{"paper_id":"a57106c3-2215-4b8c-9000-ecb41084e815","body_text":"J Endometr Pelvic Pain Disord 2017; 9(3): 158-167\nJEPPD\nISSN 2284-0265\n© 2017 Wichtig Publishing\nREVIEW\nis impaired (6). However, this recommendation is based on \nexperts’ opinion only.\nIn minimal to mild endometriosis-related subfertility \n(American Society for Reproductive Medicine [ASRM] stages \n1-2), IUI is shown to be superior to expectant management \n(7), and IUI preceded by controlled ovarian hyperstimulation \nresults in higher pregnancy rates compared to IUI alone (8). In \nmoderate to severe endometriosis-related subfertility (ASRM \nstages 3-4), firm recommendations on performing IUI are \nlacking in both the European and American guidelines (6, 9). \nTherefore, IUI as an MAR treatment option is not structurally \noffered prior to IVF in this subgroup of patients.\nHowever, in our experience, IUI (with controlled ovarian \nhyperstimulation) might be a valuable treatment option in \nmoderate to severe endometriosis patients with normal tub-\nal-ovarian function. This is supported by recent observational \ndata showing cumulative ongoing pregnancy rates of 41.3% \nafter 6 treatment cycles (10). In addition, it is also suggested \nthat long-term pituitary desensitization with a gonadotropin-\nreleasing hormone (GnRH) agonist prior to the start of IUI \nshould be considered (10), since this may improve pregnancy \nrates (11, 12).\nDOI: 10.5301/jeppd.5000299\nPregnancy rates after intrauterine insemination in \nmoderate to severe endometriosis: a systematic review \nand meta-analysis of observational studies\nLisette E.E. van der Houwen1, Anneke M.F. Schreurs1, Roel Schats1, Pam Kaspers2, Cornelis B. Lambalk1, Peter G.A. Hompes1, \nVelja Mijatovic1\n1  Department of Obstetrics and Gynecology, Division of Reproductive Medicine, Academic Endometriosis Center VUMC, VU University Medical \nCenter, Amsterdam - The Netherlands\n2 Medical Library, Vrije Universiteit Amsterdam, Amsterdam - The Netherlands\nIntroduction\nEndometriosis is a benign, estrogen-dependent gyneco-\nlogical disease in which fecundity is commonly impaired (1). \nTreatment of endometriosis-related subfertility is widely de-\nbated in literature (2-5). The evidence to perform surgery \nand/or use medically assisted reproduction (MAR) tech-\nniques, including intrauterine insemination (IUI) and in vitro \nfertilization (IVF), was updated in 2014 (6).\nIn women with moderate to severe endometriosis, sur -\ngery or IVF might be advised, especially when tubal function \nABStRAC t\nTo evaluate the efficacy and safety of intrauterine insemination (IUI) in moderate to severe endometrio-\nsis patients, a systematic review and meta-analysis was conducted since the role of this treatment strategy \nin these patients is a matter of debate in the literature. Systematic searches were performed in PubMed,  \nEMBASE, Cinahl, and The Cochrane Library from inception to September 1, 2016. Studies including moderate \nto severe endometriosis patients reporting pregnancy rates after IUI were selected. The primary outcome \nwas live birth after IUI treatment compared to expectant management. Secondary noncomparative outcomes \nwere live birth and clinical pregnancy, which were presented as weighed mean pregnancy rates. Nineteen \narticles (2 unclear design, 11 retrospective, 6 prospective) were included for the analysis. Our primary out -\ncome measure was only addressed by one study, showing an odds ratio of 1.77 (95% confidence interval  \n[CI], 0.86-3.63) on live birth favoring IUI versus no treatment. The calculated weighed mean live birth and \nclinical pregnancy rate per patient was 20.3% (95% CI, 11.2-29.4) and 32.7% (95% CI, 21.3- 44.0), respec-\ntively. This meta-analysis of observational data showed that IUI could be a feasible treatment in moderate to  \nsevere endometriosis. Whether this treatment should be structurally offered prior to in vitro fertilization \nneeds to be investigated in a randomized, controlled trial, including time-to-pregnancy, safety, and cost-  \neffectiveness.