{"paper_id":"6ec76489-115a-46ca-bfd7-68faa036508e","body_text":"Controlled ovarian hyperstimulation (COH)\nalong with intrauterine insemination (IUI) is commonly\nused to infertile couples with patent fallopian\ntube. IUI is simple, non-invasive and cost-effective\ntechnique ( 1 ). During IUI, pretreated semen\nis concentrated in a small volume of 0.2-0.5 ml and\nsplashed by a catheter into the uterine cavity ( 2 ,  3 ).\nDifferent studies have been reported a pregnancy\nrate per cycle of 15-20% ( 4 - 6 ). The pregnancy rate\ndepends on artificial insemination technique, the\ntype of ovarian stimulation [Clomid or injectable\ngonadotropins, with or without gonadotropin-releasing\nhormone (GnRH)], the age of patients and\nthe cause of infertility ( 1 ).\nFallopian tube sperm perfusion (FSP), an alternative\nprocedure, has been reported to improve\npregnancy rate in comparison with IUI ( 7 - 9 ). The FSP was first described by Kahn et al. ( 7 ) and\nshown a pregnancy rate per cycle of 26.9% in\npatients with unexplained infertility. In FSP\ntechnique, sperm preparation is identical to that\nused in IUI, but the main difference is the sperm\npreparation volume of medium that is 4 ml in\nFSP, indicating higher volume in comparison\nwith IUI ( 10 ). Therefore, higher volume of insemination\nin FSP technique causes sperms to\npass directly through the fallopian tubes and to\nspread into the cul-de-sac ( 11 ). Many studies\nhave shown the higher sperm densities in the\nfallopian tubes present at the time of ovulation\nas compared with IUI ( 12 ). In a study by Ripps\net al. ( 13 ), they showed that the number of peritoneal\nspermatozoa recovered at laparoscopy\nafter IUI was very less than their number after\nuterotubal flushes. Mamas ( 14 ) proposed 10 ml\nof contrast medium in hysterosalpingography is\nsufficient to fill the uterine cavity and to pass\nthrough fallopian tube in order to spread in\nperitoneal cavity, suggesting the efficiency of\ntuboperitoneal insemination (IUTPI) method.\nThere are different method to prevent semen reflux\nin FSP technique, such as using Allis clamp on\ncervix, transcervical inflated pediatric Folley catheter\nballoon, the double nut bivalve (DNB) speculum\nwith modified tips to clamp the cervix, and\nthe fallopian sperm transfer (FAST) system( 1 , 7 ,\n 8 , 10 , 15 - 18 ). In a study by Fanchin et al. ( 1 ), they\nintroduced the FAST system, an autoblocking device\nfor FSP. They reported significant difference\nin pregnancy rate per cycle, 40% in the FSP Vs.\n20% in the IUI group.\nSince 1992, several randomized controlled studies\npublished have compared the efficacy between\nFSP and standard IUI, but they have showed conflicting\nresults ( 1 ,  9 ,  10 ,  17 ,  19 ). Since there was\nno study about FSP using FAST system in North of\nIRAN .We designed this prospective trial to evaluate\nand to compare the pregnancy rate per cycle\nbetween FSP using FAST system and IUI in patients\nwith unexplained infertility.\n\nThis prospective randomized study was conducted\nat the IVF Unit, Department of Gynecology\nand Obstetrics, Imam-Khomeini Hospital,\nMazandaran University of Medical Sciences,\nSari, North of Iran, from March 2011 to February\n2012. After a basic infertility work up, patients\nwith unexplained infertility were included\nin this study with the following indications:\nnormal ovulatory cycle, normal spermiogram,\nnormal hysterosalpingography, and normal\nlaparoscopy finding. Patients with abnormal\nsemen morphology and hormonal assay, abnormal\nhysterosalpingography, age more than\n35 years, polycystic ovarian syndrome (PCOS)\nand endometriosis, body mass index (BMI)>28\nkg/m 2 ,duration of infertility>10 years, and history\nof treatment with assisted reproductive\ntechniques(ART) were excluded. After obtaining\ninformed consent, all patients underwent\nsimilar controlled ovarian stimulation protocol\nusing clomiphene citrate and human menopausal\ngonadotropin (hMG) injection. The protocol\nconsisted of clomiphene citrate (tablet 50 mg,\nIran Hormone, Iran) 100 mg per day from day\n3 to 7 of the menstrual cycle and a single intramuscular\ninjection of hMG (Merional, IBSA,\nSwitzerland) 75-150 IU daily (single dose) until\nthe follicle diameter reach to 18 mm. Cycles\nwere monitored from day 10 by transvaginal\nultrasound (Honda 2000, japan) to measure the\nnumber and the diameter of the growing follicles\nand endometrial thickness. The maturation\nof two to three follicles was considered optimal.