On the Concept of Elective Single Embryo Transfer (eSET)
OPINIONs 004: July 21, 2014
CHR is seriously concerned about the increasing propagation and utilization of elective single embryo transfer (eSET) without allowing patients appropriate input into the decision-making process. We consider such practices unethical, as they reduce patients' pregnancy chances with in vitro fertilization (IVF) with, at best, questionable benefits in return. CHR considers the utilization of eSET only indicated in cases where patients, specifically, do not wish to conceive twin pregnancies and/or have medical contraindications to carrying twin pregnancies. CHR's opinion is based on a careful statistical analysis of published literature, with conclusions published by CHR investigators in a number of peer-reviewed manuscripts.
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These conclusions suggest that, contrary to widely held opinions, twin births do not significantly increase adverse outcomes in comparison to combined outcomes of two consecutive singleton births, which is the statistically correct method of comparing risks. CHR's position on eSET deviates from other published professional opinions but, in our opinion, reflects the best interests of infertility patients and their repeatedly expressed desires, exhaustively investigated and published in the medical literature in innumerable studies; yet, these patient opinions and desires are not, or not enough, considered by proponents of eSET.
Elective single embryo transfer (eSET) is a relatively new concept in in vitro fertilization (IVF). Initially proposed by European colleagues,1 it is now also gaining an increasing following in the USA, as indicated by the most recent update of the Practice Committees of the American Society for Reproductive Medicine (ASRM) andSociety for Assisted Reproductive Technology (SART) on criteria for number of embryos to transfer,2 and an initial summary published in a follow-up to a stakeholder meeting, organized by the March of Dimes _and the_Hastings Institute, in the summer of 2012,3 in which CHR's Medical Director and Chief Scientist, Norbert Gleicher, MD, participated.
As the acronym suggests, it represents the elective (voluntary) decision to transfer only one embryo at a time, even if patients produce more good quality embryos for transfer in an IVF cycle.
Proponents of eSET argue that eSET represents the only option to minimize twin pregnancies, which they have come to consider "adverse" outcomes of infertility treatments, including IVF. Some European proponents, indeed, have recently argued that eSET should even be standard treatment in women above age 40.4
In some European countries and Canadian provinces, eSET has been legislated. Such legislation, at times, was part of a great bargain between providers of fertility services and the government, in which the physician community agreed to actively practice eSET, and the government, in return, offered insurance coverage for IVF services.5,6
The reasoning why colleagues and governments consider eSET favorably is complex and multifactorial. In CHR's opinion, arguments in support of eSET are, however, largely mistaken, and based on false statistical considerations. CHR, therefore, disagrees with the excessive utilization of eSET, as propagated by colleagues and professional organizations. Therefore, in the following sections of this OPINION we will contrast CHR's opinions and positions with those of proponents of eSET and offer detailed explanations for CHR's positions.
When IVF was introduced into fertility care, pregnancy rates were only in low single digits. Therefore, practitioners, in order to improve their patients' pregnancy chances, transferred what today appears like unreasonably high numbers of embryos. As IVF improved and pregnancy chances per embryo (called implantation rates) increased, high rates of multiple pregnancies became the consequence, often even of high order (triplets or more).
Multiple pregnancies represent significant risks to mothers and offspring. Indeed, the higher the order of multiples, the higher those risks. For offspring, these risks primarily relate to prematurity: the higher the order of multiples, the earlier pregnant women deliver. Multiple births are, therefore, considered "high risk" primarily because of this prematurity risk to offspring, associated with increased medical costs and long-term, often lifelong, handicaps for affected children (more about risk below).
As multiple pregnancies from IVF started to increase, worldwide medical practice was quickly adjusted by reducing the number of embryos transferred. These adjustments resulted in fewer high order multiples; rates of high order multiples, however, still remained too high. The publication of a milestone paper by British colleagues,7 however, almost immediately resulted in dramatic further shifts in worldwide practice because their study demonstrated that, in good prognosis patients, transferring more than two embryos did not further increase clinical pregnancy rates but significantly increased high order multiple births.
Note that the emphasis in the last sentence was on "in good prognosis patients," a very important point we will revisit later in a brief discussion of women with low functional ovarian reserve (LFOR).
