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Therapeutic hysterosalpingography a radiology perspective.

Introduction

Infertility is estimated to affect one in four New Zealand couples (Statistics New Zealand, 2009). Radiology departments have long performed diagnostic hysterosalpingograms (HSG) or dye studies of the uterus and fallopian tubes on women, as part of early infertility investigations.

Radiology at Green Lane Clinical Centre in Auckland has offered therapeutic HSG using poppy-seed oil Lipiodol as a non-funded treatment option for women whose fallopian tubes are already known to be patent for the last five years.

The background and procedure of diagnostic versus therapeutic HSG is described along with the possible mode of action of Lipiodol.

The New Zealand research literature around the use of Lipiodol as a therapeutic treatment is explored along with the recently published Dutch multi-centre randomised trial which reviewed the use of oil-based versus water-based contrast on pregnancy rates (Dreyer et al., 2017). Finally the implications for radiology services of such treatment innovations are discussed.

Background

Diagnostic hysterosalpingogram (HSG) with the oil soluble contrast media (OSCM) Lipiodol was the standard test for fallopian tube patency until about 40 years ago (Johnson, 2013). While the potential benefit of an increased rate of pregnancy following diagnostic HSG had been recognised for more than 60 years (Weir & Weir, 1951) the development of water soluble contrast media (WSCM) saw this progressively replace OSCM in diagnostic HSG for a number of reasons. Water soluble contrast is cheaper and less viscous and allows prompter visualisation of the fallopian tubes. There is less likelihood of contrast persisting within the pelvic cavity and therefore of complications such as intravasation resulting in allergic reactions, anaphylaxis or long-term granuloma formation in the tubes (Johnson, Farquhar, Hadden, Suckling, & Sadler, 2004). It should be noted, however, that severe adverse reactions have not been reported since 1967, with the introduction and use of fluoroscopic screening during injection (Lindequist, Justesen, Larsen, & Rasmussen, 1991). Real time screening allows the contrast injection to be immediately stopped should it extravasate out of the uterus into the lymphatic system.

Hysterosalpingogram

Diagnostic HSG provides radiographic (X-ray) evaluation of the fallopian tubes and the inside of the uterine cavity. This involves an injection of water-based contrast material (WSCM) Omnipaque 350 to outline the uterus and tubes under fluoroscopic or real time screening.

The indications for HSG include infertility, or failure to conceive after one year of unprotected sexual intercourse and assessment of the uterus for congenital or acquired abnormalities. It may also be used to assess the uterine cavity in women who have experienced recurrent miscarriages. Conversely HSG is used as post-procedural evaluation after tubal ligation or the placement of Essure devices to ensure that the fallopian tubes are occluded.

The procedure involves a team approach with the nurse carrying out the explanation and consenting process to establish a rapport with the patient. A small balloon catheter is then guided into the cervical canal or lower uterus by the Radiologist and the balloon inflated.

Typically, 10-20mls of water-based contrast material is then slowly injected through the catheter under fluoroscopy and images taken to demonstrate the uterus and the fill and free spill of contrast from the fallopian tubes. In my department, we often combine this examination with a transvaginal ultrasound scan if requested, typically with the contrast still within the uterus; if uterine filling defects are noted on the HSG, or further information is required about the uterine shape. Therapeutic hysterosalpingography is essentially the same procedure using an oil-compatible balloon catheter and a maximum of 10mls of OSCM Lipiodol. The focus is on filling the uterus rather than necessarily complete fill and spill of the fallopian tubes. Currently in our department all patients undergoing therapeutic Lipiodol HSG require prior confirmation of tubal patency either from a previous HSG or laparoscopy and dye study.

The Research

An increased pregnancy rate following diagnostic tubal patency testing with OSCM has been discussed in the literature for over half a century and was reported by Weir and Weir (1951). There have been many subsequent reports, non-randomized studies and discussion within infertility circles supporting the fertility enhancing effect of oil soluble contrast media (Johnson, et al., 2004).

In 2004 the FLUSH trial was conducted in New Zealand to determine the effectiveness of Lipiodol flushing for enhancing fertility in women with unexplained infertility (Johnson, et al., 2004). The study randomised 158 women into two groups: group A had unexplained infertility without confirmed endometriosis but patent fallopian tubes and group B had known endometriosis and patent tubes.

