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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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10 Chapter 1
Subfertility, defined as failure to conceive after 12 months of unprotected intercourse, is a major health problem that affects up to 1 in 10 couples (1,2). The inability to conceive carries a high psychological burden and couples may exceed their own physical and mental boundaries to achieve the desired pregnancy. Subfertility manifests itself as an acute and unanticipated life crisis. It creates overwhelming stress and tests coping strategies as it is unanticipated, may be unexplained and lasts for an undetermined length of time. When subfertility becomes infertility, a chronic life crisis may result (3).
The introduction of ovulation induction, intrauterine insemination with or without ovarian stimulation, and in vitro fertilization with or without assisted fertilization, has provided millions of couples with hope.
Over the past decades, these treatments have been applied in ever increasing numbers (4,5). Although millions of babies have been born as a result of these treatments, their extended use is increasingly questioned (6). To prevent overtreatment, we here re-consider medically assisted reproduction in the context of time.
Time is by definition the most important commodity we lose in life but in subfertile couples it is what it is all about. Subfertile couples may experience three different timeframes. First, there is a period of tapping the natural conception potential. Second, if not successful, a period of fertility treatment cycles may follow and finally, if treatment has failed, a third period follows in which there are still pregnancy chances left, although diminished. Couples are then forced to balance between hoping for a miracle to happen and preparing on a further live without a child. In this introduction, these three timeframes and their according pregnancy chances are discussed.
Pre-treatment phase
A woman is considered to be of ‘reproductive age’ from 15 years of age until she is 45. Increasing age has a negative influence on fecundity as the quality of oocytes and therewith pregnancy chances decline over time (7). Yet, most women generally use the first part of their 30 reproductive years focusing on nót becoming pregnant and it is only after stopping contraceptives that their truly reproductive years start.
Every month an ovulation takes place and thus, there is a chance for conception. As fertility is not absolute, it may take several attempts to come to a pregnancy (8). After the decision ‘to try for a baby’, the majority of couples conceive within the first six months of unprotected intercourse (9). After one year, 80-90% of couples have conceived. Although the remaining couples now fit the definition of subfertility, natural conception still occurs in these couples. 50% of them will conceive in the next year, followed by another 14% in the third year of starting unprotected intercourse (10). Subfertility is
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therefore not synonymous with needing treatment. Tailored expectant management can be applied in couples with an intermediate or good prognosis for natural conception within the next year, reducing the burden, costs and risks associated with fertility treatment without compromising birth rates (11,12). Currently, couples with a chance on natural conception of 30% or more are considered to have a favorable prognosis and treatment is postponed (13). Truly infertile couples, those with double-sided tubal factor and severe male infertility, will not benefit from expectant management and can be selected through fertility work up (13). In the remaining couples, prediction models can be used to determine natural conception chances which then are the basis to decide on expectant management or medical assisted reproduction.
Treatment phase
If this first period of trying to use the natural fertility potential has failed, a second period has arrived in which Medically Assisted Reproduction (MAR) can be applied. The term medically assisted reproduction has recently been introduced, and is defined as reproduction brought about through ovulation induction, ovarian stimulation, ovulation triggering, intrauterine, intracervical, and intravaginal insemination and artificial reproductive techniques, consisting of In Vitro Fertilisation (IVF) and Intracytoplasmic Sperm Injection (ICSI) (2).
In the UK, the NICE guideline ‘fertility’ advises to start treatment with IVF after two years of unsuccessful unprotected intercourse (14). In the Netherlands, IUI is started as first line therapy if the predicted chance for natural conception is below 30%. Further treatment with three cycles of IVF is advised when six cycles of IUI have failed (13). The differences in these recommendations might be explained by a lack of evidence on the effectiveness of medically assisted reproduction in couples with unexplained subfertility.
