FERTILITY AND STERILITY威 VOL. 76, NO. 6, DECEMBER 2001 Copyright ©2001 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.

A simple method for fallopian tube sperm perfusion using a blocking device in the treatment of unexplained infertility Giuseppe Ricci, M.D., Giuseppe Nucera, M.D., Cristina Pozzobon, M.D., Rita Boscolo, B.Sc., Elena Giolo, B.Sc., and Secondo Guaschino, M.D. Gynecology and Obstetrics Unit, Department of Reproductive and Developmental Science, University of Trieste, Istituto per l’Infanzia “Burlo Garofolo,” I.R.C.C.S., Trieste, Italy

Objective: To evaluate the efficacy of fallopian sperm perfusion (FSP) using a new method similar to the FAST system威 in comparison with standard intrauterine insemination (IUI) in patients with unexplained infertility. Design: Prospective, randomized, controlled study. Setting: Assisted conception service in a University Hospital. Patient(s): Women with unexplained infertility undergoing controlled ovarian hyperstimulation (COH). Intervention(s): After hCG administration, patients were randomized to either standard IUI or FSP. The women received the same treatment in the first and all subsequent cycles. A maximum of three cycles was performed. Intrauterine insemination was performed using a standard method, and fallopian sperm perfusion was performed using a commercial device for hysterosalpingography and tubal hydropertubation. Main Outcome Measure(s): Clinical and ongoing pregnancy rates. Result(s): A total of 132 cycles was completed: 66 IUI cycles and 66 FSP cycles. In the IUI group, there were 5 ongoing pregnancies, giving a pregnancy rate of 7.6 per cycle and 15.6% per patient; in the FSP group, 14 ongoing pregnancies occurred, giving a pregnancy rate of 21.2% per cycle and 42.4% per patient. The prevalence of multiple pregnancies, miscarriages and ectopic pregnancies was similar in the two insemination groups. Fallopian sperm perfusion was easy to perform, and no case of sperm reflux was observed. The procedure was well tolerated and no complications were observed. The costs were comparable with standard IUI. Conclusion(s): In the treatment of couples with unexplained infertility, the method for fallopian sperm perfusion described yields higher pregnancy rates than IUI, with no significant increase in costs or complications. However, these results need to be confirmed in larger studies before replacing IUI with FSP as standard practice. (Fertil Steril威 2001;76:1242– 8. ©2001 by American Society for Reproductive Medicine.) Key Words: Fallopian tube sperm perfusion, intrauterine insemination, unexplained infertility, ovulation induction, assisted reproductive technology Received February 16, 2001; revised and accepted June 25, 2001. Reprint requests: Giuseppe Ricci, M.D., Gynecology and Obstetrics Unit, Department of Reproductive and Developmental Science, University of Trieste, Istituto per l’Infanzia “Burlo Garofolo,” I.R.C.C.S., Via dell’Istria, 65/1, 34137 Trieste, Italy (FAX: 39-40761266; E-mail: ricci@ burlo.trieste.it). 0015-0282/01/$20.00 PII S0015-0282(01)02913-2

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In 1991, Kahn et al. (1) described a new method of assisted conception called fallopian tube sperm perfusion (FSP), combining controlled ovarian hyperstimulation (COH) and IUI with a large volume (4 mL) of sperm suspension. They used a Frydman catheter to perform FSP and an Allis clamp placed on the cervix to prevent sperm reflux (1–5). Subsequently, this technique was used by other investigators (6, 7), and other techniques have also been proposed (8 –12). Several randomized controlled studies comparing FSP and IUI have been performed, with conflicting results (5–7, 9 –14).

In the first clinical experience using a blocking device (the FAST system威), Fanchin et al. (10) reported a very high cycle pregnancy rate (PR). They observed a clinical PR per cycle of 40% in patients treated with FSP compared with a clinical PR per cycle of 20% in patients treated with standard IUI. These results were not confirmed by studies using other FSP methods, and a long debate ensued (15–18). Two important criticisms were made of Fanchin’s study: [1] the original paper did not give a breakdown of patients by diagnosis, hence their results are not comparable with those of other studies, and [2] why should a more costly de-

vice for FSP be used when the procedure can be done with a less expensive IUI catheter? Regrettably, no further studies on the FAST system威 have been published since the first report. The aim of this study was to evaluate the efficacy of Fanchin’s method in a prospective, randomized, controlled trial comparing FSP with IUI in patients with unexplained infertility, using a new, less expensive technique similar to the FAST system威.