\nA total of 10,000 IU human chorionic gonadotropin\n(hCG, Amp 5000 IU/1 cc, Darupakhsh,\nIran) was administered when at least one follicle\nhad reached a diameter of 18 mm, and 34-\n36 hours later, either standard IUI or FSP was\nperformed. According to the collected data, including\naged between<30 and 30-35 years old,\nprimary or secondary infertility, and duration of\ninfertility <5 or >5 years. On the day of hCG\nadministration, the patients were randomly, according\nto a sealed envelope, divided into group\nI (n=45) to undergo standard IUI or group II\n(n=45) to undergo FSP using FAST system. The\nstudy was approved by Ethical Committee of\nthe Institutional Review Board of Mazandaran\nUniversity of Medical Sciences.\nFor all patients, semen was prepared by the\nstandard swim-up technique. The final sperm suspension\nwas diluted in 0/5 ml and 4 ml of Ham’s\nF-10 medium for IUI and FSP groups, respectively.\nIn all cases, IUI and FSP were performed\nby a clinician and a technician. Intrauterine insemination\nwas performed using the IUI catheter (Laboratoire C.C.D., Paris, France). The catheter\nwas passed into the upper part of the uterine cavity,\nand 0.5 cc of sperm was slowly deposited. An\nair bubble was left behind the sperm suspension to\nprovide complete delivery of the sperm suspension\ninto the uterus. Patients rested for 30 minutes after\ninsemination.\nFSP was performed with FAST system’s catheter\nfrom the same company (Laboratoires C.C.D.,\nParis, France). This device is composed of a cervical\ncup made of crystal-clear plastic with two\nflexible tubings with a roller clamp on each, the\ninjection tubing and the vacuum tubing ( Fig 1 )\n( 16 ). Three different sizes of cervix adaptor were\nselected (diameters of 25, 27, and 30 mm) according\nto the size of the patient’s cervix. The syringe\ncontaining 4 cc processed semen was connected to\nthe injection tubing. A sterile 10-mL syringe was\nconnected to the vacuum tubing ( 16 ). Cervix was\nexposed by a bivalve speculum in lithotomy position,\nand the cervix was exposed and cleaned with\nphysiological saline solution. According to the\nfactory instruction, the cervical cup was grasped\nusing a grasping forceps. Afterward, the adaptor\nwas inserted into the vagina until the tip of the injection\ntubing entered into the cervix canal. Then,\nthe edge of the cup was gently pressed into the\ncervix to make sure that it was in the right place.\nFurthermore, a vacuum was immediately created\ninside the adaptor by aspirating the syringe connected\nto the vacuum tubing. The sperm suspension\nwas then slowly injected over 2 minutes ( 16 ).\nTo push all the sperm that were in the dead space\nof the tubes into the uterus, the first syringe was\ndisconnected and replaced with another sterile\n5-mL syringe filled with 1.5 mL of incubation medium.\nFSP was completed by slowly injection of\nthe medium. Then the tubing was attached to the\ninner thigh by means of a sticking plaster. After 2\nhours, the device was easily removed with a gentle\npull after opening the roller clamp of the vacuum\ntubing.\nPatients received progesterone vaginal suppositories\n400 mg per day (Cyclogest, Actavis,\nIceland) for luteal-phase support. Patients were\ninstructed to obtain a quantitative serum hCG 16-\n18 days after insemination if no menses occurred.\nA transvaginal ultrasonogram was performed at\n6-7 weeks after the last menstrual period to detect\nclinical pregnancy. A biochemical pregnancy was\ndetected by a transient elevation of serum hCG.\nFAST System for fallopian tube sperm injection (FSP).