Each group was then randomised to receive either Lipiodol flushing or no intervention. Clinical pregnancy, assessed at six months following randomisation and live birth, was the main outcome measure. Lipiodol flushing resulted in a 40 per cent versus 10.8 per cent live birth rate in women with endometriosis whereas there was a 27.1 per cent versus 14.6 per cent birth rate in those women with infertility, but without endometriosis, which was not considered statistically significant.

A two year follow-up of the women in the study showed that the benefit of Lipiodol flushing appears to only last for six months in the women with endometriosis, whereas those with unexplained infertility showed a sustained benefit for that period (Johnson et al., 2007).

Following on from the FLUSH trial (Johnson, et al., 2004), Lipiodol was offered as an innovative treatment and the first cohort of 100 women followed up. A 32 per cent pregnancy rate and a 25 per cent live birth rate was seen in women under 40 years of age with unexplained infertility and a 50 per cent, 47 per cent live birth rate in this age group with endometriosis (Brent, Haddon, Weston-Webb, & Johnson, 2006).

A prospective study of the complete innovative treatment data set of 296 women by Court et al., (2014) showed an overall clinical pregnancy rate of 44.7 per cent or 88 pregnancies from 197 procedures. The clinical pregnancy rate for the unexplained infertility group was 39.4 per cent and for the endometriosis group was 51.1 per cent.

Court et al., (2014) concluded that Lipiodol could therefore be considered as a standard treatment for both unexplained and endometriosis related infertility. Despite this compelling New Zealand evidence, an editorial in the Australian and New Zealand Journal of Obstetrics and Gynaecology commented that the flushing of the fallopian tubes with an oil-based contrast has not been embraced either within Australia or more globally and that further randomised controlled trials were required (Hart, 2014).

This year has seen the publication of a multi-centre, randomised trial in the Netherlands in which 1119 infertile women who were undergoing HSG were assigned to the use of oil-based (562 women) or water-based (554 women) contrast media (Dreyer, et al., 2017).

A total of 220 women in the oil group (39.7 per cent) and 161 in the water group (29.1 per cent) had an on-going pregnancy and 38.8 per cent of women in the oil group and 28.1 per cent in the water group had live births. Rates of adverse events were low and similar in both groups (Dreyer, et al., 2017). Interestingly this study also confirms the benefit of uterine and tubal flushing with WSCM; information that has been largely anecdotal until now.

Possible action of Lipiodol

Lipiodol is composed of iodine combined with ethyl esters of fatty acids of poppy seed oil (Johnson, et al., 2004). Its precise action remains unclear but a number of possibilities exist. The difference in therapeutic effect for women with endometriosis in comparison to those with unexplained infertility suggest a possible immunobiological action rather than a straight tubal flushing mechanism (Johnson, 2013).

A study by Mikulska, Kurzawa, & Rozewicka (1994) showed intraperitoneal effects or a change in the production of cytokines by peritoneal macrophages and inhibition of sperm phagocytosis amongst rodents exposed to Lipiodol.

Another possibility is an endometrial bathing action, which is supported by a pregnancy rate of 47.1 per cent amongst a subgroup of 17 women with endometriosis in the study by Court et al., (2014), where Lipiodol bathed the uterus, but failed to enter either fallopian tube. It is thought that endometriosis adversely effects both the quality of the egg and potentially the receptivity of the endometrium to implantation (Johnson, 2013).

Women with endometriosis have been shown to have an overproduction of endometrial osteopontin, correct levels of which appear critical in implantation. Uterine bathing with OSCM appears to down regulate osteopontin in the endometrium and increase numbers of uterine natural killer (uNK) cells, which are likely to be important in implantation receptivity, although their precise action is unclear (Johnson, 2013).

The recent study by Dreyer et al., (2017) however, while acknowledging a possible tubal flushing mechanism, consider a direct endometrial effect unlikely as the benefit of the Lipiodol flushing persists over multiple menstrual cycles. Clearly further research is required to confirm the precise mode of action.

Discussion

Therapeutic HSG with OSCM Lipiodol clearly offers a simple, low invasive and inexpensive treatment option especially for women with endometriosis related infertility. It is expected that demand for this service will increase with publication of the Dutch multi-centre trial (Dreyer, et al., 2017) and as more women become aware of the option.

