IUI KİME? NE ZAMAN? NASIL? N.Cem FIÇICIOĞLU, MD., Ph,D., AA., MBA. Professor and Head of Gynecology & Obstetrics – IVF Center Yeditepe University Medical School. ISTANBUL - TURKEY

Subfertilite Çocuk sahibi olamıyoruz diye başvuran çiftlerin çoğu subfertil olup aylık konsepsiyon oranları düşmüştür fakat doğal yolla gebe kalabilirler “ESHRE Capri Group 1996” Bu hastaların yönetiminde çok ileri gitmeden tedavi maliyeti ve over stimulasyonunun yan etkileri düşünülmelidir. Pahalı ve invazif yöntem olan IVF öncesi hastalara daha uygun tedavi planlanabilirmiyiz ?

Tedavi seçenekleri Pasif Tedavi; Aktif Tedavi; Bekle-İzle Ovulasyon indüksiyonu Intrauterin inseminasyon (IUI) In vitro fertilizasyon (IVF) Overall, about 15% of couples diagnosed with unexplained infertility will conceive without treatment within 1 year and 35% within 2 years (Isaksson & Tiitinen, 1998). However, the cumulative pregnancy rate over 3 years without treatment has been reported to be up to 80% in some groups (Guzick et al., 1998; Hull et al., 1985). Age of the woman is the most important predictor of successful conception without treatment with the rates falling at a greater rate after age 30 years (Isaksson & Tiitinen, 1998; Hunault et al., 2004) (see Figure 11.1). Some have suggested that unexplained infertility for more than 3 years is a poor prognostic feature for future chance of pregnancy, while others have not found this (Crosignani et al., 1993; Sundstrom et al., 1997; saksson & Tiitinen, 1998). As a result, couples with unexplained infertility are often given advice on lifestyle and successful conception, and told to return in a few months if they have still not become pregnant (this is known as ‘expectant management’), but no active treatment is recommended However, expectant management is often not attractive to couples (or their clinicians), both because they have been hoping for a pregnancy for some time and also because there is a preference for active treatment. As a result, a number of therapeutic approaches have been used to actively treat unexplained infertility.

IUI endikasyonları Ejekulatuar disfonksiyon, seksüel disfonksiyon, impotans Ciddi vajinismus Servikal faktör infertilite Açıklanamayan infertilite Evre I ve II endometriyozis Male faktör

öneriler

< 40 yaş, 2 yıldır korunmasız ilişkiye rağmen gebe kalamayan hastalara IVF > 40 yaş IVF 12 siklus artifisyel inseminasyon veya ‘6 IUI’ gebe kalamayan hastalara IVF Kritik yaş 36 ve üstü !

Açıklanamayan infertilite tanısı alan hastalarda oral stimulasyon ajanları, ‘ klomifen sitrate, letrazole’ , kullanılmamalıdır İtiraz…… Bahadur G, Hum Reprod 2016

Objective: To evaluate the awareness and response of fertility clinics in the UK to the National Institute for Health and Care Excellence (NICE) guideline recommendation that intrauterine insemination (IUI) should not be offered routinely, in order to report on current practice in the UK. Design: Online questionnaire survey of fertility clinics in the UK regarding their current clinical practice of IUI, formal discussion of the guideline recommendations, and any alterations made since the recommendations. Setting: 66 UK fertility clinics licensed to provide IUI. Participants: 46 fertility clinics, including 6 clinic groups which represent 70% of all clinics and clinic groups licensed to provide IUI in April 2014 when the survey email was sent. Results: Of the 46 clinics that responded, 96% (44/46) of clinics continue to offer IUI. 98% (43/44) of those offering IUI also use ovarian stimulation. The most commonly used medications for ovarian stimulation are gonadotrophins (95%), followed by clomiphene citrate (49%) and letrozole (19%). 78% (36/46) of clinics had formally discussed NICE guideline recommendations. 17 clinics (37%) had made some changes to their practices; as a result, four clinics reported a reduction in the number of IUI cycles, six clinics had restricted the indications for IUI, and five clinics had begun informing patients of the guideline recommendations, while two did not specify. Conclusions: The majority of clinics were aware of the guideline recommendations. However, only a small proportion of clinics had made significant changes to their practice by reducing the number of IUI cycles or restricting the clinical indications for IUI. The availability of further evidence will assist NICE and clinicians in making recommendations on the use of IUI. There is a need to further explore the reasons for the lack of adherence to the recommendations. Kim D, BMJ 2015

