{"paper_id":"5285a75b-fe53-47b8-aaa8-02e64c0c4ee7","body_text":"The majority of infertile couples seek a less\ninvasive and less costly therapeutic option in assisted\nreproductive techniques (ART); intrauterine\ninsemination (IUI) is one of these options.\nOverall pregnancy rate (PR) that have been reported\nin previous studies range from as low as\n2.7 to as high as 70% ( 1 ,  2 ). The success rate depends\non combining a stimulation protocol with\ncorrect timing of insemination that includes adequate\nnumbers of prepared spermatozoa. Other\nvariables that have been studied in relationship\nwith IUI success include maternal or parental\nage ( 1 ,  3 - 11 ), the frequency of inseminations\nper cycle ( 12 ,  13 ), number of previous IUI cycles\n( 1 ,  3 ,  10 ,  11 ,  14 ), duration of infertility ( 1 ,\n 3 ,  10 ,  11 ,  15 ), sperm characteristics ( 4 ,  8 - 10 ,\n 15 - 18 ) and number of preovulatory follicles ( 3 ,\n 4 ,  8 ,  11 ,  15 ,  18 , 19 ). Other factors such as cause\nof infertility ( 6 ,  11 ,  19 ), type of infertility ( 3 ),\nfollicular size ( 20 ), ovulatory ovarian side ( 1 ),\nendometrial thickness ( 7 ,  15 ) and type of catheter\n( 8 ) have limited evidence ( 1 ). Based on our\nresearch, the etiology is seldom considered. In\na study, Ahinko-Hakamaa et al. ( 19 ) have reported\nthat the etiology of infertility is highpriority\nwhen remarkable insemination success\nrate is planned, while the impact of other variables\nsuch as woman’s age, sperm count, stimulation\nprotocol and follicle numbers on PR and\nmultiple PRs are related to different infertility\netiology groups; to our knowledge, this subject\nneeds to more research.\nThis study aims to identify the prognostic factors\nthat affect PRs in IUI treatments within different\ninfertility etiology groups. The results of this study\nmight be useful to assist with making the best individual\ndecision in the treatment of patients with\ndifferent infertility etiologies.\n\nThis study retrospectively considered the consecutive\nartificial insemination with husband semen\ncycles carried out at the Infertility Center of\nAkbarabadi Hospital located at Tehran University\nof Medical Science, Tehran, Iran, from 2008 to\n2010. The Institutional Review Board and Ethical\nCommittee of Tehran University of Medical Science\napproved this study.\nAll study couples had at least one year history\nof infertility and had undergone standard\ninfertility evaluations prior to IUI. The evaluations\nconsisted of monitoring ovulation by\nultrasound, serum hormone assays on the third\nday of the menstrual cycle [follicle-stimulating\nhormone (FSH), luteinizing hormone (LH), mid\nluteal progesterone, prolactin and thyroid hormone\nconcentrations] and at least two semen\nanalyses. Tubal patency was evaluated by hysterosalpingography\nor laparoscopy. The couple\nwas included in the tubal factor subgroup if\nonly one tube was patent.\nMale factor infertility was considered in our\nstudy when the total motile sperm count was\n<20×10 6 /ml, normal morphology <30%, or\nprogressive motility (grade A+B) <40% before\nsperm preparation. We excluded total motile\nsperm after preparation of less than 1×10 6 /ml\nfrom the study.\nOvarian factor infertility group included polycystic\novary syndrome (PCOS; diagnosed by Rotterdam\ncriteria), ovarian insufficiency (serum FSH\nlevel >9.5 IU/L on the third day of the menstrual\ncycle) and age factor (women age ≥ 35 years old).\nAnovulatory disorder was diagnosed when the\nmenstrual cycle was not regular and/or a mid-luteal\nserum progesterone concentration <10 nmol/l as\nluteal phase disorder diagnosis.\nEndometriosis diagnosis was based on the combination\nof findings of laparoscopy, history of\ndysmenorrhea and dyspareunia, observation of\nrectovaginal endometriosis during pelvic examination\nor ovarian endometrioma as seen by ultrasonography.\nAll cycles in the study underwent stimulation\nby clomiphene citrate (CC; Clomifen; Leiras,\nTampere, Finland), human menopausal gonadotropin\n(hMG) combined with CC, or human\nchorionic gonadotropin (HCG, Pregnyl; Organon,\nNetherlands). Many patients at their first\ncycles were treated with CC (50-150 mg/day)\nwhich administrated between days 3 and 7. If\nthe antiestrogenic effect of CC was unsatisfactory\nin terms of results and side effects, hMG\nwas given in the same or next cycle combined\nwith CC, or only hMG was used in the next\ncycle. For CC/hMG cycles, 100 mg CC was\nadministrated between days 3 and 7, followed by 150 IU of hMG by day 9. For cycles that\nonly were given hMG stimulation began on day\n3 with 75-150 IU/day hMG, which depended on\nthe woman’s hormonal profile, age and duration\nof infertility. The dose was adjusted according\nto ultrasonographic findings. Ovarian and endometrial\nresponses were monitored by serial vaginal\nultrasonography on cycle days 9 to 13. In all\ncycles, HCG (5000-10000 IU) was given when\nat least one follicle was greater than 18mm in\nmean diameter. A transvaginal ultrasound measured\nendometrial thickness on the day of HCG\ninjection. Standard IUI was performed 36-40\nhours after administration of HCG.