Hum. Reprod. Advance Access originally published online on October 27, 2005
Human Reproduction 2006 21(3):694-700; doi:10.1093/humrep/dei363
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Trends in embryo transfer practices and multiple gestation for IVF procedures in the USA, 1996–2002
Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
1 To whom correspondence should be addressed at: DRH, CDC Mailstop E-61, 1600 Clifton Road, Atlanta, GA 30329-1902, USA. E-mail: mtr6{at}cdc.gov
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Abstract |
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BACKGROUND: Increasing use of IVF in the USA has been a major contributor to the rising national multiple birth rate. Many have advocated that reducing the number of embryos transferred is essential for addressing the IVF-associated multiple birth problem. METHODS: A population-based sample of 506 072 IVF transfers performed in the USA in 1996–2002 was used to investigate trends in embryo transfer practices and to determine whether any changes in practice patterns have impacted the multiple gestation risk associated with IVF. RESULTS: The proportion of procedures in which
3 embryos were transferred declined significantly for most patient groups between 1996 and 2002. However, declines for some groups were not sizeable (from 79 to 73% and from 76 to 71% for fresh, non-donor procedures among women aged 38–40 and 41–42 years respectively) and transferring 3 embryos remained the norm for all groups. As of 2002, single embryo transfer had not increased for most groups and remained uncommon. Some declines in overall multiple gestation rates were observed, although multiple gestation risk associated with 2 embryos transferred increased significantly for all groups. CONCLUSIONS: Despite changes in embryo transfer practices, multiple gestation risk remains high, in part due to increased multiple gestation rates associated with the transfer of two embryos.
Key words: embryo transfer/IVF/multiple gestation
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Introduction |
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The rising multiple birth rate in the USA over the past two decades has been driven in large part by the increasing use of assisted reproductive technology (Reynolds et al., 2003b
; Wright et al., 2005). Assisted reproduction includes infertility treatments in which both oocytes and sperm, or embryos, are handled outside of the body for the purpose of establishing a pregnancy (i.e. IVF–transcervical embryo transfer, gamete and zygote intra-Fallopian transfer, ICSI, frozen embryo transfer, and donor embryo transfer). In 2002, an estimated 17.1% of all multiple births in the USA were attributable to assisted reproduction [15.5% of twins and 43.8% of triplet and higher order (triplet/+) births], although assisted reproduction-conceived infants accounted for only 1.1% of live births that year (Wright et al., 2005). Multiple birth is associated with numerous adverse infant and maternal health outcomes, including pregnancy complications, preterm delivery, low birthweight, cerebral palsy and other disabilities, and infant death (Spellacy et al., 1990; Gardner et al., 1995; Kiely, 1998; Senat et al., 1998; Martin and Park, 1999; ESHRE Capri Workshop Group, 2000; Kinzler et al., 2000; Martin et al., 2002; Pharoah, 2002; Nowak et al., 2003). Given the strong association between number of embryos transferred and multiple birth risk (Wright et al., 2005), assessment of embryo transfer practices is essential to understanding the multiple gestation and birth risk associated with assisted reproduction.
A recent ecological analysis based on data compiled from the Centers for Disease Control and Prevention’s (CDC) annual assisted reproduction success rate reports highlighted that, for IVF procedures using embryos derived from patients’ own freshly fertilized oocytes, the average number of embryos transferred declined from 3.8 in 1997 to 3.1 in 2001 (Jain et al., 2004). However, this analysis was limited in that assessment of average number of embryos transferred assumes a uniform linear increase in multiple gestation risk with each additional embryo transferred. In fact, previous detailed studies from the same data source indicate that the pattern of the relation between embryos transferred and multiple birth risk varies by maternal age (Wright et al., 2005). At younger ages, a linear relationship is observed, while at older ages, the pattern is less pronounced and suggestive of a threshold in risk at high order embryo transfers. Moreover, at all ages, the most marked differential in multiple gestation risk is observed between one and two embryo transfers. Thus, while questions remain about the impact on total pregnancy and live birth rates, a practice change from double to single embryo transfer would have a greater population impact on multiple gestation risk than a change from transferring 4 to 3 embryos. Additionally, a previous analysis of multiple birth rates and insurance coverage for assisted reproduction indicated that a reduction in the number of embryos transferred was only one of three factors underlying reduced multiple birth risk in a state with mandated assisted reproduction insurance coverage (Reynolds et al., 2003a). Lower embryo implantation rates among higher order embryo transfers and higher fetal loss rates among triplet or higher order gestations were also important factors.
