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How good a solution is single embryo transfer (SET) for fertility patients?

26 January 2009

By Norbert Gleicher

MD, Medical Director, Center for Human Reproduction, New York

Appeared in BioNews 492
On the European side of the Atlantic single embryo transfer (SET) is increasingly becoming standard practice. As a consequence of legislation, as in Belgium, of professional dogma, as in most Scandinavian countries, or the product of the regulatory prowess of the Human Fertilisation and Embryology Authority (HFEA), as in the UK; SET appears on the march towards practice dominance all over Europe.

As PGS (preimplantation genetic screening) demonstrated so well in recent history, popularity and wide acceptance of a new practice should not be accepted as confirmation of its clinical value. PGS was introduced into general IVF practice presumably to improve IVF outcomes, but was ultimately shown to achieve exactly the opposite in older women (1,2). The even more aggressive introduction of SET into daily IVF practice is in danger of proving to be equally disappointing.

SET is now being introduced in place of two-embryo transfer (TET), which, a number of years ago, replaced the worldwide practice of multiple embryo transfer (MET). Then, like now, the rational behind this policy change was to reduce multiple pregnancy rates after IVF, an eventuality which predisposes women to premature deliveries and a multitude of adverse outcomes for mothers and offspring.

When Templeton and Morris published their groundbreaking paper in the New England Journal of Medicine in 1988, it changed clinical IVF practice worldwide to TET (3). They correctly argued two principal points: that transfer of only two embryos would decrease the incidence of high order (triplets and more) multiple pregnancies and associated risks for mothers and offspring, and that they could achieve these risk reductions without adversely affecting pregnancy chances for patients undergoing IVF. Templeton and Morris, thus, followed classical paradigms in medical quality of care improvements; they demonstrated improved patient outcomes without exacting a significant compensatory cost. Interventions in medicine should always be made to improve either risk/benefit or cost/benefit ratios, and in recommending to TET policy, they very likely did both.

Let us now turn to current attempts at introduction of SET. The argument here is, once again, that SET, in comparison to TET, reduces multiple pregnancy risks. Superficially, this mimics the earlier arguments made by Templeton and Morris, but in reality it does not: maternal and neonatal risks of triplet, or even higher order pregnancies, are considerable. The risks of twin pregnancies, while still in principle higher than those of singleton pregnancies are, however, significantly lower than those of high order multiples. In other words, while the switch from MET to TET dramatically reduced risks to mothers and offspring, a switch from TET to SET also does so, but only to a much lesser degree.

Because the potential risk improvements from TET were so dramatic, any risk/benefit assessment would have been in favour of TET, regardless of any significant cost implications. But, remarkably, Templeton and Morris demonstrated that switching from MET to TET in younger patients did not negatively affect pregnancy chances and therefore did not impact on the cost/benefit ratio. In contrast, the suggested risk benefits from SET, in comparison to TET, are much smaller and, perhaps more importantly, in switching from TET to SET there is a significant reduction in pregnancy chances (4).

Whenever risk/benefit narrows, it behoves us to investigate more carefully: are we really certain about the assumed benefits and risks or are we only estimating? When risk/benefit is wide, small changes in calculations will not change the overall ratio; when ratios are very narrow in the first place, any small error in either assumed risks or benefits may, actually, reverse the ratio, as demonstrated by PGS (2).

So, let us investigate more carefully by starting with alleged benefits from SET. Nobody, of course, would argue with twin deliveries if it weren't for the alleged higher risks, including cerebral palsy and maternal complications. But do such risk factors, obtained retrospectively after the delivery, really apply to the prospective paradigm of an infertility situation?

We don't believe so, and here is why: new infertility patients, when starting treatments, in the vast majority of cases want more than one child to complete their families (5). A couple desirous of two children, therefore, has two choices: they can complete their family via one twin pregnancy, or through two singleton pregnancies. A correct risk assessment for this family is, therefore, not between one twin and one singleton pregnancy, as practically all risk comparisons in the literature have been based on, but between one twin and two singleton pregnancies.

In other words, current, widely quoted risks between singletons and twins do not apply to a prospective treatment paradigm, where patients, in most cases, are looking for more than one child. There are additional correcting factors: for example, it is well established that twin pregnancies after IVF have an approximately 40 per cent lower risk profile than spontaneously conceived twins (6). So here is yet another overestimation of twin risks! In contrast, IVF singletons have a higher risk profile than spontaneously conceived singletons (6), resulting again in a relative overestimation of twin risks if two singletons after IVF have to be compared to one twin gestation.

We took all of this into account under a fertility treatment paradigm and tried to calculate more realistic risk comparisons between twin and singleton deliveries in IVF circumstances, assuming fertility patients wanted more than once child to complete their families. The results were surprisingly clear: twin pregnancies in all important outcome parameters no longer reflect higher risks to mothers and/or offspring than two consecutive singleton pregnancies (5).

What are we then left with in our risk/benefit evaluation? If there is no longer increased risk from delivering twins and if, in addition, SET reduces pregnancy chances and, thus, extols a price for no obvious return, aren't we revisiting the PGS problem all over again?

SET should, therefore, be reserved for couples/women who want only one single child to complete their family and/or women who have obstetrical contraindications to twin pregnancies. In all other patients we should welcome the occurrence of twin pregnancies as not only a delightful outcome, greatly desired by most infertility patients, but also as a low risk and cost-effective result of good infertility care (5).



SOURCES & REFERENCES
1) Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoe HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007; 357:9-17
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2) Gleicher N, Weghofer A, Barad D. Preimplantation genetic screening "established" and ready for prime time? Fertil Steril doi:10.1016/j.fertnstert.2008.01.072
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3) Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998;339:573-7
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4) Pandian Z, Templeton A, Serour G, Bhattacharya S. Number of embryos for transfer after IVF and ICSI: a Cochrane review. Hum Reprod 2005;20:2681-7
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5) Gleicher N, Barad D. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertil Steril doi:10.1016/j.fertnstert.2008.02.160
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6) Helmerhorst PM, Perquin DAM, Donker D, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systemic review of controlled studies. BMJ 2004;328:261
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