FIGURE 1 The equipment necessary for fallopian tube sperm perfusion: a cervix adaptor, a bivalve speculum, a forceps, and sterile 5-mL and 10-mL syringes.

MATERIALS AND METHODS Patients The study was designed as a prospective, randomized, controlled trial. It was carried out at the Department of Reproductive and Developmental Sciences of the University of Trieste between January 1, 1998 and March 31, 2000. Patients suffering from unexplained infertility for ⱖ2 years were enrolled. Unexplained infertility was defined as spontaneous ovulation checked by at least two biphasic basal body temperature charts and normal serum progesterone concentrations (⬎10 ng/mL) in the midluteal phase; normal FSH, LH, TSH, and prolactin serum levels; normal hysteroscopic and laparoscopic findings with regular uterine cavity and tubes; normal sperm parameters according to the WHO standards (19); and no detectable anti-sperm auto-antibodies. Informed consent was obtained from each subject before the study commenced. None of the couples had been treated by assisted reproductive techniques before entering the study. The study was approved by the Institutional Review Board of the University of Trieste and was conducted in accordance with the guidelines proposed in the latest revision of the Declaration of Helsinki.

Controlled Ovarian Hyperstimulation Starting on cycle day 2, patients received urinary human FSH (u-hFSH) (Metrodin HP, Serono, Rome, Italy) 150 IU/d. From cycle day 5, dose adjustment was performed, according to follicular development, as assessed by ultrasound scanning and measurement of serum estradiol levels. Human chorionic gonadotropin (10,000 IU) was administered i.m. to induce ovulation when at least one follicle of ⱖ18 mm in diameter was present. A single insemination was scheduled 36 hours later. The luteal phase was supported with 50 mg progesterone in oil (Prontogest, Amsa, Rome, Italy) daily, i.m., beginning on the day of insemination and continuing for at least 16 days.

Sperm Preparation Semen was collected by masturbation after 3– 4 days of ejaculatory abstinence and was allowed to liquefy at 37°C for ⱖ20 minutes before processing. Semen was prepared for FSP and IUI using a classical swim-up technique. The sample was washed with synthetic human tubal fluid (modified HTF medium, human tubal fluid HEPES buffered; 0.5% human serum albumin; both, Irvine Scientific, Santa Ana, FERTILITY & STERILITY威

Ricci. A simple method for fallopian tube sperm. Fertil Steril 2001.

CA) in a sterile 5-mL round-bottomed tube and centrifuged for 10 minutes at 300 ⫻ g. The pellet was resuspended in 0.5 mL of medium. Then 0.7 mL of fresh medium was gently layered over the specimen. The tube was inclined at an angle of 45° and incubated for 30 minutes at 37°C. It was then gently returned to an upright position and the uppermost 0.5 mL removed. For FSP, the aliquots of motile cells were resuspended in 4 mL of HTF, whereas for IUI, they were centrifuged for 10 minutes at 300 ⫻ g and the pellet was resuspended in 0.5 mL of HTF. The total number of motile spermatozoa in the inseminate was assessed.

Insemination Intrauterine insemination was performed using a Frydman catheter (CCD Laboratoires, Paris, France) attached to a 1-mL tuberculin syringe. The catheter was passed into the upper part of the uterine cavity, and 0.5 mL of sperm suspension was slowly deposited. An air bubble was left behind the sperm suspension to provide complete delivery of the sperm suspension into the uterus. Patients rested for 20 minutes after insemination. Fallopian tube sperm perfusion was performed using a commercial device for hysterosalpingography and tubal hydropertubation, Cervix-Adaptor according to Fikenntscher and Semm (Wisap, Sauerlach b., Munchen, Germany; Fig. 1). This device is composed of a cervix adaptor made of crystal-clear plastic, with two flexible tubings: the injection 1243

tubing (red) and the vacuum tubing (white), both provided with a roller clamp at the extremity. Three different sizes of cervix adaptor are available (diameters of 25, 27, and 30 mm). The cervix adaptor was selected according to the size of the patient’s cervix. The injection tubing was shortened by cutting off approximately half to reduce contact between the spermatozoa and the tubing lumen. The sperm suspension was collected by means of a sterile 5-mL syringe. The syringe was connected to the injection tubing, which it filled as far as its extremity. A sterile 10-mL syringe was connected to the vacuum tubing. No premedication was needed. A bivalve speculum was inserted, and the cervix was exposed and cleansed with physiological saline solution. The cervix adaptor was grasped lengthwise at its holding device by means of a grasping forceps. The adaptor was inserted into the vagina, and the tip of the injection tubing was pulled into the cervix canal. Then, the edge of the adaptor was gently pressed onto the cervix by pushing back the uterus, and a vacuum was immediately created inside the adaptor by aspirating with the syringe connected to the vacuum tubing. The sperm suspension was then slowly injected for approximately 2 minutes. To push all the sperm suspension into the tubes, the first syringe was disconnected and replaced with another sterile 5-mL syringe filled with 1.5 mL of incubation medium. Fallopian tube perfusion was completed by slowly injecting the medium. Then the tubing was attached to the inner thigh by means of a sticking plaster. The patient did not rest after the procedure and left with the device attached to prevent late inseminate reflux. After 4 hours, the device was easily removed with a gentle pull after opening the roller clamp of the vacuum tubing.

Laboratory Analyses

Serum 17␤-estradiol was determined by means of a solidphase, ligand-labeled, chemiluminescent immunoassay with an IMMULITE Analyzer (IMMULITE estradiol, Diagnostic Products Corporation, Los Angeles, CA), and results were expressed in picograms per milliliter.

Diagnosis of Pregnancy Patients were instructed to obtain a quantitative serum ␤-hCG 16 –18 days after insemination if no menses occurred. A transvaginal ultrasonogram was performed at 6 –7 weeks after the last menstrual period. Clinical pregnancy was defined as the presence of fetal heartbeats on ultrasound examination or a positive histological identification of ectopic pregnancy. Ongoing pregnancy was defined as the presence of fetal heart beats beyond 14 weeks of gestation. A biochemical pregnancy was detected by a transient elevation of serum hCG. A blighted ovum was defined as the presence of a sac on ultrasound examination but failure to detect the development of fetal cardiac activity. Only clinical and ongoing pregnancies were included in the data. 1244 Ricci et al.

Sample Size A power study was carried out to determine the number of cycles needed. On the basis of previous experience at our center, an 8% cycle PR for IUI treatment was used. Assuming a difference of PR per cycle of approximately 20% in favor of FSP over IUI (28% vs. 8%), as reported by Fanchin et al. (10), to obtain 80% power and type I error of .05 in a two-sided test, a sample size of at least 66 cycles per treatment was required.

Randomization On the day of insemination, the patient was randomized to undergo either FSP or IUI. The randomization protocol was produced via a random-number generator on a personal computer using a 1:1 ratio. The women were given the same treatment in the first and all subsequent cycles. A maximum of three cycles was performed.

Cost Analysis Cost analysis was carried out based on the resources used and costs during the year 2000. A distinction was made between the costs of the insemination procedure itself (sperm preparation, catheter) and general hospital costs (staff time, use of the surgery).

Statistical Methods All demographic data, clinical, and stimulation data were checked for comparability using Student’s unpaired t test. The pregnancy rates per cycle and per couple were calculated for each of the treatment groups, and the results were compared via Fisher’s exact test. The prevalence of multiple and ectopic pregnancies and miscarriages in the two groups was compared using Fisher’s exact test. Cumulative pregnancy rates were calculated using life table analysis as described by Cramer et al. (20). P values are two-sided, with .05 taken as the cutoff for statistical significance.

RESULTS Characteristics of Patients A total of 65 patients were randomized. Thirty-two patients were assigned to receive IUI and 33 FSP. Sixty-six FSP cycles and 66 IUI cycles were completed. Three cycles were cancelled before randomization because of a risk of multiple pregnancy and/or ovarian hyperstimulation syndrome and were excluded from the data. None of the cycles was cancelled after randomization. No significant differences were found between the demographic and infertility characteristics of the two groups (Table 1), suggesting that they had been adequately randomized. As regards stimulation characteristics, there were no differences in terms of days of u-hFSH administration, total dose of u-hFSH required, number of follicles ⬎16 mm in diameter, and estradiol concentrations on the day of hCG in the two groups (Table 2). There were no significant differences in the semen parameters before preparation. There was no significant dif-

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TABLE 1

TABLE 3

Main demographic and infertility characteristics in the IUI and the FSP groups.

