A Randomised Comparative Study of Standard IUI (sIUI) and Fallopian Tube Sperm Perfusion (FSP) for Clinical Pregnancy.

Objectives To compare the pregnancy rates of two methods of intrauterine insemination (IUI), i.e. standard IUI (sIUI) and fallopian tube sperm perfusion (FSP).

This prospective randomised parallel study design included 160 infertile women < 38 years of age where IUI was indicated. We recorded a detailed history and conducted a careful clinical examination with the performance of baseline investigations. Each patient was randomly allocated into two groups: Group sIUI (n = 80) and Group FSP (n = 80). The patients underwent two cycles of IUI for achieving clinical pregnancy. The conception of pregnancy among both groups was noted and compared.

The mean age of the females, mean age of the male partners, and duration of marriage in Group sIUI and FSP were comparable (p > 0.05). Compared to the sIUI group, the FSP group had significantly higher patients who conceived (15.97% vs. 6.54%, P = 0.016). In the cases with unexplained infertility, in cycle 2, in the FSP group, there were significantly more patients who conceived (21.05% vs. 0.00%, P = 0.047).

We conclude that FSP over two treatment cycles offers an advantage over the standard IUI and could replace the sIUI in specific indications such as unexplained infertility for artificial insemination. It could be used as an alternative for couples with non-tubal infertility before moving on to IVF treatment.

Clinical pregnancy, Fallopian tube sperm perfusion, Standard IUI

The prevalence of infertility is on the constant rise in developed and developing countries, especially since the last decade [1, 2]. Obesity, mental stress, higher socio-economic status, higher parents' age, unhealthy lifestyle, and environmental factors are significant contributors besides anatomical, pathological, hormonal, and immunological causes affecting reproductive system productivity [3]. Conventional treatment of medication or surgery in infertility brings success in about 85% of cases. ART is required in the other unsuccessful cases and is often combined with the conventional treatment approach. More and more infertile couples are opting for ART, which encompasses IUI and IVF. For non-tubal infertility, the IUI technique in conjunction with hormonal, controlled ovarian stimulation is done to achieve higher success rates. There are different ways to administer IUI: standard IUI and fallopian tube sperm perfusion (FSP). Standard IUI (sIUI) is the least invasive treatment to inject pretreated semen with the catheter in the uterine cavity, with success rates ranging from 5.7 to 17.7% per cycle [4]. Pregnancy rates in IUI are compromised as spermatozoa concentration at fertilisation is suboptimal [5]. Another IUI technique FSP is different and has the advantage of more volume and tubal site insemination than sIUI. Its foremost advantage in achieving higher sperm concentration in the fallopian tube thus increases chances of fertility. However, some subjects can experience pelvic discomfort because of the larger volume injected [6]. Comparative analysis of sIUI and FSP in previous studies has shown inconclusive results. Though majority study results have shown FSP to be a superior technique, literature has reports of equal efficacy of the two procedures, and scarce studies show better results with sIUI [7–9]. However, it should be noted that in these studies, the catheter used was a Foleys—device which was likely to induce uterine contractions due to uterine distension. We chose sonosalpingography cannula to remove this inherent cause for decreased pregnancy rates. We studied a regional population with two groups of comparable baseline characteristics to investigate the conception rate with sIUI and FSP.