The current study examines trends in embryo transfer practices and multiple gestation rates for assisted reproduction procedures performed in the USA from 1996 to 2002. Our aim is to document the extent to which practice patterns are shifting toward the transfer of fewer embryos, if at all, and to assess the impact such a shift might have on multiple gestation rates. We focus on the proportion of procedures in which 1, 2 and 3 embryos were transferred because these groups are quite different with respect to the type of associated multiple gestation risk. The transfer of 3 embryos puts women at substantial risk for both twin and triplet/higher order multiple gestations, but the transfer of two embryos creates a risk primarily for twin gestations, and single embryo transfer limits multiple gestation to instances of monozygotic twinning.
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Materials and methods |
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Study population
The 1992 Fertility Clinic Success Rate and Certification Act (US Congress, 1992
) mandates clinics in the USA that perform assisted reproduction treatment to report success rate data annually to CDC. Each year, the Society for Assisted Reproductive Technology creates a database of these procedures that, per contract, is shared with CDC. This database has been described in detail (Schieve et al., 2002). Between 92 and 95% of assisted reproduction clinics report data each year as required. While we do not have data to directly assess reasons for non-reporting, anecdotes suggest that many of the clinics not reporting data were smaller in size than average and many were practices that were closing or reorganizing at the time of data collection. We selected procedures initiated between 1996 and 2002 involving the transcervical transfer of IVF embryos (either through ICSI or standard IVF) into the uterus. The final sample consisted of 506 072 IVF transfers.
Data analysis
The annual proportions of procedures with 1, 2 and 3 embryos transferred were investigated separately for different types of IVF, classified according to whether the woman used her own oocytes (non-donor) or those donated by another woman (donor) and whether the embryos transferred were newly fertilized (fresh) or previously fertilized, frozen and then thawed (thawed). Data for non-donor procedures were stratified by patient age. Donor procedures were not analysed by age, because multiple gestation risk among donor procedures is not associated with patient age (Reynolds et al., 2001).
Additional analyses of embryo transfer practices restricted to procedures in which supernumerary embryos were cryopreserved for potential future use were performed for fresh, non-donor and donor procedures (n = 108 175 for fresh, non-donor; n = 22 708 for fresh, donor). This is a more homogeneous group in which patients were known to have had more embryos available than were actually transferred and therefore the embryos that were transferred were electively chosen. Whether extra embryos are cryopreserved is a function of multiple factors including patient choice, embryo availability, clinical assessment and clinic practice norms. This variable has been consistently found to be strongly associated with both increased live birth rates and multiple birth risk (Reynolds et al., 2001; Wright et al., 2005). Given the relative rarity of total single embryo transfer in the USA (Wright et al., 2005), consideration of embryo availability is particularly important for considering outcomes of single embryo transfers, as patients who elect to have 1 embryo transferred are probably different from patients who only have 1 embryo available.
Trends in overall multiple gestation rates were assessed for the four primary types of IVF, with fresh and thawed non-donor procedures stratified by age. In order to determine if factors other than changes in embryo transfer practices might be independently affecting multiple gestation rates, we also assessed trends in the multiple gestation rates associated with the transfer of 2, 3 and 4 embryos in fresh, non-donor and donor, procedures, stratified by patient age, assisted reproduction treatment type, and cryopreservation of supernumerary embryos (yes, no). A multiple gestation was defined as a pregnancy in which 2 fetal hearts were observed via ultrasound. Pregnancies with <2 hearts observed or missing fetal heart data were also coded as multiple gestations if they resulted in the delivery of 2 infants. Multiple gestation rates were calculated as multiple gestation pregnancies divided by total pregnancies.
Finally, we explored the potential impact that changing embryo transfer practices could have had on multiple gestation rates if other factors had not independently affected these rates as well. To do this, we estimated the expected multiple gestation rates for fresh, non-donor and donor, procedures for the years 1997–2002, if one assumed that the multiple gestation rates associated with 1, 2 and 3 embryos transferred from 1996 to 2002 had remained constant at the 1996 rates. That is, we estimated what the overall multiple gestation rate would have been for 1997–2002 if only the distribution of embryos transferred had changed. For each year of data from 1997 to 2002, we stratified the transfer procedures according to embryos transferred (1, 2, 3) and whether supernumerary embryos were available. For fresh, non-donor procedures, we additionally stratified by patient age (<35, 35–37, 38–40 years). (Because of small samples we were not able to include non-donor procedures among patients >40 years.) To each of these strata, we applied the corresponding 1996 pregnancy-per-transfer and multiple gestation-per-pregnancy rates and thus calculated the expected number of pregnancies, the expected number of multiple gestations, and the expected multiple gestation rates for procedures performed in 1997–2002.
