treatment options,Balance the effectiveness against the cost and side effects. (Ray et al,2012)
8Suggested Protocol for Management of Unexplained Infertility (Ray et al, 2012)
9The role of IUI in treatment of unexplained infertility
10IUI Definition Rationale Other indications of IUI Steps Advantages ComplicationsIndications of IUI in unexplained infertilityEffectiveness of IUI in unexplained infertility
11Intrauterine Insemination DefinitionIUI involves the placement of processed semen into the uterine cavity around the time of ovulation (Allahbadia and Merchant,2012).
12Rationaleincrease the rate of conception by increasing the chance that maximum number of healthy sperms reaches the site of fertilization (ESHRE,2009).
13IndicationsI. Male:1. Ejaculatory failure: ( sever hypospadius ;retrograde ejaculation; impotence)2. Male factor infertility (mild ;moderate)3. Sperm cryopreservation prior to treatment of husband cancer.4. Processed semen of HIV + husband for HIV negative women (NICE, 2013)
17Advantages of IUI Non invasive (like Pap smear). Bypass possible cervical mucous hostility.Easy: performance and trainingMinimal: cost and risk
18IUI Complications Of the procedure Antenatal & perinatal InfectionPainPsychological (guilt, anger, loss of self esteem)Of COHMultiple pregnancyOHSSAntenatal & perinatalAs pregnancies from sexual intercourse.
20ESHRE Capri Workshop Group (2009) IUI or stimulated ovary/IUI is indicated as empiric treatment for all categories of unexplained infertility20% of couples after initial work-up.Couples with mild male subfertility (20–40%)50% of those in whom conventional treatments have failed.
21NICE Guidance Feb, 2013 In the treatment of unexplained infertility The evidence does not support the use of IUI as an alternative to expectant management .IUI (with or without stimulation) should not be routinely offered (exceptions e.g. when people have social, cultural or religious objections to IVF)
22Effectiveness of IUI in treatment of unexplained infertility
23PR with different treatment Options Unexplained Infertility :PR with different treatment OptionsTreatment% pregExpectant (No treatment )1.3%Natural cycle IUI3.8%Clomiphene5.6%Clomiphene+ IUI8.3%Gonadotropins7.7%Gonadotropins+ IUI17.1%IVF/ICSI20.7%(Guzick et al )Conclusions (Cochrane, 2012 ): In stimulated cycles PR was higher with IUI compared to timed intercourse23
24NICE Guidance Feb, 2004 ; For unexplained infertility ovarian stimulation should not be offered, even though it is associated with higher pregnancy rates than unstimulated IUI, because it carries a risk of multiple pregnancy.Cochrane, 2012 ; risks and alternative treatment options of stimulated IUI should be discussed.NICE Guidance Feb, 2013 ; Do not offer oral ovarian stimulation agents (such as clomifene citrate, anastrozole or letrozole) to women with unexplained infertility.
25IUI versus alternative insemination techniques 1 } Fallopian Tube Sperm Perfusion (FSP) :Past : FSP is superior to IUI (Trout & Kemmann,1999) .Later: a meta-analysis reported no clear benefit (Cantineau et al, 2009)2} No difference between IUI and Intraperitoneal insemination (IPI) (Noci et al,2007)3} Intrauterine tuboperitoneal insemination (IUTPI) is superior to IUI &FSP (CPR/cycle 29.4% ) (Mamas, 2006)4} IUI is superior to Intracervical insemination ICI (Besselink et al,2008).
26IUI Vs. IVF for unexplained infertility Starting treatment with IUI rather than IVF was either cheaper or more cost-effective than IVF in unexplained infertility (Goverde et al., 2000).Cochrane, 2012 (Pandian et al, 2012)IVF may be more effective than IUI+SO.Due to lack of data from RCTs the effectiveness of IVF for unexplained infertility relative to expectant management, clomiphene citrate and IUI alone remains unproven.
27NICE Guidance Feb, 2013For people with:unexplained infertility,mild endometriosis ormild male factor infertility,who are having regular unprotected sexual intercourse:advise them to try to conceive for a total of 2 years before IVF will be considered .