A prospective randomised parallel study was carried out in the IVF centre of a tertiary care hospital, New Delhi, for 18 months (October 2018 until March 2020) after getting clearance from the ethical committee of the institute. The sample size calculation was based on the study by Cantineau et al. [10] who observed an odds ratio of 0.36 in clinical pregnancy (sIUI: FSP). Taking this as the reference value, the minimum sample size with 80% power of study and 5% level of significance is 160 patients. So a total of 160 subjects were taken (80 in each group: sIUI and FSP). All infertile females < 38 years with infertility where there was an indication for IUI treatment were included. Patients with moderate to severe endometriosis, fibroids, bilateral tubal damage/obliteration, and requiring IVF (in vitro fertilisation) were excluded from the study. After informed consent, detailed history was taken regarding the duration of infertility, contraception use, menstrual cycle regularity, parity, past medical and surgical intervention, and previous/present medication. A detailed clinical examination was conducted, and baseline investigations were performed. The hospital ovarian stimulation protocol was taken as standard and was common to both groups. When the follicle size reached > 17 mm, injection hCG trigger 10,000 IU IM was given. Randomisation of patients was done at this juncture. In the randomisation technique, we considered blocks of size four where every four patients randomised; two received sIUI and the other two received FSP. The random numbers were generated by function RANDBETWEEN (). After 36 h of the trigger, insemination was performed by either method as per the allocated intervention. The method of sperm preparation used was the ‘swim-up technique’, where motile spermatozoa swim up into a culture medium, and density gradients, which through separate centrifugation spermatozoa according to their density [11]. Semen was processed within 30 min after collection [11], and was inseminated preferably within 60 min of preparation. The patient was laid in the lithotomy position. The cervix was exposed using a bivalve speculum or Sims speculum with an anterior wall retractor. Vagina was cleaned with saline, and cervical mucus was removed. Prepared semen was concentrated into a small volume of 0.5 ml/4 ml, and the cannula was loaded without keeping any dead space. The IUI cannula in sIUI was introduced into the cervical canal to reach 1–2 cm from the uterine fundus, and the sample was injected slowly over 1–2 min, and sonosalpingography catheter in case of FSP was used with the same technique and slow insemination was done over 5–6 min avoiding reflux. Both the cannulas were removed gently, slowly after waiting for 30–45 s. Any trauma to the cervix or endometrium was avoided as this can reduce pregnancy rates. The patients were asked to rest for 15–20 min after the procedure. Two cycles of each modality were performed. The patient and the doctor were not blinded to the procedure. In pregnancy, the patient was removed from either group or similarly, the second cycle was continued with the patients who did not conceive in the first cycle. The primary outcomes were clinical pregnancy rates, ectopic pregnancy, blighted ovum, and pregnancy of unknown location. The secondary outcomes were the occurrence of complications like cervical bleeding, vasovagal attack, and uterine cramps. Statistical Analysis The study parameters were entered in MS Excel and analysed using SPSS version 21.0. The data presentation was done in the tables and graphs. The quantitative variables were represented as n(%), and the qualitative variables were represented as median (interquartile) or mean ± standard deviation, depending upon the normality. The comparison of the two groups was made by unpaired t-test/Mann–Whitney test and Chi-square test/Fisher's exact test. A P-value of < 0.05 was considered statistically significant.