\nThe husband’s semen was collected by masturbation\ninto sterile container after 2-4 days\nabstinence from coitus. After 10-15 minutes of\nliquefaction atroom temperature, each sample\nwas examined by World Health Organization\n(WHO) guidelines ( 21 ). The continuousdensity\ngradient centrifugation technique (three-layer\nPercoll) was performed using Allgrade® 50/100.\nThe sperm pellet was resuspended in 3 ml of\nHam’s-F10+3% BSA medium to obtain the required\nsperm concentration. The final pellet\nwas gently covered with 0.5 ml of medium and\nincubated for 30-60 minutes at 37˚C. All semen\nanalyses were performed in the hospital laboratory\nby a single technician. Normal values\nsuggested by the WHO guidelines were used to\nanalyze semen quality.\nIUIs were performed 36 hours after the administration\nof HCG. The procedure was carried\nout using an intrauterine catheter (Gray\ncolor catheter, ORI Medical Products, India)\nwith a one-ml-syringe. The IUI catheter was\ngently directed into the uterine lumen, and one\nml sperm suspension slowly infused. The women\nwere placed supine position for 10-15 minutes\nafter IUI. After insemination, each patient\nreceived 400mg vaginal or rectal suppositoryor\n100mg intramuscular progesterone daily, which\nfollowed as the same dosage after pregnancy\nfor 6-12 weeks. Two weeks after insemination,\nplasma β-HCG levels were measured routinely.\nClinical pregnancy was determined as transvaginal\nultrasonographic observation of intrauterine\ngestational sac.\nThe variables considered for multiple regression\nanalysis were female age, male age, duration\nof infertility, infertility etiology, number of\ncycles, stimulation protocol, number of preovulatory\nfollicles, the diameter of the dominant\nfollicle, endometrial thickness and inseminated\nmotile sperm count (IMC). Categorical\nvariables were compared using the chi-square\ntest. All statistical analyses were performed using\nSPSS for Windows software, version 16.0\n(SPSS Inc., Chicago, IL, USA). The significance\nvalue for all analyses was p<0.05.\n\nTotally, 1348 insemination cycles of 632 couples\nwere included. For each couple, one to six\ninsemination cycles were performed. Table 1\nshows PRs per cycle and different variables frequencies\naccording to different etiology groups.\nWomen in unexplained group had the highest\nclinical PR per cycle (19.9%), while the lowest\nrate among women belonged to multiple factors\ngroup (10.6%) with existence of a significant\ndifference (p=0.04).\nIn the male factor group, the PR per cycle was\n18.1%. Older women and long infertility duration\nnegatively affected PR, but the relationship\nwas not statistically significant (p=0.09, p=0.1).\nOvulation induction with sequential CC/hMG\nhad a significantly better result. We found similar\nresult in terms of PR per cycle in cases with\nover 5 million IMC versus those with 1- 5 million\n(20.1 vs. 15.2%; p<0.05).\nIn cases of unexplained infertility, the PR per\ncycle was 19.9%. However, PR decreased with\nincreasing infertility duration, particularly if the\nduration was greater than 5 years in primary infertility\ncases. The highest PRs were seen after\nCC/hMG stimulation (26.3%) in women with secondary\ntype of infertility (26.8%) and men with\nIMC>30×10 6  (22%), but the tendency didn’t reach\nstatistical significance (p=0.08, p=0.2 and p=0.06,\nrespectively).\nIn the ovarian factor group, the PR per cycle\nwas 13.8%. The best PRs were observed in\nwomen aged between 30 and 34 years (20.8%),\nwith 2-3 preovulatory Follicles (37.8%) and infertility\nduration between 1 and 3 years (20.8%).\nOnly infertility duration (p=0.03) and number\nof preovulatory follicles (p=0.01) were statistically\nsignificant.\nIn couples with multiple factors for infertility,\nthe PR per cycle was 10.6%. With the exception of\ninfertility duration and IMC (p=0.005 and p=0.01),\nother variables had no significant effect on PR.\nIn women with tuboperitoneal infertility, the PR\nper cycle was 17.3%. The best PRs were seen after\nCC/hMG stimulation (23.3%), IMC >30×10 6 \n(23.5%) and infertility duration between 1 and 3\nyears (33.3%). In this group, only infertility duration\nwas statistically significant (p=0.008).