Diagnostic image quality of hysterosalpingography: ionic versus non ionic water soluble iodinated contrast media
Department of Biomedical Imaging, University of Malaya, Kuala Lumpur, Malaysia
Objective: To compare the diagnostic image quality
between three different water soluble iodinated contrast media in
Material and method: In a prospective randomised
study of 204 patients, the diagnostic quality of images obtained
after hysterosalpingography were evaluated using Iopramide (106
patients) and Ioxaglate (98 patients). 114 patients who had undergone HSG
examination using Iodamide were analysed retrospectively. Image quality was
assessed by three radiologists independently based on an objective set of
criteria. The obtained results were statistically analysed using Kruskal-Wallis
and Mann-Whitney U test.
Results: Visualisation of fimbrial rugae was
significantly better with Iopramide and Ioxaglate than Iodamide. All contrast
media provided acceptable diagnostic image quality with regard to
uterine, fallopian tubes outline and peritoneal spill. Uterine opacification
was noted to be too dense in all three contrast media and not optimal for the
assessment of intrauterine pathology. Higher incidence of contrast
intravasation was noted in the Iodamide group. Similarly, the numbers of
patients diagnosed with bilateral blocked fallopian tubes were also higher in
the Iodamide group.
Conclusion: HSG using low osmolar contrast media
(Iopramide and Ioxaglate) demonstrated diagnostic image qualities similar to
HSG using conventional high osmolar contrast media (Iodamide). However, all
three contrast media were found to be too dense for the detection of
intrauterine pathology. Better visualisation of the fimbrial outline using
Ioxaglate and Iopramide were attributed to their low contrast viscosity. The
increased incidence of contrast media intravasation and bilateral tubal
blockage using Iodamide are probably related to the high viscosity. © 2009
Biomedical Imaging and Intervention Journal. All rights reserved.
Keywords: Hysterosalpingography, contrast media
Hysterosalpingography (HSG) refers to the radiographic
evaluation of the uterine cavity and fallopian tubes after injection of a
radio-opaque contrast medium through the cervical canal. It is commonly and the
initial investigation for evaluating fallopian tube disorders associated with
infertility . Despite recent advances in various imaging modalities to
assess the fallopian tubes such as a three-dimensional dynamic magnetic
resonance hysterosalpingography (3D dMR-HSG) and contrast enhanced
hystero-salpingo-sonography, conventional HSG still remains the imaging
modality of choice . HSG was first performed by Rindfleisch in 1910 when he
injected Bismuth solution into the uterine cavity . In 1925, Heuser used an
oil soluble medium, Lipiodol to demonstrate the uterine cavity . Thereafter,
oil soluble contrast media became the contrast media of choice for the next 50
years. However, its popularity decreased as there were reported adverse effects
such as pulmonary oil embolism, acute tubal blockage, re-activation of tubal
infection and granuloma formation. These complications were reduced
with the introduction of water soluble contrast media. Water soluble contrast media
achieved popularity for HSG in the 1960s and 1970s as it was associated with
good radiographic quality and less serious side effects . The initial water
soluble contrast media was hyperosmolar (> 1000 mosmol/kg) and ionic
accounting for most of the side effects .
Enormous efforts have taken place to develop safer
contrast media while maintaining good diagnostic image quality. In 1985, these
efforts led to the development of non-ionic low osmolar water soluble contrast
media such as Iopramide (Schering, Berlin, Germany) in Europe . Previously,
large controlled studies have mainly compared diagnostic image quality between
iodinated oil-based and water soluble contrast media in HSG. Only a few large
controlled studies have been undertaken to compare the diagnostic image quality
of low osmolar contrast media based on their ionic/non-ionic component and
Accordingly, this study was performed to compare the
diagnostic image quality of the three types of water soluble iodinated contrast
media; hyperosmolar ionic contrast medium Iodamide (Bracco, Italy), low osmolar
ionic contrast medium Ioxaglate (Guerbet, France) and low osmolar non ionic
contrast medium Iopramide for HSG. These water soluble contrast media have
different physical properties. The characteristics of the contrast media are
listed in Table 1.