Our team in the Radiology department at Green Lane Clinical Centre can see a number of challenges ahead. Already we are being asked to carry out therapeutic Lipiodol studies without prior testing of fallopian tube patency. This raises a number of concerns as we do see women with blocked fallopian tubes in the absence of any significant history. Filling a hydrosalpinx or blocked, dilated fallopian tube with Lipiodol is likely to cause further problems.

From our experience, the viscosity of Lipiodol causes more uterine spasm and often slow or incomplete filling of the fallopian tubes and is therefore not ideal for assessing tubal patency. Also, we currently identify uterine polyps, often missed at previous transvaginal ultrasound, in early HSG images in around 20 per cent of women. These would be obscured by the much denser Lipiodol contrast and may therefore remain undetected. It is important as a service that we keep up with the latest literature and offer our expertise to the discussion to ensure that we cause no harm and offer the best possible outcomes for our patients.

Conclusion

Lipiodol flushing of the uterus and fallopian tubes is simple, low cost and minimally invasive in comparison with other infertility treatment options. It is effective in enhancing fertility in women with unexplained infertility with the greatest benefit apparent in women with endometriosis.

FOOTNOTE:

This article is based on the presentation that won the Debbie Booth Memorial award sponsored by Obex Medical for the best Medical Imaging paper, at the 43rd Annual Perioperative Nurses College conference in Dunedin.

References

Brent, K., Haddon, W., Weston-Webb, M., & Johnson, N. (2006). After the FLUSH trial: A prospective observational study of lipiodol flushing as an innovative treatment for unexplained and ednometriosis-related infertility. Australian and New Zealand Journal of Obstetrics and Gynaecology 46(4), 293-297.

Court, K. A., Dare, A. J., Weston-Webb, M., Hadden, W., Sim, R. G., & Johnson, N. (2014). Establishment of lipidol as a fertility treatment - Prospective study of the complete innovative treatment data set. Australian and New Zealand Journal of Obstetrics and Gynaecology, 54, 13-19.

Dreyer, K., van Rijswijk, J., Mijatovic, V., Goddijn, M., Verhoeve, H. R., van Rooij, I. A. J., et al. (2017). Oil-based or water-based contrast for hysterosalpingography in infertile women. New England Journal of Medicine, 376(21), 2043-2052.

Hart, R. (2014). Is there a place in infertility practice for the use of oil-based tubal flushing? Australian and New Zealand Journal of Obstetrics and Gynaecology, 54, 1-2.

Johnson, N. (2013). Review of Lipiodol treatment for infertility - an innovative treatment for endometriosis-related infertility. Australian and New Zealand Journal of Obstetrics and Gynaecology 54(1).

Johnson, N., Farquhar, C., Hadden, W., Suckling, J., & Sadler, L. (2004). The FLUSH Trial--Flushing with Lipiodol for Unexplained (and endometriosis-related) Subfertility by Hysterosalpingography: a randomized trial. Human Reproduction, 19(9), 2043-2051.

Johnson, N., Kwok, R., Stewart, A. W., Saththiananthan, M., Hadden, W., & Chamley, L. W. (2007). Lipiodol fertlility enhancement: two-year follow-up of a randomised trial suggests a transient benefit in endometriosis, but a sustained benefit in unexplained infertility. Human Reproduction, 22(11), 2857-2862.

Lindequist, S., Justesen, P., Larsen, C., & Rasmussen, F. (1991). Diagnostic quality and complications of hysterosalpingography: oil-verses water-soluble contrast media- a randomised prospective study. Radiol, 179, 69-74.

Mikulska, D., Kurzawa, R., & Rozewicka, L. (1994). Morphology of in virto sperm phagocytosis by rat peritoneal macrophages under influence of oily contrast medium (Lipiodol). Acta Eur Fertil, 25, 203-206.

Weir, W., & Weir, D. (1951). Therapeutic value of salpingograms in infertility. Fertility and Sterility 2(6), 514-522.

By Shona Matthews
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Title Annotation:medical imaging
Author:Matthews, Shona
Publication:The Dissector: Journal of the Perioperative Nurses College of the New Zealand Nurses Organisation
Date:Sep 1, 2017
Words:2100
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