In many clinics, hysterosalpingography (HSG) currently is the first choice for diagnosis of tubal pathology. An iodine-containing contrast is used, of which there are two types: oil-based and water-based contrast media. In Dutch clinics there is a variation in the type of contrast used. Considerations on the choice of contrast may include diagnostic properties, influence on the chance of pregnancy, risks (including risk of infection, (oil) embolism, miscarriage, ectopic pregnancy), patient preference, costs (effectiveness). Patients have picked up that there is research that shows oil-based contrast could increase the chance of pregnancy, hence this is often their preferred choice of contrast. With this initial question we focus on this primary outcome measure as well as other advantages and disadvantages.

Population: Women of infertile couples (at low risk of tubal pathology) undergoing hysterosalpingography

Intervention: OSCM

Comparator: WSCM

_{1. Risk of Bias: serious. Due to many areas of the Risk of bias based on Cochrane 'Risk of bias' assessment tool being labeled as unclear; Imprecision: serious. Due to overlap of the upper limit of the 95% confidence interval with the minimal clinically important difference;}

_{2. Risk of Bias: serious. Inadequate concealment of allocation during randomization process, resulting in bias, Inadequate blinding/lack of blinding of participants and personnel, potentially causing bias, Selective outcome reporting; Imprecision: serious. Due to the optimal information size which was not achieved;}

_{3. Risk of Bias: serious. Inadequate concealment of allocation during randomization process, resulting in bias, Inadequate blinding/lack of blinding of participants and personnel, potentially causing bias, Selective outcome reporting; Imprecision: serious. Due to the optimal information size which was not achieved;}

_{4. Risk of Bias: serious. Inadequate concealment of allocation during randomization process, resulting in bias, Inadequate blinding/lack of blinding of participants and personnel, potentially causing bias, Selective outcome reporting; Imprecision: serious. Due to overlap of the upper limit of the 95% confidence interval with the minimal clinically important difference;} 

_{5. Risk of bias: serious. Retrospective data analysis introducing possible ascertainment and selection bias. Imprecision: serious. Due to the optimal information size which was not achieved.}

_{6. Risk of bias: serious. Retrospective data analysis introducing possible ascertainment and selection bias. Imprecision: serious. Due to the optimal information size which was not achieved.}

_{7. Inconsistency: serious. The magnitude of statistical heterogeneity was high, with I^2: 80%.; Imprecision: serious. Due to overlap of the upper limit of the 95% confidence interval with the minimal clinically important difference;}

_{8. Risk of bias: serious. Retrospective data analysis introducing possible ascertainment and selection bias. Imprecision: serious. Due to the optimal information size which was not achieved.}

_{9. Risk of bias: serious. Frequent loss to follow-up. Imprecision: very serious. No events and low number of participants.}

_{10. Imprecision: very serious. Due to overlap of both the lower and upper limit of the 95% confidence interval with the minimal clinically important difference.}

_{11. Risk of bias: serious. Retrospective data analysis introducing possible ascertainment and selection bias. Imprecision: serious. Due to overlap of the lower limit of the 95% confidence interval with the minimal clinically important difference;} 

_{12. Imprecision: very serious. Due to overlap of both the lower and upper limit of the 95% confidence interval with the minimal clinically important difference.}

_{13. Risk of bias: serious. Retrospective data analysis introducing possible ascertainment and selection bias. Imprecision: very serious. Due to overlap of both the lower and upper limit of the 95% confidence interval with the minimal clinically important difference;} 

_{14. Inconsistency: serious. Due to not being able to pool the studies because of differences in how the outcome was assessed. Imprecision: serious. Due to the optimal information size which was not achieved.}

_{15. Imprecision: very serious. Due to overlap of both the lower and upper limit of the 95% confidence interval with the minimal clinically important difference.}

_{16. Risk of bias: serious. Inadequate concealment of allocation during randomization process, resulting in bias, Inadequate blinding/lack of blinding of participants and personnel, potentially causing bias, Selective outcome reporting; Imprecision: very serious. No events and low number of participants.}

