What is the most relevant standard of success in assisted reproduction?

The next step to improving outcomes of IVF: consider the whole treatment

E.M.E.W. Heijnen1,2,3, N.S. Macklon1 and B.C.J.M. Fauser1,2

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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 Focusing on the whole...
 Healthy baby
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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


    Introduction
 Top
 Abstract
 Introduction
 Focusing on the whole...
 Healthy baby
 The integrated picture
 References
 
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., 2004Go). 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., 2002Go; Vail and Gardener, 2003Go) 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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Table I. Assessment of IVF treatment outcome: towards the optimal numerator and denominator

 

    Focusing on the whole treatment: consequences for clinical practice
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Patient friendly stimulation protocols
Around 50% of those who initiate IVF will not conceive (Stolwijk et al., 2000Go). 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., 1999Go) and are therefore deprived of additional chances of conceiving. This is not only due to costs or poor prognosis (Goverde et al., 2000Go), but also to the stress and side effects associated with the treatment itself (Olivius et al., 2004Go). 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, 2000Go). 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., 1999Go; Macklon and Fauser, 2000Go; de Jong et al., 2001Go; Hohmann et al., 2003Go).

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, 2004Go). We would agree that the ideal numerator for determining IVF outcome is a term singleton baby. However, Dickey et al. (2004)Go 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., 1995Go; Russell et al., 2003Go), 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., 2002Go).


    Healthy baby
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 Abstract
 Introduction
 Focusing on the whole...
 Healthy baby
 The integrated picture
 References
 
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., 2004Go). 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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 Abstract
 Introduction
 Focusing on the whole...
 Healthy baby
 The integrated picture
 References
 
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., 2003Go; Gerris et al., 2004Go), 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., 2004Go). 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, 2002Go; De Sutter et al., 2002Go; Gerris et al., 2004Go). 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.


    References
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 Abstract
 Introduction
 Focusing on the whole...
 Healthy baby
 The integrated picture
 References
 
Bouchard P and Fauser BC (2000) Gonadotropin-releasing hormone antagonist: new tools vs. old habits. Fertil Steril 73, 18–20.[CrossRef][Medline]

Collins J (2002) An international survey of the health economics of IVF and ICSI. Hum Reprod Update 8, 265–277.[Abstract/Free Full Text]

de Jong D, Macklon NS, Eijkemans MJ, Mannaerts BM, Coelingh Bennink HJ and Fauser BC (2001) Dynamics of the development of multiple follicles during ovarian stimulation for in vitro fertilization using recombinant follicle-stimulating hormone (Puregon) and various doses of the gonadotropin-releasing hormone antagonist ganirelix (Orgalutran/Antagon). Fertil Steril 75, 688–693.[CrossRef][Medline]

De Sutter P, Gerris J and Dhont M (2002) A health-economic decision-analytic model comparing double with single embryo transfer in IVF/ICSI. Hum Reprod 17, 2891–2896.[Abstract/Free Full Text]

De Sutter P, Van der Elst J, Coetsier T and Dhont M (2003) Single embryo transfer and multiple pregnancy rate reduction in IVF/ICSI: a 5-year appraisal. Reprod Biomed Online 6, 464–469.[Medline]

Dickey RP, Sartor BM and Pyrzak R (2004) What is the most relevant standard of success in assisted reproduction?: No single outcome measure is satisfactory when evaluating success in assisted reproduction; both twin births and singleton births should be counted as successes. Hum Reprod 19, 783–787.[Abstract/Free Full Text]

Fauser BC, Devroey P, Yen SS, Gosden R, Crowley WF Jr, Baird DT and Bouchard P (1999) Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum Reprod 14, 2681–2686.[Free Full Text]

Fauser BC, Bouchard P, Coelingh Bennink HJ, Collins JA, Devroey P, Evers JL and van Steirteghem A (2002) Alternative approaches in IVF. Hum Reprod Update 8, 1–9.[Abstract/Free Full Text]

Gardner MO, Goldenberg RL, Cliver SP, Tucker JM, Nelson KG and Copper RL (1995) The origin and outcome of preterm twin pregnancies. Obstet Gynecol 85, 553–557.[Abstract/Free Full Text]

Gerris J, De Sutter P, De Neubourg D, Van Royen E, Van der Elst J, Mangelschots K, Vercruyssen M, Kok P, Elseviers M, Annemans L et al. (2004) A real-life prospective health economic study of elective single embryo transfer versus two-embryo transfer in first IVF/ICSI cycles. Hum Reprod 19, 917–923.[Abstract/Free Full Text]

Goverde AJ, McDonnell J, Vermeiden JP, Schats R, Rutten FF and Schoemaker J (2000) Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis. Lancet 355, 13–18.[CrossRef][Medline]

Helmerhorst FM, Perquin DA, Donker D and Keirse MJ (2004) Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 328, 261.[Abstract/Free Full Text]

Hohmann FP, Macklon NS and Fauser BC (2003) A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 88, 166–173.[Abstract/Free Full Text]

Hunault CC, Eijkemans MJ, Pieters MH, Te Velde ER, Habbema JD, Fauser BC and Macklon NS (2002) A prediction model for selecting patients undergoing in vitro fertilization for elective single embryo transfer. Fertil Steril 77, 725–732.[CrossRef][Medline]

Land JA and Evers JL (2004) What is the most relevant standard of success in assisted reproduction?: Defining outcome in ART: a Gordian knot of safety, efficacy and quality. Hum Reprod 19, 1046–1048.[Abstract/Free Full Text]

Macklon NS and Fauser BC (2000) Regulation of follicle development and novel approaches to ovarian stimulation for IVF. Hum Reprod Update 6, 307–312.[Abstract/Free Full Text]

Min JK, Breheny SA, MacLachlan V and Healy DL (2004) What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: the BESST endpoint for assisted reproduction. Hum Reprod 19, 3–7.[Abstract/Free Full Text]

Murray S, Shetty A, Rattray A, Taylor V and Bhattacharya S (2004) A randomized comparison of alternative methods of information provision on the acceptability of elective single embryo transfer. Hum Reprod 19, 911–916.[Abstract/Free Full Text]

Olivius C, Friden B, Borg G and Bergh C (2004) Why do couples discontinue in vitro fertilization treatment? A cohort study. Fertil Steril 81, 258–261.[CrossRef][Medline]

Osmanagaoglu K, Tournaye H, Camus M, Vandervorst M, van Steirteghem A and Devroey P (1999) Cumulative delivery rates after intracytoplasmic sperm injection: 5 year follow-up of 498 patients. Hum Reprod 14, 2651–2655.[Abstract/Free Full Text]

Russell RB, Petrini JR, Damus K, Mattison DR and Schwarz RH (2003) The changing epidemiology of multiple births in the United States. Obstet Gynecol 101, 129–135.[Abstract/Free Full Text]

Stolwijk AM, Wetzels AM and Braat DD (2000) Cumulative probability of achieving an ongoing pregnancy after in-vitro fertilization and intracytoplasmic sperm injection according to a woman's age, subfertility diagnosis and primary or secondary subfertility. Hum Reprod 15, 203–209.[Abstract/Free Full Text]

Vail A and Gardener E (2003) Common statistical errors in the design and analysis of subfertility trials. Hum Reprod 18, 1000–1004.[Abstract/Free Full Text]

Submitted on April 28, 2004; accepted on May 20, 2004.