reproductive technology multiple gestations: some progress, some answers, more questions. William Gibbons, M.D., David Grainger, M.D., M.P.H., Marcelle ...
Continuous quality improvement and assisted reproductive technology multiple gestations: some progress, some answers, more questions William Gibbons, M.D., David Grainger, M.D., M.P.H., Marcelle Cedars, M.D., Tarun Jain, M.D., Nancy Klein, M.D., and Judy Stern, Ph.D., for the SART Research Committee Writing Group Birmingham, AL
The past decade has seen a fall in the number of embryos transferred accompanied by a reduction in the rate of higher order multiple pregnancies occurring from U.S. assisted reproductive technology (ART) cycles, which is temporally related to voluntary adherence to embryo transfer guidelines. The twin rate has remained relatively constant. The ability to continue the reduction in multiple pregnancies while maintaining advocacy positions for both patient couples and offspring will best occur with attention to scientific, sociologic, economic, and provider issues. (Fertil Steril 2007;88:301–4. 2007 by American Society for Reproductive Medicine.)
In this issue of Fertility and Sterility, the Society for Assisted Reproductive Technology (SART) Writing Group demonstrates that the institution of SART/American Society for Reproductive Medicine (ASRM) guidelines have had a significant impact in reducing both the number of embryos transferred and the incidence of high order multiple (HOM) pregnancies (1). Much progress is still required, however, before our goal of a healthy singleton birth for all couples is achieved. We also have pointed to some of the issues that have resulted in multiple pregnancies and to current technical limitations compromising the ability to further reduce multiple pregnancies and, in particular, twin gestations. The endeavor to markedly reduce the twinning rate with current embryo selection strategies, except in highly selected populations, appears to result in lower fresh pregnancy rates (2). So to decide to actively lower the twin rate, the majority of the U.S. ART community may have to change its priorities from ‘‘the best chances of pregnancy with minimal risk of HOM’’ to ‘‘the best chance of a singleton pregnancy with no likelihood of multiple pregnancy.’’ Should this be the only goal? To effect this change, there will need to be a comprehensive dialogue between reproductive endocrinologists, neonatologists, perinataologists, and patients that outlines the effects on mother and baby of a twin pregnancy (see adjoining editorials). The dialogue will need to include the balance between advocacy for patients and for in vitro fertilization (IVF) offspring. Patient acceptance of the advantages of exchanging lower birth rates for lower twin rates is vital, which to date has not occurred. What options are there to deal with the biological and sociological barriers to further reduction in the rate of all Received June 15, 2006; revised April 23, 2007; accepted April 24, 2007. The Society for Assisted Reproductive Technology (SART) Research Committee Writing Group. Reprint requests: William Gibbons, M.D., 9000 Airline Highway, Suite 670, Baton Rouge, Louisiana 70815 (FAX: 225-922-3730; E-mail: wgibbons@ crmbr.com).
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multiple pregnancies, including twins? By what mechanisms can we drive the current systems toward an acceptable solution of the issue of twining while maintaining the faith of our current patients and the health of their future children? We discuss some of the technical and sociopolitical issues that confront the field of ART, and we discuss directions that solutions might take. INCREASING SCIENTIFIC KNOWLEDGE TO ALLOW IMPROVED EMBRYO SELECTION Multiple embryos are transferred due to the inability to select a single embryo that will lead to a live birth. Governmental funding for research in IVF has been restricted. Allocation of valuable scientific resources would allow researchers to enhance their ability to select the embryos with the greatest likelihood for implantation. Our article addresses some of the current limitations to embryo selection. Not only must the techniques be possible, they must also be practical from the standpoint of cost, availability, and timeliness. It is heartening to see such National Institutes of Health (NIH) programs as the National Cooperative Program on Female Health and Egg Quality, which attempts to address endogenous and exogenous factors affecting oocyte quality. Scientific investigation of the observed increase in health risks relating to imprinting, preterm birth, and malformations warrants immediate attention. The causation of these adverse outcomes, whether related to ovulation induction, laboratory culture technique, or the infertile couples themselves, must be clarified. Improved research funding is essential for such studies. ALTERING THE STRUCTURE OF INSURANCE COVERAGE FOR ART The linkage of savings from neonatal intensive care unit costs for premature deliveries from multiple gestations with the IVF coverage for IVF cycles that impose strict limits on embryo transfer number has been shown to work in Europe. In some European countries, couples are allowed six IVF cycles
Fertility and Sterility Vol. 88, No. 2, August 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