\nKeywords: Endometriosis, Intrauterine insemination, Meta-analysis, Pregnancy, Recurrence\nAccepted: August 3, 2017\nPublished online: August 25, 2017\nCorresponding author:\nLisette E.E. van der Houwen\nDepartment of Reproductive Medicine\nVU University Medical Center\nP .O. Box 7057\n1007 MB Amsterdam, The Netherlands\nl.vanderhouwen@vumc.nl\n\nvan der Houwen et al\n 159\n© 2017 Wichtig Publishing  \nIn view of the current lack of guidance, we aimed to per -\nform a systematic review and meta-analysis of observational \ndata, investigating the efficacy and safety of IUI (with ovarian \nstimulation) and the additional effect of preceded long-term \npituitary desensitization with a GnRH agonist in patients with \nmoderate to severe endometriosis to endorse future ran-\ndomized trials.\nMethods\nSearch strategy\nBoth MOOSE (13) and PRISMA (14) guidelines were used \nto conduct this meta-analysis. To identify all relevant publica-\ntions, we performed systematic searches in the bibliographic \ndatabases PubMed, EMBASE.com, Cinahl, and The Cochrane \nLibrary (via Wiley) from inception to September 1, 2016. \nThe search terms included controlled terms (e.g., MeSH in \nPubMed, EMtree in EMBASE.com, Mesh Headings in Cinahl) \nand free-text terms. We used free-text terms only in The \nCochrane Library. Search terms expressing “endometriosis” \nwere used in combination with search terms comprising \n“intra-uterine insemination (IUI) treatment.” No limitations \nwere used. The Medline search strategy is presented as sup -\nplementary material (available online at www.j-endometrio-\nsis.com); the search strategies for the other databases were \nbased on this strategy. The references of the identified arti-\ncles were also searched for relevant publications.\nSelection process\nL.H. and A.S. independently selected articles by title and \nabstract, which were then coded, but did not show author, \nyear, or journal, to limit selection bias by investigators. To \nbe included, peer reviewed articles, including randomized, \ncontrolled trials (RCT) and observational studies with and \nwithout a control group of patients receiving no treatment, \nneeded to report on absolute pregnancy numbers per patient \nand/or per IUI treatment cycle in specifically moderate to se-\nvere endometriosis patients. To prevent a limited selection \nof papers, all IUI treatment strategies (i.e., with ovarian hy -\nperstimulation with clomiphene citrate, recombinant follicle-\nstimulating hormone [FSH] or human menopausal gonadotro-\nphins, and unstimulated cycles) were included. Only articles \nreporting primary data were selected. Studies were excluded \nif they (i) presented nonprimary data; (ii) were in languages \nother than English, Dutch, German, French, or Spanish; and \n(iii) included IUI treatment cycles performed with donor se -\nmen. Through discussion, consensus was formed regarding \ndoubtful articles.\nData assessment\nThe full texts of the selected articles were obtained for \nfurther review. Two reviewers (L.H. and A.S.) independent -\nly evaluated the papers using a standardized record form, \nchecking whether all the necessary data were provided in \nthe article. Disagreement between the reviewers on indi-\nvidual items were identified and solved during a consensus \nmeeting.\nData extraction\nDetails about the following elements were extracted and \ntabulated independently by two investigators (L.H. and A.S.) \nfrom the publications: study design, treatment outcomes, \nnumber of patients with moderate to severe endometriosis, \nnumber of treatment cycles, IUI treatment characteristics \n(i.e., medication used for controlled ovarian hyperstimula -\ntion, use of preceding long-term pituitary desensitization and \nits duration), and treatment outcomes (definition of pregnan-\ncy, number of pregnancies, pregnancy rate per cycle and per \npatient). No unpublished data were used.