In all analyses, trends were assessed using Mantel–Haenszel 
2-tests. This study was approved by the CDC’s institutional review board.
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Results |
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Table I displays the characteristics of the 506 072 IVF procedures performed between 1996 and 2002, by year. The number of procedures performed increased by 92% during this period, from 49 680 to 95 563. The distributions of patient age and IVF type were relatively consistent across years: Approximately 44% of all procedures were performed on women aged <35 years. More than 70% of transfers used newly fertilized embryos derived from the patients’ own oocytes (fresh, non-donor). For about one-third of transfers the patient had supernumerary embryos cryopreserved for future use, and thus was known to have elected to have transferred fewer embryos than were available.
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Table II presents the proportion of IVF procedures in which 1, 2 and 3 embryos were transferred, by IVF type and, for non-donor procedures, by patient age. Among fresh, non-donor procedures, single embryo transfer rates did not change much from 1996 to 2002, although changes did reach statistical significance for some groups. Although these rates were fairly low for all years in all age groups, they did increase with age (
4, 6, 8, 10 and 14% for ages <35, 35–37, 38–40, 41–42 and >42 years respectively). In contrast, sizeable increases were observed in the proportion with 2 embryos transferred and declines seen in the proportion with 3 embryos transferred for most groups. The shift from 3 to 2 embryos transferred was most pronounced for younger women and became less marked with each successive increase in age. Among women aged <35 years, the proportion with 2 embryos transferred increased by 394% from 8.7% in 1996 to 43.0% in 2002, while the proportion with 3 embryos transferred declined 40% from 87.2 to 52.3%. In contrast, among women aged 41–42 years, the relative increase in 2 embryos transferred was only 21% and the relative decrease in 3 embryos transferred was just 6%. No significant change in embryos transferred was observed for women aged >42 years.
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Among fresh, donor procedures, the proportion transferring a single embryo remained very low throughout, never >2.6%. An increase of 609% was seen in the transfer of 2 embryos (from 6.5 to 46.1%) and a corresponding 44% decrease was observed in the transfer of 3 embryos (from 91.8% to 51.4%).
For thawed, non-donor procedures in which the patient was aged <41 years and for thawed, donor procedures overall, significant increases were observed in the proportion of single embryo transfers. Even so, the overall proportion of single embryo transfers remained low (
12%) for these groups. As with fresh, non-donor and donor procedures, significant increases in the proportion with 2 embryos transferred and decreases in the proportion with 3 embryos transferred were seen.
Embryo transfer data for the subset of procedures with supernumerary embryos cryopreserved (i.e. known elective transfer of fewer embryos than available) indicate that, while there has been a substantial shift to transferring 2 in lieu of 3 embryos among these patients, almost none elected single embryo transfer (Table III). While single embryo transfer rates did show statistically significant increases for younger women using their own oocytes and for women using donor oocytes, the rate was never >1.3% for any group. The shift from 3 to 2 embryos transferred notwithstanding, the proportion transferring 3 embryos was >40% for all groups in 2002 and was particularly high (>80%) among women aged 38 years who used their own oocytes.
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Although fewer embryos were transferred for most groups, during the same time period pregnancy rates increased from 33.7 to 42.2% for fresh non-donor procedures, 46.3 to 58.0% for fresh donor procedures, 20.8 to 31.3% for thawed non-donor procedures, and 26.8 to 34.9% for thawed donor procedures. Among fresh and thawed non-donor procedures, the direction and magnitude of these trends was similar across age groups (data not shown).
Among fresh non-donor procedures from 1996 to 2002, statistically significant declines in the proportion of pregnancies that were triplet/+ gestation were observed for women aged <35 years (15.3 to 7.5%), 35–37 years (12.4 to 8.6%) and 38–40 years (8.6 to 5.6%). These notable improvements in rates of triplet/+ gestations, were offset somewhat by concurrent increases in twin gestations. Thus, the total decline in multiple gestation pregnancies, while statistically significant, was less than expected; rates dropped from 45.7 to 42.2% for women aged <35 years, from 40.3 to 39.1% for women aged 35–37 years, and from 32.9 to 30.4% for women aged 38–40 years. Although the triplet/+ gestation rate also appeared to decline among women aged >40 years, the trends were not significant and the multiple gestation rate remained stable (total multiple gestation rate for women aged >40 was 18.4% in 1996 and 19.3% in 2002). Among women using fresh, donor procedures, the triplet/+ gestation rate declined from 14.8 to 7.2%, the twin rate increased from 31.7 to 39.7%, and thus there was no change in the total multiple gestation rate (46.5% in 1996 to 46.9% in 2002). For thawed embryo procedures (both donor and non-donor), trends were in the same direction but less marked (data not shown).