Patients and Methodology
A prospective, randomised, double-blind study was designed
to compare the diagnostic image quality between low osmolar ionic contrast
medium Ioxaglate and low osmolar non-ionic contrast medium Iopramide for HSG on
204 patients. These are the total number of patients who had undergone HSG
between August 2006 and September 2007. The 204 patients were randomly assigned
to receive either Iopramide (106 patients) or Ioxaglate (98 patients). 114
patients who had undergone HSG study using Iodamide, which is a hyperosmolar
ionic contrast medium, between August 1998 and September 1999 were analysed
retrospectively. This was because the production of this contrast medium was stopped
in year 2000, hence prospective analysis could not be carried out. All these
patients were referred for HSG in the authors' department because of primary or
secondary infertility. Patients who have undergone unilateral
salpingo-oophrectomy and those with history of pelvic discharge (pelvic
inflammatory disease), recent dilatation and curettage, possible pregnancy and
patient with history of contrast media allergies were not included in this
study. The patientís age and race were recorded for equal distribution of these
contrast media. All patients completed a consent form before undergoing the
procedure. Patients did not know which contrast medium was used. The protocol
was approved by the ethical research committee at the authors' institution.
The examination was performed between day 7 and day 10 of
menstrual cycle or in patients who have abstained from sexual intercourse since
their last menses.
A 5 French (F) hysterosalpingo (HS) foley balloon catheter
was used for cervical cannulation. Leech Wilkinson cannula was used in the
retrospective study in those patients who received Iodamide. Patients received
no pre-medication. The radiologists who performed the procedures were unaware
of the type of contrast medium used. Under fluoroscopic guidance, 5-10 ml of
the contrast medium warmed to body temperature was injected until free
peritoneal spillage occurred or tubal obstruction was demonstrated. In cases of
tubal spasm the examination was repeated after 5 minutes following intravenous
administration of 10 milligram of hyoscine butylbromide (Buscopan).
All radiographs were acquired using high kilovolts
technique (90-120kV) adjusted by automatic exposure control. Three standard
views were obtained: one frontal (when the contrast medium filled the uterus) and
two obliques (when peritoneal spillage or presumed tubal blockage was seen
during fluoroscopy). The images were printed on hardcopies using standard
Three radiologists blinded to the contrast media used
independently assessed the images based on an objective set of criteria. The
uterine cavity opacification referred to the uterine contrast density. The
uterine cavity, fallopian tube and free peritoneal spillage outline were graded
based on their sharpness. As for the fimbriaes, assessment was made based on
the ability to see the longitudinal rugations of the ampullary portion of the
fallopian tubes. A 4-point scoring system was applied for image analysis. All
the images were scanned through to select the reference images for the scoring
system which were agreed upon by the three radiologists. Diagnostic quality was
considered excellent (score 3) when there was good opacification and clear
delineation of the analyzed structure was achieved. Radiographs were classified
as poor (Score 1) when there was poor contrast opacification but anatomic
delineation and visibility were adequate for diagnosis. Anything better was
given a score of 2. Radiographs were deemed unacceptable (Score 0) when the
opacification and the delineation of the anatomical structure interfered with
diagnosis. Interpretation discrepancies were resolved by consensus discussion.
The images were analysed and results were tabulated.
Non-parametric independent samples test (Kruskal-Wallis) was used to
statistically evaluate the obtained results. When significant difference was
noted, non-parametric independent Mann Whitney U test was then used to see
which of the two contrast media led to the difference. A p value of less than
0.05 (p<0.05) was considered significant.
No significant differences were observed between the three
contrast media groups with regard to age and race distribution. These findings
are summarised in Table 2. Radiographic imaging quality was considered good to
excellent with no significant differences (p > 0.05) between the
three contrast media with regard to uterine outline, fallopian tube outline and
free peritoneal spillage outline. However, visualisation of fimbrial rugae was
significantly better (p <0.05) with Iopramide and Ioxaglate than Iodamide. In
some cases of tubal disease, the tubes, fimbrae, and peritoneal distribution
were not visualised, thus the scoring was not possible and these cases were not
included in the study. Uterine opacification was noted to be excellent but too
dense in all three contrast media. The results from the evaluation in terms of
diagnostic image quality are summarised in Table 3.