\nOutcomes\nThe primary outcome concerned the efficacy of IUI treat-\nment defined as live birth rate after IUI compared to expectant \nmanagement. Secondary outcomes were biochemical; clinical; \nongoing pregnancy per patient and per cycle; the efficacy of \npreceded treatment with a GnRH agonist; and recurrence of \nendometriosis.\nStatistical analysis\nTo calculate the odds ratio (OR) of live birth in RCTs and \nobservational (comparative) studies, forest plots were con-\nducted with a 95% confidence interval (95% CI) by using Re -\nview Manager (version 5, The Cochrane Library). In case of  \nobservational, noncomparative studies, statistical analysis was \nperformed to calculate and plot the weighed mean pregnancy \nrate with a 95% CI of the included studies by using Microsoft  \nExcel (15). Plots of weighed mean clinical pregnancy and live \nbirth were composed. Heterogeneity was tested using the Q \ntest and I² test (16).\nResults\nSearch results\nFigure 1 presents the selection process of the literature \nsearch. The search generated a total of 913 references: in \nPubMed, in EMBASE.com, in Cinahl, and in The Cochrane Li -\nbrary. After removing duplicates of references that were se-\nlected from more than one database, 646 titles and abstracts \nwere examined. Of these titles and abstracts, 259 full texts \nwere selected for further investigation. After reading the full \ntexts, 18 articles were selected. An additional 2 articles were \nadded to the selection after screening references. One article \n(17) was excluded due to overlapping data resulting in a final \nselection of 19 articles.\nOverview of studies\nCharacteristics of the retrieved articles are presented in \nTable I. No RCTs were found comparing IUI treatment with \nexpectant management in moderate to severe endometrio-\nsis patients. One prospective observational study published \nby Keresztúri et al (18) compared IUI treatment with expect -\nant management in surgically treated endometriosis pa-\ntients. From all other included studies, noncomparative data \n\nEfficacy of IUI in moderate to severe endometriosis\n160 \n© 2017 Wichtig Publishing\nFig. 1 - Flowchart.\nconcerning IUI treatment in moderate to severe endome -\ntriosis patients were extracted. One RCT compared an ultra-\nlong GnRH agonist protocol with 2 weeks of GnRH agonist \ntreatment prior to ovarian hyperstimulation with IUI (11). \nIn 5 studies, inclusion was limited from moderate to severe \nendometriosis patients (10, 19-22). In all other studies, mod-\nerate to severe endometriosis patients were a subgroup of \nincluded patients (18, 23-34).\nPrimary outcome\nKeresztúri et al (18) performed the only prospective nonran-\ndomized study that was included in our meta-analysis, which in-\nvestigated the benefit of surgery followed by IUI with controlled \novarian hyperstimulation over surgery followed by no treat -\nment during a follow-up period of 12 months. No significant \ndifference was shown between the groups with an OR of 1.77 \n(95% CI, 0.86-3.63) (Fig. 2). In this study, no long-term pituitary \ndesensitization with a GnRH agonist was performed.\nSecondary outcomes\nTreatment outcomes are presented in Table II. Twelve \nstudies reported on clinical pregnancies (11, 18, 19, 21, 23, \n25, 26, 28-31, 33). The calculated weighed mean clinical \npregnancy rate was 13.4% per treatment cycle and 32.7% per \npatient with a 95% CI of 7.4-19.4 and 21.3-44.0, respectively \n(Fig. 3). The test for heterogeneity showed a Q of 11.5 and 7.8 \nper cycle and per patient, respectively, and an I\n2 of 39.0% and \n0% on pregnancy rate per cycle and per patient, respectively, \nusing the random effects model for both values.\nNine studies reported on live births (10, 11, 18, 19, 23, 25, \n26, 28, 29). The calculated weighed mean live birth rate per \ncycle and per patient was 5.6% (95% CI, 3.0-8.2) and 20.3% \n(95% CI, 11.2-29.4), respectively (Fig. 4). The test for hetero-\ngeneity showed a Q of 8.1 and 7.4 per cycle and per patient, \nrespectively, and an I\n2 of 25.9% and 5.4% on pregnancy rate \nper cycle and per patient, respectively, using the random ef -\nfects model for both values.