Intrauterine insemination forun explained infertility Infertilità inspiegata Dr Franco Lisi Specialista in ostetricia e ginecologia Responsabile reparto PMA Clinica Villa Mafalda

Infertilità Inspiegatao

Infertilità sine causa

Infertilità inspiegata

Definizione infertilità inspiegata significa che una coppia non concepisce dopo 1 anno di rapporti sessuali

vaginali non protetti , con le indagini basiche per infertilità non evidenzianti nessuna patologia

(RCOG guidelines,1998; Randolph,2000; ASRM,2006).

Incidenza 15% 30% delle coppie infertili(ASRM,2006)

Quali sono le 3 principali variabili della fertilità Fattore ovulatorio

Fattore seminale

Fattore Tubarico

Quali sono i 3 esami indispensabili nella diagnostica di infertilità

Diagnosi di ovulazione

Esame del liquido seminale

Isterosalpingografia

Diagnostica di base nella diagnosi di infertilità

Normale spermiogramma di base secondo I

criteri dell’OMS (WHO ,2010).

Tube di Falloppio pervie valuate con ISG.

Ovulazione confermata dall’innalzamento

del progesterone nella fase medio luteale.

Nell’infertilità inspiegata: la causa non é definita, pertanto il trattamento é empirico (ASRM,

2006).

Expectant Incoraggiare Spiegare Informare

Active IUIIUI Oral stimulating agents (CC / Oral stimulating agents (CC /

letrozole)letrozole) CC+ CC+ IUIIUI Gonadotropin injections with or Gonadotropin injections with or

without without IUIIUI IVF/ICSIIVF/ICSI Alternatives:Alternatives:

Bromocriptine, Danazol, Tubal flushing.

Fattore tubarico

Esame di prima scelta ISTEROSALPINGOGRAFIA

Esame di seconda scelta SONOISTEROSALPINGOGRAFIA

Fattore ovulatorio

Non eseguire i dosaggi al 7° 14° 21° gg

L’esame ( FSH, LH, E2, PRL, AMH) si esegue una sola volta al 2° o 3° giorno del ciclo

Fattore maschile Esecuzione dello spermiogramma

tenendo presenti i valori fissati dall’OMS

Trattamento

Dipendente da:○ Disponobilità di risorse ,

○ Età dei pazienti

○ Durata dell’ infertilità.

Il protocollo standard è: ○ Progredire dai trattameni semplici a quelli complessi

○ Balanciare l’efficacia contro il costo e gli effetti collaterali (Ray et al,2012)

Suggested Protocol for Management of Unexplained Infertility (Ray et al, 2012)

The role of IUI in treatment of unexplained infertility

IUI Definition Rationale Other indications of IUI Steps Advantages Complications Indications of IUI in unexplained infertility Effectiveness of IUI in unexplained infertility

Intrauterine Insemination

Definition

IUI involves the placement of processed semen into the uterine cavity around the time of ovulation (Allahbadia and Merchant,2012).

Rationale increase the rate of

conception by increasing the chance that maximum number of healthy sperms reaches the site of fertilization (ESHRE,2009).

IndicationsI. 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)

II. Female:

1.Cervical factor infertility

2. Endometriosis

3. Ovulatory dysfunction

4. Combined non-tubal infertility factors

III. Combined:

1. Unexplained infertility

2. Immunological infertility

Steps

Patient selection & counseling.

Natural cycle IUI

Stimulated cycle IUI (Ovarian stimulation)

Monitoring of treatment

Sperm preparation

Insemination

Advantages of IUI

• Non invasive (like Pap smear).

• Bypass possible cervical mucous

hostility.

• Easy: performance and training

• Minimal: cost and risk

IUI Complications

Of the procedure

Infection Pain Psychological (guilt,

anger, loss of self esteem)

Of COH Multiple

pregnancy OHSS

Antenatal & perinatal

As pregnancies from sexual intercourse.

IUI Indications in Unexplained Infertility

ESHRE Capri Workshop Group (2009)

IUI or stimulated ovary/IUI is indicated as empiric treatment for all categories of unexplained infertility

20% of couples after initial work-up. Couples with mild male subfertility (20–40%)

50% of those in whom conventional treatments have failed.

NICE 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)

Effectiveness of IUI in treatment of unexplained infertility

(Guzick et al. 1998.)Conclusions (Cochrane, 2012 ): In stimulated cycles PR was higher with IUI compared to timed intercourse

Treatment % pregExpectant (No treatment ) 1.3%Natural cycle IUI 3.8%Clomiphene 5.6%Clomiphene+ IUI 8.3%Gonadotropins 7.7%Gonadotropins+ IUI 17.1%IVF/ICSIIVF/ICSI 20.7%20.7%

Unexplained Infertility :PR with different treatment Options

NICE 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.

IUI 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).

IUI 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.

For people with:

○ unexplained infertility,

○ mild endometriosis or

○ mild 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 .

NICE Guidance Feb, 2013

IUI 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)

Favorable Predictors of IUI Outcome

Factors related to couples

Factors related to therapy

A.Couple:1.Female age ≤ 35y (Morshedi et al, 2003 )

2.Shorter duration of infertility .3. Type of infertility (Guven et al,2008)

Type of infertility Pregnancy ratePrimary inf. 7.9%Secondary inf. 21.4

A.Couple:

4. First treatment cycles (≤ 4). Pregnancies resulting from IUI occur during the first 3-4

treatment cycles (88-95.5%; respectively) (Morshedi et al,2003).

Aboulghar et al, 2001, suggested a maximum of 3 COH/IUI cycles for treatment of unexplained infertility

However ,others recommended up to 6 cycles (Dickey et al, 2002; Morshedi et al,2003; Ray et al, 2012).

5. Cause of infertility: (Bourn Hall clinic, 1999 ;Tay et al,2007; Wang et al,2008).

Overall CPRs/cycle Higher 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%)

B. 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).

.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 ?

4.Time of insemination ,preferably between D13 &16.

5 .Endometrium: adequate thickness with trilaminar pattern

(Tomlinson et al ,1996)

Measures 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).

4. 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).

How to improve IUI results?Measures to↓ complications:

1. Natural cycle IUI: ↓ PR

2. Mild ovarian stimulation : low dose GnH

3. Cycle cancellation {> 3 follicles ≥ 16mm or; > 8 follicles ≥ 12mm}

4. Selective follicular reduction. (not routine)

4. Conversion to IVF cycle

How 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).

3. 10 -15minutes bed rest after IUI (Saleh et al,2000 ; Custers et al, 2009 )

4. Cervical mucous aspiration before IUI (Paasch et al, 2007)

5. Timed intercourse within 12 -18 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)

1. Treatment of unexplained infertility is empiric as no obvious abnormality was detected.

2. Treatment of unexplained infertility is very much dependent on availability of resources and patients’ age and duration of infertility .

3. OH with IUI is a simple ,cost-effective, least invasive first-line treatment for Unexplained infertility.

4.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.

7.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.

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