Objective: To study the effectiveness of an intrauterine insemination (IUI) program compared to no treatment in subfertile couples with unexplained subfertility and a poor prognosis on natural conception. Study design: A retrospective matched cohort study in which ongoing pregnancy rates in 72 couples who voluntarily dropped out of treatment with IUI were compared to ongoing pregnancy rates in 144 couples who continued treatment with IUI. Couples with unexplained subfertility, mild male subfertility or cervical factor subfertility who started treatment with IUI between January 2000 and December 2008 were included. Couples were matched on hospital, age, duration of subfertility, primary or secondary subfertility and diagnosis. Primary outcome was cumulative ongoing pregnancy rate after three years. Time to pregnancy was censored at the moment couples were lost to follow up or when their child wish ended and, for the no-treatment group, when couples re-started treatment. Results: After three years, there were 18 pregnancies in the stopped treatment group (25%) versus 41 pregnancies in the IUI group (28%) (RR 1.1 (0.59–2.2)(p = 0.4)). The cumulative pregnancy rate after three years was 40% in both groups, showing no difference in time to ongoing pregnancy (shared frailty model p = 0.86). Conclusions: In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples. In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples. Scholtena I , E J Obst & Gynec and Reprod Bio 2017

IUI STOP-GAP tedavi , beklerken veya IVF yerine subfertilte de empirik tedavi olarak çok sık kullanılmaktadır

Veltman-Verhulst SM, 2016 IUI versus TI or expectant management both in stimulated cycle Live birth rate (all cycles) There was no evidence of a difference between the two treatment groups (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs; n = 208; I2 = 72%; moderate quality evidence). The evidence suggested that if the chance of achieving a live birth in TI was assumed to be 26%, the chance of a live birth with IUI would be between 23% and 50%. IUI in a natural cycle versus IUI in a stimulated cycle An increase in live birth rate was found for women who were treated with IUI in a stimulated cycle compared with those who underwent IUI in natural cycle (OR 0.48, 95% CI 0.29 to 0.82; 4 RCTs, n = 396; I2 = 0%; moderate quality evidence). The evidence suggested that if the chance of a live birth in IUI in a stimulated cycle was assumed to be 25%, the chance of a live birth in IUI in a natural cycle would be between 9% and 21%. IUI in a stimulated cycle versus TI or expectant management in a natural cycle There was no evidence of a difference in live birth rate between the two treatment groups (OR 0.82, 95% CI 0.45 to 1.49; 1 RCT; n = 253; moderate quality evidence). The evidence suggested that if the chance of a live birth in TI or expectant management in a natural cycle was assumed to be 24%, the chance of a live birth in IUI in a stimulated cycle would be between 12% and 32%.

The Cochrane Library, 2012

The Cochrane Library, 2012

Toplam motil sperm sayısı, İnsemine edilen sperm sayısı IUI sonrası gebeliği etkileyen faktörler >36 yaş Kadın yaşı İnfertilite süresi ve nedeni Ovülasyon Monitörizasyonu Folikül sayısı / E2 Luteal destek gebelik IUI Toplam motil sperm sayısı, İnsemine edilen sperm sayısı Sperm hazırlama İnseminasyon aşaması metodları, teknik, zamanlama Doğal siklus, KOH. İnfertilite süresi> 2 yıl Ombelet W, RBM Online 2014

Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome, Huttunen SN Human Reproduction, 1999

Açıklanamayan infertilite Probability of a spontaneous live birth without treatment in a woman with either primary (no previous pregnancies) or secondary (previous pregnancies) infertility of 2 years duration, who is having regular intercourse and where she has normal ovulation, patent fallopian tubes and a partner with normal sperm motility (40%). Age of the woman is the most important predictor of successful conception without treatment with the rates falling at a greater rate after age 30 years Overall, about 15% of couples diagnosed with unexplained infertility will conceive without treatment within 1 year and 35% within 2 years (Isaksson & Tiitinen, 1998). However, the cumulative pregnancy rate over 3 years without treatment has been reported to be up to 80% in some groups (Guzick et al., 1998; Hull et al., 1985). Age of the woman is the most important predictor of successful conception without treatment with the rates falling at a greater rate after age 30 years (Isaksson & Tiitinen, 1998; Hunault et al., 2004) (see Figure 11.1).

The woman’s age was the strongest predictor of success in all indications, with an ongoing pregnancy rate per couple of 38.5% for the under 30s and 12.5% for the over 40s Merviel P, Fertility and Sterility 2010