_{17. Risk of Bias: serious. Due to many areas of the Risk of bias based on Cochrane 'Risk of bias' assessment tool being labeled as unclear; Imprecision: serious. Low number of events.}

_{18. Risk of Bias: serious. Inadequate concealment of allocation during randomization process, resulting in bias, Inadequate blinding/lack of blinding of participants and personnel, potentially causing bias, Selective outcome reporting; Imprecision: very serious. Due to overlap of both the lower and upper limit of the 95% confidence interval with the minimal clinically important difference;} 

_{19. Risk of Bias: serious. Due to concerns about the calculation of the costs and generalizability to the Dutch situation. Imprecision: serious. Due to the optimal information size which was not achieved.}

_{20. Risk of bias: serious. Retrospective data analysis introducing possible ascertainment and selection bias. Imprecision: serious. Due to the optimal information size which was not achieved.}

_{21. Risk of Bias: serious. Due to concerns about the calculation of the costs and generalizability to the Dutch situation. Imprecision: serious. Due to the optimal information size which was not achieved.}

_{22. Risk of bias: serious. Retrospective data analysis introducing possible ascertainment and selection bias. Imprecision: serious. Due to the optimal information size which was not achieved.}

Table 1. Characteristics of included studies

Results

1. Probability of spontaneous pregnancy (critical outcome)

1.1 Ongoing pregnancy (rate)

Ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, from the first day of the last menstrual cycle of pregnancy within 6 months after HSG, was reported by Dryer (2017) and Zhang (2022).

Dreyer (2017) found an ongoing pregnancy rate of 220/554 (39.7%) in the oil-based group and 161/554 (29.1) in the water-based group with a Rate Ratio of 1.37 (P value <0.001).

Zhang (2022) found ongoing pregnancy was confirmed in the oil-based group in 136/473 (29.1%) women, while an ongoing pregnancy was confirmed in 96/479 (20.1%) women in the water-based group (RR 1.44, 95% CI 1.14 to 1.80). This difference was considered clinically relevant in favor of oil-based contrast.

Van Welie (2020) reported ongoing pregnancies at a follow-up of 3 years after HSG treatment. In the oil-based group, 426/550 (77%) women had a confirmed ongoing pregnancy, while an ongoing pregnancy was confirmed for 394/557 (71%) women in the water-based group (RR 1.09, 95% CI 1.02 to 1.17). This difference was considered not clinically relevant.

Van Rijswijk (2020) reported ongoing pregnancies at a follow-up of 5 years after HSG treatment. In the oil-based group, 444/555 (80.0%) women had a confirmed ongoing pregnancy, while an ongoing pregnancy was confirmed for 419/559 (75.0%) women in the water-based group (RR 1.07, 95% CI 1.00 to 1.14). This difference was considered not clinically relevant.

1.2. Clinical pregnancy (rate)

Clinical pregnancy was reported in Alper (1986), De Boer (1988), Dreyer (2017), Lindequist (1994), Rasmussen (1991), Spring (2000) and Zhang (2022). A clinical pregnancy was confirmed in 594/1667 (35.6%) of the women in the oil-based group, and in 500/1883 (26.6%) in the water-based group (RR 1.30, 95% CI 1.15 to 1.48). This difference was considered clinically relevant in favor of oil-based contrast (Figure 1).

Figure 1. The effect of oil-based contrast versus water-based contrast on clinical pregnancy

_{OSCM: oil-soluble contrast media, WSCM: water-soluble contrast media, CI: Confidence Interval}

_{Source: Wang (2020), Zhang (2022)}

2. Diagnostic value (important outcome)

The diagnostic value was reported by Zhang (2022) and was– in accordance with the European guidelines on quality criteria – based on the following five criteria: 

1. uterus opacification or uterine outline;
2. fallopian tube outline;
3. fimbrial rugae;
4. fallopian tube spillage;
5. peritoneal distribution.

A total image quality score was calculated from the five criteria, ranging from 0 to 15 (with higher scores indicating higher image quality).

The diagnostic quality was higher in the oil-based group (11.6 ± 3.4) in comparison with the water-based group (9.5 ± 3.1, p<0.001) (MD 2.10, 95% CI 1.69 to 2.51).

