{"paper_id":"fd9cfea3-787e-47f6-b1c4-f1a314eb14ed","body_text":"Intrauterine\ninsemination (IUI) is the therapeutic process of placing washed spermatozoa\ntranscervically into the uterine cavity for the treatment of infertility. IUI theoretically allows a relatively higher\nnumber of motile spermatozoa to reach the oocyte [ 1 ]. The rationale for washing sperm is to remove\nprostaglandins, infectious agents, and antigenic proteins as well as to remove\nimmotile spermatozoa, leucocytes, and immature germ cells. The process allows the concentration of\nspermatozoa in a small volume of culture media and then the concentrated\nspermatozoa is placed into the uterus through a transcervical catheter.\nThe general process of\nartificial insemination has been used to treat a variety of physiological and\npsychological male and female infertility disorders such as severe hypospadius,\nretrograde ejaculation, impotence, and vaginismus. IUI, in the past, has been\nused as treatment for poor postcoital tests and immunologic infertility [ 2 ]. Currently, IUI is used to treat moderate male\nfactor infertility and unexplained infertility. Another common use of IUI is to enhance the efficacy of treatment by\novulation induction for ovulatory disorders [ 1 ]. The simple\nand noninvasive nature of IUI has allowed it to be performed by nurses in some\ncenters with analogous pregnancy rates to the procedures performed by\nphysicians [ 3 ]. Factors that may\ninfluence IUI outcome include the use of ovulation induction agents, semen\nanalysis parameters, techniques used for sperm preparation, and the timing and\nnumber of inseminations.\nThe resource\nallocation for advanced infertility services is asymmetric, with the expertise\nand technology more concentrated in the larger cities and resource-rich\nwesternized countries [ 4 ]. In this review, we address the clinical\nsituation in the majority of the occasions, in which the infertility technology\nthat is available for treatment of patients may be limited. Outside the technologically advanced\ncenters, the majority of the infertility patients have fewer options for\ntreatment. The roles for IUI and\nconsiderations for its advantageous use in this limited technology setting are\nconsidered in this manuscript. This review is divided into\ntwo parts. In the first, the efficacy\nand cost-effectiveness of IUI are discussed, and, in the second part, the\nevidence is presented for the beneficial clinical practice of IUI in limited\ntechnology settings.\n\nInfertility is defined as\nfailure to achieve pregnancy for one year or more without use of contraception\nduring the childbearing period and affects approximately 10–15% of couples [ 5 ]. In 1995, The\nNational Survey of Family Growth reported that 9.3 million women between 15–44\nyears (15% of women of reproductive age) made use of infertility services in\nthe United States. These services included medical advice,\ntesting for both couples, drugs for ovulation induction, corrective surgery for\ntubal blockage, and assisted reproductive technologies (ARTs) [ 6 ]. The costs of\ninfertility evaluation and therapy were evaluated in a study conducted by Stovall et al. [ 7 ]. They\nfound that the costs of infertility services ranged from 0.36 to 1.03% of a\ntotal health care plan with an average of 0.8%. In a 3-year period, they found that infertility cost was $680 921\nof $86 445 642 total health care plan costs.\nIn addition to its economic\ncosts, infertility has a major psychological impact. Oddens et al. reported that infertile women\nhad depressive and anxiety symptoms four times more frequently than fertile\nwomen [ 8 ], and the rate is comparable to\nwomen with cancer and coronary heart disease [ 9 ]. The presence of such psychological disorders may have a negative impact\non infertility treatment outcomes, as it was reported that IVF success rates in\nthe first 5 cycles may be lower in depressed women compared to the\nnondepressed [ 10 ].