Goldman MB, Fertil Steril. 2014 An RCT to compare treatment initiated with 2 cycles of COH/IUI to immediate IVF in older women with unexplained infertility demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group Cumulative clinical pregnancy rates per couple after the first 2 cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. There were 36% fewer treatment cycles in the IVF arm compared to either COH/IUI arm and couples conceived a pregnancy leading to a live birth after fewer treatment cycles. Objective—To determine optimal infertility therapy in women at the end of their reproductive potential. Design—Randomized clinical trial. Setting—Academic medical centers and private infertility center in a state with mandated insurance coverage. Patients—Couples with ≥ 6 months of unexplained infertility; female partner aged 38–42. Interventions—Randomized to treatment with 2 cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. Main Outcome Measures—Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after 2 treatment cycles and at the end of treatment. Results—154 couples were randomized to receive CC/IUI (N=51), FSH/IUI (N=52), or immediate IVF (N=51); 140 (90.9%) couples initiated treatment. Cumulative clinical pregnancy rates per couple after the first 2 cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatment, 71.4% (110/154) of couples conceived a clinically recognized pregnancy and 46.1% delivered at least one live-born baby. 84.2% of all live born infants resulting from treatment were achieved from IVF. There were 36% fewer treatment cycles in the IVF arm compared to either COH/IUI arm and couples conceived a pregnancy leading to a live birth after fewer treatment cycles. Conclusions—An RCT to compare treatment initiated with 2 cycles of COH/IUI to immediate IVF in older women with unexplained infertility demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group Goldman MB, Fertil Steril. 2014

Wendy K, uptodate 2011

The ESHRE Capri Workshop Group1Human Reproduction Update, Vol. 15, No The ESHRE Capri Workshop Group1Human Reproduction Update, Vol.15, No.3 pp. 265–277, 2009 Advanced Access publication on February 23, 2009 KOH Protokolleri Klomiphene citrate ve IUI, en sık kullanılan IUI protokolü olup, gebelik oranı ortalama 7% /siklus FSH ovarian stimulasyon ve IUI tedavide başarı orta derecede daha iyi 12%, multiple gebelik ortalama 13%.

Üç soru?? FSH/IUI ? veya tedavi yok? KOH Protokolleri FSH/IUI ? veya tedavi yok? FSH/IUI, CC/IUI göre daha mı etkili ? FSH/IUI sadece IUI göre daha mı üstün ?

FSH/IUI / Tedavi uygulanmayan durumdan daha mı başarılı ? ESHRE Capri Workshop Group Kısa süreli infertilite 2-3 yıl: FSH/IUI (4.3%) ve tedavisiz (4.6%), gruplarda “en azından açıklanamayan infertillerde” gebelik oranları arasında fark yok Fakat 3 yıldan uzun süreli infertil gruplarda “12% --- 3%”gibi daha iyi bir gebelik oranı sağlamakta. “11 FSH-IUI siklusuna ilave 1 gebelik” Guzick 1999.Steures 2006 İnfertilite süresi önemli bir prognostik faktör!

FSH/IUI--- CC / IUI göre daha mı etkili? Pregnancy rates following IUI combined with ovarian stimulation using either anti-estrogens or FSH. Live birth rates could not be assessed (Cantineau et al., 2007). FSH/IUI--- CC / IUI göre daha mı etkili? 7 çalışma 556 çiftAçıklanamayan infertilite, mild male faktor ve mild endometriosis, evet FSH-IUI da gebelik oranları daha yüksek, %5.7 fark anlamlı değil j

açıklanamayan infertilite , Live birth rate per couple following IUI with or without FSH ovarian stimulation (Verhulst et al., 2006) FSH/IUI sadece IUI göre daha mı üstün ? Evet Canlı doğum oranları anlamlı olarak FSH-IUI sikluslarında Doğal siklus-IUI göre daha yüksek, 12 IUI siklusuna ilave 1 gebelik açıklanamayan infertilite ,

In ovulatory women undergoing IUI, ovarian stimulation with LE and HMG, but not with CC, LE, HMG or CC combined with HMG, significantly improved the pregnancy and live birth rates. In anovulatory women undergoing ovarian stimulation and IUI, there are no significant differences in pregnancy and live birth rates among the various stimulation protocols. Objective To evaluate the impact of ovarian stimulation on the outcome of intrauterine insemination (IUI). Design Retrospective analysis. Setting A single university-based centre. Population A total of 5109 couples with 8893 cycles. Methods The outcome of IUI with different protocols for ovarian stimulation was examined. Main outcome measures The live birth rate (LBR), twin pregnancy rate and ovarian hyperstimulation syndrome (OHSS). Results In ovulatory women without ovarian stimulation, the LBR was 7.6%. Stimulation with clomifene citrate (CC), letrozole (LE), human menopausal gonadotrophin (HMG), CC or LE combined with HMG achieved LBRs of 6.1, 5, 7.9, 8 and 12.2%, respectively. LE combined with HMG achieved a significantly improved LBR compared with no stimulation. HMG stimulation was associated with a higher rate of twins (7.4%) than no stimulation (0%, P < 0.01). In ovulatory women, the LBR appeared lower in CC and LE compared with no stimulation (P > 0.05). In anovulatory women, ovarian stimulation with CC, LE, HMG, CC or LE combined with HMG achieved LBRs of 11.3, 5.1, 11.8, 12.6 and 13.6%, respectively. No significant difference was observed. There were no triplet pregnancies or OHSS in stimulated cycles. Conclusions In ovulatory women, ovarian stimulation with LE combined with HMG achieved a significantly improved live birth rate. HMG stimulation resulted in a high risk for twins. Liu J, BJOG 2016

