Steven Ory, M.D., Vanessa Weitzman, M.D., Wayne S. Maxson, M.D., David I Hoffman, M.D., Marcelo J. Barrionuevo, M.D., Daniel R. Christie, M.D., Marc R. Gualtieri, M.D., Laurice Bou Nemer, M.D., Gene F. Manko, M.D., Leila Grass, Kathleen A. Miller, D.H.Sc.
Single embryo transfer (SET) for Assisted Reproductive Technology (ART) has been globally embraced as the standard of care and most effective strategy for reducing the incidence of multiple pregnancy, the most significant and common complication of ART(1). Considerable progress has been made in reducing high order multiple (HOM) pregnancy since 1998. However, little progress has been made in reducing the incidence of twins until recently. After 30 years of successive increases in the US twin birth rate, a 4% decline was noted between 2014 and 2018 (2). In 2016, non-donor ART with fresh embryos conferred a 19.6% risk of twin delivery and frozen embryos were associated with a 14.2% twin rate (3). Less than 40% of all fresh embryo transfers utilized SET. Overall a twin rate of 9.7% per egg retrieval and 8.1-11.9% (based on age group) per FET was reported for women under 38 (4). This compared to 3.3% risk of twin pregnancy in the general population. ART accounted for 18,890 of the 128,774 infants (14.7%) born in twin deliveries in the US in the most recent year for which complete data is available (5). Over 27% of all ART deliveries resulted in pre-term or very preterm deliveries in all categories reported with multiple pregnancy representing the greatest risk factor (4). In addition, ART twin pregnancies are associated with increased risk of placenta previa, cesarean delivery, low birth weight, and a higher risk of congenital malformations, all associated with additional subsequent morbidity (6). IVF twins have higher rates of respiratory complications, sepsis and jaundice. In contrast, singletons resulting from SET have comparable risks for adverse perinatal outcome to non-ART singletons and both have substantially lower risk than twin pregnancies resulting from embryo transfer of two or more embryos (7).
The mean health care cost to patients and insurers was estimated to be $26,922 for ART-conceived singleton deliveries, $115,238 for ART-conceived twins, and $434,668 for ART-conceived triplets and higher-order infants 8). The economic savings from reducing iatrogenic multiple gestations to singletons was estimated to produce a potential annual cost savings of approximately $1.3 billion by reducing ART-related preterm births (9) and 6.3 billion by reducing preterm births after both ART and non-ART fertility treatments (10).
While a few countries (e.g. Belgium, Sweden, and Turkey) have mandated SET, broader application of SET has been inconsistent, especially in the US (11). In April 2017 ASRM and SART issued new guidance calling for SET to be the standard first line choice for all women younger than 38 (12). Their recommendations included performance of SET up to age 42 if a confirmed euploid embryo was available. Age 42 was the oldest age for which ASRM guidance was offered. The new guidelines were, in part, prompted by an extensive international experience attesting to the efficacy of SET and SET coupled with chromosomal analysis in older women. Recent studies have confirmed that the cumulative pregnancy rate with serial SET is superior to transferring a comparable number of embryos at one time (13). This realization, along with the additional maternal and neonatal advantages, eliminated any meaningful advantage of transferring more than one embryo in a well performing ART program. While some progress has occurred since then, more than one embryo in women <35 was still placed in 20% of embryo transfers performed in frozen cycles and 30% of fresh cycles in 2018 (4).
Impediments to Adoption of SET
Multiple factors have been identified that have impeded broader implementation of SET (14). These include the need to achieve optimal and competitive success rates, lack of appreciation of the inherent risks of multiple pregnancy, patient and provider preferences and economic drivers. These obstacles have been largely mitigated by recent developments. There have been technologic advancements in the laboratory and clinical aspects of ART which have produced progressive, incremental increases in implantation rates (IR) since 1980 that have only plateaued in the past 10 years. Acceptable and competitive IR with SET are the result.
Patients have largely been unaware of the fetal and maternal risks of multiple pregnancy and many providers have underestimated them in the past but there is compelling evidence that a more intensive and comprehensive presentation of risks impacts preferences and practices of patients and providers (15). Many couples have requested multiple embryo transfer (MET) because of an overriding concern for the costs incurred from having to potentially undergo multiple embryo transfers even after they are advised that the cumulative pregnancy rate with successive SET cycles exceeds a single MET cycle. Before we transitioned to a mandatory SET center but after we had committed to more intensive patient education effort of the benefits of frozen embryo transfer (FET), our patient financial councilors advised us of considerable resistance on the part of the patients to accept SET. The reason usually cited was the anticipated additional financial burden of having to incur the expense of multiple programmed cycles. Structuring financial packages either by third party payers or ART clinics that in essence offer an unlimited number of FETs until pregnancy is achieved mitigates much of this concern. Once a clinic has determined the average number of cycles necessary for success, amortizing such charges becomes feasible.