\nSeven studies included patients undergoing long-term pitu-\nitary desensitization using GnRH agonists prior to IUI treatment \n(10, 11, 21, 22, 24, 28, 33). However, no studies included a con-\ntrol group of IUI treatment with no preceding GnRH agonist \nuse. One trial (11), which used a randomized, controlled set -\nting to compare ultra-long treatment of at least 6 weeks with \n2 weeks of GnRH agonist pre-treatment, showed an OR of 3.53 \n(95% CI, 0.34-37.15; p = 0.29).\nThe rate of recurrence of endometriosis was reported in 1 \nstudy (10). Recurrence of endometriosis, which was defined \nas recurrence of or increase in patient’s complaints within 12 \nmonths after the last IUI treatment attempt, was seen in 24 \nout of 65 patients (36.9%), requiring no intervention (n = 2),  \nmedical intervention (n = 13), and interference with the con-\ntinuation of IUI treatment or laparoscopic surgery (n = 9).\nDiscussion\nIn our meta-analysis, observational (noncomparative) data \nwere plotted by calculation of the weighed mean pregnancy \nrate, showing favorable pregnancy rates after IUI in this group \nof endometriosis patients. To our knowledge, this is the first \nsystematic search and meta-analysis that has investigated the \npregnancy rates of patients with moderate to severe endo-\nmetriosis undergoing IUI treatment. We were able to com-\nbine a reasonable amount of articles for this specific research \ngoal. Unfortunately, no RCTs could be identified. Therefore, \nour primary outcome measure could only be addressed by 1 \nstudy, showing a nonsignificant difference favoring IUI with \ncontrolled ovarian hyperstimulation compared with expect -\nant management (18).\nInterpretation of the study results is difficult, since the in-\ncluded studies investigated a variety of treatment strategies \nand populations as presented in Table I. The best available \nevidence was provided by Keresztúri and colleagues (18) in -\nvestigating a treatment strategy of laparoscopic surgery fol -\nlowed by IUI with controlled ovarian hyperstimulation in all \nstages of endometriosis in a prospective cohort compared to \nno treatment after surgery. For the total group of endome-\ntriosis patients (all ASRM stages), surgery followed by IUI with \ncontrolled ovarian hyperstimulation was more beneficial than \n\nvan der Houwen et al\n 161\n© 2017 Wichtig Publishing  \ntABLE I - Characteristics of included studies\nReference Design Population Purpose IUI strategy GnRH  \nanalogue\nAbuzeid et al (19) Retrospective cohort Moderate to severe endo -\nmetriosis patients receiving \nsurgery for infertility\nTo investigate the effect of unilat-\neral versus bilateral adnexal involve -\nment on pregnancy\nNot specified; IUI was performed in \na subgroup of patients after surgery \nin male factor infertility, or ovulatory \ndisorder (resistant to CC) or after 6 \nmonths of natural conception. Some \npatients opted to directly start with \nIUI with COH.\nNot specified\nAlborzi et al (20) Prospective RCT Endometriosis with uni- or \nbilateral cysts receiving differ -\nent methods of laparoscopic \nsurgery\nTo compare the response to COH \nafter (i) fenestration and coagula-\ntion of an unilateral endometrioma; \n(ii) cystectomy of an unilateral en -\ndometrioma; (iii) cystectomy at one \nside and fenestration and coagula -\ntion at the other side in bilateral \nendometrioma\nCOH with CC and hMG\nOvulation: 10.000 IU hCG\nInsemination: 34-36 h after hCG\nLuteal support: not specified\nNot specified\nel Amrani et al \n(21)\nRetrospective cohort Patients with endometriosis \nASRM III or IV receiving sur-\ngery for infertility\nTo define the best surgical strategy \nin moderate to severe endometrio -\nsis patients with infertility\nNot specified; IUI was performed in a \nsubgroup of patients after 2 months \nof GnRH analogue treatment after \nsurgery. Other patients waited on a \nspontaneous conception or received \nIVF. Treatment allocation dependent \non age, the presence of male factor \ninfertility, and surgical findings.