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

Singleton live births should also include preterm births

U.B. Wennerholm1 and C. Bergh

Department of Obstetrics and Gynecology, Institute for the Health of Women and Children, Sahlgrenska University Hospital, East, 416 85 Göteborg, Sweden

1 To whom correspondence should be addressed. Email: wennerholm{at}swipnet.se


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An intensive debate is ongoing in this journal concerning the most appropriate endpoint after assisted reproduction techniques. The endpoint suggested by the first authors was Birth Emphasizing a Successful Singleton at Term (BESST). We have evaluated the most appropriate endpoint from different perspectives: patients, public, health authorities, obstetric and IVF clinics. We find singleton live birth highly relevant as an outcome parameter as multiple pregnancies are the main factor responsible for the overall poorer obstetric and neonatal outcome in IVF pregnancies, and multiple pregnancies are mostly an avoidable iatrogenic complication. However, our proposal is that both preterm and term singletons should be included since the prematurity rate is an outcome that is largely uninfluenced by the IVF clinics. In conclusion, we propose singleton live birth per cycle initiated as the most appropriate main outcome after assisted reproduction. Prematurity should in addition be reported separately as a secondary outcome.

Key words: assisted reproduction/outcome/success rate


    Introduction
 Top
 Abstract
 Introduction
 (Live) Birth is appropriate
 Successful is inappropiate
 Singleton is appropriate
 (Only) Term singleton is...
 Exclusion of singletons with...
 References
 
Although one single outcome hardly fully describes the results of IVF, we consider that a variable which promotes singleton births and is easily understood by patients, the public and health authorities would be highly valuable. Such a variable should be well-defined, easily calculated by IVF clinics and comparable between different clinics and nations.

The lead debate article by Min et al. (2004)Go suggests BESST (Birth Emphasizing a Successful Singleton at Term) to be such a variable. Our comments on this suggestion are the following:


    (Live) Birth is appropriate
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 Abstract
 Introduction
 (Live) Birth is appropriate
 Successful is inappropiate
 Singleton is appropriate
 (Only) Term singleton is...
 Exclusion of singletons with...
 References
 
Including only live births avoids at least some of the problems associated with making international comparisons owing to differences in the way births are registered in different countries. While there are no international differences in the definition of live births (World Health Organization, 1977Go) there is wide variation in the definition of stillbirths or late fetal deaths. Stillbirths or late fetal deaths are registered from 16 weeks of gestation in Norway and from 20 weeks of gestation in the USA and Australia, whereas in England, Sweden and New Zealand the boundary for registration is 28 weeks. Although relatively few pregnancies end between 16 and 28 weeks of pregnancy, these pregnancies contribute disproportionately to mortality.


    Successful is inappropiate
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We think that ‘successful’ as a concept is out of place: first, successful is not defined either in the literature or by the authors; second, agreement as to what is meant by successful will hardly be achieved even nationwide; third, there are no figures for spontaneously conceived pregnancies for comparison.


    Singleton is appropriate
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There are numerous data and international agreement that multiple pregnancies and births are the most frequent and most serious iatrogenic complication of assisted reproduction treatment (ESHRE Capri Workshop Group, 2000Go; Adashi et al., 2003Go). This complication is associated with increased mortality and morbidity for both mothers and fetuses. We have previously suggested different strategies to avoid multiple births in assisted reproduction treatment (Hazekamp et al., 2000Go). In that paper, we discussed a change in transfer policy and suggested that clinics endeavour to implement single embryo transfers (SET). We then proposed ‘birth (= maternity) per embryo transferred’ as the best outcome parameter since it is a statistical criterion that promotes a policy aiming at singletons and the results will be best when a low number of embryos are transferred. However, ‘birth per embryo transferred’ is probably not so easily understandable by patients, public and health authorities.

The main strategy for reducing the multiple birth rates would be to transfer fewer embryos per transfer and particularly increase the number of SET. Reported data after SET show satisfactory pregnancy or delivery rates (Gerris et al., 1999Go; Vilska et al., 1999Go; Martikainen et al., 2001Go; Tiitinen et al., 2001Go, 2003Go) at least for women with good prognosis after IVF.

Min et al. (2004)Go suggest including only stimulated IVF cycles, i.e. the results after frozen–thawed cycles would be excluded. However, SET yields more impact on frozen–thawed cycles, since more embryos are frozen. We suggest that results from frozen cycles should be reported in the same way as for stimulated cycles, i.e. singleton live births, but separately. In fact there are more arguments for transferring single embryos in thawed than in fresh cycles since embryos can be frozen and thawed one by one without further losses.


    (Only) Term singleton is inappropriate
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Preterm birth is the major clinical problem associated with perinatal mortality, serious neonatal morbidity and moderate to severe childhood disability in prosperous countries.

Preterm birth is related to gestational age and is defined by the World Health Organization as birth before 37 completed weeks or 259 days of gestation.