All the patients involved in this study had a score of 2
and above for demonstration of uterine outline regardless of which contrast
media was used. No differences existed among the three water soluble contrast
As for the fallopian tubes, the image quality was good to
excellent in all contrast media with a score of 2 and above (86.7% with
Iodamide, 77.9% with Iopramide and 84.7% with Iodamide). There were 3 patients
in the Iopramide group with non-diagnostic fallopian tube outline (Score 0). No
patient had a score of 0 in the Iodamide group. Even though no significant
difference was noted, the scoring of the fallopian tube was slightly better in
the Iodamide group.
The scoring of the fimbrial rugaes showed an evident
difference amongst the three contrast media. Only 62.8% of the Iodamide group
were rated 2 and above in comparison to 75% and 77.6% of the Iopramide and
Ioxaglate group respectively. This difference, even though small, was
statistically significant (p <0.05). Further analysis was carried out to
investigate which of the two contrast media led to the differences by using a
non-parametric independent Mann Whitney U test. There was a significant
difference between Iodamide and Iopramide and also between Iodamide and
Ioxaglate. Iopramide and Ioxaglate showed comparable scores for the fimbrial
The image quality of the peritoneal spillage was not
significantly different. Majority of the scorings were high with 96.9% of the
Iodamide and 100% of both Iopramide and Ioxaglate showing ratings of 2 and
With regard to contrast opacification of the uterine
cavity, all the patients involved in this study had good to excellent scores.
The uterine cavity opacification refers to the uterine contrast density. It was
found that 98.2% patients from the Iodamide group, 98.1% patients from the
Iopramide group and 99% patients from the Ioxaglate group had excellent scores
but were too dense for diagnosing intrauterine pathology. The remaining had a
score of 2.
The number of patients with both unilateral and bilateral
blocked tubes were 37% in Iodamide, 29.3% in Iopramide and 31.6% in Ioxaglate
and statistically, no significant differences exist. However, when the three
contrast media were re-analysed with regard to the diagnosis of bilateral
blocked tubes alone, there were significant differences noted (p< 0.05).
There were 14.9% of patients from the Iodamide group who demonstrated bilateral
blocked tubes in comparison to only 4.7% from Iopramide group and 7.1% from
Ioxaglate group. These findings are summarised in Table 4.
Contrast intravasation was the only immediate complication
which was recorded and analysed. 19 patients had demonstrated contrast
intravasation, of which 18 of them had lymphatic intravasation and 1 patient
had venous intravasation. Of these 19 patients, 15 of them had their
examination performed with Iodamide and 4 patients used Iopramide. There was a
significant difference in the incidence of contrast intravasation between the
three contrast media. The incidence of contrast intravasation with bilateral
blocked tubes in these 19 patients was further associated. Of the 15 patients
who received Iodamide, 7 patients had blocked tubes while the other 8 patients
had normal tubes. Similarly, there was equal incidence of blocked and normal
tubes in the 4 patients who used Iopramide. None of these 19 patients were
diagnosed with hydrosalpinx. The incidence of contrast intravasation into the
lymphatic and venous system is shown in Table 5.
HSG is mainly performed to assess radiographic signs of
peritubal adhesions such as convoluted tubes, vertical tubes, loculation of
contrast medium in peritoneum, fixed laterodeviation of the uterus and
congenital uterine abnormalities. An ideal contrast agent for HSG should
provide excellent radiopacity to delineate the uterine cavity and tubes and
should be non-toxic and non-irritating to endometrial, tubal, and peritoneal
surfaces. Oil-based contrast media was not included in this study as the
outcome of the study may not have contributed to the future. Lindequist et
al. had performed two large prospective randomised studies in 1991 and 1994
comparing oil-based and water soluble contrast media with regard to diagnostic
image quality and concluded that both water soluble and oil-based contrast
media are comparable when it comes to uterine opacification, fallopian tube and
free peritoneal spillage outline. Fimbriae and uterine outline are not as well
demonstrated by oil-based ethiodised poppy seed oil due to its high viscosity
(25mPa.s, at 37 0 Celsius) [5, 8].
In this study all the three water soluble iodinated
contrast media demonstrated comparable and excellent image quality of the uterine
cavity, fallopian tubes and free peritoneal spillage, And no significant
differences exist between the three contrast media . The natural ability of
these water soluble contrast media to mix with the watery mucous surface within
the uterus probably contributes to the excellent visualisation of this
Adequate viscosity is required to prevent such rapid
filling of the uterine cavity leading to excessive spillage into the peritoneal
cavity before radiographs are obtained. The demonstration of the fallopian
tubes were slightly better in the Iodamide group due to its higher viscosity
which raises its transit time within the fallopian tube thus allowing enough
time before the radiograph is obtained. Iopramide, having the lowest viscosity
among the three studied contrast media, flows rapidly through the fallopian
tubes (short transit time) thus does not stay long enough within the fallopian
tubes before the radiograph is obtained. This explains why there were more
patients in the Iopramide group that had non-diagnostic fallopian tubes (Score
0) in comparison to Iodamide (Figure 1).
Although the three contrast media demonstrated fairly good
visualisation of the fimbrial rugaes, an evident difference was seen between
the three contrasts. Good and clear visualisation of the fimbrial rugaes were
required in order to grade the image quality as good or excellent which was in
favour of Iopramide and Ioxaglate (Figure 2). It is possible that the high
viscosity of the Iodamide prevents proper coating of the mucosal surface of the
fimbrial rugaes thus leading to its poor visualisation. Previous studies
comparing fimbrial rugae outline using low viscosity water soluble contrast
media and high viscosity ethiodised-poppy seed oil also showed poor
demonstration with the latter contrast media [5, 8].
†The radiopacity depends primarily on the percentage of
organically bound iodine in each contrast medium. Iodamide contains 249 mg of
organically bound iodine while Iopramide and Ioxaglate contain 300 mg and 320mg
I/ml respectively (Table 1). Contrast media with an iodine content of 200-300
mg/ml produce adequate density for diagnostic images. The iodine concentration
of all the three contrast medium is high. Therefore, it is not surprising that
all the three contrast media provided sharp image of the uterine cavity with
great contrast density as others have demonstrated. These results are also
comparable with previous studies [5, 8]. Even though the three contrast media
demonstrated superior opacification of the uterine cavity, they were too dense
for the detection of intrauterine pathology (Figure 3). The uterine cavity
opacification refers to the uterine contrast density. An excellent score for
uterine contrast opacification does not necessarily mean it is ideal for the
detection for uterine pathology. Ideal uterine cavity opacification refers to
the ability of uterine contrast density to detect intrauterine pathology
without obscuring them. The ability to see the posterior uterine wall was the
criteria that used to determine ideal uterine cavity opacification. This
assessment showed that 98.2 to 99% of the patients from all three contrast
media showed uterine contrast opacification that was too dense for the
detection of intra-uterine pathology. Siegler et al. had indirectly
emphasised that point in his study. He commented on the danger of overfilling
the uterine cavity with contrast material when evaluating the shape of the
uterus in search of submucosa myomas, endometrial polyps, or synechiae. He said
that increasing amounts of contrast material can obscure the classic findings
of a submucosa myomas seen as a filling defect of a distorted, enlarged cavity
. Thus, based on the findings of this study, further studies are required
for optimising the diagnostic quality of uterine opacification, hence to
improve the diagnostic potency of intra-uterine pathology and further reducing
false negative result.
The number of patients with both unilateral and bilateral
blocked tubes was almost similar amongst the three contrast media. However, a
significant difference was evident in the diagnosis of bilateral blocked tubes
which were in favour of Iodamide. The diagnosis of bilateral blocked tubes were
2-3 times higher in the Iodamide group in comparison to Iopramide and Ioxaglate
groups. The sample size of this study is large and the contrast media were
randomised among the patients. Thus the detection of bilateral blocked tubes
should be roughly the same. It is assumed that the increased detection of
bilateral blocked tubes in the Iodamide was attributed to its higher viscosity.
The higher viscosity of Iodamide prevents smooth flow through the fallopian
tubes causing it to pool within the tubes which led to the apparent blockage of
the fallopian tubes (false positive). This group of patients would have
probably demonstrated patent tubes if Iopramide or Ioxaglate, which have lower
viscosity, were used instead. Previously, many studies have shown the potential
therapeutic effect of oil-based contrast media post-HSG in achieving pregnancy
[8, 10-12]. Many hypotheses were postulated as to the therapeutic effect of the
oil-based contrast media which might more effectively flush out tubal plugs
involved with proximal tubal blockage. Goodman et al. hypothesised that
peritoneal lymphocyte proliferation and macrophage phagocytosis were
significantly inhibited by ethiodol which may have contributed to the increased
post-HSG pregnancy rate . It is postulated that the previously
believed therapeutic effect of the oil-based contrast media may not be actually
true and the patients involved probably did not have completely blocked tubes
in the first place. Thus the clinical importance of the findings of this study
findings questionable. To the knowledge of the authors, the effect of low
viscosity water soluble contrast media on the apparently blocked tubes has not
been investigated and such investigations are warranted.
This study showed that patients from the Iodamide group
recorded higher number of contrast intravasation in comparison to Iopramide and
Ioxaglate. Further analysis of this group of patients with contrast
intravasation showed that there were equal numbers of blocked and normal tubes
implying that the contrast intravasation is not just related to blocked tubes.
The increased viscosity of Iodamide inadvertently resulted in excessive
pressure during the injection of contrast material. Our results are comparable
to that of previous studies . Venous and lymphatic contrast
intravasation was considered a serious side effect in HSG in the past, causing
pulmonary embolism. This risk was reduced with the use of low viscosity
oil-based and water soluble contrast media. None of the patients with water
soluble contrast intravasation developed immediate pulmonary or anaphylactoid
symptoms. In a larger series, embolic complications were not reported at all
. The infrequent incidence of complications from a practical
standpoint seems to be a minor problem.
Radiographically, early contrast intravasation appears as
filling of multiple thin beaded channels following an ascendant course.
Although venous and lymphatic channels can often be identified by their
anatomy, contrast intravasation into uterine and ovarian veins can sometimes be
mistaken for tubal filling. This becomes a disadvantage and results in false
positive results (Figure 5).
This study did have some limitations. The HSG examination
was not done by the same investigator. Several authors have shown the
importance of consistency in injection pressure and spot film timing in
carrying out HSG procedures. Differences in both of these aspects have been
shown to have a great effect on visualisation of anatomic contours as well as
the assessment of tubal patency, filling and contrast intravasation. In
addition to this, Leech Wilkinson cannula was used in HSG during the era of
Iodamide. Thus, the appearance of Leech Wilkinson cannula on the HSG hard
copies gave a clue to the radiologist on the type of contrast media used when
interpreting the results, hence causing biasness in reader reliability. Besides,
there was no variety of pathology seen in this study to suggest the adequacy of
the density of contrast media. Contrast opacification of the uterus needs
re-evaluation regarding optimal technique and contrast viscosity. Hence it is
proposed that further studies are carried out for optimising the diagnostic
quality of uterine opacification.
Low osmolar contrast media (Iopramide and Ioxaglate) had
diagnostic image quality comparable to the conventional high osmolar
(Iodamide). No significant difference was found regarding density of uterine
opacification, delineation of the uterus and fallopian tubes, or spillage into
the peritoneal cavity. Better visualisation of the fimbrial outline using
Ioxaglate and Iopramide was attributed to the low contrast viscosity. The
increased incidence of bilateral tubal blockage and contrast intravasation are
probably related to the high contrast viscosity. All three contrast media were
too dense for the detection of intra-uterine pathology and needs further evaluation.