\nTwo months\nBurwinkel  \net al (23)\nRetrospective cohort Infertile couples receiving IUI To determine a relationship of basal \nFSH and age to ovarian responsive -\nness and pregnancy\nCOH with hMG\nOvulation: ? IU hCG\nInsemination: 36-40 h after hCG\nLuteal support: not specified\nNot specified\nDaru et al (24)\na Unclear Infertile patients with endo -\nmetriosis receiving surgery \nand GnRH agonist treatment\nTo investigate if IUI with COH follow-\ning surgery and GnRH agonist treat -\nment increases pregnancy rate in \ninfertile patients with endometriosis\nCOH with FSH and hMG.\nOvulation: 10.000 IU hCG\nInsemination: 36 h after hCG\nLuteal support: not specified\nGnRH agonist for 6 months\nDickey et al (25)\nb Prospective cohort Couples receiving IUI with \nhMG\nTo determine characteristics associ -\nated with pregnancy and multiple \ngestation after IUI with hMG\nCOH with hMG alone, with or after CC\nOvulation: 10.000 IU hCG or LH surge\nInsemination: 24-36 h after hCG or LH \nsurge\nLuteal support: not specified\nNot specified\nDickey et al (26) Prospective cohort Couples receiving IUI with CC \n(anovulatory cycles or luteal \ninsufficiency)\nTo determine characteristics associ -\nated with pregnancy and multiple \ngestation after IUI with CC\nCOH with CC cycle day 3-7\nOvulation: 5.000-10.000 IU hCG or LH \nsurge\nInsemination: 2-40 h after hCG, 2-28 h \nafter LH surge.\nLuteal support: Not specified\nNot specified\nTo be continued\n\nEfficacy of IUI in moderate to severe endometriosis\n162 \n© 2017 Wichtig Publishing\nReference Design Population Purpose IUI strategy GnRH  \nanalogue\nDodson and \nHaney (27)\nReview including ret-\nrospective cohort\nInfertile couples receiving IUI To determine cycle fecundity of \nIUI with hMG in couples without \nanatomic pelvic distortion\nCOH with hMG  \nOvulation: 5.000 IU hCG \nInsemination: 36-40 h after hCG \nLuteal support: 2.500 IU hCG day 3 \nand 6\nNot specified\nvan der Houwen \net al (10)\nRetrospective cohort Moderate to severe endome -\ntriosis patients receiving IUI\nTo investigate the efficacy and \nsafety of 2 different IUI treatment \nstrategies; (i) 3 times IUI in the \nnatural cycle followed by up to 3 \ncycles IUI with COH; (ii) IUI directly \ncombined with COH\nCOH with hMG or FSH\nOvulation: 10.000 IU hCG\nInsemination: 42 h after hCG\nLuteal support: not specified\nA subgroup of patients re -\nceived a GnRH agonist for \nat least three months\nvan der Houwen \net al (22)\nProspective cohort Moderate to severe endo -\nmetriosis patients receiving \nIUI, IVF or IVF with preced -\ning long-term GnRH agonist \ndesensitization\nTo investigate patient satisfaction \nconcerning one ART treatment cycle\nCOH with or without hMG or FSH\nOvulation: 10.000 IU hCG\nInsemination: 42 h after hCG\nLuteal support: not specified\nA subgroup of patients \nreceived GnRH agonist for \nat least three months\nKeresztúri et al \n(18)\nProspective cohort Patients with endometriosis \nreceiving IUI versus no treat-\nment following surgery (non -\nrandom allocation)\nTo investigate if IUI has a significant \neffect on pregnancy in infertile \npatients with endometriosis after \nlaparoscopic surgery\nCOH with CC and hMG\nOvulation: 10.000 IU hCG\nInsemination: 36 h after hCG and sub-\nsequent day (double insemination)\nLuteal support: no luteal support\nNo GnRH agonist pre-\ntreatment\nKim et al (11) RCT ultra-long versus \nshort GnRH agonist \ndesensitization\nPatients with endometriosis \n(ASRM I-IV) undergoing IUI\nTo compare the ULP and LP with \nGnRHa desensitization for ovulation \ninduction with IUI\nCOH with FSH and hMG\nOvulation: 10.000 IU hCG\nInsemination: 36-40 h after hCG\nLuteal support: 50 mg progesterone \ndaily\nULP: ≥6 weeks GnRHa \ndesensitization\nLP: 2 weeks GnRHa\ndesensitization\nLodhi et al (28) Retrospective cohort Endometriosis patients receiv -\ning GIFT or IUI\nTo compare the effectiveness of \nGIFT and IUI with COH in endome -\ntriosis patients\nCOH with FSH or hMG\nOvulation: 10.000 IU hCG\nInsemination: 42 h after hCG\nLuteal support: not specified\nMid-luteal pituitary de -\nsensitization with a GnRH \nagonist\nStepniewska  \net al (29)\nRetrospective cohort Infertile patients with bowel \nendometriosis\nTo determine the influence of bowel \nendometriosis on fertility in patients \nwho (i) underwent colorectal seg -\nmental resection; (ii) had evidence \nof bowel endometriosis without \nbowel resection; and (iii) underwent \nsurgery for moderate to severe en -\ndometriosis with DIE without bowel \ninvolvement\nNot specified; A subgroup of patients \ntried to conceive after surgery; those \npatients tried to conceive spontane -\nously, received IUI or IVF.\nNot specified\ntABLE I - Continued\nTo be continued\n\nvan der Houwen et al\n 163\n© 2017 Wichtig Publishing  \nReference Design Population Purpose IUI strategy GnRH  \nanalogue\nGöker et al (30) Retrospective cohort Patients with endometriosis, \nmale factor, tubal factor or \nunexplained infertility\nTo evaluate the efficacy of IUI with \nCOH in endometriosis\nCOH with FSH or hMG\nOvulation: 10.000 IU hCG\nInsemination: 24 h after hCG\nLuteal support: not specified\nNot specified\nTay et al (31) Retrospective cohort Infertile couples receiving IUI To analyze the influence of patient \nand treatment characteristics on \nthe cumulative pregnancy rate\nCOH with CC and FSH\nOvulation: 5.000 IU hCG\nInsemination: 36 h after hCG\nLuteal support: 200 mg twice daily \nvaginally administered progesterone\nNot specified\nVollenhoven  \net al (32)\nRetrospective cohort Infertile couples receiving IUI To determine the effectiveness of \nIUI with hMG and to identify prog -\nnostic factors for pregnancy\nCOH with hMG\nOvulation: 10.000 IU hCG\nInsemination: 18-24 h and/or 36-48 h \nafter hCG\nLuteal support: 25 mg twice daily \nprogesterone vaginally\nNot specified\nWu et al (33) Retrospective cohort Endometriosis patients receiv -\ning IUI after laparoscopic \ntreatment of endometriosis\nTo investigate if the presence and \namount of peritoneal fluid is cor-\nrelated to severity of endometriosis \nand pregnancy outcome of IUI \ntreatment\nCOH with FSH\nOvulation: 250 ugr hCG\nInsemination: 36 h after hCG\nLuteal support: progesterone 600 mg/\nday during 2 weeks and 1500 IU hCG \non day 6\n2 months\nYovich and  \nMatson (34)\nUnclear Nontubal infertility couples \nreceiving IUI\nTo determine any relationship be-\ntween pregnancy rate after IUI and \nthe underlying disorder\nCOH with hMG and/or CC\nOvulation: 5.000 IU hCG or LH surge\nInsemination next three mornings\nLuteal support: non specified\nNot specified\na Overlap of patient with Keresztúri et al (18) cannot be excluded.\nb Overlap of patients with Dickey et al (26) cannot be excluded.\nART = assisted reproductive technology; ASRM = American Society of Reproductive Medicine; CC = clomiphene citrate; COH = controlled ovarian hyperstimulation; DIE = deeply infiltrating endometriosis; \nFSH = follicle-stimulating hormone; GIFT = gamete intrafallopian transfer; GnRH = gonadotropin-releasing hormone; hCG = human chorionic gonadotrophin; hMG = human menopausal gonadotropin; IU = \ninternational units; IUI = intrauterine insemination; LH = luteinizing hormone; LP = long protocol; RCT = randomized controlled trial; ULP = ultra-long protocol. \ntABLE I - Continued\n\nEfficacy of IUI in moderate to severe endometriosis\n164 \n© 2017 Wichtig Publishing\ntABLE II - Pregnancy rates\nReference p atients c ycles Biochemical pregnancy Clinical pregnancy Ongoing pregnancy Live birth\nn n n per pt per cycle n %/pt %/cycle n %/pt %/cycle n %/pt %/cycle\nAbuzeid et al (19) 29 51 - - - 14 48.3% 27.5% - - - 11 37.9% 21.6%\nAlborzi et al (20)a 81 149 48 59.3% 32.2% - - - - - - - - -\nel Amrani et al (21) 22 - - - - 15 68.2% - - - - - - -\nBurwinkel et al (23) 15 37 - - - 3 20.0% 8.1% - - - 3 20.0% 8.1%\nDaru et al (24)a 38 - 17 44.7% - - - - - - - - - -\nDickey et al (25) - 114 - - - 6 - 5.3% - - - 5 - 4.4%\nDickey et al (26) 82 213 12 14.6% 5.6% 10 12.2% 4.7% - - - 7 8.5% 3.3%\nDodson and Haney \n(27)\n- 65 9 - 13.8% - - - - - - - - -\nvan der Houwen  \net al (10)\n65 245 - - - - - - 15 23.1% 6.1% 12 18.5% 4.9%\nvan der Houwen  \net al (22)\n25 25 4 16.0% 16.0% - - - 2 8.0% 8.0% - - -\nKeresztúri et al (18) 68 - - - - 31 45.6% - - - - 28 41.2% -\nKim et al (11) 41 41 - - - 14 34.1% 34.1% 10 24.4% 24.4% 4 9.8% 9.8%\nLodhi et al (28) 14 16 - - - 5 35.7% 31.3% - - - 2 14.3% 12.5%\nStepniewska et al \n(29)\n6 - - - - 4 66.7% - - - - 3 50.0% -\nGöker et al (30) 17 - - - - 4 23.5% - - - - - - -\nTay et al (31) - 48 - - - 5 - 10.4% - - - - - -\nVollenhoven et al \n(32)\n8 15 3 37.5% 20.0% - - - - - - - - -\nWu et al (33) 47 47 - - - 11 23.4% 23.4% - - - - - -\nYovich and Matson \n(34)\n23 49 2 8.7% 4.1% - - - - - - - - -\na Unclear definition of pregnancy used, stated in this table as biochemical pregnancy.\nN = number; pt = patients.\nFig. 2 - Forest plot on live \nbirth rate.\nsurgery alone in terms of live birth (OR 1.85; 95% CI, 1.09-\n1.34; p = 0.02). For patients with stage III/IV endometriosis, \nthis effect was less pronounced (41.2% vs. 28.4%; p = 0.29). \nThis difference, favoring IUI treatment, did not reach statisti-\ncal significance, which was possibly due to a lack of power.\nSurgery in moderate to severe endometriosis patients \nseeking for natural conception is recommended by the The \nEuropean Society of Human Reproduction and Embryology \n(ESHRE) guideline (6), since surgery compared to expectant \nmanagement improves spontaneous pregnancy rates (level \nB evidence). However, prior to IVF/intracytoplasmic sperm \ninjection (ICSI) surgical treatment of moderate to severe en-\ndometriosis (i.e., performing cystectomy) should be carefully \nconsidered, taking into account the lack of evidence that per-\nforming a cystectomy improves pregnancy rates; the  possible \nloss of functional ovarian tissue (especially in repetitive ovar-\nian surgery); the accessibility of follicles; and patients’ pain \ncomplaints. Whether surgery of moderate to severe endo-\nmetriosis prior to IUI affects pregnancy rates has not been \ninvestigated. However, it can be hypothesized that laparo-\nscopically treating peritoneal disease in moderate to severe \nendometriosis patients (without performing cystectomy \nin the absence of endometriosis-related pain complaints), \nmay be more beneficial in improving pregnancy rates with \nIUI compared to IUI alone, as it is already shown for natural \nconception (35) (level A evidence) and pregnancy after IVF \n(36) (level C evidence). Unfortunately, the studies included in \nour meta-analysis reported no data on surgical interventions.\nPerforming surgery also results in the ability to calculate \nthe endometriosis fertility index (EFI) score as described by \n\nvan der Houwen et al\n 165\n© 2017 Wichtig Publishing  \nFig. 3 - Weighed mean \nclinical pregnancy rate.\nFig. 4 - Weighed mean live \nbirth rate.\nAdamson and Pasta to predict pregnancy rates in patients \nattempting nonIVF conception (37). This fertility index is al-\nready externally validated (38), and recent studies focus on \nthe possibility to use this tool to select patients who should \nbe offered IVF/ICSI (39, 40). Whether IUI can be performed \nprior to IVF/ICSI at specific cut-off values of the EFI score has \nnot yet been investigate.\nNext to the variety of strategies and populations, different \nIUI treatment strategies have been described in the included \nstudies, such as those concerning IUI in a natural cycle and \nIUI with controlled ovarian hyperstimulation, including anti-\nestrogens (clomifenecitrate), recombinant follicle stimulat -\ning hormone (FSH) and/or human menopausal gonadotropin \n(hMG). It is worth noting that in subfertile couples, gonado -\ntrophins are superior to antiestrogens regarding pregnancy \nrates after IUI (41), but this has never been evaluated in mod-\nerate to severe endometriosis patients.