Establishing a cause of infertility in women can be a long drawn out process that can cause much physical and emotional pain. Up to 35% of infertile women suffer from a tubal disorder (Ahinko-Hakamaa, Huhtala, & Tinkanen, 2007) and may require some form of diagnostic testing to confirm this. Usually a tubal patency examination is the first diagnostic test carried out when starting any investigation of female infertility. (Exacoustos et al., 2009). The gold standard for tubal patency diagnosis is laparoscopy with chromopertubation (Chan, Ng, Tang, Chan, & Ho, 2005) which involves surgery under general anaesthetic. A laparoscope is inserted into the women's pelvis and dye is injected to assess for any obstruction. (NICE, 2004). Even though this procedure is the gold standard it has some risks as any operational procedure has which can include mortality and morbidity. (Hamed, Shahin, & Elsamman, 2009). The cost of admitting a patient and the burden on the patient has meant that NICE (2004) guidelines recommend that laparoscopy only be performed once an x-ray hysterosalpingogram (HSG) or hysterosalpingo-contrast-sonography (HYCOSY) has been carried out first and a problem has been established.
HSG is an inexpensive radiographic procedure that uses a contrast medium to obtain fluoroscopic images of the contrast flowing through the fallopian tubes. (Simpson, Beitia, & Mester, 2006). Tubal patency is established by the presence of contrast spill at the fimbrial end of the fallopian tube. (Kiyokawa et al., 2000). HSG is often associated with pain and discomfort due to the contrast causing tubal spasms which briefly obstruct the tube and can cause false positives. (Exacoustos, et al., 2009). It also uses ionising radiation to the reproductive area which can be damaging when potentially testing on a fertile patient. (Hamed, et al., 2009). A more patient friendly test is two-dimensional (2D) HYCOSY, which is now commonly used in infertility departments and involves transvaginal sonography with the introduction of a positive or negative contrast medium into the uterus and fallopian tubes. (Exacoustos, et al., 2009). In some studies it shows that 74% of patients prefer HYCOSY to HSG, with HYCOSY producing less pain for the patient and also enabling the assessment of extrauterine structures. (Hamed, et al., 2009). Two-dimensional (2D) HYCOSY may seem a suitable examination to replace laparoscopy as the gold standard but it does come with problems. In most of the procedures the whole tube cannot be seen in one plane as the fallopian tube is very tortuous, making the observation of free spill at the fimbrial end of the tube difficult. (Sladkevicius, 1999). This means that the procedure is very operator dependent and often is inconclusive in its results. (Kiyokawa, et al., 2000).
Three-dimensional (3D) HYCOSY is the next step to overcome the problems experienced with 2D HYCOSY, HSG and laparoscopy. 3D HYCOSY allows the three planes - transverse, coronal and sagittal to be simultaneously displayed, accurately calculating any required volumes. (Merz, 1999). From this the fallopian tubes can be visualised more easily and the whole tube can be seen. The volumes and images produced by some systems can then be stored similar to HSG, for other clinicians to view at a later date and this takes away the problem of operator dependency found in 2D HYCOSY. (Exacoustos, et al., 2009).
The first study to involve 3D HYCOSY was Kiyokawa, et al., (2000) and used 3D-B mode ultrasound and a sterile saline solution as the negative contrast. (See literature summary table 2 in appendix D). Only 25 infertile women were used in the study and the gold standard used was HSG. From this first study in 3D and previous studies in 2D HYCOSY it is clear that the type of contrast used is very important. The use of a sterile saline solution is limited as "the surrounding bowel and fimbrial ends have similar echogenicity and it is not easy to visualise spillage of the saline-air mix at the distal portion of the tubes." (Exacoustos, et al., 2008, p.325). A positive contrast agent has been shown to have better results than a negative contrast and can simulate HSG findings. (Boudghène et al., 2001). Sankpal, Confino, Matzel, and Cohen, (2001) also carried out a 3D HYCOSY study with a negative contrast agent and concordance rates were 86% with the gold standard used and it was acknowledged that if a positive contrast agent was used like Echovist then the accuracy would have been greater.
