HyFoSy with ExEm®: Proven accuracy with minimal invasiveness

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According to the American Society for Reproductive Medicine, a woman’s best reproductive years are in her 20s. Fertility gradually declines in the 30s, particularly after age 35.3

Each month that she tries, a healthy, fertile 30-year-old woman has a 20% chance of getting pregnant. That means that for every 100 fertile 30-year-old women trying to get pregnant in one cycle, 20 will be successful and the other 80 will have to try again. By age 40, a woman’s chance is less than 5% per cycle, so fewer than five out of every 100 women are expected to be successful each month.3

The American College of Obstetricians and Gynecologists recommends an infertility evaluation if a woman has failed to conceive after a year of having regular sexual intercourse without using birth control. In women older than 35, an evaluation is recommended after six months of trying.4

Numerous studies have shown that oral contraceptive use is associated with a short-term delay of two to six months in fertility compared to other contraceptive methods.5

Causes of infertility

According to Levaillant et al in some cases the cause of infertility is unknown. In 30% of cases, infertility is caused by anomalies of the fallopian tubes and the uterine cavity. Defects in the fallopian tubes account for between 11% to 30% of cases.1

Pelvic inflammatory disease is by far the most common cause of tubal defects. Other causes include previous pelvic surgery, endometriosis, fibroids, and pelvic tuberculosis. 6,7

The European Society of Human Reproduction and Embryology guidelines advocate semen analysis and ovulation assessment before a test of tubal patency is performed.7

Evaluation of tubal infertility

Treatment of tubal infertility is largely dependent on the site and extent of the disease. Accurate evaluation of the fallopian tubes is crucial because an incorrect diagnosis may result in unnecessary tubal reconstructive surgery or in vitro fertilisation.7

The gold standard tubal patency evaluation is a laparoscopy and dye test (lap-and-dye). However, according to Levaillant et al, the test is invasive, must be done under general anaesthesia, and is costly.1 Exalto and Emanuel add that it is also associated with a risk of intra-abdominal bleeding, and visceral damage.8

A hysterosalpingography (HSG) is recommended as first-line evaluation during a fertility work-up. However, HSG is associated with several risks (such as peritonitis and iodine allergy), exposes patients to ionising radiation, is associated with discomfort, or even abdominal pain.1,6,8

To address these risks, a new, less invasive examination of tubal patency with ultrasound was developed known as hysterosalpingo-contrast-sonography (HyCoSy) using either contrast media or saline. HyCoSy allows assessment of the outline of the uterine cavity and patency of the fallopian tubes and is performed with standard transvaginal ultrasonography equipment as an office procedure. The accuracy of HyCoSy was found to be comparable with that of HSG.9

At first, saline/air or different contrast media were used. However, the echogenic contrast medium used in HyCoSy was found to potentially cause allergic reactions and is therefore no longer licensed for gynaecological use.1,6

This led to the development of a new, more stable, echogenic medium in the form of foam introduced in 2010 as a first-line office tubal patency test. The foam is created by rigorously mixing 5ml ExEm®-gel (containing hydroxyethyl cellulose and glycerol, IQMedical Ventures BV, Rotterdam, The Netherlands) with 5ml purified ExEm®-water. The ExEm®-foam, with a viscosity of 270cP and containing 94.12 % water, is sufficiently fluid to pass the Fallopian tubes and in the meantime sufficiently stable to show echogenicity for at least five minutes, which is an advantage over saline.8  

Hysterosalpingo-foam sonography (HyFoSy) has been shown to have the same accuracy as a lap-and-dye, and is comparable to HSG.1,6,7 HyFoSy is a minimally invasive, well-tolerated technique and has the advantage of being carried out relatively quickly (around 15 min for HyFoSy plus 15 min for pelvic examination).1

ExEm® gel is considered to be safe, as the components are well known and have been used intravenously and in the abdominal cavity for other medical purposes. There are no known serious side effects (one case report of hypersensitivity has been published).1

Usefulness of HyFoSy as first-line tubal patency testing

Emanuel et al (2011) were the first to evaluate HyFoSy as the preferred routine office procedure for tubal patency testing. Successful procedures were performed in 92% of the participants (n=73). In 78% of cases, there was no further need for HSG. Some 19% of the participants conceived within a median of three months following the procedure. They concluded that HyFoSy is a successful procedure to demonstrate tubal patency 9

Since then, numerous other studies have confirmed the benefit of HyFoSy as first-line tubal patency testing. The FOAM study (2015) included infertile women (n=1026) between 18 and 41 years old who were scheduled for tubal patency testing during their fertility work-up. The primary outcome for the comparison of the HyFoSy- and HSG-based strategies was ongoing pregnancy leading to live birth within 12 months after inclusion in an intention-to-treat analysis.6