\n\nIn 2001 in the United\nStates, 108 130 ART cycles were carried out in 385 programs, with 79 042 cycles\nbeing IVF [ 11 ]. In 2003 in Europe, 365 103 ART cycles were accomplished in 1008 clinics, with 132 932 cycles being IVF [ 12 ]. Despite this increase in the use of these\ntreatment modalities, they are still costly, invasive, and associated with\ndrawbacks. In the year 2001, the median cost of IVF in the US\nwas extrapolated to be $9 226\nper cycle and $56 419 per delivery. Outside the US, this cost was calculated to be $3 531 per cycle and\n$20 522 per delivery [ 13 ]. The high cost of IVF deepens on the gap between\nthe number of IVF cycles performed and the treatment needs of infertile\ncouples.\nIn addition to its costs,\nthe use of IVF is associated with other undesirable outcomes. These include preterm delivery, leading to\nincreased risk of newborn prematurity and its concomitant costs and morbidity, and increased rates of multiple gestations [ 14 ]. In the US, in the year 2003, 48 756\ninfants were born from ARTs, accounting for 1% of all births. Fifty-one percent of this number resulted\nfrom multiple gestations. Furthermore,\nthe incidence of low birth weight and preterm delivery among singleton infants\nborn from ARTs were 9% and 15%, respectively, while low birth weight occurred in\n94% among triplets and higher order multiple gestations [ 15 ]. In a meta-analysis to assess the\nperinatal outcome in singletons following IVF [ 16 ], Jackson et al. reported\nincreased fetal risks of preterm birth, low and very low birth weights, small\nfor gestational age, neonatal intensive care unit admissions, stillbirth,\nneonatal mortality, and cerebral palsy as well as increased maternal risks of\npre-eclampsia, placenta previa, gestational diabetes, and caesarean delivery. Furthermore, there may be an increased\nincidence of major birth defects (renal and musculoskeletal) and autosomal\nreciprocal-balanced translocations among infants born after IVF/ICSI compared\nto naturally conceived infants [ 17 ,  18 ].\n\nThe limitations\nof IUI are few. They included the\npotential risk of infection from uterine catheterization and injection of the\nsemen specimen. However, this risk has\nbeen reported to be 0.01–0.2%. In\naddition, ectopic pregnancies and spontaneous miscarriages may occur, which is\nnot different from other infertility treatment modalities [ 19 ]. The production of antisperm antibodies is\nanother hypothetical drawback of the use of IUI. The incidence of multiple pregnancy and\novarian hyperstimulation syndrome (OHSS) with IUI may occur and is related to\nthe use of ovarian stimulation with IUI. The risk of OHSS may be decreased by use of low-dose drug regimens,\nclose monitoring, and strict cycle cancellation criteria.\nRegarding the perinatal outcomes of IUI conceptions, Gaudoin et al.\nreported in a retrospective cohort study that ovulation induction combined with\nIUI was associated with increased risk of preterm birth and low birth weight [ 20 ]. However, other studies did not\ndescribe such associations [ 21 ,  22 ].\n\nThe pregnancy rate of IUI is reported\nto 10–20% per patient, but the reported rates range from as low as 5% to as\nhigh as 70% [ 23 ]. Based on the etiology of infertility, the\nhighest rates were reported when IUI was used in patients with anovulation who\nwere undergoing ovulation induction therapy at the time of the IUI treatment,\nmale factor infertility, and unexplained infertility. In patients with endometriosis, the pregnancy\nrates were the lowest [ 24 ]. The number of mature follicles (17 mm in\ndiameter or more) is another prognostic factor in IUI success, where the\npresence of 3-4 mature follicles was associated with higher pregnancy rates and\na lower incidence of high-order multiple pregnancies [ 25 ]. Other prognostic factors included female age, infertility duration and\namount of motile sperm [ 26 ].