Number of spermatozoa in the semen sample and inseminate in the IUI and the FSP groups.

Characteristic

Parameter

No. of patients Age (y) Body mass index (kg/m2) Duration of infertility (mo)

IUI

FSP

32 34.8 ⫾ 4.6 20.6 ⫾ 2.9 42.0 ⫾ 16.9

33 35.5 ⫾ 3.5 21.1 ⫾ 2.0 40.2 ⫾ 15.8

Note: Values are means ⫾ SD; differences between the IUI group and FSP group were not statistically significant for all values (Student’s t-test).

Sperm concentration before swim-up (⫻106) Progressive motility before swim-up (%) Inseminated progressive motility sperm count (⫻106)

IUI

FSP

121.3 ⫾ 63.8

107.1 ⫾ 64.6

52.3 ⫾ 12.7

56.9 ⫾ 16.2

23.5 ⫾ 17.2

24.3 ⫾ 19.7

Note: Values are means ⫾ SD; differences between the IUI group and FSP group were not statistically significant for all values (Student’s t-test).

Ricci. A simple method for fallopian tube sperm. Fertil Steril 2001.

Ricci. A simple method for fallopian tube sperm. Fertil Steril 2001.

ference in the mean number of progressively motile sperm inseminated between the IUI and the FSP groups (Table 3).

Outcome of Treatment In the FSP group, there were 16 clinical pregnancies, of which 14 were ongoing, and in the IUI group there were 6 clinical pregnancies, of which 5 were ongoing. The differences between the two groups treated, both in PR per cycle and PR per patient, were statistically significant (Table 4). The proportion of multiple pregnancies was similar in both treatment groups. Two pregnancies resulted in spontaneous abortion; one at 11 weeks of amenorrhea in the FSP group and one at 9 weeks of amenorrhea in the IUI group. There was one ectopic pregnancy in the FSP group. In the patients treated with IUI, no case of ectopic pregnancy was observed. These differences were not statistically significant (Table 4). In the FSP group, the number of motile inseminated spermatozoa was not significantly different between those patients who achieved pregnancy and those who did not (mean 24.8 ⫾ 15.3 vs. 24.1 ⫾ 20.7 ⫻ 106, respectively). The same was observed for the IUI group (mean, 25.3 ⫾ 12.1 vs. 23.3 ⫾ 20.7 ⫻ 106, respectively). Life table analyses for IUI and FSP groups are shown in Table 5. The cumulative probability of pregnancy after three cycles was 0.219 for IUI

TABLE 2 Controlled ovarian hyperstimulation characteristics in the IUI and the FSP groups. Characteristics No. of cycles No. of days of stimulation Total dose of FSH required (IU) No. of follicles of ⬎16 mm in diameter Estradiol on the day of HCG (pg/mL)

IUI

FSP

66 9.3 ⫾ 2.1 1,087 ⫾ 504 2.0 ⫾ 1.2

66 9.1 ⫾ 2.4 1,027 ⫾ 581 2.1 ⫾ 1.5

778 ⫾ 391

813 ⫾ 358

Note: Values are means ⫾ SD; differences between the IUI group and FSP group were not statistically significant for all values (Student’s t-test). Ricci. A simple method for fallopian tube sperm. Fertil Steril 2001.

FERTILITY & STERILITY威

group patients and 0.545 for FSP group patients (P⫽.0389). None of the patients was lost to follow-up.

Complications of Treatment In the FSP group, insemination was easily performed in all patients, and no case of sperm reflux was observed. None of the patients in the group experienced significant discomfort, because the cervix adaptor allowed easy and painless plugging of the cervix canal. In most patients, a light negative pressure was sufficient to apply the device. None of the women complained that having to keep the device in the vagina after FSP had particularly restricted their activities. No complications such as cervical bleeding, vasovagal episodes, uterine cramping, or pelvic infections were observed. In the IUI group, insemination was carried out after the standard procedure, and no difficulties were encountered. No complications were recorded.

Costs of Treatment

Costs were calculated in Euros, at a rate of 1 Euro ⫽ 0.9553 US$ (as of March 31, 2000). FSP does not require more staff assistance than IUI; although the procedure lasts about 3– 4 minutes longer, patients do not have to rest afterwards, so the increased time involved for staff is negligible, and the surgery is busy for less time than for IUI; moreover, it saves patients’ time too. Although patients have to keep the device on for some hours after the procedure, they are able to carry out all their activities with few restrictions. The cervix adaptor costs approximately 13% less than Frydman’s catheter, whereas in FSP, the total cost of the medium is approximately 40% higher than in IUI. Overall, FSP costs approximately 3 US$ per cycle more than IUI.

DISCUSSION To date, a total of 14 studies (1–14) have been published on FSP. In 9 of these studies, FSP was compared with IUI and different results were obtained: in 4 studies, the pregnancy rate was significantly higher than that for IUI (5, 10 – 12), whereas the other 5 failed to find any statistically 1245

TABLE 4 Pregnancy outcome in the IUI and the FSP groups. Outcome Clinical pregnancy rate per cycle (%) Clinical pregnancy rate per patient (%) Ongoing pregnancy rate per cycle (%) Ongoing pregnancy rate per patient (%) Prevalence of miscarriages (%) Prevalence of ectopic pregnancies (%) Prevalence of twin pregnancies (%) Prevalence of triplet pregnancies (%)

IUI

FSP

P value

Power

9.1 (6/66) 18.8 (6/32) 7.6 (5/66) 15.6 (5/32) 16.6 (1/6) 0 (0/6) 16.7 (1/6) 0 (0/6)

24.2 (16/66) 48.5 (16/33) 21.2 (14/66) 42.4 (14/33) 6.3 (1/16) 6.3 (1/16) 12.5 (2/16) 6.3 (1/16)

.0339 .0177 .0452 .0282 NS NS NS NS

0.55 0.61 0.54 0.58 — — — —

Note: NS ⫽ not significant. Ricci. A simple method for fallopian tube sperm. Fertil Steril 2001.

significant differences (6, 7, 9, 13, 14). In these studies, FSP was used to treat different types of infertility. However, it is only for unexplained infertility that comparable, numerically sufficient data are available, whereas for other types of infertility, such as male factor, endometriosis, tubal factor, ovulatory dysfunction, and cervical mucus inadequacy, the number of women treated in the various studies is very small; hence it is not possible to make valid statistical comparisons. A recent metaanalysis (12), which considered only women affected by unexplained infertility, has concluded that FSP, in patients with this type of infertility, is more effective than IUI. However, this meta-analysis brings together studies that are not directly comparable to each other because different stimulation protocols, study populations, and FSP techniques were used. The same technique was used only in two of the studies considered by this metaanalysis, and opposite conclusions were reached: in the first study (5), there was a significant difference in favor of FSP, whereas in the second study (6), IUI had a higher PR than FSP, although the difference was not statistically significant. Hence, it cannot be said that the superiority of FSP over IUI has been ascertained. Fanchin et al. (10) have reported highly interesting results using a new method of FSP with a blocking device, (the

FAST system威) but this method has not yet been tested by other investigators. The PR observed by Fanchin et al. (10) with this technique of FSP is much higher (40%) than that in all other studies published, especially if we consider that it deals with a population with various types of infertility. Fanchin et al. (10) did not report PRs according to different infertility categories, hence comparison with other studies is difficult. Moreover, no other author has reported better results from FSP compared with IUI in an unselected infertile population. To evaluate the real efficacy of this technique and to obtain results that are comparable with those of other studies, we have used it in a series of women with unexplained infertility in a prospective randomized study and compared it with standard IUI. One of the most important criticisms of the FAST system威 concerns its high cost (18). To reduce costs to a similar level as IUI, we have developed a similar method that, however, uses a less expensive commercial device for hysterosalpingography and hydropertubation with flexible plastic tubings. We found clinical and ongoing PRs with FSP that were significantly higher than those with IUI. However, the study only had sufficient power to detect a ⬎20% difference in PRs per cycle. Because the observed difference was smaller, the power of these results was only 54 and 58%, respec-

TABLE 5 Life-table analysis of pregnancy for IUI and FSP groups. IUI

Cycle no. 1 2 3

FSP

Probability of pregnancy per cycle

Cumulative probability of pregnancy

Probability of pregnancy per cycle

Cumulative probability of pregnancy

0.063 0.091 0.083

0.063 0.148 0.219

0.152 0.286 0.250

0.152 0.394 0.545

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tively. Therefore, we were unable to reproduce the results of Fanchin et al. (10) in clinical and ongoing cycle PRs with FSP. Our percentage success rates with FSP seem to be closest to those found by Kahn et al. (5), Mamas (11), and Trout and Kemmann (12). It should be said, however, that more recently, Fanchin et al. (17), in evaluating a much larger series of patients with FSP, reported a much lower clinical (20.3%) and ongoing (18.1%) cycle PR, although these results have never been published in detail in a scientific paper. The PR per cycle in women with unexplained infertility treated with standard IUI in previous studies ranged from 5.7% to 17.7% (21–27). This is comparable with the PR of 9.1% observed in patients in the IUI group in this study. Kahn et al. (5) and Gregoriou et al. (6) observed a significantly higher mean number of motile spermatozoa inseminated in the FSP group than in the IUI group. We found no differences in the motile spermatozoa counts in inseminates between the two insemination groups, in accordance with results from other investigators (9 –13). In our study, the number of motile inseminated spermatozoa was not significantly different between those patients who achieved pregnancy and those who did not; this is consistent with previous reports (3, 5, 23, 28). The technique we described is similar to the method described by Fanchin et al. (10) and offers the same advantages compared with other techniques: it does not require clamping of the cervix, does not involve the catheter penetrating into the uterine cavity, and never requires traction on the cervix, thus avoiding trauma and cervical and/or endometrial bleeding. Hence it also can be easily employed in all patients also in cases of cervical canal stenosis. Moreover, at least in theory, it should be possible to avoid some of the drawbacks of the FAST system威. No rigid catheter is used, and therefore there is less discomfort; an efficient and painless plugging of the cervix canal can be easily obtained. A light negative pressure, lower than what is required for hysterosalpingography, is usually sufficient to apply the cervix adaptor. The device is well tolerated and can be kept in place by patients for several hours without discomfort, so that late inseminate reflux is completely avoided in all cases. An analysis of costs showed that the total cost of FSP carried out with our method is a little higher than IUI. The only cost differences between the two insemination techniques concern the consumption of a greater amount of media (approximately 5 mL) for sperm preparation and insemination, whereas the cost of the device is a little lower than the catheter for IUI. In conclusion, for patients with unexplained infertility, the FSP technique described results in higher PRs, compared with standard IUI, with no significant increase in costs or FERTILITY & STERILITY威

complications. However, these results need to be confirmed in larger studies with adequate power before replacing IUI with FSP as standard practice.

Acknowledgments: The authors thank Gina Cervi of the Gynecology and Obstetrics Unit, University of Trieste, Trieste, Italy for her technical assistance and Dr. Veronica Casotto and Dr. Monica Da Fre` of the Epidemiology Unit, Istituto per l’Infanzia, Trieste, Italy for their statistical advice.

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22. Martinez AR, Bernardus RE, Voorhorst FJ, Vermeiden JPW, Schoemaker J. Pregnancy rates after times intercourse or intrauterine insemination after human menopausal gonadotropin stimulation of normal ovulatory cycles: a controlled study. Fertil Steril 1991;55: 258 – 65. 23. Dodson WC, Haney AF. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility. Fertil Steril 1991; 55:457– 67. 24. Ombelet W, Puttemans P, Bosmans E. Intrauterine insemination: a first-step procedure in the algorithm of male subfertility treatment. Hum Reprod 1995;10(Suppl 1):90 –102. 25. Campana A, Sakkas D, Stalberg A, Bianchi PG, Comte I, Pache T, et al. Intrauterine insemination: evaluation of the results according to the

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woman’s age, sperm quality, total sperm count per insemination and life table analysis. Hum Reprod 1996;11:732– 6. 26. Guzik DS, Carso SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, et al. Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N Engl J Med 1999;340: 177– 83. 27. Goverde AJ, McDonnell J, Vermeiden JPW, Schats R, Rutten FFH, Schoemaker J. Intrauterine insemination or in-vitro fertilization in idiopathic subfertility and male subfertility: a randomized trial and cost-effectiveness analysis. Lancet 2000;355:13– 8. 28. Horvath PM, Bohrer M, Shelden RM, Kemmann E. The relationship of sperm parameters in superovulated women undergoing intrauterine insemination. Fertil Steril 1991;52:288 –94.

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