Trial Oversight

The Water versus Oil (H2Oil) trial was approved by the ethics committee and institutional review board of the Academic Medical Center, Amsterdam, and by the board of directors of all participating hospitals. Trial oversight was provided by the ethics committee of the Academic Medical Center. In each of the participating centers, data monitoring in accordance with the Good Clinical Practice guidelines was performed by dedicated research nurses. All participants provided written informed consent. The first, second, and last authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol, which is available with the full text of this article at NEJM.org.

Trial Participants

Participants in the H2Oil trial were recruited from 27 hospitals (4 academic, 12 teaching, and 11 nonteaching hospitals) in the Netherlands. Gynecologists in these hospitals collaborate in a nationwide consortium for women’s health research (the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynecology; www.studies-obsgyn.nl).

Women were eligible to participate in the trial if they were between 18 and 39 years of age, had spontaneous menstrual cycles, and had been trying to conceive for at least 1 year and if there was an indication for evaluation of tubal patency by means of hysterosalpingography.13 Exclusion criteria were known endocrine disorders (e.g., the polycystic ovary syndrome, diabetes, hyperthyroidism, and hyperprolactinemia), less than eight menstrual cycles per year, a high risk of tubal disease (as indicated by a history of pelvic inflammatory disease, previous chlamydia infection, or known endometriosis), iodine allergy (since the contrast mediums under study both contained iodine), and a total motile sperm count after sperm wash of less than 3 million sperm per milliliter in the male partner (or a total motile sperm count of <1 million sperm per milliliter when an analysis after sperm wash was not performed).

Randomization and Trial Intervention

Potential participants were informed about the trial by their doctors or dedicated research nurses. After they provided written informed consent, the women were, preferably just before hysterosalpingography, randomly assigned in a 1:1 ratio to the use of oil contrast (Lipiodol Ultra-Fluid, Guerbet) (the oil group) or water contrast (Telebrix Hystero, Guerbet) (the water group). Randomization was performed by the doctors or research nurses with the use of a secured online randomization program (ALEA, FormsVision) with random block sizes of 2, 4, or 6, stratified according to hospital. This randomization program was overseen by an independent data manager. Owing to the difference in imaging between the use of oil-based contrast and water-based contrast, and, since our outcome of ongoing pregnancy was objective, the trial was not blinded with respect to participants and caregivers.

Hysterosalpingography was performed according to local protocols. The contrast medium could be infused into the uterus with the use of a cervical vacuum cup, metal cannula (hysterophore), or balloon catheter. During the infusion of approximately 5 to 10 ml of contrast medium, four to six radiographs that were obtained to evaluate the patency of both fallopian tubes were examined by a gynecologist or radiologist.

Subsequently, couples received expectant management or the women underwent intrauterine insemination. Expectant management was indicated when the predicted likelihood of natural conception within 12 months after hysterosalpingography, as based on the prognostic model of Hunault,14,15 was 30% or greater. Intrauterine insemination was offered when this likelihood was less than 30%, when mild male infertility (defined as a total motile sperm count between 1 million and 3 million sperm per milliliter) was present, or after a period of expectant management without natural conception. Intrauterine insemination was initiated after a minimum of 2 months of expectant management after hysterosalpingography and could be performed with or without mild ovarian hyperstimulation, according to local protocols. Mild ovarian hyperstimulation, aiming for two or three follicles, was achieved with clomiphene citrate or exogenous gonadotropins.

Outcome Measures

The primary outcome measure was ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, with the first day of the last menstrual cycle for the pregnancy within 6 months after randomization. Secondary outcome measures were clinical pregnancy (defined as a gestational sac detected on ultrasonography), live birth (defined as a live birth after 24 weeks of gestation), miscarriage (defined as the absence of a fetal heartbeat on ultrasonography or spontaneous loss of pregnancy before 12 weeks of gestation), ectopic pregnancy (defined as an embryo implanted outside the uterine cavity), and pain scores after hysterosalpingography, measured by means of the Visual-Analogue Scale for Pain (scores range from 0.0 to 10.0 cm, with higher scores indicating more severe pain).

Costs were a prespecified secondary outcome, but this analysis is not included in this article. We also compared the time to pregnancy resulting in an ongoing pregnancy (calculated from the first day of the last menstrual period plus 4 weeks).

Statistical Analysis

We calculated that the trial would need to include 1080 women (540 in each group) to obtain a power of 80%, with an alpha error of 5%, to detect a difference of 7 percentage points between the trial groups in rates of ongoing pregnancies. This difference was considered by the clinical investigators to be clinically meaningful, over an anticipated control rate of 18% after hysterosalpingography.10,11 Since the trial compared two interventions used routinely in clinical practice and was expected to recruit quickly, an interim analysis was not performed.

Categorical data were reported as absolute numbers and percentages. Normally distributed continuous variables were summarized as means with standard deviations, and nonnormally distributed continuous variables were reported as medians with interquartile ranges. Apart from conventional baseline data, we also compared the likelihood of natural conception within 12 months after hysterosalpingography (calculated with the use of the prognostic model of Hunault) in the two trial groups after completion of the fertility workup to see whether the chance of getting pregnant was similar in the two groups.14,15

All data were analyzed according to the intention-to-treat principle. Univariate rate ratios or relative risks and 95% confidence intervals were calculated for the primary and other binary outcome measures, and the chi-square test was used to assess statistical significance. Continuous outcomes were analyzed with the use of an independent t-test or the Mann–Whitney U-test as appropriate. We used Kaplan–Meier curves with a log-rank test to compare the groups with respect to the time to pregnancy resulting in an ongoing pregnancy. Two-sided P values of less than 0.05 were considered to indicate statistical significance. No adjustment was made for multiple comparisons. SPSS software, version 22.0 (IBM), and R software, version 3.3.1 (R Project for Statistical Computing), were used for statistical analyses.