\nPregnancy rates per cycle according to etiology\n*; Values were presented as % (number of pregnancy /number f cycles).\nThe overall PR was 16% and 35.1% per cycle and per\ncouple, respectively. Pregnancy outcomes per couple\nare shown in table 2. There was no significant relationship\nbetween pregnancy occurrence per couple\nand cause of infertility (p=0.1). Women in male factor\ngroup had the highest miscarriage rate (15.4%), while\nthe lowest rate among women belonged to multiple\nfactors group (4.5%) with existence of a significant\ndifference (p=0.03). Multiple pregnancies were observed\nonly in patients with ovulatory dysfunction\n(0.7%) and those with unexplained infertility (0.9%).\nLogistic regression analysis revealed the following\nfive predictive variables regarding pregnancy\nin stimulating IUI cycles: i. number of preovulatory\nfollicles (p=0.02), ii. duration of infertility\n(p=0.015), iii. age (p=0.019), iv. infertility etiology\n(p=0.05) and v. stimulation regimen (p=0.01)\n( Table 3 ). When the analysis included only cycles\nin women<35 years old (n=1110), age did not affect\nthe IUI cycle outcomes, while the remaining\npredictive variables remained significant.\nTable 4 shows that the pregnancy outcome per cycle\nand couple in each subgroup of ovarian factor\ngroup, while the patients in PCOS subgroup had\nhigher PR in comparison with other subgroups.\nPregnancy outcome of intrauterine insemination cycles per couple according to infertility etiology\nLogistic regression analysis for predicting the success of intrauterine insemination\na; Odds ratio, b; Confidence interval and c; Odds ratio in contrast to the poorest category.\nPregnancy rates per couple and per cycle in different diagnosis in ovulatory factor group\n\nOur findings show that infertility etiology has\nan important role in the prognosis of IUI cycles.\nAdditionally, differences in factors affect the PR,\nwhich is in agreement with a study by to Ahinko-\nHakamaa et al. ( 19 ), but in contrast to study of Basirat\nand Esmaeilzadeh ( 22 ).\nOur results confirm that IUI is the best firstline\ntreatment in cases of mild and moderate\nmale factor infertility. We observed the best\nresults in cases with IMC ≥5×10 6  (not significant)\nand infertility duration less than 5 years.\nIn contrast to the recent studies ( 19 ,  23 ,  24 ) and\nin agreement with results published by other investigators\n( 1 ,  11 ,  17 ), we found no association\nbetween PR and IMC. This may be due to different\ndefinitions of male factor in each study;\nwhereas, we performed pre-treatment sperm\nscreening and excluded couples with progressively\nmotile sperm counts after preparation of\n<1×10 6 /ml. One of our limitations related to retrospective\nnature of study was the missing data\nin sperm’s morphology, so we could not evaluate\nthe impact of this variable on results.\nIn cases of unexplained infertility, the cost/efficacy\nbalance between IUI and  in vitro  fertilization\n(IVF) is a debate. In a prospective-randomized\nstudy, Goverde et al. ( 25 ) have reported\nthat IUI was as effective asand less costly than\nIVF in treatment of unexplained and male factor\ninfertilities. In a study, Hughes ( 26 ) recommended\nIUI as first-line treatment in couples\nwith unexplained infertility when the woman’s\nage and duration of infertility were appropriate.\nIn our study, the best results in unexplained\ncases were seen in couples who had primary\ninfertility, less than 5 years infertility duration\nand IMC ≥10×10 6 .\nIn our study, the PR per cycle in the ovarian\nfactor infertility group was lower than the\nresults obtainedin a study by Ahinko-Hakamaa\net al. ( 19 ) (13.8 versus 18.2%), and the reason\nbehind this was the type of cases in the ovarian\nfactor infertility group (n=133), which were\ndivided into following two main categories: i\novarian factor without specific diagnosis as\nPCOS; age factor; and hypothalamic amenorrhea\n(n=34), ii ovarian factor with PCOS diagnosis\n(n=81); age factor (n=16); and hypothalamichypothalamic\namenorrhea (n=2) as shown in table\n4. Also, table 4 indicates that PR per couple\nand per cycle in PCOS subgroup are 44.4% and\n16.5%, respectively.\nIt shows that we can recommend IUI treatment\nas first-line treatment in women with\nPCOS diagnoses and infertility duration less\nthan 5 years , but in the patients with an ovulatory\nwithout specific diagnosis subgroup, the\nPR per couple (23.5%) and per cycle (11.8%)\nwere lower than patients with PCOS subgroup.\nIt seems that women in an ovulatory factor\ngroup with PCOS diagnosis need to more cycles\nto become pregnant.