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if they agree to standards limiting the embryo transfer number. Evaluation of health costs has indicated that a reduction in caring for HOM pregnancies would make this a cost-effective position and make patients more accepting of limiting embryo transfer numbers. This strategy would also have the marked benefit of allowing couples to reach ART at a younger age, when better egg quality would result in higher pregnancy rates, further enhancing cost effectiveness. This policy, however, has resulted in reported pregnancy rates that are lower than those reported in the United States (3, 4). Reducing the economic burden to patients while strictly adhering to embryo transfer guidelines is an important component of any further reduction in HOM pregnancies in the near term until the science of embryo selection improves. Because of the lack of linkage of ART costs with neonatal savings, implementation of such coverage has been complicated. Insurers have routinely argued against the inclusion of infertility treatment coverage as a basic policy benefit, claiming that the added costs of ART, especially IVF, will contribute greatly to increased medical care costs. They state that this could force employers to ultimately scale back or withdraw their benefit plans entirely and add to the number of uninsured (thus, scaring state legislatures). In a May 2006 study commissioned by RESOLVE: The National Infertility Association, William Mercer Company surveyed the experiences and attitudes of companies nationwide, both large (over 1000 employees) and small (under 200 employees). Among more than 600 employers that provided infertility coverage to their employees, 91% acknowledged that the impact of providing such coverage on their medical care costs was insignificant. In fact, 75% of these employers indicated that providing such coverage and their image as a ‘‘family friendly’’ employer has been a measurable advantage in recruiting and retaining valued employees. The study also suggested that employers not providing infertility coverage would reconsider their decision if they could be shown evidence of other employers’ positive experiences. Overcoming the reticence of insurers and employers has not been the sole problem; ART providers are ambivalent about insurance coverage because of the generally inadequate compensation and inconsistent, variable coverage across insurance plans. REAPPRAISING THE NATIONAL REPORTING SYSTEM Annually, by law, ART clinics report their live birth rates, stratified by age, diagnosis, and other variables. Although each report is accompanied by a warning against attempting to compare clinic success rates, the lay press annually publishes lists of the ‘‘best’’ clinics. This information is further disseminated through Internet sites and clinic advertising. There is the perception, expressed in medical journal articles and the national press, that the ART report may subtly (or not so subtly) affect ART clinic practice, not always for the better (5). In our report, clinics with lower implantation rates were sustaining acceptable live birth rates by transferring more embryos, which produced higher triplet rates as well. Even 302
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with the statements cautioning against comparing clinics, what are patients expected to do with the data? Can we say that there is any difference between two clinics of average size whose success rates are 38% and 43%? If the national reporting system is part of the problem, how do we address it? Can we protect the public, maintain trust, and alter data presentation to downplay small differences in pregnancy rates between clinics while emphasizing successful results in the form of singleton pregnancies? Schieve et al. have suggested emphasizing singleton pregnancy as the primary outcome in the national reporting system (6, 7), but such a change requires that patients see singletons as more desirable than twins. Others have suggested reporting implantation rates to more accurately reflect embryo quality (and likely program quality) (8). The former approach does not reflect embryo or laboratory quality in that a compromised program may transfer high numbers of embryos to sustain their pregnancy rate. The latter approach is currently implemented for SART clinics on the SART Web site. Although implantation rate may reflect embryo quality and may potentially be a better reflection of laboratory competence, it could also merely reflect greater patient selection by a clinic. Another consideration is to downplay small differences in pregnancy results by reporting clinic rates as 1 standard deviation from the national mean. This would simplify reporting and remove some of the competitive pressure on clinics generated by the fact that many patients assign significance to small percentage differences in pregnancy rates. However, it is not clear that this would adequately serve consumer interest (or satisfy the competitive nature of ART businesses). Currently, SART is working with RESOLVE and the American Fertility Association to obtain their feedback as to what information they would like to have about ART programs, as they also recognize the problems with the ART reporting system and have voiced support for seeing it evolve. Do we consider more significant changes in reporting to emphasize something other than fresh embryo-transfer pregnancies that would also change embryo-transfer strategy? One possible change is to adjust reporting to include the total reproductive potential (TRP) of a single IVF retrieval. The TRP is the pregnancy rate accumulating from the fresh plus all frozen transfers resulting from a single egg harvest. Published reports show similar (though slightly lower) pregnancy outcomes from transfer of one fresh embryo followed by transfer of one embryo in a frozen cycle, rather than transferring two embryos in the fresh cycle. There is a marked reduction in multiple pregnancy with this treatment paradigm (9, 10). This change would also mean changing the reporting to span more than 1 year to allow for the frozen embryo transfers to be included in the calculations. The past inability to link ART results to patients in a vertical fashion and across clinics is a weakness of the current reporting system. It limits our understanding of ‘‘family-based’’ results (i.e., whether a couple had ever conceived). One of the benefits of SART having a data set independent from the Centers for Disease Control and Prevention (CDC) data is the greater flexibility in making alterations Vol. 88, No. 2, August 2007
in how outcome data can be shown. To markedly alter the reporting system, all participants—the government, clinics, and in particular, patients—must come together and agree.
uate courses, plenary sessions, and oral/poster presentations. These educational programs at our national meeting have emphasized reduction of the number of embryos transferred and the multiple pregnancy issue.
