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Medically assisted reproduction in the context of time
Scholten, I.
Publication date
2015
Document Version
Final published version
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Citation for published version (APA):
Scholten, I. (2015). Medically assisted reproduction in the context of time.
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General discussion and
implications for future
research
102 Chapter 8
In this thesis, we focused on medically assisted reproduction in the context of time, accounting for different time frames. In succession, subfertile couples can enter a pre-treatment phase, a treatment phase and a post-treatment phase. Time is an important modality in reproductive medicine, but seems to be an underexposed topic. The passage of time will cause a selection in couples trying for a baby. Over time, couples get pregnant and the group will weed out. The group of couples entering a next phase is a selection of the initial group. Superfertile couples have already conceived and the prognosis of the group left is worse than the initial prognosis of the whole group (1). This mechanism of selection should be kept in mind when deciding if and when to treat subfertile couples. In a cohort of couples starting to conceive, there will always be couples not able to conceive naturally, despite a completely normal fertility-work-up (2). Over time, it will become clear to which group couples belong: the fertile group, the less fertile group or the infertile group. However, if there is a benefit of treatment in some couples, using the passing of time to tell us who to treat means lost time to those couples and may lead to definitive sterility. Proper identification of couples in need of treatment is thus necessary to prevent both over- but perhaps more importantly, undertreatment. Although leaders in the field of reproductive medicine emphasize the importance of preventing overtreatment (3), not much attention has been paid to preventing undertreatment, e.g. starting treatment too late or not starting treatment at all.
Another underexposed topic is the final size of the family. In numerous studies on treatments in reproductive medicine, the ultimate goal of subfertile couples is considered to be parenting a healthy child. However, it is plausible that couples with a wish for a child aim to create a family, therewith aiming to parent more than one healthy child. Although the long term chance of having a child is considered to be quite good for newly referred subfertile couples (4), little evidence is available on the long term chances for subfertile couples to have more than one child. Two studies established that subfertility is associated with reduced odds of having a larger family and in one of these studies it was confirmed that the longer the time to first pregnancy, the lower the odds on having a larger family (5,6).
Currently, in the Netherlands we calculate the prognosis on natural conception for couples with unexplained subfertility after fertility work up. Depending on this prognosis, treatment or expectant management for six to twelve months is advised (7–9). Yet, most couples not conceiving after this period of expectant management return to the clinic asking for the next step. Up to now, evidence lacks on the best advice for these couples. Just re-using the model of Hunault to calculate the couples’ prognosis is not appropriate, as it will overestimate chances due to selection of couples. In this thesis we presented a dynamic prediction model for natural conception (chapter 2). This newly developed model accounts for the principle of selection over time when calculating couples’ chances. The clinician will be able to predict a couples’ chances at different points in time, therewith allowing a
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prediction after an initial period of expectant management to decide again whether treatment adds value or not. The currently presented model incorporates data from a single imputation, but the work is in progress with a multiple imputed set to make the results more robust. Although external validation of this model is necessary before it can be implemented, it is a promising tool that allows repeated measurements.
If, after a period of expectant management, a couple has not conceived, treatment might be indicated. The quintessence of medically assisted reproduction is that multiple cycles of treatment are applied to hopefully increase pregnancy chances. Yet, we found that the majority of randomized clinical trials on medically assisted reproduction only report on a single cycle of treatment (chapter 3). Not every research question needs multiple cycles to be answered and for those explanatory trials single cycle reporting can be sufficient. Yet, in estimating the effectiveness of a treatment, clinical practice should be mimicked and pragmatic trials should preferably report on multiple cycles. The clinical significance of the trials on medically assisted reproduction is therefore limited and we should implement the results of such trials with caution.
Even if multiple cycles are reported, following couples for an even longer amount of time might give additional information on the effectiveness of a treatment. In this thesis, we studied three different cohorts of couples for three years, focusing on cumulative pregnancy rates. In the first study, couples with poor prognosis who started treatment with intra-uterine insemination (IUI) were compared to couples with poor prognosis who voluntarily stopped treatment after a maximum of two cycles of treatment (chapter 4).We chose the design of a retrospective matched cohort study since the current practice is to offer treatment to these couples and therewith, a prospective trial with expectant management as an intentional treatment arm was until recently not an option. Although this design leads to a cohort representing only a selection of the couples that usually visit our clinics, this cohort might have an even poorer prognosis. Therewith an overestimation of both treatment effect or effect of expectant management is excluded. The study shows that after three years, the cumulative pregnancy rates between the two groups do not differ. So, looking at the long term outcome instead of the per cycle outcome, intrauterine insemination might not be useful in these couples, despite its widespread and common practice.