This study resonated and found such quick universal acceptance because it offered a substantial clinical benefit (reduction of high order multiples, which his universally accepted as an adverse outcome of IVF) at no clinical cost to patients (since pregnancy rates were the same whether 2 embryos were transferred or more). Worldwide practice, therefore, changed almost instantly, resulting in a dramatic drop in high order multiples.
It was at this point that Finnish colleagues for the first time proposed the concept of eSET.1 Their argument was that, while lower than in high order multiples, even twins were still associated with increased maternal and neonatal risks, including prematurity, cerebral palsy and other complications. Consequently, they argued, twin pregnancies should also be considered adverse outcomes of IVF.
The following section will explain why switching from multiple-embryo to 2-embryo transfers (2ET), which had become standard practice in favorable prognosis patients after publication of the above-cited study by British investigators,7 is conceptually very different from switching from 2ET to eSET, as proposed by the Finnish colleagues.1
What differentiates 2ET and eSET concepts?
We noted above that the genius of the British study was the ability to demonstrate that 2ET diminished an undisputedly harmful consequence of IVF without negatively affecting IVF pregnancy chances. 2ET, therefore, was unquestionably in the best interest of favorable prognosis patients.
Yet, circumstances in association with eSET are very different: Innumerable studies have demonstrated that, even in favorable prognosis patients, a switch from 2ET to eSET significantly reduces pregnancy chances.8 In contrast to the earlier noted switch from multiple-embryo transfers to 2ET, patients, here, do have to pay a compensatory price for reducing the allegedly increased risks from twin in comparison to singleton pregnancies (the emphasis here is on "alleged': for further detail see below). This, of course, immediately creates a very different risk/benefit assessment because no such down side existed in the prior practice pattern change to 2ET.
Whenever risk/benefit assessments are not absolute, patients, and their rights to self-determination, come into play. In other words, where risk/benefit considerations are blatantly obvious, it appears appropriate to adjust practice patterns on a professional level. When such considerations are less obvious, however, it appears ethically wrong to exclude patients from actively participating in the decision-making process. In this case, the consideration whether reduction in potential risks to mother and offspring may be worth a significant loss in pregnancy chances, ethically, cannot exclude patient participation.
CHR feels strongly about this point, not only because of basic ethical considerations but also because multiple studies have unequivocally demonstrated that, even well-educated fertility patients, in a large majority, still see twin pregnancies as a desirable IVF outcome9 and are consciously willing to accept the alleged risks to improve IVF pregnancy chances.10
Proponents of eSET point out that, combined, a fresh cycle eSET, followed by a frozen-thawed eSET, produce similar pregnancy chances as a 2SET, yet, in addition, offers the additional benefit of significantly reduced twin pregnancy rates.11 This argument has, indeed, been the backbone for legislative mandates in some European countries,5 a Canadian province6 and for recommendation by authoritative professional bodies.2,3
CHR, however, rejects this argument because (i) combined pregnancy rates from two consecutive eSET cycles, one fresh and one frozen-thawed, still lag by approximately 7% in comparison to pregnancy rates in 2ET cycles; (ii) two cycles in place of one requires additional efforts from patient and service provider; (iii) there is an increase in treatment costs; (iv) there is an increase in treatment time; and (v) there is never a guarantee that a frozen embryo will survive thawing.
Imposing eSET as a policy on patients usurps their rights of self-determination, and, in CHR's opinion, is unethical. This, of course, does not mean that the option of eSET should not be discussed with qualified patients (as to who may be qualified, see below). After receiving full informed consent, the ultimate decision to undergo eSET or 2ET should, however, be the patients'.
Do twin pregnancies, indeed, represent increased risk?
The preceding section assumed that twin pregnancies, indeed, result in significantly increased risks to mothers and offspring in comparison to singleton pregnancies. However, as CHR investigators documented in a number of publications, this assumption is, in fact, incorrect.12,13
The notion of increased risk for twin pregnancies stems from the non-surprising obstetrical observation that twin pregnancies demonstrate more risks to mothers and offspring than singleton pregnancies. This is, of course, not surprising since the former produces two offspring while the latter results in the birth of only one child. Proper statistical methodology requires comparisons of similar outcomes. In other words, for an obstetrician, it is entirely appropriate to conclude that a woman, pregnant with twins, is at a higher risk than a mother with a singleton pregnancy; however, in the prospective treatment paradigm of a fertility specialist, such a conclusion is statistically categorically incorrect.