More detailed trends in multiple gestation rates by number of embryos transferred and supernumerary embryo status are presented in Table IV for four groups of patients; women <35, 35–37 and 38–40 years of age who underwent fresh, non-donor IVF, and women of all ages who underwent fresh, donor IVF. From 1996 to 2002, the multiple gestation risk associated with transferring 2 fresh, non-donor embryos increased 81% among women aged <35 years (from 21.7 to 39.2%) and more than doubled among those aged 35–37 years (15.5 to 33.5%) and 38–40 years (9.8 to 24.0%). This risk also more than doubled (21.3 to 46.0%) for women of all ages using fresh, donor procedures. After stratification by supernumerary embryo status, significantly increased multiple gestation risk associated with 2 embryos transferred remained for all groups.
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The multiple gestation rate associated with 3 embryos transferred increased for only one subgroup (fresh, non-donor aged 35–37 years). No change in risk was seen for 4 embryos transferred. By 2002, the large increases in multiple gestation risk with 2 embryos transferred combined with the stagnant risks with 3 embryos transferred resulted in a substantial reduction in the multiple gestation risk differential between groups with 2 and 3 embryos transferred.
The increased multiple gestation rates associated with 2 embryos transferred resulted in smaller declines in the overall multiple gestation rate than would have been expected given the extent of the shift away from 3 embryo transfers from 1996–2002 (Table V). For example, the estimated multiple gestation rate for fresh, non-donor procedures among women aged 40 years in 2002 would have been 36.4% had multiple gestation rates associated with 2 embryos transferred not increased, rather than the actual rate of 39.5%.
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Discussion |
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The number of infertile couples benefiting from assisted reproduction treatment continues to increase along with the rising popularity of these treatments. However, in addition to monitoring treatment success, adverse consequences such as multiple birth and related adverse sequelae must also be considered. Our data suggest that embryo practice patterns are moving in the right direction, but more work may be needed. The proportion of IVF procedures in which
3 embryos were transferred declined between 1996 and 2002 overall and for most subgroups. However, transferring 3 embryos remained the norm in 2002. Additionally, most of the decline reflected a shift to transferring 2 embryos, with no meaningful increase observed in the proportion of single embryo transfers among fresh, non-donor or donor procedures. Among patients known to have had >1 embryo available, rates of single embryo transfer did not reach 1.5%. Coinciding with the shift from transferring 3 to 2 embryos were substantial increases in multiple gestation rates associated with 2 embryos transferred from 1996–2002. Overall, this rate nearly or more than doubled for the groups investigated. In fact, the multiple gestation rate associated with transferring 2 embryos in 2002 was in many cases comparable to the rate associated with transferring 3 embryos in 1996. Thus while the downward shift in number of embryos transferred did appear to have some impact on the total multiple gestation rate, estimates of expected multiple gestation rates for 1997–2002 suggest that the impact was mitigated by the marked increase in twinning with double embryo transfers.
While the declines observed in triplet/+ gestation pregnancies are certainly encouraging, it is important to note that in 2002, triplet/+ births associated with assisted reproduction treatment were still substantially increased compared to the total US population and thus assisted reproduction treatment is still estimated to account for >40% of all triplet births in the USA (Wright et al., 2005). In this analysis and presentation, we intentionally focused on the total multiple gestation risk; twin gestations and births are themselves associated with markedly higher risk for adverse perinatal and child outcomes compared with singletons (ESHRE, 2000). Moreover, given that the vast majority of multiple gestations in all years of the study were twins, the population attributable risks for the numerous adverse outcomes associated with multiple gestation are likely to be much higher for assisted reproduction treatment twin than triplet/+ births. Indeed, there is growing consensus that assisted reproduction treatment success is optimally defined as a singleton live birth (ESHRE, 2001; World Health Organization, 2001; Evers, 2002; Hogue, 2002; Adamson and Baker, 2004; Cohen and Jones, 2004; Healy, 2004; Min et al., 2004; Schieve and Reynolds, 2004).
