Hum. Reprod. Advance Access originally published online on June 24, 2004
Human Reproduction 2004 19(9):1936-1938; doi:10.1093/humrep/deh368
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What is the most relevant standard of success in assisted reproduction?
The next step to improving outcomes of IVF: consider the whole treatment
1 Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam and 2 Department of Reproductive Medicine, University Medical Centre, Utrecht, The Netherlands
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Erasmus Medical Center, Dr Molewaterplein 40, 3015GD Rotterdam, The Netherlands. Email: e.heijnen{at}azu.nl
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Abstract |
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 Top Abstract IntroductionFocusing on the whole...Healthy babyThe integrated pictureReferences |
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Changing the way in which successful IVF treatment is defined offers a tool to improve efficacy while reducing costs and complications of treatment. Crucial to this paradigm shift is the move away from considering outcomes in terms of the single IVF cycle, and towards the started IVF treatment as a whole. We propose the most informative end-point of success in IVF to be the term singleton birth rate per started IVF treatment (or per given time period) in the overall context of patient discomfort, complications and costs. These end-points are important not only for patients, but also for clinicians, health economists and policy makers. Such an approach would encourage the development of patient-friendly and cheaper stimulation protocols with less stress, discomfort and side effects. The combination of mild ovarian stimulation with single embryo transfer may provide the same overall pregnancy rate per total IVF treatment, achieved in the same amount of time for similar direct costs, but with reduced patient stress and discomfort, and the near complete elimination of multiple pregnancies. This would offer major health and indirect cost benefits. If IVF success rates were to be expressed in terms of delivery of a term single baby per IVF treatment (or in a given treatment period), the introduction of single embryo transfer on a large scale would be facilitated.
Key words: health economics/IVF/live birth rate/singleton birth/treatment outcome
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Introduction |
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TopAbstractIntroductionFocusing on the whole...Healthy babyThe integrated pictureReferences |
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A recent debate article in Human Reproduction proposed that ‘the singleton, term gestation, live birth rate per cycle initiated should be considered the best endpoint for assisted reproduction technology (ART)’ (Min et al., 2004
). It was suggested that this outcome definition reflects precisely what a subfertile couple wishes to know when they embark an ART treatment. In our view, IVF outcomes should be defined in broader terms that reflect the interests both of the couple and those providing health care. A couple embarking on IVF are presently focused on the traditional numerators and denominators of outcome, as shown in Table I. The goal of their treatment is the chance of having a healthy baby after completing an IVF treatment consisting of a series of IVF cycles and subsequent replacement of frozen embryos. This should be weighed against the associated discomfort, complications and costs that they will encounter along the way. The outcome of a single cycle is of interest, but only as part of the whole treatment. The information that patients, providers and policy makers require is the chance of delivering a healthy baby per treatment started (Fauser et al., 2002; Vail and Gardener, 2003) or per defined treatment period. Should these criteria become the means by which IVF outcomes are measured, a number of beneficial consequences would ensue.
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Focusing on the whole treatment: consequences for clinical practice |
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TopAbstractIntroductionFocusing on the whole...Healthy babyThe integrated pictureReferences |
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Patient friendly stimulation protocols
Around 50% of those who initiate IVF will not conceive (Stolwijk et al., 2000
). This is partly due to the high drop-out rates after an unsuccessful IVF cycle. European data reveal that up to 25% of patients who undergo a first IVF cycle refrain from further treatment (Osmanagaoglu et al., 1999) and are therefore deprived of additional chances of conceiving. This is not only due to costs or poor prognosis (Goverde et al., 2000), but also to the stress and side effects associated with the treatment itself (Olivius et al., 2004). By expressing results in terms of the delivery of a healthy baby per treatment started (or in a given time period), clinicians and scientists will be encouraged to develop and apply patient-friendly stimulation protocols with less stress and discomfort, and fewer side effects and chance of complications such as the ovarian hyperstimulation syndrome.