\nThe cost effectiveness of IUI has been studied. In a retrospective cohort study [ 27 ],\nVan Voorhis et al. reported $8 674 as the cost per delivery for IUI alone,\n$7 808 for clomiphene combined with IUI, $10 282 for human menopausal\ngonadotropin (hMG) combined with IUI and $43 138 for IVF. The authors supported the use of IUI (any modality)\nas being cost effective, before ART, for infertile couples with patent tubes,\nfemale age 38 years or less, and a sperm count of 10 × 10 6  motile spermatozoa\nin a post wash sample. For those with\nblocked tubes, IVF-ET was found to be a cost-effective practice compared to\nsurgery. In a prospective study, based\non cost effectiveness, Karande et al. did not recommend IVF as first-line\noption for infertile couples [ 28 ]. In a prospective-randomized study, Goverde et\nal. found that IUI was as effective as and less costly than IVF in treatment of\nunexplained and male factor infertility [ 29 ]. Peterson et al. reported that four cycles of\ncontrolled ovarian hyperstimulation (COH) combined with IUI were superior to\nIVF and less expensive than single IVF cycle [ 30 ]. Even when the same stimulation protocols were\nused, the cost per pregnancy for IUI was less than half that of IVF [ 31 ]. Cohlen et al. conducted a Cochrane review to\nanalyze the effectiveness of IUI versus timed intercourse both in natural and\nstimulated cycles in cases of male factor infertility [ 32 ]. A search of Medline (January 1966-present),\nEMBASE ( http://www.embase.com/ ), DDFU (  http://www.ovid.com/site/catalog/DataBase/893.jsp?top=2&mid=3&bottom=7&subsection=10 ), BIOSIS (Philadelphia, USA), SCI (  http://www.thomsonreuters.com/products_services/scientific/Science_Citation_Index_Expanded ) and hand searching of references from identified\nstudies resulted in 43 studies related to research topic being retrieved. They used 17 studies in the systematic review\nand their data were pooled in the meta-analysis. In their final conclusions,\nCohlen et al. reported that IUI with COH was more cost-effective compared to\nIVF [ 32 ]. A more recent study, by\nPashayan et al., however, offered evidence that IVF as a first-line treatment\nfor couples with unexplained and mild male factor infertility was less costly\nthan IUI followed by IVF (for IUI treatment inability to achieve pregnancy) [ 33 ].\n\nWhich is more effective: IUI in a natural\ncycle or combined with ovarian stimulation? In a meta-analysis that included only randomized controlled trials, Hughes\nreported a significant improvement in fecundity with the use of IUI and\nfollicle stimulating hormone (FSH). He\nfound more than two-fold increase in fecundability for either IUI or FSH\ntreatment alone, while he found a five-fold increase when IUI and FSH are combined\ntogether [ 34 ]. In the Cochrane review by\nCohlen et al. referenced above, conducted to\nassess the effectiveness of IUI versus timed intercourse [ 32 ], IUI in a natural cycle was compared to IUI combined with controlled\novarian hyperstimulation. Data from four\ntrials were included in the meta-analysis for this comparison. Although there was no significant difference\nbetween IUI in natural cycles and IUI combined with ovarian hyperstimulation in\ncases with male factor infertility, the results suggested increased conception\nwith ovarian hyperstimulation (odds ratio: 1.8 with CI: 0.98–3.3). In their conclusion, Cohlen et al. \nrecommended the use of IUI in natural cycles for cases with severe semen defect\n(a total motile sperm count of less than 10 × 10 6 , but with more than\n1 × 10 6  motile sperm after preparation). In cases of less severe semen defect, IUI\nwith ovarian hyperstimulation was recommended. A large randomized study in the US confirmed the effectiveness of\ncombining ovarian stimulation with IUI [ 35 ]. The study reported an overall\npregnancy rate per couple of 33% for IUI with ovarian stimulation and an\noverall pregnancy rate of 18% for IUI alone. Data of this study were included in the Cochrane review, discussed\nabove, which was accomplished to assess the effectiveness of IUI in the\ntreatment of unexplained infertility. Verhulst et al. conducted a Cochrane review to assess the effectiveness\nof IUI in the treatment of unexplained