A total of 175 women were screened, among which 160 were found to be eligible for participation in the study. Out of them, 80 patients were in Group sIUI and 80 in Group FSP. The participant flow diagram is shown in Fig. 1. The mean age of the females in Group sIUI was 28.58 ± 3.58 years, and FSP was 28.77 ± 4.31 years, and the mean age of the male partners in Group sIUI was 31.5 ± 3.46 years, and FSP was 32.28 ± 4.3 years (p > 0.05). The mean duration of marriage was 6.18 ± 3.43 years in Group sIUI and 6.72 ± 3.56 years in Group FSP (p > 0.05). The mean duration of infertility in Group sIUI was 4.22 ± 2.31 years, and in Group FSP was 4.81 ± 2.53 years (p > 0.05). There was no significant difference in the distribution of primary/secondary infertility between sIUI and FSP (P > 0.05). There was no significant difference in the distribution of clinical indication between sIUI and FSP (P > 0.05). The clinical indication was an ovulatory defect in the majority of patients in sIUI and FSP; 35% in sIUI and 37.50% in the FSP, followed by other clinical indications in 32.50% of patients in sIUI and 30% of patients in FSP (Table 1). Table 1. | Demographic characteristics | sIUI (n = 80) | FSP (n = 80) | P value | |---|---|---|---| | Age (years) of female | 29 (25.75–30) | 28.5 (25–31.5) | 0.988$ | | Age (years) of male | 31 (29–34) | 32 (29.75–35) | 0.238$ | | Duration of marriage (years) | 5 (4–8.25) | 6 (4–9) | 0.331$ | | Duration of infertility (years) | 4 (2.75–5) | 4(3–5.25) | 0.118$ | | Primary/secondary infertility | ||| | Primary infertility | 54 (67.50%) | 54 (67.50%) | 1* | | Secondary infertility | 26 (32.50%) | 26 (32.50%) | | | Clinical indication | ||| | Endometriosis | 3 (3.75%) | 3 (3.75%) | 1# | | Ovulatory defect | 28 (35%) | 30 (37.50%) | 0.742* | | Cervical factor | 0 (0%) | 1 (1.25%) | 1# | | Male factor | 3 (3.75%) | 2 (2.50%) | 1# | | Unexplained | 22(27.50%) | 21 (26.25%) | 0.858* | | Others | 26 (32.50%) | 24 (30%) | 0.733* | *Chi-square test, #Fisher’s exact test, $Mann–Whitney test, median (IQR), n(%) Compared to sIUI, FSP group had comparable days of stimulation (p = 0.401), comparable number of large follicles > 17 mm (1 vs. 2, p = 0.139). The protocol of HCG trigger, sperm insemination characteristics, and the associated complications like a retrograde spill and blood on catheter tip were comparable (Table 2). Table 2. | Variables | sIUI (n = 151) | FSP (n = 144) | P value | |---|---|---|---| | Day of stimulation | ||| | D2 | 60 (39.74%) | 50 (34.72%) | 0.401# | | D3 | 91 (60.26%) | 93 (64.58%) | | | D4 | 0 (0%) | 1 (0.69%) | | | Number of follicles > 17 mm diameter | 2 (1–2) | 1 (1–2) | 0.139$ | | Ruptured/unruptured follicles | ||| | Not ruptured | 69 (45.10%) | 70 (48.61%) | 0.544* | | Ruptured | 84 (54.90%) | 74 (51.39%) | | | Day of hCG trigger | 12 (11–13) | 12 (11–13) | 0.344$ | | On the day of hCG (mm) | 8 (6.8–10) | 8.2 (7.075–9.525) | 0.895$ | | On the day of FSP/sIUI (mm) | 8.5 (7.4–10.2) | 8.9 (8–10.05) | 0.224@ | | Day of FSP/sIUI | 14 (13–15) | 14 (13–15) | 0.479$ | | Volume (mL) (semen prewash) | 2.5 (1.5–3) | 2.5 (1.5–3) | 0.936$ | | T/C (mil/mL) (semen prewash) | 60 (50–75) | 60 (50–70) | 0.7$ | | Motility (%) (semen prewash) | 60 (60–65) | 60 (60–60) | 0.179$ | | T/C (mil/mL) (semen postwash) | 50 (40–65) | 55 (40–65) | 0.531$ | | Motility (%) (semen postwash) | 85 (80–90) | 90 (80–90) | 0.55$ | | Blood on catheter tip | ||| | No | 139 (90.85%) | 130 (90.28%) | 0.866* | | Yes | 14 (9.15%) | 14 (9.72%) | | | Retrograde spill | ||| | No | 140(91.50%) | 122 (84.72%) | 0.103* | | Yes | 13 (8.50%) | 22 (15.28%) | *Chi-square test, #Fisher’s exact test, $Mann–Whitney test, @independent t-test, median (IQR), n(%) We found that after cycle 1, the FSP group had a slightly higher pregnancy rate as compared to sIUI but statistically, the difference was not significant (20% vs. 8.75%, p = 0.071). The occurrence of ectopic pregnancy was seen in 2 cases with FSP as compared to a single case with sIUI (p = 1). A single case of twin pregnancy was noted in the group FSP, and no twin pregnancy occurred with sIUI. During cycle 2, only 64 patients in FSP and 73 in sIUI received the treatment. Among them, the FSP group had a slightly higher pregnancy rate as compared to sIUI, but statistically, the difference was not significant (10.94% vs. 4.11%, P = 0.188). Overall, after 2 cycles, as compared to sIUI group, FSP group had significantly higher patients who conceived (15.97% vs. 6.54%, P = 0.016) comparable to ectopic pregnancy (1.39% vs. 0.65%, P = 0.613) and twins (0.69% vs. 0.00%, P = 0.485). The conception rates among sIUI and FSP during different cycles of therapy are shown in Fig. 2. In the cases with unexplained infertility, in cycle 1, FSP and sIUI groups had a comparable number of patients who conceived (9.52% vs. 9.09%, P = 1). In contrast, in cycle 2, in the FSP group, there were significantly more patients who conceived (21.05% vs. 0.00%, P = 0.047). The overall combination of cycles 1 and 2 showed no difference in FSP and sIUI groups in terms of patients who conceived (15% vs 4.76%, P = 0.15). (Fig. 3).