It might have perhaps been assumed that from these studies, all further work in 3D HYCOSY would have involved a positive contrast but this is not the case. The reason given by Sankpal, et al., (2001) was that Echovist had only been approved for use in Europe not allowing any studies in the United States (US) to be carried out involving its use. This may explain why Echovist was not used in the US but other contrasts were available, such as Optison which has approval for its use since December 31st, 1997 before the first known 3D HYCOSY study. (United States Department of Health and Human Services, 2009). This contradicts Sankpal, et al.'s (2001) explanation of why a positive contrast was not used when others were available, while clearly from previous works it would have increased accuracy. Of the European studies carried out, all used a form of positive contrast. (Exacoustas, et al., 2008; Kupesic & Plavsic, 2007; Sladkevicius, Ojha, Campbell, & Nargund, 2000). Concordance rates with the gold standard in successful 3D HYCOSY patients ranged from 91-99% using a positive contrast, (Chan, et al., 2005; Kupesic & Plavsic, 2007; Exacoustos, et al., 2008) whilst a negative contrast had a 64-94% concordance rate. (Kiyokawa, et al., 2000; Sankpal, et al., 2001; Ali, Kassem, Hefny, & Amin, 2005). This demonstrates that the accuracy range is smaller and more accurate with a positive contrast.
Within the seven studies found, sample sizes ranged from 15 - 116 patients (see literature summary table 2 in appendix D) and none of the investigations claimed to have had a planned sample size before the start of the trial. Sample size is of great importance for any clinical trial as too few patients would mean that an anomaly with one patient could change the results by a large percentage and not represent the true results. Schulz and Grimes (2005) state that "investigators should properly calculate sample sizes and adequately describe the key details in their published report." (p.1348). Using the sample size formula, with the standard normal distribution table (both found in Appendix E), the sample sizes used for such trials should range between 31 and 121 women depending on the confidence level used. (90% confidence level - 31 women, 95% confidence level - 43 women, 99% confidence level - 74 women and 99.9% confidence level - 121 women). This uses a 15% margin of error to compare with HSG's accuracy to laparoscopy of 85.2% (Horowitz, Orvieto, Rabinerson, Yoeli, & Bar-Hava, 2006). Even assuming that a 90% confidence level was used, 4 (Chan, et al., 2005; Exacoustas, et al., 2008; Kiyokawa, et al., 2000; Sankpal, et al., 2001) out of the 7 studies, used less than 31 patients. This only makes the reader assume that problems were found in allocating patients for the studies and if this was the case - why?
Chan, et al., (2005) used 21 patients of which only 34 fallopian tubes were able to be assessed, out of the original 42. Due to four patients being unable to carry out the procedure successfully, the concordance rate fell from 91% to 74% when including all participants. This rate is potentially the difference between a successful and an unsuccessful study. Kupesic and Plavsic, (2007) gathered 268 women for their study of which 116 were subjected to the 3D HYCOSY procedure. The concordance rate for the 3D B-mode ultrasound was 98.3% and 99.1% for the 3D power doppler ultrasound. Both of these procedures showed a much higher accuracy and if an examination on a patient was not possible, the accuracy rate would have only dropped 0.9% per person, as a larger sample size was used, instead of Chan, et al.'s (2005) 4.8% per person. It would be unfair to discredit Chan, et al.'s (2005) work with an overall concordance rate with laparoscopy at 74%, therefore the bigger picture should be looked at and noted that a 91% concordance rate was found within the successful patients. Perhaps if a larger sample size had been used in the study then the difference may have not been so great, but then again the amount of unsuccessful patients may have been greater too.
Nearly all of the studies use the fallopian tube as a unit rather than the actual patient. This embellishes the results and makes for a better read but is not a true reflection of the results. (Coppus & Mol, 2006). Ali, et al., (2005) was the only study to use the patient as a unit and still managed to achieve a 94% concordance rate with the gold standard used. Fifty patients were enrolled on the study and only a sterile saline solution was used. The study does not mention whether a single operator carried out all the sonograms, therefore due to the high concordance rates, perhaps it can be speculated that a group of experienced sonographers carried out the examinations to achieve the best results. Obviously this is just an assumption but verifies the requirement for operator information in the written study to be known especially when it is recognised that 2D HYCOSY is highly operator dependant. (Kiyokawa, et al., 2000).
HSG sensitivity is 85.2% and specificity is 85.2% when compared with laparoscopy. (Horowitz, et al., 2006). Since HSG has now become the gold standard in many hospital trusts, at least before establishing a problem (NICE, 2004), it can be assumed that the sensitivity and specificity rates need to be similar or higher in 3D HYCOSY to warrant the usage of this new diagnostic test. The 3D HYCOSY studies have produced some sensitivity and specificity rates that are higher than HSG and it overcomes some of the problems encountered with HSG and 2D HYCOSY. It may be achieving positive results, but 3D HYCOSY is still in its infancy and shows by the modest literature available and the small patient exposure. With more clinical trials and larger sample sizes, 3D HYCOSY may soon be the preferred choice for clinicians and patients alike.
