32 Chapter 2 from the primary analysis. In addition, it can be argued that, in the first year after HSG, unobserved heterogeneity might not yet play a role and that the observed decrease in hazard ratio can be explained by either one of the former mechanisms. In terms of strengths and limitations, this secondary analysis was performed using data from a well-designed multicentre RCT with a long follow-up period of 3–5 years. Using an objective outcome measure, ongoing pregnancy, the risk of bias was minimal. Only women with unexplained or mild male infertility were included; they were below 39 years of age, did not have known endocrinological disorders and had a low risk of tubal pathology based on their medical history. Therefore, it is questionable whether the findings are generalizable to infertile women who do not share these features. Additionally, it should be noted that the main outcome in this study was ongoing pregnancy, whereas in clinical practice live birth is the desired outcome. However, there are several reasons to justify the use of ongoing pregnancy as a proxy for live birth in fertility research (19). The finding that the fertility-enhancing effect of oil-based contrast lasts for a substantial amount of time promotes the hypothesis that the mechanism of action lies in the Fallopian tubes, implying that tubal flushing during HSG dislodges debris, mucus plugs or small adhesions in the proximal parts of the Fallopian tubes, thereby resolving an ‘unexplained’ fertility factor (8, 20). Our findings are less consistent with the other suggested mechanisms, as it was postulated here that an effect in the endometrium or alteration in the immune response in the peritoneum would be a temporary effect. Making the assumption that the HSG using oil-based contrast does dislodge debris, mucus, etc. from the Fallopian tubes, this would mean that they are essentially ‘cured’, which here means that their tubes are once more fully operational and they are back to their ‘normal’ state of fertility. However, the ‘normal’ fertility potential varies considerably between women (21, 22). This inherent difference between women in terms of their chance of conception might explain why not all women in this subgroup conceive within the first couple of cycles after being ‘cured’: some of them with lower potentials take much longer, for example more than 1 year, to conceive. Additionally, it has been postulated that oil could emulsify debris in Fallopian tubes, facilitating the removal of debris more efficiently (23). Furthermore, the two contrast media have many differences in chemical and physical characteristics, for example oilbased contrast (Lipiodol Ultra-Fluid®, Guerbet, France) has a lower viscosity. The oilbased contrast also contains a higher iodine concentration than the water-based contrast used here (Telebrix Hystero®, Guerbet, France). There is currently very limited evidence regarding the impact of these differences, and future studies are needed.
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