Should single-embryo transfer be mandatory in patients undergoing IVF?

PRO: Using SET in good-prognosis patients is safe and highly effective infertility care.   

By Brad Van Voorhis, MD

Dr. Van Voorhis is Vice Chair, Department of Obstetrics and Gynecology, and Division Director, Reproductive Endocrinology and Infertility, University of Iowa Carver College of Medicine, Iowa City.

He has no conflict of interest to disclose with respect to the contents of this article.

It is a physician’s professional responsibility to transfer a single embryo to patients with a good prognosis during in vitro fertilization (IVF). I make this statement based on several observations. First, the risks of multiple birth, including twins, after IVF are substantial for both the mother and children. Second, recent developments in IVF allow practitioners to perform single-embryo transfer (SET) with high efficacy, particularly when considering the cumulative pregnancy rate (outcomes with both fresh and frozen embryo transfer) from a given IVF stimulation cycle. Third, as professionals, we are expected to regulate our own behavior. If physicians do not take the lead in practicing and mandating safe and effective clinical care, then who will?

Finally, physicians should take the lead in health care expenditure reduction, which society is demanding. SET has consistently been shown to lower the rates of multiple birth and premature delivery, thereby leading to marked reductions in health care costs.

Couples presenting for IVF often desire twins, feeling that this will complete their family more quickly. Many are ignorant, however, of the health risks posed by twin gestations. It is a health care professional’s responsibility to provide the relevant education. IVF-conceived twin pregnancies are riskier than singleton pregnancies in terms of both maternal and newborn complications. The most obvious difference is in the preterm delivery rate, which is 6 to 7 times higher than that of singletons and leads to much more frequent neonatal intensive care unit admissions.¹

Some have argued that if a family desires 2 children, the complications of twins should be compared with 2 consecutive IVF singleton pregnancies. This analysis was performed recently in Sweden and revealed significantly higher rates of maternal and neonatal complications, with a sevenfold increase in birth before 32 weeks among the twin gestations.² This leads to much higher health care costs, estimated to exceed $1 billion annually for care of preterm births from IVF-conceived multiple gestations.³

Above all, couples presenting for IVF want to get pregnant. Fortunately, the practice of IVF has undergone a remarkable transformation in its relatively short history, resulting in substantial increases in the pregnancy rate. In the early years of IVF, multiple embryos were routinely transferred, yet pregnancy rates were less than 20%, even in the best programs. Improvements in ovarian stimulation protocols, insemination techniques, embryo culture conditions, and embryo transfer practices have led to pregnancy rates that often exceed 50% for good-prognosis patients. New developments in embryo selection techniques hold great promise for pushing these rates even higher.

Physicians have recognized these advances and have reduced the number of embryos transferred in good-prognosis patients, which has led to a marked reduction in higher-order multiple pregnancies (triplets and above) after IVF. However, 2 embryos are still commonly transferred even in good-prognosis patients and, although the rates are slowly increasing, SET remains uncommon. SET comprises only 11.7% of transfers in women under the age of 35 in the most recent national IVF data, resulting in a 30.8% twinning rate among women in this age group.

Can couples achieve pregnancy at the same rate with SET as with double-embryo transfer (DET)? It depends on how this is rate is calculated. Studies have found higher pregnancy rates with DET than with SET in a “fresh” cycle. However, if one looks at the cumulative pregnancy rate achieved by transferring one embryo in the fresh cycle followed by the transfer of another cryopreserved embryo in a “frozen” cycle, the rates are equivalent.⁴ Therefore, the chance of a couple achieving a pregnancy is equivalent with the SET strategy as long as one is willing to accept a 2- to 3-month delay for frozen embryo transfer, should it become necessary. That also comes at a small increase in cost for the frozen cycle. Recent innovations in embryo cryopreservation are leading to improved outcomes for cryopreserved embryo transfers. These outcomes are now nearly equivalent to those of fresh embryo transfers.

Society grants physicians privileges and benefits but expects us to self-regulate and internally monitor practices. In 2009, the American Society for Reproductive Medicine (ASRM) issued guidelines stating that for younger patients (<35 years) with a favorable prognosis (no prior failed cycles, good-quality embryos, and extra embryos to freeze), consideration should be given to transferring one and no more than 2 embryos.

At our center, we have taken this a step further by establishing a SET policy that mandates that a single embryo be transferred under these circumstances. Patients are educated about the risks of twins and about our clinic policy at their first visit. Patient autonomy is preserved because care can be sought elsewhere. However, we find that patients are accepting of the policy after they understand our dedication to achieve both a high pregnancy rate and a safe, healthy pregnancy outcome.

In published data, we have demonstrated that good-prognosis patients who qualify for the mandatory SET policy have a very high birthrate in the fresh cycle and a cumulative pregnancy rate that exceeds 80%.^5,6  We find that when we emphasize these outcomes and the cumulative pregnancy rate in particular, many patients are not only accepting but indeed excited about qualifying for SET. Our program-wide multiple birth rate has been dramatically reduced by our increased utilization of SET.

It is time for physicians to accept our responsibility to “first do no harm” in providing safe and highly effective infertility care through the practice of SET in good-prognosis patients.

REFERENCES

1. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004;328:261–265.

2. Sazonova A, Källen K, Thurin-Kjellberg A, Wennerholm UB, Bergh C. Neonatal and maternal outcomes comparing women undergoing two in vitro fertilization (IVF) singleton pregnancies and women undergoing one IVF twin pregnancy. Fertil Steril. 2013;99(3):731–737.