Folikül sayısı ? 3 preovulatuar folikül varlığında gebelik oranı en yüksek %16.3, bir folikül varlığında %5.7 Huttunen SN 1999, Tomlinson 1996,Hughes 1998, Erdem A 2008 Kuzey Avrupa ülkelerinde iyi bir prognoz göstersede multipl folikül gelişimine çoğul gebelik riski nedeniyle sıcak bakılmıyor ve siklus iptal nedeni sayılmakta NICE National Institute for Clinical Excellence,2004 Ülkemizde >2 16 mm follikül , yönetmelik gereği IUI uygulaması iptal

Ongoing pregnancy rate per couple with one cycle of FSH/IUI with and without GnRH antagonist treatment. In seven RCTs, the average ongoing pregnancy rate was only 5.3% greater withGnRH antagonist treatment (95% CI: 1.5, 9.2). This means that it would take 20 cycles of GnRH antagonist administration to have one pregnancy more than without GnRH antagonist treatment Lambalk et al., 2006).

Intrauterine insemination used for treating male factor infertility has little chance of success when the woman is older than 35 years, the number of motile spermatozoa inseminated is <5 x 106, or normal sperm morphology is <30%. Badawy. Fertil Steril 2009.

Lemmens L, Fertil Steril 2016 Intrauterine insemination is especially relevant for couples with moderate male factor infertility (sperm morphology %4%, NIPMS 5–10 million). In the multivariable model, however, the predictive power of these sperm parameters is rather low Hic bir sperm parmetresi gebelik için predictive degere sahip değil, ancak sperm morfoloji %4 ve toplam insemine edilen progressive motil sperm sayısı5-10 milyon ile pozitif ilişki bulunmuştur. Objective: To investigate the value of sperm parameters to predict an ongoing pregnancy outcome in couples treated with intrauterine insemination (IUI), during a methodologically stable period of time. Design: Retrospective, observational study with logistic regression analyses. Setting: University hospital. Patient(s): A total of 1,166 couples visiting the fertility laboratory for their first IUI episode, including 4,251 IUI cycles. Intervention(s): None. Main Outcome Measure(s): Sperm morphology, total progressively motile sperm count (TPMSC), and number of inseminated progressively motile spermatozoa (NIPMS); odds ratios (ORs) of the sperm parameters after the first IUI cycle and the first finished IUI episode; discriminatory accuracy of the multivariable model. Result(s): None of the sperm parameters was of predictive value for pregnancy after the first IUI cycle. In the first finished IUI episode, a positive relationship was found for%4% of morphologically normal spermatozoa (OR 1.39) and a moderate NIPMS (5–10 million; OR 1.73). Low NIPMS showed a negative relation (%1 million; OR 0.42). The TPMSC had no predictive value. The multivariable model (i.e., sperm morphology, NIPMS, female age, male age, and the number of cycles in the episode) had a moderate discriminatory accuracy (area under the curve 0.73). Conclusion(s): Intrauterine insemination is especially relevant for couples with moderate male factor infertility (sperm morphology %4%, NIPMS 5–10 million). In the multivariable model, however, the predictive power of these sperm parameters is rather low Lemmens L, Fertil Steril 2016

Gebelik oranları yüksek hastalar; Anovulasyon Normal over reservi <38 yas Bifoliküler gelişim Toplam insemine edilen progresive motil sperm sayısı>1 milyon Objective: To identify the prognostic factors for pregnancy after intrauterine insemination with the husband's sperm (IUI-H). Design: Retrospective study. Setting: A single university medical center. Patient(s): 851 couples, for 2,019 IUI-H cycles. Intervention(s): After controlled ovarian stimulation, IUI-H performed 36 hours after ovulation triggering or 24 hours after a spontaneous luteinizing hormone (LH) surge. Main Outcome Measure(s): Clinical pregnancy rate per cycle (PR) and delivery rate per cycle (DR). Result(s): The overall PR was 14.8% and DR 10.8%. Higher PR and DR were observed for patients presenting with ovulation disorders (particularly polycystic ovary syndrome) or with male infertility. Secondary infertility in the woman appeared to be a positive prognostic factor as did a basal follicle-stimulating hormone (FSH) level %7 IU/L and ovulation triggering over spontaneous LH rise. The other parameters influencing the results were the women's age, the number of mature follicles obtained (R2), the endometrial thickness (10–11 mm), and the number of progressive motile spermatozoa inseminated (>1 million). Conclusion(s): In women aged ≤38 years, IUI-H should be considered as an option, particularly in cases of female infertility from ovulation disorders, in cases of a normal ovarian reserve, in cases of secondary infertility, or when ≥1 million progressive sperm are inseminated. Bifollicular stimulation is required. In other cases, in vitro fertilization should be discussed as the first-line treatment In women aged ≤38 years, IUI-H should be considered as an option, particularly in cases of female infertility from ovulation disorders, in cases of a normal ovarian reserve, in cases of secondary infertility, or when ≥1 million progressive sperm are inseminated. Bifollicular stimulation is required. In other cases, in vitro fertilization should be discussed as the first-line treatment Dinelli L, Fertil Steril 2014

Toplam insemine edilen progressive motil sperm sayısı The pregnancy rate was only 4.05% if less than 2.000.000 motile spermatozoa were used, but this rose to 14.55% when more than 2.000.000motile spermatozoa were inseminated. We therefore conclude that IUI can be performed when the NMSI exceeds 2.000.000. With this recommendation, IUI with husband’s spermatozoa can be used to treat many more infertile couple Toplam insemine edilen progressive motil sperm sayısı <2 milyon.. %4.05 gebelik , > 2 milyon %14.55 gebelik Intrauterine insemination (IUI) is an effective, noninvasive, relatively simple and cheap method of infertility treatment. Many factors that affect IUI outcomes have been studied. However, there is no consensus about the optimal number of motile spermatozoa inseminated (NMSI) required for a reasonable chance of pregnancy after IUI. In this retrospective study, we aimed to assess the relationship between NMSI and the pregnancy rate after IUI with husband’s spermatozoa. Couples who had either primary or secondary infertility for more than one year were recruited from the Department of Reproduction, Nanjing Maternity and Child Health Hospital, China, between January 2007 and December 2010. Overall, 1153 IUI cycles with husband’s spermatozoa were performed in 645 women after ovarian stimulation. Factors that have previously been associated with a successful fertilisation after IUI were assessed. A total pregnancy rate of 13.88% was obtained. The pregnancy rate was only 4.05% if less than 2 9 106 motile spermatozoa were used, but this rose to 14.55% when more than 2 9 106 motile spermatozoa were inseminated. We therefore conclude that IUI can be performed when the NMSI exceeds 2 9 106. With this recommendation, IUI with husband’s spermatozoa can be used to treat many more infertile couples. Cao S, Andrologia 2013

Sperm parameters most frequently examined were: inseminating motile count after washing: cut-off value between 0.8 and 5 million; (ii) sperm morphology using strict criteria: cut-off value 5% normal morphology; (iii) total motile sperm count in the native sperm sample: cut-off value of 5–10 million; (iv) total motility in the native sperm sample: threshold value of 30%. In conclusion, the literature did not reveal level 1 evidence on the relationship between sperm quality and IUI success. Although more prospective observational cohort studies and well-organized retrospective analyses are urgently needed, this structured review indicates that IMC >1 million with IUI is probably the best cost-effective treatment before starting IVF, irrespective of sperm morphology. More answers to the question as to when to perform IUI in male factor infertility cases will never be obtained until more multicentre prospective trials according to standard protocols are organized. Despite the current ongoing debate concerning cost-effectiveness of IUI versus IVF in moderate male factor infertility, other factors might be important, such as the well-known differences between both strategies in risk profile and patient satisfaction. Ombelet W, RBM Online 2014

Yıkama sonrası sperm sayısının önemi Yıkanma örneğındeki her ekstra 1 milyon sperm gebelik şansını %2 arttırır Puschek et all PCRS abstracts 2009 PASQUALOTTO et al. Journal of Assisted Reproduction and Genetics, 1999

Toplam insemine edilen progressive motil sperm sayısı(NMSI) <5-10 milyon NMSI>5milyon ve kadın yaşı>35 NMSI>5milyon ve morfoloji<%4, veya %30 IUI başarı IVF

Couples in which the DFI of the male partner is high can avoid prolonged attempts to become spontaneously pregnant or referral for intrauterine insemination, both having low chances of leading to conception. The mean DFI was 16.2% (median 15%, range 4–50%). The percentage of men with DFI 20%, in the cohort of fertile men with normal standard sperm parameters was 10.5% (95% CI 6.29–17.0%), this value being significantly lower than those found in men from ‘unexplained infertility couples’ (p = 0.005). K. Oleszczuk, Andrology, 2013

Sperm hazırlama IUI öncesi seminal plazmanın uzaklaştırılması prostaglandinin yol açacağı uterine kontraksiyonları ve pelvik enfeksiyonları önlemek için gereklidir. Sperm hazırlama metodlarının sistematik değerlendirmesinde en iyi methodu seçmek için randomize kontrollü çalışmalar yetersizdir.” Boomsma et al., 2007”