The question that the fertility specialist faces prospectively for a woman who desire at least two more children to complete her family is this: how can this patient be best helped to achieve this goal in the safest, quickest and least costly way?
Incorrectly assuming for a moment that twins, indeed, can be produced on demand, the answer is that such a patient has two choices: either she can deliver two offspring in one twin pregnancy, or she has to conceive twice with consecutive singleton pregnancies. Assessments of risk comparisons, therefore, have to compare risks between one twin and two singleton pregnancies, and not, as in the above-described obstetrical paradigm, between one twin and one singleton pregnancy.
As Dr. Gleicher recently summarized in an invited editorial,13 when maternal and neonatal risks of twin pregnancies after IVF are assessed correctly in this fashion, practically no significant excess of clinical risks remains detectable for twin pregnancies.
The concept of two consecutive singleton pregnancies has an additional weakness in that not even the best fertility specialists can guarantee patients a successful second conception and delivery. This is, of course, particularly true in women with LFOR already at the time of their first pregnancy attempt. The concept of two consecutive singleton pregnancies in place of an immediate twin pregnancy is, therefore, in a significant proportion of infertile women, not even a realistic comparison, once again suggesting that basic ethical considerations and patients' right to self-determination have to give patients without medical contraindications to twin pregnancies the absolute right to choose between eSET and 2ET.
Women with LFOR
LFOR is in older women a normal feature of aging (generally above age 40) but can also occur in younger women with a diagnosis of premature ovarian aging (POA), often also called occult primary ovarian insufficiency (OPOI). The literature and national IVF outcome reporting registries unequivocally demonstrate that a diagnosis of LFOR results in the lowest pregnancy chances of any infertility diagnosis. LFOR patients, therefore, most definitely are not good prognosis patients, and are, therefore, not even subject to arguments in favor of 2ET discussed earlier. Therefore, to consider them candidates for eSET,4 in CHR's opinion, appears contraindicated. Indeed, there, is no evidence in the literature that, even with blastocyst-stage embryo transfer, eSET offers any outcome advantages in IVF except in favorable prognosis patients.14
A main reason is that ovarian aging is not only associated with lower oocyte (egg) production but also with poorer egg and embryo quality. CHR, therefore, very strongly believes that women with LFOR are almost never candidates for eSET. Indeed, we believe that suggestions to the contrary, as recently proposed by our Finnish colleagues, who were also initial proponents of eSET,4 are, likely, outright harmful to women with LFOR. Since eSET is often performed at blastocyst stage, this conclusion is further supported by the observation that cumulative pregnancy rates are higher with embryos transferred at cleavage stage (day-3 after fertilization) than with transfer at blastocyst stage (days 5/6 after fertilization).15
CHR's position on this issue is further supported by a recent report from the Centers for Disease Control and Prevention (CDC) with CHR's Vitaly A. Kushnir, MD, as co-author, which reported on national IVF outcomes. The report, for the first time, judged IVF outcomes not by clinical pregnancy rates but by what the _CDC_considered "ideal obstetrical outcomes" (i.e., the birth of a full-term singleton infant).16 While CHR does not agree with this definition of "ideal" IVF outcome, it was, nevertheless, noteworthy that once women reached their mid-30s, "ideal" outcomes (i.e., delivery of singleton, term infants) clearly increased with increasing numbers of embryos transferred (up to 5 embryos).
What these data well demonstrate is, therefore, the very obvious fact that, since implantation and pregnancy chances per embryo decline with advancing female age, if fertility treatment is to be successful, increasing numbers of embryos have to be transferred. Moreover, because implantation chances per embryo decrease, such practice does not create excessive risks for multiple births.
We believe in this OPINION to have demonstrated that (i) twin pregnancies in a prospective fertility treatment paradigm do not carry increased risk over singleton pregnancies. Moreover, (ii) even if such risks are assumed, patients are entitled to make a conscious choice to accept these risks in order to achieve better pregnancy rates in IVF by preferring 2ETs over eSET.
CHR, for these two main reasons, considers eSET only indicated if patients have normal FOR and specifically do not wish to have twins, or if women have medical contraindications to carrying twins. Otherwise, we consider the possibility of a twin pregnancy as a result of IVF a favorable treatment outcome.
CHR also considers claims of increased short-term and long-term medical costs for twins inaccurate, as no published study on the subject ever considered the lifelong earning power of a second twin. As the birth of an IVF child has been calculated to offer society considerable financial net benefits,17 there can be little doubt that society loses financially by fewer (twin) births.