3. Bromer JG, Ata B, Seli M, Lockwood CJ, Seli E. Preterm deliveries that result from multiple pregnancies associated with assisted reproductive technologies in the USA: a cost analysis. Curr Opin Obstet Gynecol. 2011;23(3):168–173.

4. McLernon DJ, Harrild K, Bergh C, et al. Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials. BMJ. 2010;341:c6945.

5. Kresowik JD, Stegmann BJ, Sparks AE, Ryan GL, Van Voorhis BJ. Five years of a mandatory single-embryo transfer (mSET) policy dramatically reduces twinning rate without lowering pregnancy rates. Fertil Steril. 2011;96(6):1367–1369.

6. Kresowik JD, Sparks AE, Van Voorhis BJ. Clinical factors associated with live birth after single embryo transfer. Fertil Steril. 2012;98(5):1152–1156.

NEXT: Regulation is not the best way to reduce multifetal gestations. >>

CON: Regulation is not the best way to reduce multifetal gestations.

Eric D. Levens, MD, and Micah J. Hill, DO

Dr. Levens is Director of Research at Shady Grove Fertility Reproductive Science Center, Rockville, Maryland.

Dr. Hill is an Assistant Professor in the Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

Neither author has a conflict of interest to disclose with respect to the contents of this article.

As assisted reproductive technology (ART) has become more successful, there has been a simultaneous reduction in multifetal gestation because of the efforts of professional societies such as the ASRM. In the decade following the first published voluntary embryo transfer guidelines, live birth rates per initiated cycle rose by 35% among women <35 years, while multifetal gestation rates declined by approximately 20%. Despite these improvements, some have proposed a mandatory SET policy to further curb the risks of multifetal gestation.¹

ART is one of the most regulated areas of medicine through both executive and legislative action. Proponents of mandatory SET cite the use of regulation to significantly reduce multifetal gestation while failing to recognize potential pitfalls.

A mandatory SET policy has the potential to significantly reduce pregnancy success. Randomized controlled trials have demonstrated a 10% to 50% reduction in ART pregnancy rates with SET. While studies of SET have focused on selecting the highest-quality embryo to maximize implantation, our ability to select top-quality embryos remains limited. Employing embryo selection utilizing embryo morphology, metabolomics, and embryo biopsy for euploidy, for example, still failed to deliver live birth rates above 75% even in patients with the best prognoses.^2,3 Consequently, SET will continue to result in lower live birth rates than will multiple-embryo transfer.

Should a mandatory SET policy be adopted, there would be a concomitant rise in the number of ART cycles required, thus increasing treatment costs. Moreover, patients often desire twin gestations as the best treatment outcome (a 2-for-1 mentality). In one study, 41% of patients surveyed sought twins as the desired outcome.⁴

The reduction in per-cycle pregnancy rates and the limitations on patient and physician autonomy are the main pitfalls to a mandatory SET policy. Regulation is not the solution to reducing multifetal gestation. Appropriate patient selection and patient education regarding the benefits of elective SET are the keys to solving this problem. In our practices, we have been long-time advocates of increased use of elective SET among appropriately selected patients (eg, <38 years of age, first ART cycle, high-quality blastocyst morphology).^5,6 Programs that seek to offer elective SET must demonstrate high baseline pregnancy rates, have a successful embryo cryopreservation program, and demonstrate judicious patient selection and informed consent.

Rather than broad mandatory SET policies, we suggest using policy to promote patient autonomy by establishing payment structures consistent with the best patient outcomes (high pregnancy rates with low multifetal gestation rates). For example, policies should incentivize SET by reducing fees for the transfer of cryopreserved supernumerary embryos if SET proves to be unsuccessful. Continued research should focus on developing more effective technologies for embryo selection to yield improved implantation rates.

Finally, physicians should be willing to offer patients clear counsel about the risks of multifetal gestation and to encourage good-prognosis patients to elect SET. A complement to these approaches, not a mandatory policy, would allow patients and physicians to work together to increase the appropriate utilization of SET and to improve patients’ chances of delivering healthy singletons.
 

References

1. Janvier A, Spelke B, Barrington KJ. The epidemic of multiple gestations and neonatal intensive care unit use: the cost of irresponsibility. J Pediatr. 2011;159:409–413.

2. Hill MJ, Richter KS, Heitmann RJ, et al. Trophectoderm grade predicts outcomes of single-blastocyst transfers. Fertil Steril. 2013;99(5):1283–1289.

3. Forman EJ, Hong KH, Ferry KM, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013;100(1):100–107.

4. Child TJ, Henderson AM, Tan SL. The desire for multiple pregnancy in male and female infertility patients. Hum Reprod. 2004;19(3):558–561.

5. Csokmay JM, Hill MJ, Chason RJ, et al. Experience with a patient-friendly, mandatory, single-blastocyst transfer: the power of one. Fertil Steril. 2011;96(3):580–584.

6. Norian JM, Levens ED, DeCherney AH, Adamson GD. How should we proceed? The American experience. In: Gerris J, Adamson GD, DeSutter P, Racowsky C, eds. Single Embryo Transfer. Cambridge, UK: Cambridge University Press, 2008:269–282.

Disclaimer: The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of Defense or the US government. This work was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH.