AUTHORS: Dr. Col (Retd) G S Shekhawat, MD(Obst & Gyn) * (Corresponding. Author), Dr Priyanka S, MBBS+
PLACE OF RESEARCH WORK: Assisted Reproductive Technology center, Armed Forces Medical College/ Command Hospital (Southern Command), Pune-411040 and 92 Base Hospital PIN -901218 C/O 56 APO
ADDRESS OF THE AUTHORS:
* Associate professor, Dept of Obstetrics & Gynecology, Smt Kashibai Navale Medical College, Narhe, Pune-411041, Maharashtra.
Email: gsshekhawata@yahoo.co.in, Tel :( M) 9372897090,
+Medical Officer, Smt Kashibai Navale Medical College, Narhe, Pune-411041, Maharashtra.
INTELLECTUAL CONTRIBUTIONS:
Study concept: Dr G S Shekhawat
Drafting and Manuscript revision: Dr Priyanka S
Statistical analysis: Dr Priyanka S
Study supervision: Dr G S Shekhawat
ABSTRACT:
Background: Controlled ovarian hyper stimulation (COH) combined with intrauterine insemination (IUI), using a volume of 0.5 mail of inseminate is commonly offered to couples with non tubal infertility. Another method is Fallopian tube sperm perfusion (FSP) which is based on a pressure injection of 4 ml of sperm suspension while attempting to seal the cervix to prevent semen reflux. This technique ensures the presence of higher sperm density in the fallopian tubes at the time of ovulation than standard IUI. The aim of this study was to compare the efficiency of IUI and FSP in the treatment of infertility.
Methods: 200 consecutive patients with infertility in 404 stimulated cycles were included in the study. Those randomized to standard IUI included 100 patients in 184 cycles [158 Clomiphene citrate/human menopausal gonadotrophin cycles and 26 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group A). Patients subjected to FSP included 100 patients in 220 cycles (193 Clomiphene citrate/human menopausal gonadotrophin cycles and 27 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group B). Swim up semen preparation technique was used in all cases. Insemination was performed in both groups 34-37 hours after hCG administration. Standard IUI was performed using 0.5 ml of inseminate. In FSP 4ml inseminate was used.
Results: In group A (184 IUI cycles in 100 patients), 22 clinical pregnancies (presence of gestational sac with fetal cardiac activity) occurred (11.95% per cycle over four cycles). In group B, (220 cycles of FSP in 100 patients), 48 clinical pregnancies occurred (21.81%per cycle over four cycles) and this difference was statistically significant (p<0.05).
Conclusions: For non-tubal sub fertility, the results indicate clear benefit for FSP (Fallopian tube sperm perfusion) over IUI (Intrauterine insemination).
Key Words: Intrauterine insemination, Fallopian tube sperm perfusion, Non-tubal infertility.




FIGURE 1
Intrauterine insemination versus Fallopian tube sperm perfusion in non-tubal infertility
Author(s) take full responsibility for the content of their article, including originality, copyrights, and compliance with all relevant Internet laws and guidelines. Articles are not edited for content by the Internet Medical Journal.
PLACE OF RESEARCH WORK: Assisted Reproductive Technology center, Armed Forces Medical College/ Command Hospital (Southern Command), Pune-411040 and 92 Base Hospital PIN -901218 C/O 56 APO
ADDRESS OF THE AUTHORS:
* Associate professor, Dept of Obstetrics & Gynecology, Smt Kashibai Navale Medical College, Narhe, Pune-411041, Maharashtra.
Email: gsshekhawata@yahoo.co.in, Tel :( M) 9372897090,
+Medical Officer, Smt Kashibai Navale Medical College, Narhe, Pune-411041, Maharashtra.