Zamanlama? HCG uygulamasından 32-36-40 saat sonra LH yükselmesi tespitinden 24 saat sonra LH yükselmesi sonrası HCG yapıldığında gebelik oranları daha yüksek Kosmas I Fertil Steril 2007 Fuh W Human reprod 1997

Tek/ Çift uygulama IUI Tek uygulama ile çift uygulama arasında gebelik oranları açısından fark yok Polyzos Fertil Steril 2010 NICE Guidance Feb. 2004 Cantineau et al., 2003

Kaç kez IUI ? Gebelikler genellikle ilk uygulanan sikluslarda meydana gelir Gebeliklerin %88’ i ilk 3 siklusta %95.5’i ilk dört siklusta , Dört denemeden sonra IUI uygulamasına devam etmek önerilmemektedir. Morshedi M et al, 2003Custers M Human Reprod 2008 Predictive factors for pregnancy after intrauterine insemination (IUI): An analysis of 1038 cycles and a review of the literature Merviel P, et all., Fertility and Sterility Vol. 93, No. 1, January 2010

Kateter tipi “Sert vs Yumuşak” The Cochrane Library, 2010 Yumuşak kateter veya sert kateter ? ; gebelik oranları arasında fark yok Aou Setta Human Reprod.2006 Miller PB Fertil Steril 2005 Van der Poel N Cochrane 2010 Yumuşak kateterle gebelik oranı, sert katetere göre istatistiki olarak anlamlı yüksek sırasıyla %15.3, %7, p<0.01 Merviel Fertil Steril 2010

IUI sonrası yönetim Yatak istirahati IUI sonrası 10- 15 dk istirahat gebelik oranına  pozitif etki ? HCG günü ve 12- 24 saat sonra ilişki önerilebilir Luteal faz desteği ?

Luteal phase support with vaginal progesterone improved the success of intrauterine insemination cycles when recombinant follicle-stimulating hormone was used for ovulation induction Eurp j obst gyneco and reprod biol, 2011

Objective: To evaluate the effect of progesterone (P) for luteal phase support after ovulation induction (OI) and intrauterine insemination (IUI). Design: An updated systematic review and meta-analysis. Setting: Not applicable. Patient(s): Patients undergoing OI-IUI for infertility. Intervention(s): Exogenous P luteal support after OI-IUI. Main Outcome Measure(s): Live birth. Result(s): Eleven trials were identified that met inclusion criteria and constituted 2,842 patients undergoing 4,065 cycles, more than doubling the sample size from the previous meta-analysis. In patients receiving gonadotropins for OI, clinical pregnancy (relative risk [RR] 1.56, 95% confidence interval [CI] 1.21–2.02) and live birth (RR 1.77, 95% CI 1.30–2.42) were more likely in P supplemented patients. These findings persisted in analysis of live birth per IUI cycle (RR 1.59, 95% CI 1.24–2.04). There were no data on live birth in clomiphene citrate or clomiphene plus gonadotropin cycles. There was no benefit on clinical pregnancy with P support for patients who underwent OI with clomiphene (RR 0.85, 95% CI 0.52–1.41) or clomiphene plus gonadotropins (RR 1.26, 95% CI 0.90–1.76). Conclusion(s): Progesterone luteal phase support is beneficial to patients undergoing ovulation induction with gonadotropins in IUI cycles. The number needed to treat is 11 patients to have one additional live birth. Progesterone support did not benefit patients undergoing ovulation induction with clomiphene citrate or clomiphene plus gonadotropins. Progesterone luteal phase support is beneficial to patients undergoing ovulation induction with gonadotropins in IUI cycles. The number needed to treat is 11 patients to have one additional live birth. Progesterone support did not benefit patients undergoing ovulation induction with clomiphene citrate or clomiphene plus gonadotropins Green KA, Fertil Steril 2017

Peeraer K, Fertil Steril 2017 Objective: To evaluate the effect of luteal phase support (LPS) in intrauterine insemination (IUI) cycles stimulated with gonadotropins. Design: Randomized multicenter trial. Setting: Academic tertiary care centers and affiliated secondary care centers. Patient(s): Three hundred and ninety-three normo-ovulatory patients, <43 years, with body mass index%30 kg/m2, in their first IUI cycle, with at least one patent tube, a normal uterine cavity, and a male partner with total motile sperm count R5 million after capacitation. Intervention(s): Gonadotropin stimulation, IUI, randomization to LPS using vaginal progesterone gel (n ¼ 202) or no LPS (n ¼ 191). Main Outcome Measure(s): Clinical pregnancy rate, live-birth rate, miscarriage rate, and duration of the luteal phase. Result(s): The primary outcome, the clinical pregnancy rate, was not statistically different between the treatment group (16.8%) and the control group (11%) (relative risk [RR] 1.54; 95% confidence interval [CI], 0.89–2.67). Similarly, the secondary outcome, the livebirth rate, was 14.9% in the treatment group and 9.4% in the control group (RR 1.60; 95% CI, 0.89–2.87). The mean duration of the luteal phase was about 2 days longer in the treatment group (16.6 2.2 days) compared with the control group (14.6 2.5 days) (mean difference 2.07; 95% CI, 1.58–2.56). Conclusion(s): Although a trend toward a higher clinical pregnancy rate as well as live-birth rate was observed in the treatment group, the difference with the control group was not statistically significant. Although a trend toward a higher clinical pregnancy rate as well as live-birth rate was observed in the treatment group, the difference with the control group was not statistically significant. Peeraer K, Fertil Steril 2017