infertility [ 36 ]. Their primary search yielded\n198 articles related to the topic, but hand searching of their abstracts\nresulted in 25 trials included in the review. It was found that live birth rate per couple was significantly higher\nwhen IUI was combined with ovarian hyperstimulation compared to IUI alone (OR\n2.07, 95% CI: 1.22–3.5) [ 36 ]. However, this review did not\nfind studies assessing expectant management versus IUI in unexplained\ninfertility. At the same year of\npublication as the above Cochrane review, Steures et al. published a randomized\nclinical trial comparing ovarian hyperstimulation combined with IUI versus\nexpectant management for couples with unexplained infertility [ 37 ]. This study reported no higher\npregnancy rates for ovarian hyperstimulation combined with IUI overexpectant\nmanagement in couples with unexplained infertility.\nThe National Institute for Clinical Excellence (NICE) in the United Kingdom\nrecommended, with\nlevel I evidence, that when IUI is used to treat male factor infertility,\novarian stimulation should not be offered. This conclusion was based on two trials [ 29 ,  32 ]. Supporting this recommendation\nis the results of a randomized clinical trial conducted in the Netherlands by\nSteures et al. [ 38 ]. This study reported similar\npregnancy rates when IUI alone or IUI combined with ovarian hyperstimulation\nwere used to treat couples with abnormal postcoital tests and poor prognosis\nfor spontaneous pregnancy. For\nunexplained infertility, both IUI alone and IUI combined with ovarian\nhyperstimulation appear to be more effective than expectant management alone [ 39 ].\nWhat drugs should be used for ovarian hyperstimulation combined with IUI?\nGonadotropins with and without gonadotropin-releasing hormone (GnRH)\nagonist/antagonist have been studied, along with recombinant human FSH\n(rFSH). Ragni et al. reported that the\ndaily use of 50 IU of rFSH, combined with a GnRH antagonist, ganirelix, for\novarian stimulation prior to IUI resulted in a live birth rate per couple of\n25.7% [ 40 ]. When the same dose of rFSH was used on alternate days, rFSH produced a\nlive birth rate of 2.9% [ 40 ]. In another study, 50 IU daily of rFSH was found similar to 75 IU daily\nof urinary FSH (uFSH) in the outcomes of the number of follicles >17 mm and\ndays of stimulation [ 41 ]. The clinical pregnancy rates were 12.7% for rFSH and 11.9% for uFSH [ 41 ]. Thus, the more expensive rFSH was not a cost-effective drug for\ninduction of ovulation in IUI cycles. Conversely, Demirol and Gurgan compared rFSH to uFSH and hMG in IUI\ncycles, and found rFSH and IUI produced a clinical pregnancy rate of 25.9%\ncompared to 13.8% for uFSH and 12.5% for hMG [ 42 ]. When rFSH and clomiphene citrate (CC) were compared for ovulation\ninduction with IUI in couples with unexplained and male factor infertility, the\ncumulative pregnancy rate was 38% for CC-IUI group versus 34.3% for the\nrFSH-IUI group [ 43 ].\nRecently Cantineau and Cohlen performed a\nCochrane review to evaluate different ovarian stimulation protocols\n(antiestrogens, aromatase inhibitors, and gonadotropins with or without GnRH\nagonists/antagonists) [ 44 ]. All published randomized controlled trials\n(RCTs) comparing different stimulation protocols before IUI were searched in\nthe Menstrual Disorders and Subfertility group's Central register of the\nControlled Trials, Medline, and EMBASE. 81 studies were identified, but only 43 trials met the inclusion\ncriteria. Of the different comparisons\ndone in this review, letrozole was not more effective than CC (OR 1.2, 95% CI:\n0.64–2.1). The analysis also\nrevealed that gonadotropins, in low-dose regimens (50–75 IU), were the most\neffective agents when ovarian stimulation was combined with IUI. Although less effective than gonadotropins,\nantiestrogens were more cost effective in IUI therapy. Neither a higher dosage\n(>75 IU gonadotropins) nor the addition of GnRH agonists was more\neffective. Conversely, the higher dosage\nand the GnRH agonists were associated with increased costs and risks of\nmultiple gestations and of OHSS. A\nsystematic review by Costello assessed the effectiveness of CC and IUI in the\ntreatment of ovulatory infertility [ 45 ]. Seven RCTs were included in this review. The meta-analysis of this review showed a\ncycle pregnancy rate of 14.3% for CC combined with IUI versus 6.4% for natural\ncycle IUI.