INTELLECTUAL CONTRIBUTIONS:
Study concept: Dr G S Shekhawat
Drafting and Manuscript revision: Dr Priyanka S
Statistical analysis: Dr Priyanka S
Study supervision: Dr G S Shekhawat
ABSTRACT:
Background: Controlled ovarian hyper stimulation (COH) combined with intrauterine insemination (IUI), using a volume of 0.5 mail of inseminate is commonly offered to couples with non tubal infertility. Another method is Fallopian tube sperm perfusion (FSP) which is based on a pressure injection of 4 ml of sperm suspension while attempting to seal the cervix to prevent semen reflux. This technique ensures the presence of higher sperm density in the fallopian tubes at the time of ovulation than standard IUI. The aim of this study was to compare the efficiency of IUI and FSP in the treatment of infertility.
Methods: 200 consecutive patients with infertility in 404 stimulated cycles were included in the study. Those randomized to standard IUI included 100 patients in 184 cycles [158 Clomiphene citrate/human menopausal gonadotrophin cycles and 26 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group A). Patients subjected to FSP included 100 patients in 220 cycles (193 Clomiphene citrate/human menopausal gonadotrophin cycles and 27 Letrozole/FSH cycles exclusively for polycystic ovarian disease patients] (group B). Swim up semen preparation technique was used in all cases. Insemination was performed in both groups 34-37 hours after hCG administration. Standard IUI was performed using 0.5 ml of inseminate. In FSP 4ml inseminate was used.
Results: In group A (184 IUI cycles in 100 patients), 22 clinical pregnancies (presence of gestational sac with fetal cardiac activity) occurred (11.95% per cycle over four cycles). In group B, (220 cycles of FSP in 100 patients), 48 clinical pregnancies occurred (21.81%per cycle over four cycles) and this difference was statistically significant (p<0.05).
Conclusions: For non-tubal sub fertility, the results indicate clear benefit for FSP (Fallopian tube sperm perfusion) over IUI (Intrauterine insemination).
Key Words: Intrauterine insemination, Fallopian tube sperm perfusion, Non-tubal infertility.
Introduction
Intrauterine
insemination (IUI) with mild ovarian stimulation has been used for
many years in the treatment of non tubal infertility. During IUI,
pretreated semen is concentrated in a small volume of 0.5 ml and
deposited by a catheter into the uterine cavity. The overall
pregnancy rates reported in the literature ranged from 5.7% to 17.7%
per cycle [1]. Although the number of available oocytes can be
increased by ovarian stimulation, the pregnancy rates in IUI are
still not promising, mainly because of suboptimal spermatozoa at the
site of fertilization [2]. An alternative procedure, termed Fallopian
tube sperm perfusion (FSP), has been reported with improved pregnancy
rates in comparison with IUI [3, 4, and 5]. In FSP, sperm preparation
is identical to that used in IUI, but the spermatozoa are diluted in
a larger volume of medium up to 4 ml [6]. This volume has been
considered sufficient for bilateral passage of the spermatozoa
through the fallopian tubes. Theoretically, this would increase the
density of capacitated spermatozoa near the oocytes and result in
higher pregnancy rates. A prospective randomized study was designed
to determine whether FSP resulted in higher pregnancy rates than IUI.
Material &
Methods
Two hundred
infertile patients, aged 17 to 39 years, undergoing 404 consecutive
cycles of ovarian stimulation were studied from June 2007 to Jan
2009. Institutional board approval was obtained. These patients
underwent a basic infertility workup including confirmation of tubal
status by hysterosalpingogram or laparoscopy and hormone profile
including serum follicle stimulating hormone (FSH), luteinizing
hormone (LH), prolactin and thyroid hormone tests. Menstrual cycle
day 3 basal transvaginal ultrasonography was done in all cases to
rule out ovarian cysts prior to ovulation stimulation. Exclusion
criteria were age > 39 years, obstructed fallopian tubes and cases
with marked oligospermia sperm count<10X106per ml).
The patients were
classified for purpose of etiology of infertility as having mild and
moderate endometriosis; ovulatory disorders (hormonal profile and
transvaginal sonography characteristic of polycystic ovarian
syndrome); cervical hostility (poor properly timed post-coital test);
male sub fertility (as per WHO criteria) [7]; unexplained infertility
(where no infertility causes were found).
These patients
underwent ovulation induction with either Clomiphene citrate and
Human menopausal gonadotrophin (351 cycles in 174 patients) or
Letrozole and FSH used exclusively for polycystic ovarian disease
patients (53 cycles in 26 patients). The ovarian stimulation protocol
of clomiphene and hMG (Human menopausal gonadotrophin) was used in
170 patients. It consisted of clomiphene citrate 100 mg daily on
days 3-7 of the cycle, and 75 IU daily of hMG (Human menopausal
gonadotrophin) on days 6-9 of the cycle. For some of the women, hMG
was increased to 150 IU in subsequent cycles, depending on the
previous ovarian response. Rotterdam ESHRE consensus workshop
criteria (2003) was used for diagnosis of PCOS. In all PCOS patients
(26 patients), who had been on Metformin 500 mg t.i.d , Letrozole was
given orally in a dose of 2.5mg/day for 5 days starting from day 3 of
a spontaneous or progesterone induced menstrual bleeding . Inj
purified FSH 75 IU administered on 6-9 day of menstrual cycle.
Cycles were
monitored from day 9 onwards by transvaginal ultrasound measurement
of the number and diameter of the growing follicles along with the
thickness and morphology of the endometrium. A dose of 10,000 IU
human chorionic gonadotrophin (hCG) was administered when at least
one leading follicle had reached a diameter of 18 mm and at least 8
mm endometrial thickness with tri laminar ‘halo’ appearance seen.
Patients were called 34 to 36 hours later, and either standard IUI
(group A: 184 cycles in 100 patients) or FSP (group B: 220 cycles in
the 100 patients) was performed. The patients were counseled about
the two alternative procedures and informed consents were obtained
before randomization. Patients were allocated randomly to standard
IUI or FSP on the day of insemination in the first cycle itself,
according to even or odd serial number in the register. Maximum of
four cycle treatments of IUI or FSP were considered for those
patients who could not conceive in previous attempts. However those
who failed to conceive with IUI were offered IUI only and vice versa.
132 male partners
were normozoospermic with count > 20X106 sperm per ml, >50%
motile with forward progression (categories a and b) within 60 min of
ejaculation and > 60% morphologically normal spermatozoa (WHO
criteria) [7]. Male partners with sperm count ranging from 10X106 to
20X106 were asked to produce a second semen sample within 2 hours of
the first sample on the day of insemination. Sixty-eight males having
sub fertility as per WHO criteria did consent to the study. However
04 could not produce a second sample at the time of IUI, and 1
patient had total sperm immotility and was excluded from the study.
A fresh ejaculate was delivered in a sterile 60 ml jar by
masturbation on the day of insemination. Neat semen was left at room
temperature for liquefaction for 30 minutes.The liquefied semen
samples were analyzed for density and motility using a fixed-depth
counting chamber (Makler). The liquefied ejaculate was transferred
to a labeled sterile 14 ml round-bottomed disposable centrifuge tube
(Falcon No.2095) and 4 ml flushing media (Medicult) added to it.
After thorough mixing the sample was centrifuged at 5000 rpm for 10
minutes. Then, the supernatants were discarded and the pellet was
resuspended and mixed in 3 ml of fresh flushing media (Medicult) and
centrifuged for second wash again at 5000 rpm for 10 minutes. Once
again the supernatants were discarded. Each pellet was now gently
layered with 0.5 ml for IUI and 4 ml for FSP of universal IVF media
(Medicult), and incubated at 37oC in a humidified incubator with 5%
Carbon dioxide for 1 hour. Post wash semen analysis was done in all
cases using Makler’s counting chamber before insemination.
Intrauterine
insemination was performed with conventional catheter using 0.5 ml of
inseminate. To eliminate dead space problem, IUI catheter was first
attached to syringe and then inseminate was aspirated. In FSP 4ml
inseminate was used and backflow of inseminate was occluded at the
cervical opening by the long size Allis clamp (Figure-1), which was
suitably modified by attaching cervical occluding prongs with rubber
cushions to avoid trauma to the cervix and was kept in place for
about 3 to 4 minutes after insemination. In both groups, the patient
rested for 30 minutes after insemination and received oral micronized
progesterone 100 mg, two tablets per day for luteal-phase support.
Values were recorded
as mean ± SD using Microsoft Excel version 4. Statistical analysis
were performed using student’s t-test for testing significance of
difference between the means and the X2test to compute p-values for
testing the agreement between proportions. MedCalc statistical
software (Meriakerke, Belgium) version 9.5.0.0 was used for all
statistical analysis. The significance was defined as p < 0.05.
Results
The patient
characteristics for group A and B were not significantly different
concerning patient’s age (28.42 ± 2.78 years and 28.19 ± 2.80
years), type of sterility (primary infertility 74% versus 72%
respectively) and duration of infertility (5.6 ± 2.1 and 5.3 ± 1.9
years respectively). The clinical indications for IUI or FSP were
also not significantly different for the two groups (endometriosis
12% versus 12%, polycystic ovarian syndrome 34% versus 36%, cervical
4% versus 4%, unexplained 18% versus 12% and male factor sub
fertility 32% versus 36% respectively). The ovarian stimulation
protocol for group A and B were not significantly different
(clomiphene citrate/hMG 85% versus 87% and Letrozole/FSH 15% versus
13% respectively). The parameters of cycle monitoring for group A
and B including number of follicles=18 mm diameter(3.93±1.37 versus
3.90±1.17), endometrial thickness on the day of hCG administration
(9.19±0.58mm versus 9.14±2.1mm) and the number of
spermatozoa(38.83±16.57X106 versus 36.68±13.44X106) inseminated
were not significantly different. However the day of hCG
administration (12.8±3.4 versus 11.1±2.1) was significantly
different between the two groups as shown in table-1 and 2.
Clinical pregnancy
was defined by the presence of fetal cardiac activity, detected by
ultrasound examination. Pregnancy rates were similar when compared
for the etiology of infertility: for ovarian (PCOS) cause (17.7%
versus 21.8%), endometriosis cause (8.4% versus 10.1%), male
infertility (12.8% versus 16.4%) and unexplained infertility (14.4%
versus 24%) for the two groups, respectively as shown in table-3.
There was statistically significant difference (p<0.05) in the
overall pregnancy rate per cycle over four treated cycles (11.95% per
cycle for IUI versus 21.81% per cycle for FSP over four cycles) as
shown in table-4. Two missed abortions and one twin pregnancy
occurred among the patients in group A (IUI). Three missed abortions
and two twin pregnancies occurred among the patients in group B
(FSP). However, this limited number of abortions and multiple
pregnancies are too low to allow testing for statistical
significance. Three cases of mild ovarian hyper stimulation syndrome
(OHSS) occurred in both groups.
Discussion
The purpose of this
prospective, randomized study was to study pregnancy rates in couples
with nontubal infertility when treated with FSP (inseminate volume 4
ml), in comparison with standard IUI (inseminate volume 0.5 ml).
Pregnancy rates were 21.81 and 11.95% respectively over four
treatment cycles. The same protocols for ovarian stimulation were
used in both groups. There was no statistically significant
difference regarding the age of the patients treated, mean number of
follicles, endometrial thickness on the day of hCG administration and
the total number of motile spermatozoa inseminated. However the day
of hCG(12.8±3.4 for FSP versus 11.1±2.1 for IUI) administration was
statistically different between the two groups (p value <0.05).
Kahn et al. reported
the first clinical experience with FSP. In their study, they used a
Frydman catheter for FSP and reported a pregnancy rate per cycle of
26.9% in patients with unexplained infertility and of 2.7% to 7.7% in
patients with other etiologies. These excellent results, particularly
in patients with unexplained infertility, were confirmed by other
studies [8]. Some investigators used a paediatric Foley catheter or
cervical clamp double-nut bivalve speculum and very encouraging
results were reported by Fanchin et al, in which FSP using an auto
blocking device (FAST system) doubled their pregnancy rates from 20%
to 40% [1].The different types of catheters used for IUI have been
compared but no study reports a significantly higher rate of
pregnancy with any one type of catheter [9, 10].
The FSP increases
the intrauterine pressure(70-200 mmHg) necessary for a flush influx
of spermatozoa directly into the fallopian tubes. The high pregnancy
rate per cycle for FSP as compared with standard IUI can be due to
several causes as follows: firstly, the pressure injection of
inseminate can either remove and/or circumvent transitory or partial
obstruction of fallopian tubes, such as that created by thick mucus
or tubal polyps; secondly, the concentration of motile spermatozoa
around the oocytes after FSP is higher than that obtained after
standard IUI; and thirdly, FSP leads to inseminate overflowing into
the pouch of Douglas. The more accepted hypothesis is the existence
of a similar mechanical effect created following a
hysterosalpingography [10].
In this study, we
tried to evaluate FSP not only in patients with unexplained
infertility but also in patients with other causes of infertility
including male causes. Two different stimulation regimes were used;
however, the distribution of the two types of stimulation protocols
(clomiphene citrate/hMG and Letrozole/FSH) appeared homogenous in
both studies groups.
Clinical pregnancy
was defined by the presence of fetal cardiac activity, detected by
ultrasound. When comparing the pregnancy rates in both IUI and FSP in
relation to the etiology of infertility, it is found to be
statistically similar as shown in table-3. Though the pregnancy rates
of FSP in PCOS and unexplained infertility group of patients is
superior to IUI, this finding is statistically not significant. This
analysis revealed that couples suffering from any specific
etiological sub fertility did not benefit from FSP over IUI.
However, there was
statistically significant difference in the overall pregnancy rate
per cycle over four cycles of treatment (11.95% per cycle over four
cycles for IUI versus 21.81% per cycle for FSP over four cycles) as
shown in table-4(p value<0.009). Pregnancy rates improved in
subsequent attempts with FSP in comparison to IUI. The cumulative
pregnancy rates even after the second attempt, over two cycle
treatment, were statistically significant (p value <0.03), however
there was no statistical difference when each attempt of treatment
cycles was compared between the two groups (p value >0.05).
Four studies [2, 4,
6, and 11] mentioned a maximum of three cycles per couple; one study
[12] reported a maximum of four cycles. We also allowed maximum of
four cycles treatment of IUI or FSP before considering them for In
vitro fertilization and embryo transfer (IVF-ET).
The type of
catheter has no impact on the pregnancy rate after intrauterine
insemination [13]. We suitably modified the long size allis clamp, by
attaching cervical occluding prongs with rubber cushions, which was
kept in place for about 3 to 4 minutes after insemination to prevent
any significant reflux. Mild reflux does not seem to influence the
results of the FSP but the significant reflux (> 0.4 ml) may
reduce the pregnancy [14]. If more than 1 ml comes back in the
catheter, the operator needs to wait for a few minutes and
re-inseminate again. All the authors agreed that women tolerated
the FSP technique very well. In our study some patients complained of
post insemination pelvic transient pain, more so in FSP than in IUI.
Other interesting domain of FSP application is the immunological
infertility in the presence of anti-sperm antibodies [15, 16].This
aspect could not be studied in this study because pre and post FSP
anti-sperm antibody assay was not done.
In this study by
comparing the overall results, we conclude that FSP over four cycles
of treatment offers an advantage over the standard IUI, and can
replace the IUI for all its indications because of its better
pregnancy rates. However FSP is more expensive than IUI due to the
increased media usages. It could be used as an alternative for
couples with non tubal infertility before embarking on IVF-ET
treatment.
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FIGURE 1
Intrauterine insemination versus Fallopian tube sperm perfusion in non-tubal infertility
Author(s) take full responsibility for the content of their article, including originality, copyrights, and compliance with all relevant Internet laws and guidelines. Articles are not edited for content by the Internet Medical Journal.