Today there is a great deal of evidence of an increased preterm rate for IVF singletons compared with naturally conceived singletons (Helmerhorst et al., 2004Go; Jackson et al., 2004Go). In a systematic review, Helmerhorst et al. found, for singletons compared with matched controls, a relative risk (RR) of 3.27 (95% CI 2.03–5.28) for very preterm birth (<32 weeks) and 2.04 (95% CI 1.80–2.32) for preterm birth (<37 weeks) in pregnancies after assisted conception. Results of the non-matched studies were similar. In a recent meta-analysis including 15 studies comprising 12 283 IVF and 1.9 x 106 spontaneously conceived singletons, an odds ratio of 2.0 (95% CI 1.7–2.2) for preterm birth was found (Jackson et al., 2004Go). To our knowledge, no study has so far compared the outcome for SET singletons resulting from mild stimulation protocols with IVF singletons in general.

Women with assisted pregnancies differ from other women in many characteristics that influence outcome, including age, parity and socioeconomic status and the underlying subfertility. In the population-based Swedish registry study we found a risk ratio of 2.04 (1.85–2.26) for preterm birth. After stratification for maternal age, parity and duration of infertility the RR decreased to 1.48 (95% CI 1.30–1.68) (Bergh et al., 1999Go).

The reported incidence of preterm birth in the international literature varies from 6 to 15% of all deliveries depending on the geographical and demographic features of the population studied (Slattery and Morrison, 2002Go). There has been a tendency towards higher reported rates in recent years which has been attributed to several factors including increased obstetric interventions, use of assisted reproduction techniques and increased rate of multiple pregnancies.

Preterm birth may be categorized according to three different modes of clinical presentation: medically indicated (iatrogenic) preterm birth, preterm pre-labour rupture of the membranes (PPROM) and preterm labour (PTL) (Savitz et al., 1991Go). PTL and PPROM are often combined and called spontaneous (idiopathic) preterm birth. The aetiology of preterm birth is multifactorial. Those risk factors found in association with preterm birth can be divided into three groups: those associated with factors related to sociobiological variables (maternal age and parity, marital status, race and ethnicity, cigarette smoking, environmental stress, work, nutrition, maternal size, interpregnancy interval, alcohol, coffee and substance abuse), past obstetric history (previous preterm birth, previous abortion) and complications of the current pregnancy (elective preterm birth, multiple gestation, insufficient antenatal care, male sex, uncertain gestation, congenital malformation).

In spite of increasing knowledge about epidemiological risk factors, research efforts to date have failed to result in any improvement in prediction and prevention of preterm delivery.

Owing to all the above reasons, the differences between populations in terms of ethnicity and sociodemographic factors make comparisons in preterm birth rate complicated (Savitz et al., 1991Go). The preterm birth rate for black women is almost twice that for white women of comparable age in the USA (McGrady et al., 1992Go; Schieve and Handler, 1996Go; Ananth et al., 2001Go).

Thus preterm birth is a heterogeneous perinatal problem both in terms of aetiology and numerous associated risk factors, and more important, the rate of preterm birth in singletons cannot be influenced to any huge extent by the individual IVF clinics but is mainly a result of the specific IVF population being treated.


    Exclusion of singletons with a congenital malformation is inappropriate
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 (Live) Birth is appropriate
 Successful is inappropiate
 Singleton is appropriate
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 Exclusion of singletons with...
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Min et al. (2004)Go also discuss excluding singletons with congenital malformations but state that this would be problematic since there are various methodological pitfalls concerning the registration of congenital malformations. These include different classifications (inclusion or exclusion of minor anomalies and anomalies evident only on ultrasound and even inclusion and exclusion of terminated pregnancies); are dependent on the follow-up time, e.g. if surveillance is extended to a protracted time after birth; the extent of the neonatal examinations; and who is performing the examination—a general practitioner or a well-trained geneticist (Simpson, 1996Go).

Preferably, registration of congenital malformations in an assisted reproduction population should include: a prospective surveillance for major anomalies, defined as those causing death, severe disability or requiring surgery. Prospective surveillance should ideally include collection of information at the time pregnancy is diagnosed, surveillance during pregnancy to exclude teratogenic influences, and a systematic neonatal anomaly examination. Today, this goal is impossible to achieve worldwide.

In summary, we propose that singleton live birth per cycle initiated is the most appropriate main outcome and that the preterm birth rate be reported separately as a secondary outcome.


    References
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 (Live) Birth is appropriate
 Successful is inappropiate
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ESHRE Capri Workshop Group (2000) Multiple gestation pregnancy. Hum Reprod 15, 1856–1864.[Abstract/Free Full Text]

Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Van de Meerssche M and Valkenburg M (1999) Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: a prospective randomized clinical trial. Hum Reprod 14, 2581–2587.[Abstract/Free Full Text]

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Submitted on May 4, 2004; accepted on June 3, 2004.