Hum Reprod, 2010

ECONOMY DIFFERENTIAL COST OPPORTUNITY COST SUNK COST

Açıklanamayan infertilite Tedavi seçeneği Gebelik oranı Maliyet Expectant management %1-3 <50 dolar IUI %4-6 300 Klomifen sitrat 100 Klomifen sitrat+ IUI %7-9 400 Gonadotropin %4-10 2000 Gonadotropin+ IUI %9-16 2300 IVF %20-40 12000 Uptodate , 2012

/canlı doğum, sırasıyla. Maliyet analizi “ BİR MODELDE “AÇİKLANAMAYAN VEYA MİLD ERKEK FAKTÖRÜ” , MATEMATİKSEL” “PASHAYAN ET AL., 2006” IVF: £12 600 IUI + IVF: £13 100 S-IUI + IVF: £15 100 /canlı doğum, sırasıyla. 6 siklus IUI + IVF = £ 174.200 “ 54 ilave IVF siklusu, 14 c.d.” 6 siklus s-IUI + IVF= £438.000 “136 ilave IVF siklusu, 35 c.d.” x Açıklanamayan infertilite ve mild male faktor de primer teklif IVF olması hem daha ucuz hemde daha efektif “Pashayan et al., 2006”

Tedavi planı Standart protokol 3 siklus CC / IUI…..3 siklus FSH /IUI …6 siklus IVF Alternatif protokol hızlandırılmış, 3 siklus CC /IUI ….FSH/IUI yok…. 6 siklusa kadar IVF IVF ‘e güç yettiğinde IUI gereksiz ! mi? Hızlandırılmış kolda %65 standart kolda % 64 klinik gebelik , hızlandırılmış kolda daha kısa sürede gebelik elde edilir. Ortalama IVF siklusları standart kolda 1.1 hızlandırılmış olanda 1.4., hızlandırılmış kolda 2.642 dolar tasaruf/hasta başı ve 0.06 daha fazla gebelik “Reindollar et al., 2007” EVET ! 35 yaşın altı 3 yıldan az infertilite süresi olanlarda IVF seçimi premature bir seçim olur. The ESHRE Capri Workshop Group1Human Reproduction Update, Vol.15, No.3 pp. 265–277, 2009 Advanced Access publication on February 23, 2009,

6ay bekleme-IUI-IVF / IUI-IVF 3 yıl sonında sonuc aynı Infertility outcomes can be influenced by many factors. Although a number of treatments are offered, deciding which one to use first is a controversial topic. Although IVF may have superior efficacy in achieving a live birth with a reasonable safety profile, the availability of cheaper and less invasive treatments preclude its absolute use. For this reason, certain patient groups with ‘good prognosis’ infertility are traditionally treated with less invasive treatments first Lina N Huang, RBM Online 2015 Helsinki ESHRE 2016 38 < ıyı prognozlu 3 ıuı / 1 IVF 532 /34 gebelık Custers ve ark 6ay bekleme-IUI-IVF / IUI-IVF 3 yıl sonında sonuc aynı Hollanda Mal An. 3 IUI / 1IVF %47 / 52 gebelık 2117 euro ucuz

Geislera EM, E J Obst & Gynec and Reprod Bio 2017 IUI/COH is a simple treatment that produces good live birth rates, especially in younger patients and/or those with previous parity. More than 90% of total live births with IUI/COH is achieved during the first two cycles. As a retrospective, observational study, there is no comparator group and therefore we cannot comment on the relative efficacy of up to three IUI cycles over expectant management in a similar cohort. Our study suggests that probabilities of success can be used to individualise treatment decisions and that there is merit in continuing to offer IUI before resorting to IVF for certain patients Objective: To determine the per cycle chance of a live birth and to identify factors that may support a more individualised application of IUI in view of National Institute for Health and Care Excellence (NICE) updated guideline on fertility 2013. Study design: A retrospective, cohort study of 851 couples (1688 cycles) with unexplained, mild endometriosis, one patent Fallopian tube (with ovulation occurring in the corresponding ovary), mild male factor or ovulatory dysfunction, who initiated their first cycle of IUI/COH during the study period 2009–2013 and completed up to 3 cycles. Exclusion criteria included donor sperm and diminished ovarian reserve. Success factors and probabilities were determined based on live birth rates. Results: Mean age was 33.8 3.3 years and mean duration of subfertility was 2.28 1.47 years. Independent associates of successful outcome factors were lower age (AOR 0.93; 95%CI 0.89–0.98, p = 0.007) and multiparity (AOR 1.72; 95%CI 1.17–2.52). Live-birth rates declined independently of other factors from 15.3% (n = 130/851) in cycle 1–7.0% (n = 19/273) in cycle 3 (AOR 0.76; 95%CI, 0.62–0.93, p = 0.008). Per cycle probabilities of live birth ranged from 21.4% to 5.1% dependent on age, cycle number and previous parity. The unadjusted cumulative pregnancy rate for live birth per cycle started, over three cycles, was 34.9% with a multiple live birth rate per cycle started of 5.4%. The associates of live birth amongst those with unexplained sub-fertility only (n = 632, first cycle attempt) were also analysed, yielding similar results. Conclusions: IUI/COH is a simple treatment that produces good live birth rates, especially in younger patients and/or those with previous parity. More than 90% of total live births with IUI/COH is achieved during the first two cycles. As a retrospective, observational study, there is no comparator group and therefore we cannot comment on the relative efficacy of up to three IUI cycles over expectant management in a similar cohort. Our study suggests that probabilities of success can be used to individualise treatment decisions and that there is merit in continuing to offer IUI before resorting to IVF for certain patients. Geislera EM, E J Obst & Gynec and Reprod Bio 2017

IUI-Kümülatif gebelik oranı %5-20 Kadın yaşı >38 - 40 İnfertilite süresi uzadıkça Ciddi male faktör varlığında Başarı Merviel P, Fertil Steril 2010 Harris ID, Fertil Steril 2010

Özet… İyi prognoza sahip “genç, infertilite süresi kısa olan ”çiftlerde canlı doğum oranları tedavisiz daha iyi “” Hasta seçimi oldukça önemlidir Kadın Yaşı …… < 36 - 38 İnfertilite süresi….=<4 – 6 Follikül sayısı “İdeal sitimulasyon en az iki folikül >16 mm, hCG verildiği gün E2 >500 pg/mL” Toplam insemine motil sperm sayısı…. 5 milyon > IUI uygulama kararı ve sayısı, hastanın yaşı, over reservi ve infertilite süresi , sper sayısı dikkate alınarak belirlenmelidir

TEŞEKKÜRLER

In couples with unexplained subfertility, one cycle of IVF–eSET cost an additional €900 per couple compared with three cycles of IUI–ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. (24%-21%) When IVF–eSET results in higher ongoing pregnancy rates (38%-21%), IVF would be the preferred treatment Couples with unexplained subfertility are often treated with intrauterine insemination (IUI) with ovarian stimulation, which carries the risk of multiple pregnancies. An explorative randomized controlled trial was performed comparing one cycle of IVF with elective single-embryo transfer (eSET) versus three cycles of IUI–ovarian stimulation in couples with unexplained subfertility and a poor prognosis for natural conception, to assess the economic burden of the treatment modalities. The main outcome measures were ongoing pregnancy rates and costs. This study randomly assigned 58 couples to IVF–eSET and 58 couples to IUI–ovarian stimulation. The ongoing pregnancy rates were 24% in with IVF–eSET versus 21% with IUI–ovarian stimulation, with two and three multiple pregnancies, respectively. The mean cost per included couple was significantly different: €2781 with IVF–eSET and €1876 with IUI–ovarian stimulation (P < 0.01). The additional costs per ongoing pregnancy were €2456 for IVF–eSET. In couples with unexplained subfertility, one cycle of IVF–eSET cost an additional €900 per couple compared with three cycles of IUI–ovarian stimulation, for no increase in ongoing pregnancy rates or decrease in multiple pregnancies. When IVF–eSET results in higher ongoing pregnancy rates, IVF would be the preferred treatment When IVF–eSET results in higher ongoing pregnancy rates, IVF would be the preferred treatment. if a clinic has a cumulative ongoing pregnancy rate of 21% with IUI and an ongoing pregnancy rate of 38% or higher with IVF–eSET, IVF–eSET is more cost-effective and should be the treatment of choice. When IVF–eSET results in higher ongoing pregnancy rates, IVF would be the preferred treatment. if a clinic has a cumulative ongoing pregnancy rate of 21% with IUI and an ongoing pregnancy rate of 38% or higher with IVF–eSET, IVF–eSET is more cost-effective and should be the treatment of choice. Van Rumste, RBM online. 2014