In the past decades, several randomized clinical trials were performed to assess the effectiveness of IUI, all in different patient groups with different treatment protocols. The Cochrane review on this topic concludes that there is evidence that IUI with mild stimulation increases the live birth rate compared to IUI alone. Yet, a statement on the effectiveness of IUI compared to no intervention could not be given (15). One trial compared live birth rate after IVF to expectant management in couples with non tubal infertility, in which couples with unexplained subfertility formed only a minute subgroup (n=51) and was thus not designed and powered to find an answer on the effectiveness of IVF in these couples (16). A recently published trial compared IUI with mild stimulation to immediate IVF in couples with unexplained subfertility and a poor prognosis. Treatment with IVF was found not to be superior to treatment with IUI (17).
In view of the available evidence, the question – even in 2015- remains in whom to start medically assisted reproduction and when to start.
12 Chapter 1
Also in this second time period of treatment, one must realize that medically assisted reproduction is characterized by repeated treatment cycles. Just as for natural conception, in medically assisted reproduction cumulative pregnancy rates rise with additional cycles (9,18). One treatment cycle can therefore not be seen as independent and effectiveness can only be assessed when multiple cycles and -in some instances- even multiple treatments are reported (19). In this respect, the cumulative live birth over a given period of time instead of per cycle success has been proposed as the primary outcome of trials (20). It was already acknowledged years ago that randomization should be performed at the first cycle and the allocated treatment continued thereafter, since a per cycle analysis or a cross-over design may lead to overestimation of treatment success (21). In addition, multiple cycle follow up reflects how a treatment works in daily practice. Couples might switch treatments between cycles, natural conception can occur or couples can drop out of treatment (22). Single cycle analysis does not account for the above and thus estimates of effectiveness from the first treatment cycle are not representative for the further course of treatment. Extrapolating a single cycle analysis can lead to judging a treatment as more effective than it actually is, which can lead to overtreatment and unnecessary costs (21).
Post-treatment phase
After unsuccessful treatment, subfertile couples enter the next period , in which there is still some fertility potential left. Cohort studies show natural conception rates of 18-24% in couples in the years after finishing treatment (23,24), although this figure might be biased by couples becoming pregnant in between treatment cycles and therefore stopping treatment. This phenomenon of residual fertility potential after ending a randomized clinical trial is often overlooked in the assessment of effectiveness of interventions since the time horizon included in RCTs does usually not exceed six months and follow up after the trial has ended is rarely performed.
Nevertheless, in the end, despite all the effort, there will be couples who do not conceive. The effect of remaining childless reaches beyond a woman’s reproductive years. Twenty years after finishing unsuccessful fertility treatment, childlessness is still an important theme in the life of these women. The effects are on both a personal and on interpersonal and social levels. When leaving behind their fertile years, these women are still confronted with the child that is missing. While their peers are becoming grandparents, they move from childlessness to grandchildlessness (25).
BACKGROUND OF THE RESEARCH IN THIS THESIS
In this thesis, we focus on reproduction in the context of time. To do so, we divided time in three time frames: pre-treatment phase, treatment phase and post-treatment phase.
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The pre-treatment phase includes the time in which couples use their natural conception chances. The difficulty lies in determining the moment a couple should switch to the next phase. The Hunault model is nowadays used in the Netherlands to decide whether expectant management should be applied (13,26). This model is designed to be used once: after finishing fertility work-up. In clinical practice doctors are tempted to use it again after a period of expectant management to decide on further treatment. In doing so, they do not realize that the couples that are not pregnant after a period of expectant management are a selection of the initial group included after fertility work up. This selection has a poorer prognosis than the initial group, as time has elapsed without them conceiving, while the couples that left the group are now pregnant (8). Using the Hunault model again after a period of expectant management to decide on further treatment or not would overestimate their chances. The first aim of this thesis was to develop a model that can be used repeatedly in the same couple, using the patient characteristics that are also incorporated in the Hunault model.
In the treatment phase, multiple cycles of treatment are applied to hopefully increase pregnancy chances. At the start of this thesis, it was unclear if trials on medically assisted reproduction were designed to include several treatment cycles to assess the effectiveness of an intervention as practiced in real life. The second aim of this thesis was to assess whether trials on medically assisted reproduction report multiple cycles and which factors are associated with this.
