Elective single embryo transfer: a North American perspective

One of the most exciting aspects of modern medicine has been the rapid advances in the care of the infertile couple that have been made with the use of assisted reproductive technologies (ART) and, particularly, IVF.

Since the birth of the first IVF baby in 1978, the use of this technology has burgeoned worldwide, giving hundreds of thousands of infertile individuals the opportunity to become parents. In a 1999 publication, it was estimated that one in every 150 children born in the USA was conceived with ART [1]. With improved pregnancy rates and increasing availability, this number has clearly increased in the intervening years. According to the 2003 National Summary of Assisted Reproductive Technology Success Rates published by the CDC in 2005, 122,872 IVF cycles were performed in 399 reporting US clinics, resulting in the birth of 48,756 infants [2].

As IVF success rates have continued to improve, an increasing focus of attention has been on minimizing the risks of multiple pregnancies without significantly sacrificing the likelihood of conception which, in the past, has been a difficult balance to achieve. There has been a 65% increase in the rate of twin births since 1980. According to the 2000 CDC report, of 35,025 infants born from ART procedures in the USA during that year, 44% were twins and 9% were high-order multiple pregnancies (> twins) [3]. It has been calculated that 40% of the triplets born in the USA were due to ART procedures [4]. Both maternal and neonatal risks, including perinatal mortality, premature birth, cerebral palsy and other severe handicaps, are significantly increased in multiple pregnancies. In 2002, 15% of all preterm deliveries were due to multifetal gestation [5].

It is logical to expect that the incidence and degree of multiple pregnancy would be directly related to the number and quality of embryos transferred. Interestingly, it has been shown that pregnancy rates are not significantly affected, but that triplet rates are dramatically increased, when more than two embryos are transferred to women considered to have a good prognosis for conception (<35 years of age with no prior failed IVF cycles and sufficient additional embryos available for cryopreservation) and who, therefore, are also at higher risk of multiple pregnancy [2].

As a result, in 1999 the Society for Assisted Reproductive Technology (SART) and the American Society for Reproductive Medicine (ASRM) published a revision to their initial guidelines on the number of embryos to be transferred, recommending that, barring extenuating circumstances, no more than two embryos should be transferred to this group of women [6]. The net effect of the widespread implementation of these guidelines in US clinics was a significant decrease in the incidence of high-order multiple pregnancies, despite an increase in live birth rates [7]. Given that the reduction of the twin birth rate was not the goal of these guidelines, the incidence of twin pregnancies did not change during this same time period.

In order to take it one step further and drastically reduce the incidence of twins resulting from IVF, elective single embryo transfer (eSET) must be considered. Several studies in a younger patient population, employing eSET in comparison with transfer of two cleavage-stage (6–8 cell) embryos 2–3 days after oocyte retrieval, have demonstrated that twin rates can be significantly reduced using this approach. It is important to note that in prospective randomized trials, live birth rates were reported to be somewhat lower with eSET, although this can be compensated for by the subsequent transfer of cryopreserved embryos [8]. Overall healthcare costs are also lower [9]. However, despite decreasing the incidence of twins, the majority of trials report rather low live birth rates of generally less than 40% per elective single cleavage-stage embryo transfer [10,11]. In a fee-for-a-service healthcare system, these outcomes may not be acceptable to the average patient.

By contrast, the elective transfer of single embryos at the more highly developed and differentiated blastocyst stage, 5 days after oocyte retrieval, may go a long way toward solving the dilemma of balancing safety with efficacy. Particularly in younger women, transfer of blastocyst-stage embryos results in higher implantation rates (the likelihood that a single embryo will implant) than those achieved with cleavage-stage embryo transfers [12]. Thus, it would be logical to assume that eSET outcomes should be improved with single blastocyst transfers. However, as the embryo is cultured for more prolonged time periods, its nutritional needs become progressively more complex. This requires more sophisticated culture media and a highly proficient and stable laboratory environment.

Two prospective randomized trials have addressed this issue. Gardner and colleagues reported a 61% ongoing pregnancy rate with no twins after blastocyst-stage eSET in a series of IVF patients with a mean maternal age of over 35 years [13]. By contrast, patients receiving two blastocysts had a 73% ongoing pregnancy rate, a difference that was not significant. However, 47.4% of these pregnancies were twins. More recently, Papanikolau and colleagues reported the results of a randomized trial comparing cleavage- versus blastocyst-stage eSET in a group of women over 36 years of age undergoing their first or second IVF cycle [14]. Significantly higher live birth rates were noted in the latter group (37.3 vs 24.2%). As a result of this dramatic difference, the study was terminated prematurely after completion of an interim analysis of 50% of the planned number of patients to be treated.

As a result, the SART and the ASRM have recently further revised the guidelines regarding the number of embryos transferred in favorable prognosis patients over 35 years of age to be no more than one blastocyst-stage or one or two cleavage-stage embryos [15]. The efficacy of these guideline changes will be evaluated over the next several years.

One of the obstacles to achieving widespread implementation of eSET in the USA to date has been a lack of patient acceptance of the concept. This stems in part from a general perception that transfer of multiple embryos will lead to higher pregnancy rates and that twins represent a desirable outcome, despite education regarding risks [16]. There is clearly also a financial pressure to reduce the number of treatment cycles required to achieve a pregnancy. The role of a federal- or state-mandated embryo transfer policy, which has been implemented in several nations, in which fertility care is federally funded has been felt to be overly intrusive in a healthcare system in which financial responsibility rests with the patient or her insurance carrier. However, as success rates continue to increase and new guidelines are more universally implemented, patient acceptance and third-party payor incentive for the implementation of eSET in appropriately selected patients will undoubtedly increase. This will result in increased safety for mothers and their babies without compromising the efficacy of IVF.

In a very short period of time, IVF has progressed from a controversial curiosity with limited success to a highly efficient and well-accepted approach to the management of infertility. Advances in embryo culture techniques have made it possible to drastically reduce the risks associated with multiple pregnancy by allowing efficient elective single blastocyst-stage embryo transfer. The concept of sequential embryo assessment will enable the analysis of genetics, metabolism and precise quantitative expression of secretory factors of each embryo in a noninvasive fashion. With the application of enhanced embryo selection techniques, the likelihood of conception can be maximized and the risks minimized in the very near future.