28IUI in stimulated cycles may be considered while waiting for IVF or when in women with patent tubes, IVF is not affordable(ESHRE Capri Workshop Group, 2009)
29Favorable Predictors of IUI Outcome Factors related to couplesFactors related to therapy
301.Female age ≤ 35y (Morshedi et al, 2003 ) Couple:1.Female age ≤ 35y (Morshedi et al, 2003 )2.Shorter duration of infertility .3. Type of infertility (Guven et al,2008)Type of infertilityPregnancy ratePrimary inf.7.9%Secondary inf.21.4
314. First treatment cycles (≤ 4). Couple:4. First treatment cycles (≤ 4).Pregnancies resulting from IUI occur during the first 3-4 treatment cycles ( %; respectively)(Morshedi et al,2003).Aboulghar et al, 2001, suggested a maximum of 3 COH/IUI cycles for treatment of unexplained infertilityHowever ,others recommended up to 6 cycles(Dickey et al, 2002; Morshedi et al,2003; Ray et al, 2012).
325. Cause of infertility: (Bourn Hall clinic, 1999 ;Tay et al,2007; Wang et al,2008). Overall CPRs/cycleHigher PR with :Unexplained infertility (9.2% to 22% )Ovulatory dysfunction (19.2%)Modest PR → Cervical factor (16.4%)Poor PR:Endometriosis (11.9%)Immunological infertility (10% )♂ factor → the best PR with ejaculatory disorders (13.3%)
33B. Therapy: (Allahbadia and Merchant,2012). 1. Use of CC/HMG-FSH compared with CC only .2. Follicular dynamic :- AFC > 5 (Ombelet et al, 2003)- Preovulatory follicles : 2–3 follicles≥ 16 mm with uniformly high-grade vascularity and E2 levels >500 pg/mL on the day of hCG administration. (Steures et al, 2004; Bhal et al ,2001) .
34.3. Sperm parameters: generally Processed total motile sperm count ≥ 10 million, 24 h survival > 70%, and normal sperm morphology of >4% (according to Kruger’s criteria) predict pregnancy outcome with 94% sensitivity, 86% specificity (Guven et al, 2008;Abdelkader & Yeh ,2009).(12.3 vs 2.8%)Initial sperm count, motility ?
35adequate thickness with trilaminar pattern 4.Time of insemination,preferably between D13 &16.5. Endometrium:adequate thickness with trilaminar pattern(Tomlinson et al ,1996)
36Measures does not affect IUI results 1. US monitoring & HCG induction of ovulation versus urinary LH monitoring of ovulation.HCG allow final follicular maturation (Kosmas et al, 2007)2. GnRH agonist and antagonist. ↑complications (Allahbadia and Merchant,2012).3. Double IUI versus single IUI (Polyzos et al,2009).
374. Type of catheter: no significant difference in PR when using the softer Wallace catheter or the less pliable Tomcat catheter during IUI, with the standard gentle non touch technique (Smith et al ,2002).However , Merviel et al ,2010 recommended soft catheter.5 . Luteal phase support do not appear major requirements in IUI cycles (ESHRE ,2009)6. Sperm preparation technique (ESHRE,2009).
39How to improve IUI results? Measures to↑ PR: 1. COH: all except sever male factor ( Risks???)(Cohlen ,2002).2. Vaginal misoprostol.????(Brown et al,2001; Barroso et al,2001).minutes bed rest after IUI(Saleh et al,2000 ; Custers et al, 2009 )4. Cervical mucous aspiration before IUI(Paasch et al, 2007)
408. Pre-insemination hydrotubation 5. Timed intercourse within h period: useful in IUI with low number of motile sperm inseminated (Huang et al, 1998).6. Postponing IUI until the observation of follicle rupture by TV sonography ( PR;25% vs 8.8%) (Kucuk ,2008).7. US guidance in IUI(Ramón et al,2009; Oztekin et al,2013)8. Pre-insemination hydrotubation(Edelstam et al, 2008; Aboulghar et al, 2010 ; Morad & Abdelhamid , 2012)
41ConclusionsTreatment of unexplained infertility is empiric as no obvious abnormality was detected.Treatment of unexplained infertility is very much dependent on availability of resources and patients’ age and duration of infertility .OH with IUI is a simple ,cost-effective, least invasive first-line treatment for Unexplained infertility.
42Conclusions4.Couples should be fully informed about the risks of IUI and COH as well as alternative treatment options.5. In unexplained infertility OH with IUI may be considered while waiting for IVF or when IVF is not affordable.6. The pregnancy rates of FSP & Standard IUI are similar.
43Conclusions7.Pre-insemination hydrotubation, US guided IUI , cervical mucous aspiration, post-insemination bed rest for 10 min and vaginal misopristol may improve IUI outcome .8. In unexplained infertility, up to 6 cycles of IUI should be considered before shifting to IVF.