In 73% of participants, conclusive tests results were concordant and 14% had discordant results. Some 105 of participants with discordant results were randomised to clinical management based on the results of either HyFoSy or HSG. In the HyFoSy group, 46% of participants had an ongoing pregnancy leading to a live birth compared to 47% the HSG arm. The mean pain score for HyFoSy on the 1–10 Visual Analogue Scale (VAS) was 3.1 for HyFoSy and 5.4 for HSG.6

In summary, this study showed that relying on either HyFoSy or HSG in infertile women leads to similar pregnancy outcomes, while HyFoSy is associated with significantly less pain. Given the similar outcomes, HyFoSy can be the preferred first-choice tubal patency test during a fertility work-up, concluded van Welie et al.6

Exacoustos et al (2015) have shown that in infertile patients’ the pregnancy rate after HyFoSy is 30% within six months. In secondary infertility the pregnancy rate is 38% within six months. Tubal flushing due to HyFoSy improves the chance of an embryo implanting and establishing a spontaneous pregnancy.12

More recently, Engels et al (2020) concluded that HyFoSy is a feasible, well-tolerated and safe technique for the evaluation of tubal patency in infertile women.10

 The median VAS score for perception of pain during HyFoSy examination was two and only 1.9 % of women reported severe pain (VAS>7). Pain was unrelated to tubal patency or tubal blockage. Three (0.32 %) complications of the technique were reported: two vasovagal episodes and a mild urinary infection.10

Apart from less pain, Rajesh et al report that no infections associated with HyFoSy have been reported in the literature. Furthermore, González et al (2022), showed that HyFoSy is also associated with less anxiety measured using the State Trait Anxiety Inventory (STAI).11

According to Ramos et al (2022) HyFoSy is a suitable technique to assess tubal patency, being as accurate as HSG, it is more patient-friendly, uses a non-embryotoxic contrast, is more cost-effective and allows a fast-track pathway to fertility treatment. It can be performed in an examination room equipped only with an ultrasound scanner. Based on these statements, HyFoSy should be the first-line diagnostic procedure to assess tubal patency.13

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  1. Levaillant J-M, Rabourdin A, Pinto M, et al. HyFoSy for Fallopian tube test, the how: Sonographic signs and standardization with a simple classifi Journal of Gynecology Obstetrics and Human Reproduction, 2022.
  2. Mathur R. Treating female and male subfertility in 2016. file:///C:/Users/rene.bosman/Downloads/1445%20-%20Raj%20Mathur%20-%20Treating%20female%20and%20male%20infertility%20in%202016_0.pdf
  3. American Society for Reproductive Medicine. Age and Fertility (booklet).
  4. American College of Obstetricians and Gynecologists. Evaluating Infertility.,after%206%20months%20of%20trying.
  5. Mikkelsen EM, Riis AH, Wise LA, et al. Pre-gravid oral contraceptive use and time to pregnancy: a Danish prospective cohort study. Human Reproduction, 2013.
  6. Van Welie N, van Rijswijk J, Dreyer K, et al. Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial. Human Reproduction, 2022.
  7. Rajesh H, Lim SL, Yu SL. Hysterosalpingo-foam sonography: patient selection and perspectives. Int J Women’s Health, 2016.
  8. Exalto N and Emanuel MH. Clinical Aspects of HyFoSy as Tubal Patency Test in Subfertility Workup. Biomed Research International, 2019.
  9. Emanuel MH, van Vliet M, Weber M, Exalto N. First experiences with hysterosalpingo-foam sonography (HyFoSy) for office tubal patency testing. Human Reproduction, 2011.
  10. Engels V, Medina M, Antolin E, et al. Feasibility, tolerability, and safety of hysterosalpingo-foam sonography (hyfosy). multicenter, prospective Spanish study. Journal of Gynecology Obstetrics and Human Reproduction, 2020.
  11. Gonzalez LS, Perez-Medina, Olalla BB, et al. Is hysterosalpingo-foam sonography (HyFoSy) more tolerable in terms of pain and anxiety than hysterosalpingography (HSG)? A prospective real-world setting multicentre study. BMC Women's Health, 2022.
  12. Exacoustos C, Tiberio F, Szabolcs B, Romeo V, Romanini E, Zupi E. Can Tubal Flushing With Hysterosalpingo-Foam Sonography (HyFoSy) Media Increase Women's Chances of Pregnancy?
  13. J Minim Invasive Gynecol. 2015 Nov-Dec;22(6S):S238. doi:10.1016/j.jmig.2015.08.836. Epub 2015 Oct 15.
  14. Ramos J, Pellicer N, Fernández-Sánchez M. Hysterosalpingography is obsolete: hysterosalpingo-contrast foam sonography should be the alternative. Reprod Biomed Online. 2022 Jun 1:S1472-6483(22)00399-6. doi: 10.1016/j.rbmo.2022.05.021.

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