\nConsiderations in Technology-Limited Settings  The evidence reviewed suggests that oral clomiphene therapy combined with IUI \nor natural cycle IUI is satisfactory first-line choices for treatment of\nunexplained and male infertility in low-technology settings. The combination of IUI and controlled ovarian\nhyperstimulation may result in a relatively higher therapeutic pregnancy rate\nfor unexplained and for male infertility. Gonadotropins are the controlled ovarian hyperstimulation agents that result\nin the highest rates of pregnancy. However, the costs associated with these drugs are higher, and the serum\nsteroid measurements and ultrasonographic monitoring require higher levels of\ntechnological capabilities.\nThe evidence reviewed suggests that oral clomiphene therapy combined with IUI \nor natural cycle IUI is satisfactory first-line choices for treatment of\nunexplained and male infertility in low-technology settings. The combination of IUI and controlled ovarian\nhyperstimulation may result in a relatively higher therapeutic pregnancy rate\nfor unexplained and for male infertility. Gonadotropins are the controlled ovarian hyperstimulation agents that result\nin the highest rates of pregnancy. However, the costs associated with these drugs are higher, and the serum\nsteroid measurements and ultrasonographic monitoring require higher levels of\ntechnological capabilities.\n\nThe\nWHO criteria for normal semen parameters are widely used [ 46 ]. In the system, an abnormal semen count is\ndefined as deviations from the normal criteria on two consecutive semen\nanalyses [ 46 ]. Studies have examined semen parameters, like\nmotile sperm concentration and normal sperm morphology, in relation to IUI\noutcome ( Table 1 ). In  Table 1 , four\ninferences could be made: most of the studies are retrospective, the number of\ninsemination cycles is fewer in the prospective studies, all but one study used\nthe inseminated motile sperm count after sperm preparation and the studies\nreported on different outcome measurements. In spite\nof the limitations outlined above, it may be deduced that reasonable IUI\nsuccess rates can still be obtained in cases of severe semen defects (normal\nmorphology 4% or less and inseminated sperm count as low as one million). This\nsupports the need for large well-designed prospective studies using standard\noutcomes.\nRegarding sperm concentration,\nOmbelet et al. in a retrospective study found that when inseminated motile\nsperm count was >1 × 10 6 , clomiphene-IUI resulted in a baby take-home rate of 21–25% after 3 cycles [ 47 ]. Even when inseminated motile sperm count was < 1 × 10 6  and\nthe normal sperm morphology >4%, clomiphene-IUI remained a treatment choice\nthat resulted in pregnancies. In a\nretrospective analysis of 3 479 IUI cycles conducted for 1039 infertile couples\n[ 48 ], Van Voorhis et al. found that a\ntotal motile sperm count per specimen of less than 10 million was associated\nwith lower pregnancy rates. On the other\nhand, a total motile sperm count above 10 million did not produce a significant\nincrease in IUI pregnancy rates.\nCohlen et al. defined a total motile sperm\ncount per ejaculate between 5 and 10 × 10 6  to be a severe semen\ndefect [ 49 ]. They reported a pregnancy rate per IUI cycle\nof 12% for couples with that count. Wainer et al. reported on the number of motile sperm inseminated [ 50 ] and found a clinical\npregnancy rate per cycle of 3.13% when the number of motile sperm inseminated was\n< 1 × 10 6 . When the number\nof motile sperm inseminated was between 5 and 10 × 10 6 , the clinical\npregnancy rate per cycle was 14%. Miller\net al. reported a cutoff point for number of motile sperm inseminated after\nsperm preparation as 10 × 10 6  [ 51 ]. Berg et al. reported successful pregnancies in patients after controlled\novarian stimulations in IUI preparations with motile sperm counts as low as\n>0.8 × 10 6  [ 52 ].