Although opinions differ on the most effective strategies for reducing the multiple birth risk associated with assisted reproduction treatment, discussions largely centre on defining appropriate embryo transfer practices for different patient groups vis-à-vis their multiple birth risk (Bertarelli Group, 2003; Adamson and Baker, 2004). Clearly, a shift to single embryo transfer would eliminate nearly all multiple births associated with assisted reproduction treatment. However, such a practice change may have trade-offs that are unacceptable to many couples and assisted reproduction treatment providers. Given the high costs of assisted reproduction treatment, limited insurance coverage in the USA, and the general perception that the chance for a live birth in a single treatment cycle with single embryo transfer is lower than for treatment cycles with double or more embryo transfer, single embryo transfer is not currently a popular option among couples seeking assisted reproduction treatment. Randomized studies, such as the recent analysis by Thurin et al. (2004), demonstrating the high efficacy of transferring one fresh embryo with the option of subsequent transfer of a thawed embryo if needed, are encouraging; however, this study, like most others to date, focused primarily on good prognosis patients and the results are not necessarily generalizable to all sub-groups of patients seeking assisted reproduction treatment (Gerris, 2005). Thus, embryo transfer decisions in the context of maintaining high pregnancy and live birth rates remains complex for many patients.
In some European countries, laws and regulations strictly limit the number of embryos that can be transferred at a time (Cohen and Jones, 2004); other countries, including the USA, have opted for voluntary guidelines (American Society for Reproductive Medicine, 2004). In November of 1999, during the time period of this study, the American Society of Reproductive Medicine revised their guidelines regarding embryo transfer practices, decreasing the recommended number of embryos transferred for some patient groups (American Society for Reproductive Medicine, 1999). We were not able to directly evaluate the impact of these guidelines because we do not have data on specific factors influencing individual provider–patient decisions about embryo transfer. Likewise, we cannot assess the impact of increased publicity regarding assisted reproduction treatment-associated multiple births, expanding assisted reproduction insurance coverage in some states, and patient education campaigns on embryo transfer practices.
There is concern that mandatory reporting and publication of clinic level-assisted reproduction success rates may actually be contributing to the high multiple gestation rates in the USA (Grifo et al., 2001). That is, pressure placed on providers to maximize success may have the undesired result of increasing multiple gestation risk via higher numbers of embryos transferred. Although it is impossible to assess whether number of embryos transferred would have declined more had the assisted reproduction reporting mandate not been enacted, the trends reported here suggest that the mandate did not lead to increased numbers of embryos transferred. In fact, this study indicates that number of embryos transferred has decreased since CDC began publishing data in accordance with the Fertility Clinic Success Rate and Certification Act (US Congress, 1992). The first reports published by CDC were in 1998 and 1999 and were based on retrospective data collection of procedures performed in 1995 and 1996. Our data show an increased tendency to transfer fewer embryos after 1998 in comparison with previous years.
The strengths of our study included the completeness and representativeness of the data and the large sample, which allowed sufficient power for multiple stratifications. That the data are observational, while appropriate for assessing trends in embryo transfer practices, raises limitations for analyses of multiple gestation and births. In considering our results one must remember that women were not randomized to receive a specific number of embryos. Thus, we cannot rule out the possibility that patient and treatment factors we could not evaluate had an influence on trends in multiple gestation risk over time. Also, patients who underwent procedures more than once throughout the period of study are represented multiple times in the dataset and cannot be linked. Although we can identify those procedures in which supernumerary embryos were cryopreserved for future use, we cannot distinguish among the remaining procedures those in which all available embryos were transferred from those in which patients elected to have fewer embryos transferred than were available but did not have supernumerary embryos cryopreserved. Nonetheless, this study demonstrates that the total rate of single embryo transfer (both elective and non-elective) remains low. Finally, the latest available population-based assisted reproduction data for the USA at the time of this study was 2002. It is not possible to assess whether these trends have continued and thus whether current embryo practice patterns are even more encouraging than those reported here. Given complexities of gathering and verifying data from >400 medical practices and the necessary time lag of 9 months if one wants to assess birth outcomes potentially associated with assisted reproduction practice, it is unlikely that any large population-based data system will afford the opportunity for accurate ‘real-time’ assessment of assisted reproduction practices and outcomes. Assessments, such as this one, however, still provide important data on the direction and magnitude of trends, and point to specific areas where further attention and monitoring are indicated.
Our study documents that, although a shift from higher order embryo transfers in favour of transferring 2 has occurred, transferring 3 embryos was still the norm in 2002. This shift has not resulted in a substantial decrease in multiple gestation rates, in part because of the increased multiple gestation rates associated with 2 embryos transferred. These data can inform the current debate regarding embryo transfer guidelines in the USA and how changes in these guidelines might achieve their desired impact of reducing multiple birth risk (American Society for Reproductive Medicine, 2004).
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Submitted on March 10, 2005; resubmitted on September 28, 2005; accepted on September 29, 2005.
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