After becoming convinced of the potential benefits to patients and technical advances and resources that made development of a successful, mandatory SET program feasible, our center made a commitment to becoming a mandatory SET program. The evolution was contingent on two changes. After noting consistently better implantation rates (IR) with FET than fresh transfers, we converted to an all -freeze (blastocyst) protocol in September 2017. After noting satisfactory IR with SET for patients under 38 and comparable IR with PGT-A in women over 37, we became a mandatory SET program in February 2018 for all patients under 42 and any patient utilizing PGT-A. Patients over 37 were encouraged but not required to utilize PGT-A.
Prior to our transition, we had long discussions with all of the physicians regarding perceived benefits and obstacles. We recognized that we were all were committed to SET in discussions among our peers, but execution often fell short of expectations when sometimes impassioned discussions ensued between patients and their physicians in the consult room, or worse, the transfer room. We instituted a policy that any deviation from SET would have to be presented to the group of physicians for endorsement in advance of the transfer and that a valid reason for the exception would be required. Most of the exceptions granted pertained to patients that had embryos frozen much earlier that were associated with a lower implantation potential. After the first few months there were very few appeals made and essentially no additional exceptions were granted after August 2018.
Additional essential steps included several in-service sessions with the rest of the clinical and laboratory staff to explain the rationale for the transition and to ensure a smooth transition. The financial counselors were also trained so that the structure of the new financial package could be lucidly presented. Lastly our rationale for having a mandatory SET was presented to the patients on the initial occasion that ART was a consideration and this message was repeated at every opportunity. Given a logical presentation of our reasoning with ample time for questions and for further consideration, the vast majority of our patients embraced it. We may have lost a few patients that were committed to trying to achieve a twin pregnancy, but we were the beneficiary of insurers that designated our center a “Center of Excellence” and directed patients to us because of our high SET rate.
With the eventual goal of mandating mandatory single embryo transfer, the laboratory made several major changes in order to facilitate a mandatory single embryo transfer program. During a six-year period (2011-2017), the transition of the IVF laboratory included:
- Starting in 2011 through June 2015, several media systems geared towards the highest production of competent blastocysts embryos were validated,
- In 2013, the installation of equipment focused on maintaining temperature and gaseous environmental stability and the eventual transition to an undisturbed culture system in 2015,
- In 2014, the refinement of the vitrification system,
- In 2016, a structured staff training and competency program,
- In 2016, the development of an artificial intelligence-based equipment monitoring system,
- And in early 2017, the integration of a robust weekly quality assurance report to interpret the true meaning of data and apply the information methodically towards laboratory improvement and the optimization of single embryo transfer.
Each refinement contributed to an enhanced environment for blastocyst embryo development; more and better blastocysts to give the clinicians the confidence to transfer one blastocyst embryo. As results improved, continuous modifications of the number of embryos to transfer and the day of transfer criteria protocols were made with the potential goal of a mandatory single embryo transfer program (Table 1). Beginning in 2012, laboratory protocols were updated to implement a more aggressive blastocyst transfer strategy and any supernumerary cleavage stage embryos after day 3 embryo transfer were cultured to blastocyst stage for cryopreservation. Blastocyst production rates became a key metric for the laboratory’s quality assurance plan and were analyzed to further execute an increase in the utilization of blastocyst transfer. In combination with revised guidelines by ASRM on the number of embryos to transfer and their recommendation for the utilization of single embryo transfer (12, 16-18), embryologists were given guidance through the laboratory standard operating procedures to determine when a patient’s cycle should be extended to later stages of development. Quarterly analyses of the percentage of blastocyst transfers as whole and by embryologist performing day 3 embryo grading provided information on the adherence to the extension of patients cycle to the blastocyst stage of development. While most embryologists were comfortable with extending cycles for patients <35 with many good quality cleavage stage embryos, many were reluctant to extend patient cycles for older patients, patients with low quality cleavage stage embryos or fewer cleavage stage embryos. This reluctance paired with the program’s high twin pregnancy rate necessitated the implementation in late 2013 of algorithmic forms to be used at the time of day 3 embryo grading to guide the embryologists in determining if a patient’s cleavage stage embryos qualified for extended culture. Additionally, continuous monitoring of the number of cleavage stage embryo transfers with supernumerary blastocysts for cryopreservation, blastocyst development rates, total cryopreservation rates and implantation rates validated the robustness of the laboratory’s culture system.