In an attempt to increase the clinical pregnancy rates with IUI, the medical field has been prompting with newer methods in comparison with the conventional methods. The closeness of the injected sperm (to the egg) in a much higher volume before getting implanted in the uterus has been the primary objective of the relatively newer FSP technique. The present study showed promising results in proving the superiority of FSP over the sIUI technique by yielding better rates of clinical pregnancy. The better clinical pregnancy rates with FSP can be ascribed to the application of increased intrauterine pressure (70–200 mm Hg), which is necessary for an influx of sperms into the fallopian tubes bypassing the partial or transitory obstruction (due to thick mucus or tubal polyps) and increasing the concentration of motile spermatozoa around the oocytes [5]. In our study, patients’ demographic and preoperative characteristics were statistically similar between the two treatment groups. This holds importance as the factors such as the number of follicles, use of drugs for ovarian stimulation, day of trigger, and semen prewash characteristics may affect the clinical pregnancy rates [12, 13]. Thus, the study holds the strength to suggest that the observed clinical outcomes and pregnancy outcomes with two different techniques, IUI and FSP, can be entirely attributed to the differential intervention. We found that after cycle 1, the FSP group had a higher pregnancy rate as compared to IUI, but statistically the difference was not significant (20% vs. 8.75%, p = 0.071). Our findings were in line with Shekhawat et al. [5] who found no significant difference in the first cycle in IUI and FSP in terms of pregnancy rate (16% vs. 24%, P = 0.158). In contrast, in the study by Mamas et al. [6], the difference in pregnancy rates in the first cycle was statistically significant with less pregnancy rate with FSP in comparison with intrauterine tuboperitoneal insemination—IUTPI (18.1% vs. 31.2%, P = 0.012). Their study was different from the current study as they compared IUTPI and FSP rather than FSP and conventional IUI. IUTPI may provide better insemination of 10 mL of inseminate into the peritoneal cavity and the pouch of Douglas where it would be mixed with the peritoneal and follicular fluids, thus accomplishing noninvasive intraperitoneal insemination by flushing the tubes [6]. In our study, during cycle 2, the FSP group had a slightly higher pregnancy rate as compared to IUI, but statistically, the difference was not significant (10.94% vs. 4.11%, p = 0.188). Our findings were in line with the study by Shekhawat et al. [5] (IUI-10% vs. FSP-24.24%, P = 0.072), where pregnancy rates had improved in subsequent attempts with FSP but statistically needs further validation. Overall, in both the cycles combined, the FSP group had a significantly higher pregnancy conception rate as compared to the IUI group (15.97% vs. 6.54%, P = 0.016). In comparison, Trout et al. [8] found no statistically significant difference between the clinical pregnancies of those who underwent FSP (18/131 5 14%) and IUI (14/137 5 10%). Ng EH et al. [7] compared pregnancy rates with single intrauterine insemination (SIUI), double intrauterine insemination (DIUI) and fallopian tube sperm perfusion (FSP) and found no significant differences. Biacchiardi et al. [9] also found no significant difference in clinical pregnancy rate after IUI and FSP. Total 127 cycles (58 FSP, 69 IUI) were performed. The clinical pregnancy rate per cycle was 21.7% for IUI and 8.6% for FSP, respectively. Since we found that FSP shows better results as compared to IUI, it may be due to the better performance of the procedure in the current scenario. The wide range of the results given by FSP enthusiasts may also be due to the different instruments used in order to facilitate the method (Allis clamp, Foley catheter, FAST system, DNB Speculum, ZUI catheter, HSG device) [6]. Interestingly, the role of FSP in unexplained fertility cannot be ignored, as we found better pregnancy rates in such patients. The findings have been in line with previous literature [14, 15]. Previously, two meta-analyses also showed that FSP is beneficial in cases of unexplained infertility after ovarian stimulation. Trout et al. [8] reported that only the patients with unexplained infertility had a statistically higher pregnancy rate with fallopian sperm perfusion (odds ratio, 4.1; confidence interval, 1.1–16.4). Cantineau et al. [10] compared the efficacy of FSP with IUI in the treatment of non-tubal subfertility and found that couples suffering from unexplained subfertility clearly benefit from FSP over IUI (OR 2.88, 95% CI 1.73–4.78). The underlying mechanism of this association of FSP with unexplained fertility may be because of the aetiology of dysfunctional fallopian tube cilia and motility or wall adhesions of the fallopian tube in these cases, which may be surpassed with increased pressure of insemination in FSP. The exact mechanism and role need to be further explored in future studies with a large sample size of unexplained infertility. It must be mentioned here that cost-wise both showed a minimal difference of rupees hundred, with FSP catheter being costlier than the standard catheter.

of the Study The procedures—sIUI and FSP—are inherently limited by negative aspects of multiple pregnancies, ectopic pregnancies, and ovarian hyperstimulation syndrome, which should be more carefully managed. Second, blinding or allocation concealment was not done in the study. However, when comparing different insemination techniques, blinding would methodologically be difficult. Although the study's sample size was good, being a single-centre hospital-based study, the efficacy of IUI and FSP may need further validation.

We conclude that FSP over two cycles of treatment attempts offers an advantage over the standard IUI and could replace the IUI for artificial insemination. Thus, it could be an alternative for couples with infertility before moving on to IVF treatment. Dr. Nahid Farooqui holds a special interest in minimally invasive surgery and reproductive medicine. She has presented various posters and papers at renowned conferences with much acknowledgment. She provides utmost care to the patients for their better outcomes. Funding No funding received. Declarations Conflict of interest There are no conflicts of interest among the authors. Ethical Approval Ethical approval for study involving human participants have been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed Consent All the participants were included after informed and written consent of themselves or their legally authorised representative in case of illiterate participants. Footnotes Nahid Farooqui is a Post Graduate Student, Department of obstetrics and Gynaecology, VMMC and Safdarjung Hospital, Delhi, India. Bindu Bajaj is a Professor, Department of obstetrics and Gynaecology, VMMC and Safdarjung Hospital, Delhi, India. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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