In counselling couples on the effectiveness of a particular treatment, the pretreatment and post treatment phases are important as well. The moment a couple starts their primary treatment, a pre-treatment phase preceded this pre-treatment. Amongst others, it’s duration determines the prognosis of the couple when entering the treatment phase (11,26). After initial treatment, other treatments or a period without treatment may be given. Collecting all this information gives a more succinct and precise view on the effectiveness of a treatment in real life, where we treat our patients over some cycles, where couples drop out of treatment, and where couples decide to pause for a while. The recently published NICE guideline on fertility advices not to routinely offer IUI to subfertile couples, but to proceed immediately to treatment with in vitro fertilization (IVF) after a period of expectant management. The authors base their recommendation for this strategy on the lack of evidence for the effectiveness of IUI in couples with unexplained subfertility and mild male subfertility (14). However, the evidence underpinning this recommendation is very scarce indeed. In view of this, the third aim of this thesis was to compare the three year ongoing pregnancy rates after IUI to no treatment in a cohort of couples with unexplained subfertility. With this design, the overall effectiveness of starting treatment with IUI is tested, rather than the effectiveness in a few months. The fourth aim of this thesis was to perform a three year follow up of a previous trial comparing ongoing pregnancy rate of couples randomized between immediate IUI or expectant management
14 Chapter 1
in couples with an isolated cervical factor. This trial found a relative risk of 1.6 (95% CI 0.91-2.6), which showed no evidence that immediate IUI is successful in couples with isolated cervical factor (27). Yet, the point estimate points to a possible beneficial effect. The three year outcome might provide additional information to decide whether immediate IUI should be advised in couples with isolated cervical factor.
The fifth aim of this thesis was to perform a three year follow up of a previous trial comparing ongoing pregnancy rates after immediate mobilisation subsequent to IUI with fifteen minutes of immobilisation subsequent to IUI. This initial study found a relative risk of 1.5 (95% CI 1.1 -2.2) favouring immobilisation (28).
One of the drawbacks of MAR is that it bears the risk of multiple pregnancies, which are known to be high risk pregnancies (29). In ART, this risk can be diminished by applying Single Embryo Transfer (SET) (30,31). Yet, a high uptake of ART, even when applying SET, might have consequences on the outcome of the offspring (32–35). The sixth aim of these thesis was to untangle the effects of both uptake of SET and utilization of ART on the amount of multiple pregnancies as this emphasizes the importance of applying ART to the right couple at the proper time.
1
OUTLINE OF THIS THESIS
Chapter 2 presents a new prediction model to predict natural conception. A previously conducted
cohort study including almost 5000 couples after fertility work-up was used to create a model that can be repeatedly used in the same couples.
Chapter 3 provides a review of a systematic collected sample of 223 RCTs on medically assisted
reproduction. We assessed whether these trials report on multiple cycles and which factors are associated with this.
Chapter 4 presents the results of a retrospective matched cohort study in which we compared
treatment with IUI versus no treatment in 72 couples with poor prognosis on natural conception. We report on the three year outcome of these couples.
Chapter 5 reports on the three year outcome of a previously published RCT comparing immediate
treatment with IUI to six months expectant management in 99 couples with isolated cervical factor subfertility.
Chapter 6 reports on the three year outcome of a previously published RCT comparing immediate
mobilisation to fifteen minute of immobilisation after IUI in 391 couples who had received up to three cycles.
Chapter 7 addresses the problem of multiple pregnancy after ART from a broader point of view.
We incorporated population statistics with ART statistics and assessed the contribution of ART multiple pregnancies on all multiple pregnancies in seven countries with differences in utilisation of ART and usage of single embryo transfer.
Chapter 8 provides discussion on the findings presented in this thesis, with recommendations for
further research.
16 Chapter 1
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