In couples with unexplained infertility and female age between 39–43 years, we found that the average chance of success in terms of cumulative live birth rate over one year and one IVF cycle is similar between waiting and immediate IVF.
Recent studies in large cohorts of infertile couples with varying female age, support the notion that IVF increases the probability of an ongoing pregnancy as compared to expectant management. However, this benefit attenuates with increasing female age . More importantly, the clinical question is more often: can we delay treatment for a certain period of time without causing harm to the patient and perhaps have them conceive spontaneously? A recent retrospective study shows that in patients with reduced ovarian reserve a delay of no more than six months is not associated with worse IVF outcomes , but the chances of achieving pregnancy without IVF have not been investigated. So, our dilemma is still open.
Treatment strategies in women of advanced reproductive age are of major interest, given the current societal norm to start having children later on [26, 27]. However, whereas Scientific Societies agree on recommending a rapid diagnostic procedure starting from the age of 35 years, there is no shared consensus regarding the best treatment strategies when common causes of female and male infertility are ruled out [16, 28, 29]. Doubts are rising that IVF could overcome the age-related subfertility in women as the quality of oocytes cannot be changed in the IVF procedure and the responsiveness of the ovaries decreases over the years increasing the risk of poor results from ovarian stimulation [30–32].
Therefore, such patients remain a controversial challenge in clinical decision making.
Our study can be reassuring for patients in the age range considered, who are cared with expectant management of at least eleven months before IVF as we did not find evidence that waiting has a negative influence on their live birth rate. These findings may also reassure couples who have experienced or will experience delays in accessing IVF treatments due to the COVID-19 pandemic, according to similar results reported by other groups .
However, couples should be advised that beyond age 39, both strategies can lead to a high probability of not reaching a live birth, confirming the importance of reproductive counselling in younger women wishing to obtain motherhood at an older age.
This finding adds to the current debate about the optimal therapeutic approach to unexplained infertility, as couples that conceive after IVF might have otherwise conceived naturally [1, 12, 33]. Thirty-seven couples (13%) included in the waiting group obtained a live birth spontaneously during the observation time. This chance was similar as the chance obtained in the only available study with the same design as the present one , but including younger patients and only 6 months of observation. In a different study regarding the waiting list for IVF in the Netherlands, the cumulative live birth rate over one year was 14%, thus also similar to our result .
In both early studies  and more recent and larger ones  IVF has proven overall to be a better approach than expectant management, even in unexplained infertility. However, as these couples can still conceive naturally, the question is thus not if couples should be treated with IVF, but when. If treatment is started later and couples might conceive naturally, they are spared unnecessary, expensive and invasive treatment [1, 36, 37]. In the present study, only one third of the live births in the waiting group were obtained after IVF. The implications would be that a certain number of IVF treatments are currently carried out without a true indication, as the live births after IVF might have occurred after prolonged expectant management anyway, thereby exposing offspring of these couples to the potential risks related to ART treatments [38, 39].
Should these findings be confirmed in larger series of patients, the protocol for treating unexplained infertility in women of older age should be reconsidered. Waiting before treatment or selecting those women who are expected to benefit most from IVF would save couples from unnecessary invasive treatments, while at the same time optimizing the allocation of economic resources.
The major strength in our study is that patients from both groups were handled by the same medical and embryologist team, following identical diagnostic and therapeutic protocols. Furthermore, in Italy the option to wait or pay for immediate access to IVF constitutes a condition that cannot be easily carried out in a prospective randomized controlled trial (RCT). Even if our study is limited by its retrospective design, RCTs on unexplained infertility that include ‘no treatment’ i.e. expectant management are lacking as clinicians might be reluctant to include such an arm. Couples may perceive further expectant management as a waste of time and are unlikely to be volunteer in a study in which they might be allocated to expectant management whereas they will receive IVF if they refuse to enter the study . Because of this lack of evidence from RCTs, most studies published so far compared different treatment arms or separate observational databases [15, 41, 42].
However, the major limitation to our methodological approach pertains to the potential selection bias associated with choosing either strategy. Although the ovarian reserve of our groups was similar (see AFC and AMH in Table 1), the study groups differed in a few baseline characteristics, which are known to be related to the chances of pregnancy, namely the prevalence of primary/secondary infertility, a history of previous miscarriage, and previous IUI/IVF. By using inverse probability weighting , these confounding variables were reasonably accounted for as shown in the Table 2 after weighting.
Couples having multiple IVF cycles in the paid group might have led to follow up timelines that are not strictly comparable. However, most of the couples in the immediate group who received multiple IVF cycles were still ‘at risk of natural conception’ for most of the year. This is likely considering that the majority of couples who received multiple cycles in the immediate group did not conceive after their first IVF cycle and remained free for several months between cycles for a potential spontaneous conception. We thus think our primary analysis remains realistic. Our sensitivity analysis on this subject showed an estimated (unadjusted) proportion of live birth of 20.8% instead of 19.5% that did not lead to different conclusions. Thus, we argue that this issue might not have a large influence on results given our study design.