In the second study we followed couples with isolated cervical factor initially randomized between immediate IUI and expectant management (chapter 5). A Cochrane review states that there is no evidence that treatment with IUI is effective over no treatment in couples with cervical factor (10). Six trials were included, of which five were judged to be of poor quality. A convincing conclusion on the effectiveness of IUI couples with cervical factor was therefore not possible. We performed follow up of the sixth, well designed, trial. After three years, in which couples received treatment according
104 Chapter 8
to local protocol, the cumulative pregnancy rates in both groups were comparable. We conclude that couples with an isolated cervical factor can be considered unexplained subfertile, as treatment strategies are the same for these couples: initial expectant management in good prognosis, followed by IUI if necessary (8). Identification of cervical factor does not add in these couples.
The third study presented the follow up of couples initially randomized between IUI with immediate mobilisation and IUI with fifteen minutes of immobilisation (chapter 6). After three years, the cumulative pregnancy rate in couples immobilizing after IUI was significantly higher. Although there was no detailed information about the mobilization status of the couples after the initial trial period, there is no valid reason for withholding women from immobilizing after IUI, since the significant effect of the first three cycles of immobilisation remains over the years.
As live does not end after finishing a trajectory of fertility treatments, pregnancy chances remain, even after unsuccessful treatment. The three year outcomes we present show cumulative pregnancy rates that gave additional information on the effectiveness of the treatment investigated. Knowledge on overall chances, including pre-treatment phase, treatment phase and post-treatment phase, can be used to proper counsel couples at the start of their reproductive career. As Proust pointed out, the essence of time is that we lose it. We do better to acknowledge this and incorporate time in our decisions on medically assisted reproduction in subfertile couples.
IMPLICATIONS FOR FUTURE RESEARCH
A next step in predicting pregnancy chances would be to develop a dynamic model that incorporates both chances on treatment-dependent and treatment independent pregnancies (11). Such a model can predict whether a couple will benefit from treatment or might have the same chances when awaiting natural conception. To develop this model large cohorts are necessary. Careful designed digital patient files may lead to automatic created prospective cohorts allowing follow up of all couples that enter our fertility clinics. We should be aware that before entering our clinic, couples already had part of their ‘pre-treatment phase’ and incorporate that information in the cohort. Furthermore, the cohort should not stop at the moment treatment is discontinued. To gain insight on pregnancy chances in the post-treatment phase, couples should be followed as long as possible, for example with yearly questionnaires.
To determine whether treatment is effective at all, we still rely on randomized clinical trials. Time has come to perform trials comparing IUI and IVF to expectant management in couples with unexplained subfertility and poor prognosis. Both IUI and IVF should, in separate trials, be compared
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to a period of expectant management. In the Dutch research infrastructure, where almost all clinics for reproductive medicine collaborate in research, the effectuation of such trials should be possible. Indeed, recently a trial has been funded in which IUI will be compared to expectant management for six months in couples with unexplained subfertility and poor prognosis. An important condition for success is that expectant management becomes the standard treatment for these couples, and that only when included in the trial, they receive treatment. The problem always lurking at the background is that many clinicians are money driven and –thus- prone to intervene. Yet, it is our moral obligation to know the effectiveness of treatment in these couples before we expose them to –possibly- unnecessary risks or- inadvertently- deny them an effective intervention.
106 Chapter 8 REFERENCES
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3. Kamphuis E, van Wely M, Repping S, van der Veen F, de Groot C, Hompes P, et al. Should the individual preterm birth risk be incorporated into the embryo transfer policy in in vitro fertilisation? A decision analysis. BJOG. 2014 Jul;
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10. Helmerhorst F, van Vliet H, Gornas T, Finken M, Grimes D. Intra–uterine insemination versus timed intercourse or expectant management for cervical hostility in subfertile couples. Cochrane Database Syst Rev. 2005;(4). 11. McLernon DJ, Te Velde ER, Steyerberg EW, Mol BWJ, Bhattacharya S. Clinical prediction models to inform
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