\nNormal sperm morphology as a predictor of\nIUI success has been examined. After controlling for sperm concentration and motility, Lee et al. found that the normal sperm morphology, using Kruger's strict\ncriteria [ 53 ], more strongly predicted IUI outcome [ 54 ]. They reported pregnancy rates per cycle of 3.8% in couples with <4%\nof Kruger's strict criteria normal morphology, 18.5% for Kruger's strict\ncriteria normal morphology of 4–9% and 29.9% when Kruger's strict criteria\nnormal morphology was above 9% [ 54 ]. These results were similar to those reported in a study by Hauser et al. \n[ 55 ], where CC-IUI resulted in a\npregnancy rates per couple of 11.1% when normal morphology by strict criteria\nwas less than 4%, 36.1% for normal morphology of 4–14% and 50% when normal\nmorphology was above 14%. The link\nbetween sperm motility and IUI success was addressed in several studies. Briefly, in these studies, total motile sperm\nof 30–50% before sperm preparation was found to be associated with positive IUI\noutcomes [ 54 ,  56 ,  57 ].\nConsiderations in Technology-Limited Settings The\nevidence reviewed suggests that IUI may be offered to couples with male factor\ninfertility, in a low technology setting, if the total motile sperm count is\nmore than 5 million per specimen.\nThe\nevidence reviewed suggests that IUI may be offered to couples with male factor\ninfertility, in a low technology setting, if the total motile sperm count is\nmore than 5 million per specimen.\n\nThe aim of semen preparation is to separate motile, morphologically\nnormal spermatozoa from the seminal plasma and from debris such as leucocytes,\nbacteria, and nonmotile spermatozoa.  Table 2  shows studies that addressed the effect of different sperm\npreparation methods on IUI outcome. As shown in the table, the number of these\nstudies is limited. Sperm wash, swim-up, and density gradient\ncentrifugation are the most commonly used methods. As shown in  Table 2 , density gradient\ncentrifugation was associated with acceptable IUI outcomes [ 58 – 62 ]. Swim-up as a procedure is also associated with\nsatisfactory IUI outcomes, comparable to density gradient centrifugation\npregnancy rates. Furthermore, other\nstudies (the preparation technique was not the primary question addressed)\nreported similar outcomes for both methods [ 47 ,  50 ]. Boomsma et al. conducted a Cochrane review \nto compare the effectiveness of the three different semen preparation techniques\n(conventional wash, swim-up procedure, and density gradient centrifugation)\nbefore IUI [ 63 ]. Only two RCTs could be included in the\nmeta-analysis regarding the clinical outcomes. This resulted in insufficient data to recommend anyone of the three\nsemen preparation techniques over the others.\nThe time intervals between semen collection, sperm processing, and\ninsemination may affect IUI outcomes. Yavas and Selub performed a retrospective study where the collection of\nsemen at the clinic was found to be better than at home. Short intervals from semen collection to\nsperm wash, from sperm wash to IUI, and from semen collection to IUI were\nassociated with higher pregnancy rates compared to semen collection at home\nwith longer time intervals [ 64 ].\nConsiderations in Technology-Limited Settings The evidence suggests that conventional sperm wash for IUI can be used\nin a low-technology setting. The\nevidence does not seem to show that anyone of the three commonly used sperm\npreparation methods results in a higher pregnancy rate than any other.\nThe evidence suggests that conventional sperm wash for IUI can be used\nin a low-technology setting. The\nevidence does not seem to show that anyone of the three commonly used sperm\npreparation methods results in a higher pregnancy rate than any other.