3. Long-term effects on fertility (important outcome)

3.1. Time to pregnancy

The time to pregnancy was reported by Zhang (2022). Time to pregnancy was shorter in the oil-based group (41.7 ± 18.5 weeks) than in the water-based group (46.1 ± 16.8 weeks) (MD -4.40, 95% CI -6.65 to -2.15). This difference was considered not clinically relevant.

3.2. Live birth rate

Live births are reported by Dreyer (2017), Rasmussen (1991), Spring (2000) and Zhang (2022). In the number of live births as reported by Zhang (2022), 4 twin-births are included in each group. A live birth occurred in 470/1401 (33.5%) of the women in the oil-based group, and in 379/1601 (23.7%) in the water-based group (RR 1.41, 95% CI 1.06 to 1.86). This difference was considered clinically relevant in favor of oil-based contrast (Figure 2).

Figure 2. The effect of oil-based contrast versus water-based contrast on live birth

_{OSCM: oil-soluble contrast media, WSCM: water-soluble contrast media, CI: Confidence Interval}

_{Source: Wang (2020), Zhang (2022)}

Van Rijswijk (2020) reported live births at a follow-up of 5 years after HSG treatment. In the oil-based group, 415/555 (74.8%) women had a live birth, while 376/559 (67.3%) women in the water-based group had a live birth (RR 1.11, 95% CI 1.03 to 1.20). This difference was considered not clinically relevant.

4. Effect on neonate (important outcome)

4.1. Thyroid function

Van Welie 2020a reported that none of the neonates conceived after HSG with oil- (n=76) or water-based (n=64) contrast had a positive screening result for congenital hypothyroidism. T4 concentrations and T4 standard deviation scores were comparable between the two groups. None of the children were currently on thyroid hormone supplementation.           

5. Risk of miscarriage (important outcome)

Miscarriage per woman was reported in Dreyer (2017), Spring (2000) and Zhang (2022). In the oil-based group, 64/1303 (4.9%) women reported a miscarriage, while 63/1301 (4.8%) women in the water-based group reported a miscarriage (RR 1.06, 95% CI 0.61 to 1.86). This difference was considered not clinically relevant (Figure 3).

Figure 3. The effect of oil-based contrast versus water-based contrast on miscarriage

_{OSCM: oil-soluble contrast media, WSCM: water-soluble contrast media, CI: Confidence Interval}

_{Source: Wang (2020), Zhang (2022)}

Van Rijswijk (2020) reported miscarriages (i.e., the amount of women with at least one miscarriage) at a follow-up of 5 years after HSG treatment. In the oil-based group, 68/555 (12.3%) women had at least one miscarriage, while 82/559 (14.7%) women in the water-based group had at least one miscarriage (RR 0.84, 95% CI 0.62 to 1.13). This difference was considered not clinically relevant.

6. Ectopic pregnancy (important outcome)

Ectopic pregnancy was reported in Dreyer (2017) and Spring (2000). In the oil-based group, 4/830 (0.5%) ectopic pregnancies were reported, while this was 6/822 (0.7%) in the water-based group (RR 0.66, 95% CI 0.18 to 2.36).      

Figure 4. The effect of oil-based contrast versus water-based contrast on ectopic pregnancy

_{OSCM: oil-soluble contrast media, WSCM: water-soluble contrast media, CI: Confidence Interval}

_{Source: Wang (2020)}

Van Rijswijk (2020) reported ectopic pregnancies at a follow-up of 5 years after HSG treatment. In the oil-based group, 7/555 (1.3%) ectopic pregnancies were reported, while this was 11/559 (2.0%) in the water-based group (RR 0.64, 95% CI 0.25 to 1.64). This difference was considered clinically relevant in favor of oil-based contrast. However, there was no statistical difference (P value .35)

7. Side effects (important outcome)

7.1. Pain

Pain was reported by Alper (1986), Dreyer (2017) and Zhang (2022).

Alper (1986) reported pain on a scale from 0 to 5 (with 0 corresponding to no pain and 5 represents severe pain). The mean pain score for women in the oil-based group was 2.9 ± 0.9, while the mean pain score for women in the water-based group was 3.2 ± 1.6 (MD -0.30, 95% CI -0.78 to 0.18). This difference was considered not clinically relevant.