As the percentage of blastocyst transfers increased, the HOM rate dropped progressively to zero but the twin rate (Figure 1) and the number of embryos transferred stayed above the national average (Figure 2) and the percentage of SET being performed (Figure 3) were below the national standards jeopardizing some of the program’s insurance contracts. Starting in August 2016, embryologists were required to document on an ASRM embryo transfer guidelines compliance form that each transfer was prepared to comply with the current ASRM guidelines to decrease the number of embryos transferred (Figure 4). Embryo transfers were prepared with the lowest number of embryos based on the ASRM guidelines unless the patient met the ASRM “unfavorable” standard. The physicians presented the elective embryo transfer to the patient at the time of transfer and the transfer record was notated “eSET offered” whether patient accepted the ASRM guidelines or not.
Elective single embryo transfer (eSET) Mandatory single embryo transfer (maSET)
At the August 2017 clinical quality improvement meeting, the analysis of quality assurance metrics demonstrated consistently better implantation rates with FET than fresh transfers and blastocyst embryos in either transfer type. A decision was made to transition to a freeze all program as well as the decision to move towards a mandatory single blastocyst embryo transfer for patients <41 and any patient utilizing PGT-A. Data also illustrated that the increase in SET was in tandem with an increase in IR and not compromising patient outcomes (Figure 5). Weekly review of blastocyst development rates, pregnancy outcomes, and implantation rates justified the rationale to incorporate mandatory blastocyst SET as standard of care in our program in February 2018.
Historically, the biggest impediment to acceptance of SET has been a preference on the part of some patients for twin offspring. This has largely been a result of a desire to complete a family in as short a time as possible, an under-appreciation of the risks of multiple pregnancy and additional, unintended economic penalties for patients electing SET, if multiple cycles were required to achieve a successful pregnancy. This economic driver has largely been eliminated in countries offering IVF coverage with obligate SET. More recently, insurance companies in the US are requiring IVF patients to have SET performed using a variety of economic models to incentivize and penalize patients and providers to pursue SET. Several ART centers and their affiliates that provide financing now offer packages structured to eliminate some of the financial disincentives to pursuing SET and there is now evidence that patients are more likely to request SET when the financial model is more favorably aligned.
The essential steps for adoption of a mandatory SET program include universal commitment of the clinicians and laboratory associates followed by intensive and consistent staff and subsequent patient education. Concerns must be addressed in an open and engaging manner.
At this phase of the evolution of ART there are still many unresolved questions particularly regarding embryo selection. Excellent results have been described with a variety of protocols.
We feel that the success of our program was in part, due to utilization of two still contentious strategies, a freeze all (blastocyst) protocol with subsequent FET and selective use of PGT-A. There are many moving parts to a successful ART program and suboptimal performance of any of them may profoundly impact results. We made a gradual, incremental transition from a program utilizing predominantly fresh cleavage stage embryos to our current model over about a six-year period after each modification was validated to improve outcome. The transition to all programmed cycles produced additional advantages in ease of patient and staff scheduling for transfers. Several studies have also confirmed that frozen embryo transfer is associated with babies having decreased risks of small for gestational age, low birth weight and preterm delivery but increased risks of large for gestational age and high birth weight and hypertensive pregnancy disorders (19).
PGT-A is also an operator dependent technology. At the time that we began recommending it for patients over 37 for embryo selection, we had preliminary evidence of improved IR. These results were subsequently expanded and confirmed when we transitioned to our current model.
In summary, the key considerations for successful implementation of our program included:
- Commitment from all of the physicians active in the program to institute mandatory SET
- Intensive education of first the staff and then the patients regarding rationale for mandatory SET and anticipated results
- Improved embryo culture and selection techniques
- Optimization of IR which for our program included embryo culture until blastocyst development was achieved, cryopreservation of all blastocysts, selective use of PGT-A (>38 initially) and primary utilization of programmed cycles for FET.
- Removing patient financial disincentives for SET
- Requiring a majority vote of all physicians to make an exception to the mandatory SET policy
- Patient and staff education
The authors would like to thank the clinical, financial and embryology laboratory staff for their commitment to the SET program and the highest level of patient care.
- Kissin DM, Boulet SL, Adashi EY. “Yes Elective Single-Embryo Transfer Should Be the Standard of Care” in Springer International Publishing Switzerland 2015 177 D.T. Carrell et al. (eds.), Biennial Review of Infertility: Volume 4, DOI 10.1007/978-3-319-17849-3_12
- Martin JA, Osterman MJK. Is twin childbearing on the decline? Twin births in the United States, 2014–2018. NCHS Data Brief, no 351. Hyattsville, MD: National Center for Health Statistics. 2019
- National Summary Report. https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2018. Accessed May 11, 2020.
- Analyses of the National ART Surveillance System (NASS) and National Vital Statistics System (NVSS) data. Written communication with the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, May 6, 2020
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