\nIt has been shown that prior long-term pituitary desen-\nsitization promotes pregnancy rates after IUI in endometrio-\nsis patients ASRM stage 2-4 (12). Besides this, the beneficial \neffect in this specific subgroup of ASRM 2-4 endometriosis \npatients (100% vs. 70% pregnancy rate) was not significant -\nly different, which is possibly due to a lack of power. This \nis in line with the results published by Kim and colleagues \n(11), investigating a modified ultra-long desensitization \nwith a GnRH agonist for 6 weeks in an RCT showing an OR \non live birth of 3.53 (95% CI, 0.34-37.15). Besides this, our \nrecently published retrospective study on IUI in moder -\nate to severe endometriosis patients showed a hazard ra-\ntio of 1.8 (95% CI, 0.6-5.1) in favor of long-term pituitary  \ndesensitization (nonsignificantly) for at least 3 months (10). \nThose results ask for more research regarding the possible \nbeneficial effect of long-term pituitary desensitization with \na GnRH agonist.\nDifferences in stimulation protocols, timing of surgical in-\nterventions, and the use of preceding treatment with a GnRH \nagonist might have influenced the outcome of our meta-anal-\nysis, and most of the included studies were not designed to \nspecifically investigate the effect of IUI in moderate to severe \nendometriosis patients. However, despite this clinical hetero-\ngeneity, calculation of the weighed mean pregnancy rate was \nstatistically the best method to combine observational data \nand calculate the effect of intrauterine insemination on preg-\nnancy rates, resulting in a level 4 evidence (grade C) recom-\nmendation. \nNext to efficacy, the safety of treatment in terms of com-\nplications and the recurrence of endometriosis should be \ntaken into account, especially in moderate to severe endome-\ntriosis patients. Recurrence of endometriosis complaints may \nlead to discontinuation of fertility treatment due to the need \nto start hormonal suppression therapy or surgical interven-\ntion. This directly results in postponement or cancellation of \nthe possibility to conceive (10), which negatively affects time \nto pregnancy. D’Hooghe and colleagues (42) have shown that \nthe endometriosis recurrence rate is higher in patients un -\ndergoing IUI than in IVF, which is explained by the result of a \nmore frequent exposure to ovulation and subsequent retro-\ngrade menstruation in IUI treatment. By limiting the amount \nof IUI treatment cycles to 3 per patient, this negative effect \nmight be negligible (10).\n\nEfficacy of IUI in moderate to severe endometriosis\n166 \n© 2017 Wichtig Publishing\nConclusion\nThis meta-analysis of observational data has shown that \nIUI could be a feasible treatment in moderate to severe \n endometriosis. Due to the lack of RCTs, no clear recommen-\ndation can be made in offering IUI treatment in moderate \nto severe endometriosis patients. Whether this  treatment \nshould be structurally performed prior to IVF must be \n investigated in a RCT, including time-to-pregnancy, safety, \nand cost effectiveness.\nDisclosures\nFinancial support: None.\nConflict of interest: None.\nMeeting presentation: The work described in this manuscript was \npresented at the 13 th World Congress on Endometriosis (2017), in \nVancouver, Canada.\nReferences\n1. Collins JA, Burrows EA, Wilan AR. The prognosis for live birth \namong untreated infertile couples. Fertil Steril. 1995;64(1):  \n22-28.\n2. Hamdan M, Dunselman G, Li TC, Cheong Y . The impact of en-\ndometrioma on IVF/ICSI outcomes: a systematic review and \nmeta-analysis. Hum Reprod Update. 2015;21(6):809-825.\n3. Johnson NP , Hummelshoj L. World Endometriosis Society \nMontpellier Consortium. Consensus on current management \nof endometriosis. Hum Reprod. 2013;28(6):1552-1568.\n4. Surrey ES. Endometriosis-related infertility: the role of the \nassisted reproductive technologies. 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