CHR' Norbert Gleicher, MD, for example, demonstrated that after introducing a mandatory eSET program, the Canadian province of Quebec lost approximately one-third of their potential IVF births because of decreases in IVF pregnancy rates and loss of second twins.18 While colleagues from Quebec see this as success, and in the short-term even claim cost savings,6 considering the potential population loss and, therefore, lifelong income loss to the province,17 the program, unquestionably, economically harms the province.
Similarly, many insurance companies are currently harming their economic self-interests because of incorrect interpretations of published literature. CHR investigators already in the year 2000 pointed out that the practice of intrauterine inseminations (IUIs) after ovarian stimulation was associated with unacceptably high risk for high order multiples.19 CHR investigators, already then, suggested that IUIs be abandoned in favor of IVF, where control of multiples was possible by controlling the number of transferred embryos.
A large majority of high order multiples in current fertility practice in the USA are results of IUI cycles.20 IVF cycles contribute only a minority of multiple births to the national picture; and, yet, IVF, rather than IUI, have become the target of scrutiny. Many insurance companies even mandate IUI cycles before approving patients for IVF cycles.
A thorough reevaluation of IVF policies at insurance companies and government agencies, therefore, appears in order.
- Vilska S, Tiitinen A, Hydén-Granskog C, Hovatta O. Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple birth. Hum Reprod 2013;28:294-297
- Practice Committees of the ASRM and SART. Criteria for number of embryos to transfer: a committee opinion. Fertil Steril 2013;99:44-46
- Johnston J, Gusmano MK, Patrizio P. Preterm births, multiples, and fertility treatment: recommendations for changes to policy and clinical practice. Fertil Steril 2014; doi:10.1016/j.fertnstert.2014.03.019
- Niinimäki M, Suikkari AM, Mäkinen S, Söderström-Antilla V, Martikainen H. Elective single-embryo transfer in women aged 40-44 years. Hum Reprod 2013;28:331-335
- De Neubourg D et al (+24 authors). The history of Belgian assisted reproduction technology cycle registration and control: a case study in reducing the incidence of multiple pregnancy. Hum Reprod 2013;28:2709-2719
- Vélez MP, Connolly MP, Kadoch IJ, Phillips S, Bissonnette F. Universal coverage of IVF pays off. Hum Reprod 2014;29:1313-1319
- Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998;339:573-577
- Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharva S. Number of embryos for transfer following in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2013;7:CD003416
- Gleicher N, Campbell DP, Chan CL, Karande V, Rao R, Balin M, Pratt D. The desire for multiple births in couples with infertility problems contradicts present practice patterns. Hum Reprod 1995;10:1079-1084
- Scotland GS, McNamee P, Peddie VL, Bhattacharya S. Safety versus success in elective single embryo transfer: women's preferences for outcomes of in vitro fertilization. BJOG 2007;114:977-983
- Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilization or intracytoplasmic sperm injection; summary of a Cochrane review. Fertil Steril 2014; doi: 10.1016/j.fertnstert.2014.04.029
- Gleicher N, Barad D. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertil Steril 2009;91:2426-2431
- Gleicher N. For some infertility patient, twins are the best outcome. Contemp Ob/Gyn 2013;2013:40-46
- Blake DA, Farquhar CM, Johnson N, Proctor M. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochran Database Syst Rev 2007;CD002118
- Gljovsky D, Blake D, Farquhar C, Bardach A. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochran Database Syst Rev 2012;7:CD002118
- Kissin DM, Kulkarni AD, Kushnir VA, Jamieson DJ. National ART Surveillance System Group. Obstet Gynecol 2014;123:239-247
- Evers JLH. International Federation of Fertility Societies, September 14, 2010 http://c.ymcdn.com/sites/www.iffs-reproduction.org/resource/resmgr/ press_room/evers_final.pdf
- Gleicher N. Eliminating multiple pregnancies: an appropriate target for government intervention? Reprod Biomed Online 2011;23:403-406
- Gleicher N, Oleske DM, Tur Kaspa I, Vidali A, Karande V. reducing the risk of high- order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med 2000;343:2-7
- Kulkarni AD, Kissin DM, Adashi EY. Fertility treatments and multiple births in the United States. N Engl J Med 2013;369:2218-2225
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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