The introduction of GnRH antagonists into clinical practice has enabled shorter treatment protocols to be applied, since, in contrast to GnRH agonists, treatment can be limited to the days in the mid-to-late follicular phase truly at risk of a premature LH rise (Bouchard and Fauser, 2000). Moreover, since this approach enables the endogenous inter-cycle FSH rise to be utilized rather than suppressed, it has opened the way to the development of mild stimulation protocols in which exogenous FSH administration is limited to the mid-late follicular phase (Fauser et al., 1999; Macklon and Fauser, 2000; de Jong et al., 2001; Hohmann et al., 2003).
Mild stimulation protocols may reduce drop-outs from IVF and therefore increase the overall number of cycles per patient, resulting in increased overall birth rates per started treatment. Shorter, patient-friendly stimulation protocols may increase efficiency, enabling more cycles to be carried out in a given period than is possible with conventional stimulation protocols. Increasing exposure to chances of becoming pregnant while reducing exposure to the complications of conventional ovarian stimulation also offers a formula for reducing costs.
Single embryo transfer
In the present debate series, Land and Evers suggest adopting an outcome measure—the corrected singleton live birth rate per cycle started—that rewards efficacy (many healthy singleton babies) and penalizes unsafety (multiple pregnancies) (Land and Evers, 2004). We would agree that the ideal numerator for determining IVF outcome is a term singleton baby. However, Dickey et al. (2004) proposed that multiple outcome measures are necessary when evaluating IVF success, and that twin as well as singleton births should be counted as IVF successes. While healthy term twins may be perceived as a good outcome, twins in general are at higher risk of neonatal morbidity and mortality (Gardner et al., 1995; Russell et al., 2003), and the current consensus is that multiple pregnancies should be prevented. One approach to the problem of reporting IVF results may be the implementation of a scoring system where singletons ‘count higher’ than twins (score 1 versus 0.5), but both are recognized as preferable to no pregnancy and higher order multiple pregnancies (score 0). In this way twin pregnancies contribute to the pregnancy rate per treatment, but are also relatively penalized (Hunault et al., 2002).
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Healthy baby |
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TopAbstractIntroductionFocusing on the whole...Healthy babyThe integrated pictureReferences |
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In this and other articles in the current debate series, the phrase ‘healthy baby’ is frequently referred to. Intuitively such an outcome is desirable, not only for prospective parents but also for health-care providers. The meaning of ‘healthy’ in this context remains to be defined. A recent study has added to concern that even singleton babies born after conventional IVF may be at increased risk of prematurity with the associated health risks (Helmerhorst et al., 2004
). By inserting the word ‘term’ into the numerator of singleton baby, additional encouragement would arise to develop IVF treatments in which the risk of prematurity was further limited. |
The integrated picture |
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TopAbstractIntroductionFocusing on the whole...Healthy babyThe integrated pictureReferences |
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Combining mild stimulation protocols with single embryo transfer is consistent with the emphasis on reducing complications for mother and child. This maybe at the price of a minor drop in pregnancy rate per cycle (De Sutter et al., 2003
; Gerris et al., 2004), but the same overall pregnancy rate per total IVF treatment may be achieved in the same amount of time, for similar costs, with less patient stress and discomfort and most importantly with the virtual elimination of multiple pregnancies. It has recently been shown that counselling on risks of multiple pregnancy may be insufficient to convince couples to opt for elective single embryo transfer (Murray et al., 2004). In contrast, if they can be reassured that their chance of achieving the goal of treatment will not be compromised, patients are receptive to the idea of transferring one rather than more embryos. Were IVF success rates to be expressed in terms of delivery of a term single baby per IVF treatment or in a certain time period, then such reassurance may be readily given, and single embryo transfer on a large scale more rapidly introduced.
We postulate that the combination of mild stimulation and single embryo transfer would reduce the overall costs of treatment, both to couples and society, partly by reducing the indirect costs related to pregnancy complications. This could be achieved despite an increased number of cycles compared with conventional IVF hyperstimulation and double embryo transfer (Collins, 2002; De Sutter et al., 2002; Gerris et al., 2004). We consider that the optimal numerator and denominator for defining outcome from IVF are the term singleton birth rate per started IVF treatment (or per given period). Widespread adoption of this definition would be an important step towards achieving these goals.
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References |
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TopAbstractIntroductionFocusing on the whole...Healthy babyThe integrated pictureReferences |
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Submitted on April 28, 2004; accepted on May 20, 2004.
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