\nThe Statistical Package for the Social Sciences\n(SPSS; SPSS Inc., Chicago, IL, USA) version 16.0\nwas used to assess the study data.We considered\n20% pregnancy rate in IUI and 34% pregnancy\nrate in FSP with α=0.05 and β=0.2 using the following\nsample size formula:\nZ=the standard normal variable unit, which at 95\npercent is equal to 1.96.\nP=proportion of the population trait. If not available,\nit can be considered 0/5.\nThe sample size assessed 90 patients. The twotailed\nt test and χ2 test were used for the statistical\nanalysis. A p value of <0.05 was considered as significant\ndifference.\n\nOut of ninety patients with unexplained infertility\nenrolled in this study, 45 patients were randomly\nallocated to IUI group (group I) and 45 patients\nin FSP group (group II).\nThe median age values in the groups I and II were 28.2 ± 4.9 and 27.1 ± 4.6 years, respectively\n(p>0.05). Our findings shows that 74% in IUI\ngroup and 72% in FSP group had primary infertility\n(p>0.05). The mean duration values of infertility\nwere 3.9 ± 3.1 years in group I and 3.8 ±\n2 years in group II (p>0.05).The median of BMI\nvalues were 26.6 ± 2.7 kg/m 2  in IUI group and 25.5\n± 2.3 kg/m 2  in FSP group (p>0.05).The patients’\nbasic characteristics were not significantly different\nbetween the two study groups.\nThe characteristics of the stimulation cycles and\noutcome are presented in  table 1 . The numbers of\nfollicles >16 mm during ovarian stimulation were\n2.2 ± 1 in group I and 2.1 ± 0.9 in group II (p>0.05).\nThe days of hCG administration in groups I and II\nwere on 12.8 ± 3.4 and on 11.7 ± 2.6 of a cycle,\nrespectively. The endometrial thickness values on\nthe day of HCG administration were 8.2 ± 1 mm\nin group I and 8.8 ± 0.9 mm in group II. The mean\nnumbers of motile spermatozoa inseminated were\n49×10 6  in group I and 51×10 6  in group II. The cycle\ncharacteristics were not significantly different\nbetween the two study groups (p>0.05).\nClinical pregnancy rate values were 8 of 45 patients\n(17.8%) in the FSP group and 9 of 45 patients\n(20%) in the IUI group (p>0.05).\nIn both groups, insemination was easily performed\nin all patients, and no case of sperm reflux\nwas observed. No complications such as cervical\nbleeding, vasovagal episodes, or uterine cramping\nwere observed. No cases of ovarian hyperstimulation\nsyndrome or cancellation of the cycle were\nobserved.\nCharacteristics of stimulation cycles and outcome in two studies groups\n¥; Values are presented as mean± SD, HMG; Human menopausal gonadotropin, IUI; Intrauterine insemination and FSP;\nFallopian tube sperm perfusion.\nAll p values are >0.05.\n\nIn this prospective randomized study, we compared\nthe relative efficacy between FSP using\nFAST system and IUI in unexplained infertility\npopulation. We demonstrated no statistically significant\ndifference between both treatment group\nin the pregnancy rate (17.8% in FSP vs. 20% in\nIUI groups) (p>0.05).The pregnancy rate with FSP\nis less than that reported by Kahn et al. ( 10 ), they\nreported 26.9% pregnancy rate in the FSP group\nversus9.8% in the IUI group (p<0.05).\nIn Fanchin and colleagues’study ( 1 ), FSP was\nperformed using an auto-blocking device (FAST\nsystem) similar to our study. Fanchin reported\n40% pregnancy rate per cycle in FSP group versus\n20% in the IUI group (p<0.05), however, they\nfailed to determine the cause of infertility in their\npatients ( 17 ). Theoretically, the direct passage of\nthe sperm preparation through the fallopian tubes\nwould increase the density of capacitated spermatozoids\nnear the oocyte and the intra-peritoneal\ncavity and by consequence increase the pregnancy\nsuccess rate ( 11 ).The pressure injection of inseminate\nin FSP can remove partial obstruction of fallopian\ntubes, created by thick mucus or tubal polyps\n( 1 ). Some authors reported pregnancy rates of\n20-40 % in FSP technique ( 1 ,  8 ,  10 ,  15 ). One metaanalysis\nstudy by Trout and Kemman ( 17 ) demonstrated\na significant difference of superiority for\nFSP concerning the unexplained infertility, 