\n\nNormal sperm is capable of fertilizing an\noocyte in the female genital tract for about 5 days, and an oocyte is\nfertilizable for 12–24 hours after ovulation [ 65 ]. The WHO conducted a large multicenter study\nthat concluded that ovulation occurred between 24 and 56 hours (average 32\nhours) after the onset of luteinizig hormone (LH) surge [ 66 ]. In another study ovulation, occurred 36–38\nhours after the onset of LH surge in natural cycles [ 67 ]. The LH surge can be detected at home using\nurinary LH kits. The monitoring for the\nurinary LH surge can start about 3 days before the expected date of\novulation. Generally, in natural cycles,\nIUI can be performed 24 hours after the onset of LH surge as detected by\nurinary LH monitoring.\nIn controlled ovarian stimulation cycles in which ovulation is triggered\nartificially, ovulation occurs 32–38 hours after human chorionic gonadotropin\n(HCG) injection [ 68 ,  69 ]. Based on the available data about the timing\nof ovulation, some investigators recommended that insemination can be carried out\nbetween 12 and 60 hours after HCG injection [ 70 – 72 ]. Other investigators found that delayed inseminations to 38–40 hours\nafter HCG injection were associated with higher pregnancy rates compared to\nearly inseminations [ 73 ]. This was not found in a study by Claman et al., who found that there was\nno significant difference in pregnancy rates between early (32–34 hours) and\nlate (38–40 hours) inseminations [ 74 ]. When HCG is used, insemination can be done\n34–40 hours after injection [ 75 ].\nA systematic review was performed by Kosmas\net al. to compare the effectiveness of HCG administration versus urinary LH\ndetection as a method of IUI timing after CC stimulation [ 76 ]. Seven studies were included in this systematic review and the\nmeta-analysis. The authors found that\nthe use of urinary LH monitoring as a method of IUI timing was associated with\nhigher pregnancy rates than the HCG administration method. They concluded that LH monitoring for IUI\ntiming is more practical, effective, and cost-effective when CC is used for\novarian stimulation [ 76 ].\nConsiderations in Technology-Limited Settings The evidence suggests that it is reasonable to perform IUI, for either \nnatural cycle IUI or for clomiphene combined with IUI, approximately 24 hours \nafter the detection of the LH surge. Urine\ntesting kits could be used to detect the LH surge.\nThe evidence suggests that it is reasonable to perform IUI, for either \nnatural cycle IUI or for clomiphene combined with IUI, approximately 24 hours \nafter the detection of the LH surge. Urine\ntesting kits could be used to detect the LH surge.\n\nSeveral studies have compared single\nversus double IUIs in an ovulatory cycle. One of the earlier studies, conducted for that purpose, reported a cycle\nfecundity of 52% when 2 inseminations 18 and 42 hours after HCG were performed\nwhile a single insemination performed 34 hours after HCG injection resulted in\na cycle fecundity of 8.7% [ 71 ]. Another study found that double\ninseminations, performed 12 and 34 hours after HCG administration, in\ngonadotropin stimulated cycles, resulted in a pregnancy rate per patient of\n30.4%, a higher pregnancy rate than that found from single inseminations\n(14.4%) performed 34 hours after HCG [ 72 ].\nOn the other hand, Ransom et al. found no\ndifference in pregnancy rates between single IUI performed 35 hours after HCG\nand double IUI done 19 and 43 hours after HCG injection [ 77 ]. These results were supported in a study by\nAlborzi et al. [ 78 ] where pregnancy rates per cycle\nwere 8.6% and 9.4% (nonsignificantly different) for single and double\nIUIs. Another study, by Casadei et al.,\nfailed to show a significant advantage of double inseminations 12 and 36 hours\nafter HCG injection over single insemination done 36 hours after HCG [ 79 ].