IMPROVING PATIENT EDUCATION Efforts to educate patients concerning the risks to the health of infants, particularly twins, are valuable and must continue. This should occur through the interaction of health professionals with their patients and should be supplemented with an ongoing informed consent process. There has never been a more important time for comprehensive informed consent, and both ASRM and SARTare pursuing initiatives in this area. In recent years, experience has accumulated concerning the higher congenital anomaly rate and preterm birth rate of ART pregnancies (11, 12). Up-front clinic policies concerning embryo transfer number should be provided within the informed consent process to reduce the confrontation between clinicians and patients (and clinicians and embryologists) over embryo transfer number. Ideally, this would be tied to financial incentives, making couples more accepting of reducing embryo transfer number, and to better science, enabling clinics to have greater faith in the selection of embryos.
The SART system for identifying consistently lower performing programs and instituting mentorship can improve outcomes. This activity is an integrated effort between the Practice, Quality Assurance, Validation, and Advertising Committees, which produce the standards for ART, provide standard operating procedures to membership, and encourage patient protection by validating individual clinic results. Peers and patients are protected by evaluation of advertising claims. This is a continuous quality improvement process. It has been shown to be successful and its importance has been underestimated. The above quality assurance processes have now begun identifying those clinics that have excess triplet rates as well as low overall success rates. In addition to negative outliers, we also look at clinics that have been successful at limiting multiple pregnancies; our purpose is to acknowledge their leadership and evaluate what has worked for them. The goal is to raise the performance of all clinics and to improve the success of ART no matter how it is defined.
SHOULD THERE BE REGULATION? We hope not. Government regulation of a field as complex and rapidly changing as ART runs a substantial risk of being encumbered by inadequate flexibility. Changes in the law are notoriously slow and struggle keep pace with a rapidly evolving technology. Variations between the state’s current regulations have already resulted in reproductive tourism. But can voluntary guidelines work? Voluntary guidelines on the number of embryos to transfer have already resulted in a marked reduction in the percentage of HOM pregnancies. Calls to further reduce embryo transfer number via legislation should only be considered within the context of a comprehensive solution to link the reduction in the costs of caring for premature HOM pregnancies to an increase in IVF ‘‘insurance’’ coverage. Furthermore, this should not be done without consideration of the limitations of current embryo selection techniques and a commitment to research. Because the payers are often the infertile couples, simplistic solutions to mandate overly restrictive embryo transfer policies without balancing the financial costs doubly penalizes these couples. If European solutions are sought, both aspects (limitation of transfer number and reduced financial burden on the infertile couple) must be implemented. Mandatory, nonelective single embryo transfer without the context of an overall plan, compromises pregnancy outcome and imposes undue financial hardship on infertile couples. Vocal proponents on both sides of this issue can be found (13, 14).
CONCLUSIONS Further reduction in U.S. ART multiple pregnancies can be approached from scientific, economic, and educational directions. Options will expand as old technologies evolve and new ones develop. There are current models available in Europe, but it is not clear that economically balanced solutions for U.S. patients, providers, and ART teams are forthcoming in the present environment. While we wait for the scientific knowledge that will end multiples gestation as an issue, greater emphasis should be placed on advocacy for offspring as well as infertile couples. The balance of patients’ needs, societal needs, and those of ART offspring require comprehensive appraisal. In our report and this editorial, we have focused on the progress that has been made toward the reduction of HOM pregnancies and the limitations we face in reducing the twinning rate. We can be proud of the results of our voluntary efforts. From here, there will be a spectrum of solutions of varying merit from which to choose. As practitioners of ART and patient advocates, we can begin to make some of these difficult choices ourselves, or we can wait until external regulation forces arbitrary and perhaps overly simplistic solutions. Worse still, we can wait until the tort system intervenes. The wrong choice is to do nothing. While we wait for the science, there are choices to be made. Let us be the ones who make them. REFERENCES
EMPHASIZING AND IMPROVING THE OVERSIGHT AND EDUCATIONAL ASPECTS OF SART Comprehensive educational efforts are being promoted by SART, along with ASRM, through the dissemination of clinical and basic research at our annual meeting, with postgradFertility and Sterility
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