22% of\npregnancy rate in FSP versus 13% in IUI. They included\nall the previous studies from 1992 to 1998,\nbut exempted Fanchin et al. ( 1 ) who didn’t detail\ntheir indications and results. Trout and Kemman’s\nmeta-analysis showed a significant improvement\nin pregnancy rates with FSP only in patients with\nunexplained infertility who underwent controlled\novarian stimulation with gonadotropin and insemination\nprotocols ( 17 ). We used clomiphene and\ngonadotropin combination for induction of ovulation\nto reduce the cost of treatment. Selecting the\ndifferent induction ovulation protocol may explain\nthe differences between their and our findings. In\nEl-Khayat and colleagues’ study, the pregnancy\nrate was significantly higher in FSP group than in\nIUI group (26.7 vs. 11.7%, respectively, p<0.04).\nThey achieved FSP via Foley catheter with 4 mL\nof inseminate in patients with mild or moderate\nmale factor infertility ( 12 ).\nIn contrast, other authors have reported the pregnancy\nrate of 9 or 14.5% in FSP technique ( 20 ,\n 21 ). The results of Panayotidis’s study didn’t show\na statistically significant superiority of the FSP\nover the IUI method for all the indications of insemination\n( 11 ). Our results are similar to Nuojua-\nHuttunen and colleagues’ study. They performed\na prospective randomized study using a Foley\ncatheter for FSP. They reported no advantage of\nFSP in comparison with the conventional IUI technique\nin women with unexplained infertility, minimal\nto mild endometriosis, mild male factor, and\novarian dysfunction. However, the Foley catheter\nis cheaper, but sometimes, there is difficult to introduce\nthis tool into the cervical canal. It might\nhave an adverse effect on the endometrium caused\nby pressure of the balloon and the substances that\nmay dissolved from the Foley catheter ( 19 ). Only\ntruly randomized controlled studies comparing\nFSP with IUI were included in this review. Eight\nstudies involving 595 couples were included in the\nmeta-analysis. Only one study reported the live\nbirth rate and there was no evidence of a difference\nbetween FSP and IUI (OR 1.2, 95% CI: 0.39\nto 3.5). There was no evidence of a difference between\nFSP and IUI for clinical pregnancy per couple\n(OR 1.2, 95% CI: 0.79-1.7). A subgroup analysis\nincluding couples with unexplained subfertility\ndid not report any difference between FSP and IUI\n(OR 1.6, 95% CI: 0.89-2.8) ( 22 ).\nSince 1992, the following different protocols\nfor ovarian stimulation are applied: clomiphene,\nalone or combined with FSH, and HMG. Different\nprotocol for induction ovulation is one of the\nfactors that could explain differences in results.\nAnother factor to explain the differences in result\nis the type of catheter used to place sperm in the\nfallopian tube. As mentioned in studies, the use of\nthe FAST system for FSP can be a little more expensive\nthan the IUI catheter, and sometimes, the\nplacement of the seal cup on the cervix is not perfect\nand needs more experience and skill ( 16 ). In\nour clinic, we perform routinely FSP with Foley\ncatheter and FAST system, so skill of clinician\ncan’t be considered as a factor for difference.\nFrom this study we conclude that FSP using\nFAST system offers no advantage over the standard\nIUI in order to increase the pregnancy rate in\nunexplained infertility. The FSP technique needs\nmore media volume for insemination, so the procedure could be more expensive. Maher Shams\nevaluated the efficacy of double FSP versus single\nFSP by Foley catheter in non-tubal infertility.\nThey showed higher pregnancy rate in double FSP\ngroups ( 23 ). Doing double FSP in unexplained infertility\ncould be a topic for our future study.\n\nFuture well-designed study in larger population\nis needed to confirm benefits of FSP. We suggest\ndouble FSP or tubo-peritoneal perfusion with 10\nml of inseminated before using other more expensive\nand invasive assisted reproductive technique\nin unexplained infertility patients.","source_license":"CC-BY-4.0","license_restricted":false}