1 Department of Obstetrics and Gynecology, Medical University of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany
2 To whom correspondence should be addressed. e-mail: georg.griesinger{at}frauenklinik.uni-luebeck.de
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Abstract |
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Key words: assisted reproduction/outcome measures/success rates
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Introduction |
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The drive towards elective single embryo transfer (eSET) |
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How to measure success after ART |
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For national statistics of ART programmes as a source of information for patients and doctors, we advocate as the denominator the number of patients that actually started ovarian stimulation, with live birth as the numerator, as this provides the most relevant information. National annual reports on success rates from England (http://www.hfea.gov.uk), Germany (http://www.deutsches-ivf-register.de) and the USA (http://www.cdc.gov/nccdphp/drh/art.htm), among others, provide this information.
Choosing the appropriate numerator for clinical studies is more complex and depends on the trial hypothesis and the intervention under study. Thus, investigators choose a variety of numerators, such as oocyte number, oocyte fertilization, embryo morphology and implantation, biochemical pregnancy, clinical pregnancy, clinical ongoing pregnancy or live birth, etc.
We advocate that investigators should remain free to choose a primary outcome parameter to detect immediately a change in outcome by a specific intervention and report studies in line with the CONSORT statement (Moher et al., 2001). However, all trialists should report the ongoing clinical pregnancy rate, defined as fetal heart activity on ultrasonography at 12 weeks of gestation, before any invasive prenatal testing, independently of whether this is the primary outcome parameter upon which a sample size estimation is based or not. This outcome parameter provides a high level of assurance since the majority of pregnancy losses occur in the first trimester. Uniformly reporting pregnancy after IVF by this outcome parameter will also facilitate incorporation of data from individual studies into meta-analyses. Beyond that, data from interim outcomes, such as number of oocytes, fertilization, implantation, biochemical pregnancy, abortion, etc., should also be provided. Ideally, a minimum consensus should be established, i.e. what outcome measures should be included in the report from a randomized controlled trial. Arbitrarily setting the primary outcome to live birth rate in studies will not only further increase the sample size necessary to achieve sufficient power for a trial, but will also increase the time until publication of data, as well as increase the effort required by both patients and doctors for follow-up and a standardized antenatal and obstetric care.
In that context, we would like to emphasize that ART is primarily established as a treatment to overcome infertility (in the sense of an inability to conceive), which is reflected by our daily clinical practice: a patient who has become pregnant by means of assisted reproduction is usually no longer attended to by the infertility specialist. Thus, as long as we have no knowledge of to what extent the ART procedure itself is causative of the likelihood of miscarriage and adverse events during pregnancy (reviewed by Lambert, 2003), it may be inappropriate to use live birtha measure that is comparatively remote from the intervention performed and studied in a clinical ART trialas a primary outcome parameter. However, if we decide to do so under the assumption that the treatment itself, rather than underlying (unknown) pathologies associated with infertility, has an impact on the course of pregnancy, gestational age at delivery, live birth and health of the neonate, we will face a variety of confounding factors in our studies imposed by the policy of prenatal diagnosis/antenatal care/obstetric care, which are far from being standardized, and which may vary considerably from centre to centre (and may even be outside a centres control).
Setting the primary outcome furthermore to the singleton pregnancy or singleton live birth is of no apparent benefit in the context of a clinical study as long as the intervention under study does not aim specifically at reducing the multiple pregnancy rate.
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Should term gestation be part of the main outcome parameter? |
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Generally, preterm birth is associated with, besides multiplicity, preterm rupture of membranes, cervical incompetence, polyhydramnion, fetal and uterine anomalies, infections, ethnicity, genetic risk, lifestyle and many other factors. Although we know that the rate of preterm deliveries after ART is higher compared with control populations even in singletons (Dhont et al., 1999; Perri et al., 2001
; Wang et al., 2002
), the specific contribution of ART treatment (e.g. ovarian stimulation, laboratory techniques) to this phenomenon remains obscure. Thus, with current understanding, gestational age at delivery is not a reasonable outcome measure of the success and the quality of an ART programme.
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Should the health of children born from IVF be included in the outcome reports? |
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In the paper by Min et al. (2004), assessment of health of the neonates in their programme was done by neonatal examinations conducted by paediatricians. A single neonatal examination of babies born from ART is insufficient to detect all health problems of the infant. From a patient perspective, reporting the healthiness of children after ART as is done by Min et al. (2004
) automatically generates the need for information regarding the children classified as not healthy and the relative risk of having a child affected by a specific disease after IVF. However, information as such is best retrieved from controlled studies employing standardized diagnostic criteria (e.g. International Classification of Disease Codes for neonatal morbidity or malformation), karyotyping and longer term follow-up regimens. Not all health problems of the neonate will be evident at birth, and adverse outcomes of the neonate are heterogenous and vary considerably in impairment of the quality of life of both infant and parents. Such issues have to be addressed at counselling with regard to the specific background of a couple, including the aetiology for infertility. In the context of registries, adding the classification healthy to the outcome report is unwarranted and of no clear benefit. However, we acknowledge the need for uniformly recording pregnancy complications, maternal morbidity, fetal morbidity/mortality and malformations in the setting of national audits.
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Conclusions |
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References |
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Dhont M, De Sutter P, Ruyssinck G, Martens G and Bekaert A (1999) Perinatal outcome of pregnancies after assisted reproduction: a casecontrol study. Am J Obstet Gynecol 181,688695.[Medline]
ESHRE Campus Course Report. (2001) Prevention of twin pregnancies after IVF/ICSI by single embryo transfer. Hum Reprod 16,790800.
Lambert RD (2003) Safety issues in assisted reproductive technology: aetiology of health problems in singleton ART babies. Hum Reprod 18,19871991.
Land JA and Evers JL (2003) Risks and complications in assisted reproduction techniques: report of an ESHRE consensus meeting. Hum Reprod 18,455457.
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 19,37.
Moher D, Schulz KF and Altman DG (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel group randomized trials. BMC Med Res Methodol 12.
Perri T, Chen R, Yoeli R, Merlob P, Orvieto R, Shalev Y, Ben-Rafael Z and Bar-Hava I (2001) Are singleton assisted reproductive technology pregnancies at risk of prematurity? J Assist Reprod Genet 18,245249.[CrossRef][Medline]
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Wang JX, Norman RJ and Kristiansson P (2002) The effect of various infertility treatments on the risk of preterm birth. Hum Reprod 17,945949.