Figure 1 Demonstration of fallopian tube outline with Iopramide (a) and Iodamide (b). Note the sharper outline of the fallopian tubes seen in the Iodamide group in comparison with Iopramide group.
Figure 2 Demonstration of fimbrial rugae outline with Iodamide (a) and Iopramide (b). Note the sharper outline of the fimbrial rugaes seen in the Iopramide group in comparison with Iodamide group.
Figure 3 This is a HSG study image using Iodamide contrast media (conventional contrast media). Note the uterine cavity is too dense for the visualisation of filling defects from an intra-uterine submucosal fibroid.
Figure 4 Note the lymphatic contrast intravasation obtained with Iodamide (a) and Ioxaglate (b). None of the patients showed immediate symptoms.
Figure 5 Venous intravasation seen as a network of thin vessels on top of uterus and in a pattern that could be confused with tubal filling.
Table 1 Chemical and Physical properties of the Contrast Media
Table 2 Comparison of patientsí data in the Iodamide, Iopramide and Ioxaglate groups.
Table 3 Scoring of image quality in different anatomical regions of interest using three different contrast media.
Table 4 The incidence of tubal blockage using three different contrast media.
Table 5 Incidence of contrast media intravasation using three different contrast media.
Abdullah BJJ, Ng KH, Rassiah P. A comparison of radiation dose and image quality in hysterosalpingography using conventional and high kilovolt techniques. J HK Coll Radiol 2001; 4:133-6.
Unterweger M, De Geyter C, Frohlich JM et al. Three-dimensional dynamic MR-hysterosalpingography; a new, low invasive, radiation-free and less painful radiological approach to female infertility. Hum Reprod 2002; 17(12):3138-41.
Rindfleisch W. Darstellung des cavum uteri. Klin Wochenscher 1910; 47:780.
Heuser C. Lipiodal in the diagnosis of pregnancy. Lancet 1925; 2:1111-2.
Lindequist S, Justesen P, Larsen C et al. Diagnostic quality and complications of hysterosalpingography: oil- versus water-soluble contrast media--a randomized prospective study. Radiology 1991; 179(1):69-74.
Intravascular contrast media. in: Stephan C, Richard N eds. A guide to radiological procedure. Edinburgh, UK: WB Saunders, 2001: 27-40.
E-Z-EM Announces Agreements with Berlex Labs for ULTRAVIST Pre-Filled Cartridge. Lake Success, New York [Online]. Available at http://findarticles.com/p/articles/mi_m0EIN/is_2003_Dec_16/ai_111302833. (Accessed 21 September 2008).
Lindequist S, Rasmussen F, Larsen C. Use of iotrolan versus ethiodized poppy-seed oil in hysterosalpingography. Radiology 1994; 191(2):513-7.
Siegler AM. Hysterosalpingography. Fertil Steril 1983; 40(2):139-58.
Rasmussen F, Lindequist S, Larsen C et al. Therapeutic effect of hysterosalpingography: oil- versus water-soluble contrast media--a randomized prospective study. Radiology 1991; 179(1):75-8.
Letterie GS, Rose GS. Pregnancy rates after the use of oil-based and water-based contrast media to evaluate tubal patency. South Med J 1990; 83(12):1402-3.
Steiner AZ, William RM, Richard LC. Oil-soluble contrast during HSG in women with proven tubal patency. Am J Obstet Gynecol 2003; 101:109-13.
La Fianza, Alfredo, Camilla F. Venous-lymphatic intravasation during Hysterosalpingography using hydrosoluble contrast medium: A technique with no complications. J Womenís Imaging 2005; 7(1):38-43.
|Received 22 December 2008; received in revised form 18 July
2009, accepted 17 September 2009
Correspondence: Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Tel.: +603-79492069; Fax: +603-79581973; E-mail: email@example.com (Hazman Mohd. Nor).
Please cite as: Mohd Nor H, Jayapragasam KJ, Abdullah BJJ,
Diagnostic image quality of hysterosalpingography: ionic versus non ionic water soluble iodinated contrast media, Biomed Imaging Interv J 2009; 5(3):e29