Dreyer (2017) reported median VAS-scores for pain (on a 0-10 cm scale). The median pain score was 4.8 (IQR: 3.0 to 6.4) in the oil-based group, and 5.0 (IQR 3.0 to 6.7] in the water-based group (p=0.28). The article does not mention whether analgesics were administered.

Zhang (2022) reported mean VAS-scores for pain (on a 0-10 cm scale, with higher scores meaning more pain). The mean pain score was 1.8 ±1.5 in the oil-based group, and 2.3 ± 1.6 in the water-based group (MD -0.50, 95% CI -0.70 to -0.30). The article does not mention whether analgesics were administered.

7.2. Infection

Infections were reported in Lindequist (1994) and Rasmussen (1991). In the oil-based group, 1/226 (0.4%) infections were reported, while 16/436 (3.8%) infections were reported in the water-based group (RR 0.23, 95% CI 0.04 to 1.28).

Figure 5. The effect of oil-based contrast versus water-based contrast on infection

_{OSCM: oil-soluble contrast media, WSCM: water-soluble contrast media, CI: Confidence Interval}

_{Source: Wang (2020)}

7.3. Allergic reaction

Zhang (2022) reported that no allergic reactions occurred during or after HSG for women who received either OSCM or WSCM.

7.4. Oil embolism

Not reported.

7.5. Intravasation

Intravasation was reported by Alper (1986), Dreyer (2017), Lindequist (1994), Rasmussen (1991) and Zhang (2022). Intravasation occurred in 35/1332 women (2.6%) in the oil-based group and in 16/1562 women (1.0%) in the water-based group (RR 3.19, 95% CI 1.52 to 6.71). This difference was considered clinically relevant in favor of water-based contrast (Figure 6).

Figure 6. The effect of oil-based contrast versus water-based contrast on intravasation

_{OSCM: oil-soluble contrast media, WSCM: water-soluble contrast media, CI: Confidence Interval}

_{Source: Wang (2020), Zhang (2022)}

A systematic review of the literature was performed to answer the following question(s):

Is there a difference in the occurrence of spontaneous pregnancies after performing an HSG with a water-based and oil-based contrast media?

Relevant outcome measures

The guideline panel considered probability of spontaneous pregnancy as a critical outcome measure for decision making; and diagnostic value, long-term effect on fertility, effect on neonate, risk of miscarriage, ectopic pregnancy, side effects, costs as important outcome measures for decision making.

The guideline panel defined the outcome measures as follows:

• Probability of spontaneous pregnancy: ongoing pregnancy (rate) and clinical pregnancy (rate)
• Long-term effects on fertility: time to pregnancy, live birth rate
• Effect on neonate: thyroid function
• Side effects: pain, infection, allergic reaction, oil embolism, intravasation

For the other outcome measures, the guideline panel did not define the outcome measures a priori but used the definitions used in the studies.

The guideline panel defined 25% difference (RR <0.8 to >1.25) for dichotomous and 0.5 SD for continuous outcomes as a minimal clinically (patient) important difference.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2010 until the 19^th of April 2024. The detailed search strategy is listed under the tab ‘Literature search strategy’. The systematic literature search resulted in 48 hits. Studies were selected based on the following criteria:

• The study population had to meet the criteria as defined in the PICO
• The intervention had to meet the criteria as defined in the PICO
• Research type: systematic review or randomized-controlled trials
• Articles written in English or Dutch

Initially, seventeen studies were selected based on title and abstract screening. After reading the full text, ten studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and seven studies were included. The systematic review of Wang 2020 defined a broader PICO than the PICO defined for this module (it also included studies about oil-based contrast media or water-based contrast media versus no treatment or a combination of oil-based and water-based contrast media versus water-based contrast media). Therefore, six randomized controlled trials included in the review were selected for the literature analysis (Alper, 1986; De Boer, 1988; Dreyer, 2017; Lindequist, 1994; Rasmussen, 1991; Spring, 2000).