\nTwo reviews were conducted to reach a\nconclusion about the number of inseminations per cycle [ 80 ]. One was a systematic review and meta-analysis [ 80 ] and the second was a Cochrane\nanalysis [ 81 ]. In the first review, by\nOsuna et al., 18 trials were retrieved from searching Medline, The Cochrane\nlibrary, and the abstract books of annual meetings of ESHRE and ASRM [ 80 ]. Only six randomized prospective studies were included in the\nreview. The pooled outcomes of the\nstudies were a pregnancy rate per cycle of 14.9% for double IUIs versus 11.4%\nfor a single IUI. This difference was\nstatistically insignificant. The\nCochrane review, by Cantineau et al., followed the same search strategies and\ndata analyses as mentioned previously [ 81 ]. From the 30 studies\nretrieved, 13 were found to provide data comparing single versus double\ninseminations. Only 3 RCTs were included\nin the review, the results of 2 of them were pooled for meta-analysis. The authors concluded that there was no\nevidence that double inseminations give rise to higher live birth rates in\ninfertile couples compared to single inseminations (OR 1.45, CI: 0.78–2.7). The \nNICE recommendation is for a single\ninsemination when offering IUI as therapy [ 39 ].\nConsiderations in Technology-Limited Settings The\nevidence suggests that single IUI insemination per ovulatory cycle should be\nconsidered. Published evidence does not\nsupport that two IUI in a single cycle results in a higher rate of\npregnancy. A single insemination will be\nless costly, with similar pregnancy outcomes.\nThe\nevidence suggests that single IUI insemination per ovulatory cycle should be\nconsidered. Published evidence does not\nsupport that two IUI in a single cycle results in a higher rate of\npregnancy. A single insemination will be\nless costly, with similar pregnancy outcomes.\n\nSome\nstudies report six treatment cycles [ 29 ,  60 ,  78 ], while others report four cycles [ 35 ,  82 ] as the number of cycles of\ntreatment with IUIs. One study reported\na cumulative probability of pregnancy of 38.2% for 6 treatment cycles and 49.5%\nfor 10 treatment cycles [ 52 ]. One of the six-cycle\nstudies, by Morshedi et al., reported that 88% of the pregnancies occurred in\nthe first 3 cycles [ 60 ]. However, a Cochrane review and the NICE guidelines support using IUI as\ntreatment for up to 6 cycles [ 32 ,  83 ]. The NICE reported, with level I evidence, that the use of up to 6 cycles\non IUI increased the chance of pregnancy for couples with mild male-factor and\nunexplained infertility and minimal to mild endometriosis. The Cochrane reviewers concluded that most\npregnancies occurred during the first 3 to 6 IUIs treatment cycles.\nConsiderations in Technology-Limited Settings The evidence suggests\nperforming a minimum of three IUI treatment cycles and a maximum of six IUI\ntreatment cycles in technology-limited setting.\nThe evidence suggests\nperforming a minimum of three IUI treatment cycles and a maximum of six IUI\ntreatment cycles in technology-limited setting.\n\nThe resource allocation of infertility services available for patients is\nasymmetric, with the highest levels in the larger cities. The evidence reviewed suggests that IUI may\nbe helpful in a low-technology medical setting. It may be considered as a good first-line treatment for couples with\nunexplained infertility, male factor infertility, and anovulation (IUI used\nconcurrently with ovulation induction). In the clinical practice of IUI in a low-technology setting, combining\noral clomiphene with IUI is as reasonable of an option as natural cycle\nIUI. For semen parameters, a motile\nsperm count above 1 million in the final specimen can serve as a cutoff point\nfor offering IUI. Conventional sperm\nwashing, density gradient centrifugation, or swim-up techniques can all be used\nfor sperm preparation before IUI, with conventional sperm washing being the\nsimplest. A single IUI per cycle should\nbe performed, and the IUI can be performed approximately 24 hours after urinary\nLH surge is detected. Couples may be\noffered 3 to 6 IUI cycles to ensure sufficient opportunity to achieve\npregnancy.","source_license":"CC-BY-4.0","license_restricted":false}