64 Chapter 4 INTRODUCTION Couples who have been trying to conceive for at least 12 months and whose fertility workup fails to reveal any abnormalities are considered to have unexplained subfertility (1, 2). In several countries intrauterine insemination (IUI) is used as first-line treatment in these couples, especially in combination with ovarian stimulation (OS), since IUI is less invasive and less costly than in vitro fertilisation (IVF) (3), despite the lack of evidence from randomized controlled trials (RCTs) regarding the effectiveness of IUI-OS (4). The two trials that compared IUI-OS to expectant management used different thresholds for the prognosis of natural conception as inclusion criteria (5, 6). In women with an intermediate prognosis to conceive naturally, i.e. an estimated probability between 30% and 40% to conceive within 12 months leading to live birth, IUI-OS was no more effective than expectant management (6). In women with a poor prognosis i.e. <30% over 12 months, IUI-OS did result in more live births than expectant management (5). In a previous study, we found that the different outcomes of these two trials might be explained by the difference in the prognosis of natural conception (7). In a Dutch cohort of 1896 couples, we found that couples with lower prognoses of natural conception had more benefit from IUI-OS in terms of a relative and absolute difference in the chance of conception compared to expectant management. Due to sample size limitations, it was difficult to identify a fixed threshold for prognoses at which point IUI-OS becomes effective. For a prognosis below 25% over one year, IUI-OS seemed effective, leading to higher chances of ongoing pregnancy in six months compared to expectant management. For higher prognosis than 40% over one year, IUI-OS was not effective and led to similar chances of ongoing pregnancy compared to expectant management. Between these thresholds, it was uncertain whether IUI-OS was effective. Replication of research findings is an essential part of medical research as many findings unfortunately cannot be reproduced in further studies (8). Addressing the same research question with different methodological approaches, such as trial and observational data, provides more evidence that a single result is not a chance finding (9, 10). More knowledge on who does and who does not benefit from IUI-OS can guide clinical practice and inform evidence-based shared decision making on when to start treatment. Because these thresholds hold great importance to patients, they should be based on solid evidence. The aim of this study was to replicate the previous result (i.e. that the benefit of IUI-OS compared to expectant management for couples with unexplained subfertility depends on the prognosis of natural conception) in an independent data source derived from an
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