\nIn the tuboperitoneal infertility group, the PR\nper cycle was high (17.3%). We had 30 cases\nwith one patent tube, 9 cases with uterine factor\nand 7 cases with mild endometriosis in this\nsubgroup. Because of the low number of endometriosis\ncases and low number of cycles in\nthis subgroup (n=98), a conclusion cannot be\ndrawn. Nevertheless, it seems that IUI in cases\nwith one patent tube can be of great benefit\nwhen female age and duration of infertility are\nappropriate.\nThe PR per cycle in the multiple factors infertility\nsubgroup was low in comparison with the study\nby Ahinko-Hakamaa et al. ( 19 ) (10.6 vs. 17.9%)\nwhich may be due to the different mixed diagnoses\nand number of cycles (209 vs. 56) between studies.\nMost couples in this subgroup had male factor plus\novulatory factor (51%). We have recommended\nthat IUI treatment could be successful in the many\nreasons infertility subgroup when female age, duration\nof infertility and total motile sperm count\nare appropriate.\nIn our study, stimulation with sequential CC/\nhMG resulted in the highest PR in all infertility\nsubgroups, which was significant in comparison\nwith hMG alone, but not CC alone. Several\nstudies have reported the superiority of FSH or\nhMG over CC alone ( 26 - 29 ), which is in contrast\nto our results. The rate of multiple pregnancies\nin our study was very low (0.7% per couple in\nthe ovulatory factor and 0.9% per couple in the\nunexplained infertility groups) when compared\nwith the study of Ahinko-Hakamaa et al. ( 19 )\nbecause we had a lower number of hMG alone\ncycles (127 vs. 673).\nThe age-related decline in female fecundity has\nbeen well documented ( 3 ). However, in several\nstudies, female age was found to be a major prognostic\nfactor to predict outcome in ovarian stimulation\n( 1 ,  3 - 11 ,  29 ). Our study has failed to find\nthis association in patients younger than 40 years\nof age, in concordance with some previous studies\n( 3 ,  11 ,  15 ). Altogether, these results indicate that\nIUI is a poor treatment option for women over 40\nyears of age.\nWe found that the PR decreased with increased\ninfertility duration, which confirmed some studies\n( 1 ,  3 ,  7 ,  10 ,  11 ,  14 ,  15 ,  22 ), yet contradicted\nothers ( 4 ,  5 ,  19 ). However, the precise limit of\nthe duration of infertility which has been shown\nto decrease IUI success is unknown. Considering\nour result and those of other studies, IUI cannot\nbe recommended for patients with long-standing\nduration of infertility. It has reported that the lower\nnumber of motile spermatozoa and older women\nhas a negative impact on PR after IUI treatment in\ncouples with infertility for over 10 years ( 9 ).\nIn our study, the highest PR (22.5%) was observed\nin cycles with three pre-ovulatory follicles,\nbeing statistically higher than in cycles with only\none follicle (6.5%). In agreement with previous\nstudies ( 8 , 11 , 15 , 19 ), we believe that multifollicular\ndevelopment may result in an increased number\nof fertilizable oocytes and a better quality endometrium\nand luteal phase, thus improving fertilization\nand implantation rates. Using ovarian stimulation\nin combination with IUI is beneficial to achieve a\nbetter IUI outcome.\nSome studies ( 1 ,  3 ,  8 ,  10 ,  11 ,  14 ) have reported\nthe number of treatment cycles as a predictive factor\nof the likelihood of pregnancy. However, in our\nstudy as with others ( 18 - 19 ), we found no relationship\nbetween PR and number of treatment cycles.\nIn our institute, five cycles of controlled ovarian\nstimulation combined to IUI were less costly than\na single IVF cycle. Considering PR per cycle and\ncost of controlled ovarian stimulation combined to\nIUI per cycle, we can suggest up to five cycles\nof IUI treatment to patients, while it is a costeffective\ntreatment in most infertile couples.\n\nIn decision making for choosing the best treatment\noptions for infertile couples should be considered the\nnumerous variables in different etiologies of infertility.\nIt must be remembered that within different etiologies\nof infertility, the number of preovulatory follicles;\nmotile sperm count; stimulation protocol; and\ndemographic characteristics of couples do not have\nthe same effect. The simple and relatively noninvasive\nnature of IUI allows physicians to choose IUI as\na cost-effective first-line treatment in most cases of infertility.\nFavorable patient characteristics for treatment\nsuccess are age <40, duration of infertility ≤5 years\nand a cause of infertility except of multiple factors.\nAdditional information on the predictors of IUI success\nto provide a more exact basis for counseling patients\non expectations and treatment options is needed.","source_license":"CC-BY-4.0","license_restricted":false}