Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo

Dr. Rebar reports that he chairs Data Safety Monitoring Committees for Myovant Sciences, Inc.

SYNOPSIS: A multicenter, randomized trial in the Netherlands documented higher rates of ongoing pregnancy and live births among infertile women who underwent hysterosalpingography with oil-based contrast compared to those who underwent the procedure with water-based contrast.

SOURCE: Dreyer K, van Rijswijk J, Mijatovic V, et al. Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med 2017;376:2043-2052.

Hysterosalpingography to assess tubal patency often is regarded as an essential part of the initial evaluation of the infertile couple. Because of numerous suggestions and smaller studies indicating a possible fertility-enhancing effect of hysterosalpingography with the use of oil contrast, investigators in the Netherlands conducted a multicenter, randomized, controlled trial in 27 Dutch hospitals to compare ongoing pregnancy rates in women with infertility undergoing hysterosalpingography with either oil- or water-based contrast. In all, 1,119 spontaneously menstruating women between the ages of 18 and 39 years with infertility of at least one year’s duration were included in the trial, with 557 women assigned to hysterosalpingography with oil-based contrast and 562 women assigned to water-based contrast. The researchers excluded individuals with a high risk of tubal disease (based on a history of pelvic inflammatory disease), previous chlamydia infection (generally on the basis of testing for antichlamydial antibodies), or known endometriosis. Hysterosalpingography showed bilateral tubal patency in 86.1% of women assigned to oil-based contrast and in 88.6% of those assigned to water-based contrast. After the procedure, couples received expectant management (58.3% of the oil-based contrast group and 57.2% of those assigned to water-based contrast) or the women underwent intrauterine insemination, either with or without “mild ovarian hyperstimulation” with either clomiphene citrate or exogenous gonadotropins to cause development of two or three ovarian follicles.

On an intention-to-treat basis, ongoing pregnancy — defined as a positive fetal heart beat on ultrasonographic examination after 12 weeks of gestation with the first day of the last menstrual period for the pregnancy occurring within six months of randomization — resulted in 39.7% of the women randomly assigned to oil-based contrast and in 29.1% of those randomly assigned to water-based contrast (rate ratio, 1.37; 95% confidence interval [CI], 1.16-1.61; P < 0.001). The median time to the onset of pregnancy was 2.7 months in the oil group and 3.1 months in the water group; 38.8% in the oil group and 28.1% in the water group had a live birth (rate ratio, 1.38; 95% CI, 1.17-1.64; P < 0.001).

COMMENTARY

The possibility that oil-based contrast material used for hysterosalpingography increases the likelihood of pregnancy has been suggested for many years.^1,2 This randomized trial would seem to confirm the advantages of oil-based contrast in certain select populations. However, the real question is whether these data are relevant to the U.S. population and couples routinely seen for infertility in the United States.

The authors have suggested that the use of oil contrast combined with expectant management may be an inexpensive treatment for some women with infertility. While this is true, it is interesting to note that the specific contrast material utilized (Lipiodol, Ultra-Fluid, Guerbet) is several-fold more expensive in the United States than it is in the Netherlands.

The authors noted that the trial involved infertile women with a low risk of tubal disease. The prevalence and incidence of chlamydia admittedly is low in the Netherlands. That is not the case in the United States. Data from the Centers for Disease Control and Prevention website indicate that 50% of women in the United States may have had chlamydia by the age of 30. In the absence of definitive data, the risk of hysterosalpingography with oil-based contrast material to result in acute pelvic inflammatory disease always has been believed to be higher than that with water-based contrast material because of the length of time the contrast material remains in the pelvis. Older practitioners like myself long have been familiar with publications indicating that administration of doxycycline prophylactically appears to reduce the risk of acute disease.³ Although the risk of acute pelvic inflammatory disease appears low, as detailed in that study, it is very real. The ability of acute disease to further increase the risk of infertility is such that I find it difficult to support the routine use of oil-based contrast in all women evaluated for infertility.

In low-risk women it may be justifiable to consider hysterosalpingography with oil-based contrast material. However, the authors concluded their paper with the observation that new tests for assessment of tubal patency in the office setting using ultrasound have been introduced. Oil-based contrast in such settings and for tubal flushing has not been evaluated. Until such time as more data are available, I find little reason to switch to the more expensive oil-based contrast material routinely in the evaluation of infertile women.

REFERENCES

1. Weir WC, Weir DR. Therapeutic value of salpingograms in infertility. Fertil Steril 1951;2:514-522.
2. Mohiyiddeen L, Hardiman A, Fitzgerald C, et al. Tubal flushing for subfertility. Cochrane Database Syst Rev 2015; May 1;CD003718. doi:10.1002/14651858CD003718.pub4.
3. Pittaway DE, Winfield AC, Maxson W, et al. Prevention of acute pelvic inflammatory disease after hysterosalpingography: Efficacy of doxycycline prophylaxis. Am J Obstet Gynecol 1983;147:623-626.