The oil-based contrast media Lipiodol, an iodised poppy seed oil, can be administered straightforwardly in a hysterosalpingogram. The FLUSH Trial1 showed enhanced spontaneous pregnancy rates in couples with unexplained infertility and especially in women with mild endometriosis-related infertility following Lipiodol administration.
A related new study is currently underway, the IVF-LuBE Trial, aiming to determine whether these positive effects exist for those undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) in women with a diagnosis of either recurrent implantation failure or endometriosis.
Consistent with the FLuSH Trial findings, it has been long perceived that there is a possible therapeutic effect associated with diagnostic tubal patency testing. This is supported by Weir and Weir.2 In 1951, they noted a possible increased pregnancy rate following hysterosalpingogram (HSG) with oil-based media. The first meta-analysis of tubal flushing3 suggested that oil-based contrast media has a greater fertility-enhancing effect than water-based media and that the effect is most pronounced in couples with unexplained infertility. Current practice for tubal patency testing has moved away from the use of oil-based to water-based contrast media. The reasons for this include lower cost, finer imaging, lower viscosity, and reduced adverse effects such as intravasation, allergic reactions and lipogranuloma formation. However, with the advent of fluroscopic screening, oil-based media have become safe to use.
How Lipiodol works
Several theories exist on how Lipiodol is thought to enhance pregnancy rates, including flushing of non-occlusive but pregnancy-hindering debris from fallopian tubes3; positively influencing the intraperitoneal environment; improving either the environment in which eggs mature or the sperm-egg interaction4,5,6; or by enhancing implantation through a direct effect on the endometrium.1 Evidence does exist to support a uterine bathing effect of Lipiodol on the endometrium in a murine model7, where changes in uterine antigen-presenting dendritic cells may make the endometrium more receptive to implantation of an embryo.
The FLUSH Trial
The FLuSH Trial – Flushing with Lipiodol for unexplained (and Endometriosis-related) Subfertility by Hysterosalpingography: a randomised trial1 randomised 158 couples to receive either Lipiodol tubal flushing by HSG with fluoroscopic screening or no intervention. Ninety-six of the couples had ‘pure’ unexplained infertility and 62 women had mild endometriosis in the context of otherwise unexplained infertility.
Follow-up occurred over the subsequent six months. Results revealed that in the purely unexplained infertility group, the pregnancy rates were 33.3 per cent for women who received Lipiodol and 20.8 per cent in the no intervention group. However, this result did not reach statistical significance, though when the data was meta-analysed with a very similar published trial8, the pooled results did show a significant beneficial effect from having Lipiodol (pregnancy RR 2.05, 95% CI 1.07-3.93). At two years follow-up, a beneficial effect lasting longer than six months was found in this group.9
What was more interesting was that in the mild endometriosis group the pregnancy rate at six months was 48.0 per cent following Lipiodol compared to only 10.8 per cent in the no intervention group (pregnancy RR 4.44, 95% CI 1.41-12.21, p=0.001), showing a highly significant beneficial effect of Lipiodol.
The FLuSH Trial has created speculation on its possible role in enhancing pregnancy rates in those undergoing an IVF or ICSI cycle. We have seen success rates for IVF/ICSI treatment continuing to improve, but we are aware that the point at which treatment fails is usually after embryo transfer. Previous studies examining treatments for IVF/ICSI implantation failure have failed to identify a solution. Any treatment shown to improve outcomes for women with recurrent implantation failure would be a key advance in IVF/ICSI fertility treatment, and Lipiodol, which may exert a positive effect in this situation, has not yet been examined in this context, leading onto the initiation of the IVF-LuBE Trial.
The IVF-LUBE Trial
This trial aims to examine the possible benefits of Lipiodol in relation to IVF/ICSI in two sub-populations in which Lipiodol would be expected to provide the most benefit in improving IVF/ICSI outcomes, that being women with recurrent implantation failure7 and women with endometriosis1.
The trial is currently recruiting and randomising women. Eligibility to enter the study consists of a woman being scheduled to undergo an IVF/ICSI cycle with a diagnosis of either or both recurrent implantation failure, defined as having three consecutive previous embryo replacements of good quality embryos without
a resultant pregnancy, or any stage of endometriosis which has been diagnosed laparoscopically. A woman must be aged 39 years or under, have infertility for a duration of 12 months or more, or an absolute cause for infertility and have both fallopian tubes confirmed as patent.
Women participating in the study are randomised approximately four to five weeks before commencing their IVF/ICSI cycle to either having the cycle as well as Lipiodol or the cycle alone. The primary outcome measured will be live birth, with secondary outcomes recorded including biochemical/clinical/viable/ongoing/ectopic and multiple pregnancies, as well as miscarriage and any adverse events.
The study is an open parallel randomised controlled trial of multi-centre design, with Auckland acting as the coordinating centre. The pilot study, which will randomise 84 women, is being undertaken as a CREI subspecialty training research project, and 27 women have been randomised so far from clinics around New Zealand. The interim results gained from this study will provide a useful foundation for the complete study that aims to recruit 350 women. To accelerate the recruitment process, overseas centres based in Australia, the united Kingdom and India have been approached to consider participating on a multi-centre basis.
I have recently given birth to twins. I take this opportunity to thank my obstetrician, Dr Tony Baird, my midwife Gail Stockwell, and the medical and midwifery staff working in the high dependency unit and on Ward 96 at Auckland City Hospital for their amazing care and support, especially through my ‘rocky’ initial postpartum period.
- Johnson NP, Farquhar CM, Hadden WE, Suckling J, Yu Y, Sadler L. The FLuSH Trial – Flushing with Lipiodol for unexplained (and Endometriosis-related) Subfertility by Hysterosalpingography: a randomised trial. Hum Reprod 2004; in press.
- Weir WC, Weir DR. Therapeutic value of salpingograms in infertility. Fertil Steril. 1951; 2:514-522.
- Watson A, Vandekerckhove P, Lilford R, Vail A, Brosens I, Hughes E. A meta-analysis of the therapeutic role of oil soluble contrast media at hysterosalpingography: a surprising result? Fertil Steril. 1994; 61:470- 7.
- Johnson J, Montoya I, Olive D. Ethiodol oil contrast medium inhibits macrophage phagocytosis and adherence by altering membrane electronegativity and microviscosity. Fertil Steril. 1992; 58:511-7.
- Sawatari Y, Hori T, Hoshiai H. Oily contrast medium as a therapeutic agent for infertility because of mild endometriosis. Fertil Steril. 1993;59:907-11.
- Mikulska D, Kurzawa R, Rozewicka L. Morphology of in vitro sperm phagocytosis by rat peritoneal macrophages under influence of oily contrast medium (Lipiodol). Acta Europaea Fertilitatis 1994; 25:203-6.
- Johnson NP, Bhattu S, Wagner A, Blake DA, Chamley LW. Lipiodol alters murine uterine dendritic cell populations: a potential mechanism for the fertility enhancing effect of Lipiodol. Fertil Steril. 2005; 83:1814-21.
- Nugent D, Watson AJ, Killick SR, Balen AH, Rutherford AJ. A randomised controlled trial of tubal flushing with Lipiodol for unexplained infertility. Fertil Steril. 2002; 77:173-175.
- Johnson NP, Kwok R, Stewart AW, Saththianathan M, Hadden WE, Chamley LW. Lipiodol fertility enhancement: Two-year follow-up of a randomized trial suggesting a transient benefit in endometriosis, but a sustained benefit in unexplained infertility. Hum Reprod. 2007; 22:2857-2862.