Fertility Treatments and Multiple Births in the United States

Transcription

1 The new england journal of medicine original article Fertility Treatments and Multiple Births in the United States Aniket D. Kulkarni, M.B., B.S., M.P.H., Denise J. Jamieson, M.D., M.P.H., Howard W. Jones, Jr., M.D., Dmitry M. Kissin, M.D., M.P.H., Maria F. Gallo, Ph.D., Maurizio Macaluso, M.D., Dr.P.H., and Eli Y. Adashi, M.D. ABSTRACT From the Women s Health and Fertility Branch, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta (A.D.K., D.J.J., D.M.K., M.F.G.); the Johns Hopkins School of Medicine, Baltimore (H.W.J.); the Eastern Virginia Medical School, Norfolk (H.W.J.); the Division of Biostatistics and Epidemiology, Cincinnati Children s Hospital Medical Center, Cincinnati (M.M.); and the Warren Alpert Medical School, Brown University, Providence, RI (E.Y.A.). Address reprint requests to Dr. Kulkarni at the Women s Health and Fertility Branch, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 477 Buford Hwy., NE, Mailstop F-74, Atlanta, GA 3341, or at eof@cdc.gov. N Engl J Med 213;369: DOI: 1.156/NEJMoa Copyright 213 Massachusetts Medical Society Background The advent of fertility treatments has led to an increase in the rate of multiple births in the United States. However, the trends in and magnitude of the contribution of fertility treatments to the increase are uncertain. Methods We derived the rates of multiple births after natural conception from data on distributions of all births from 1962 through 1966 (before fertility treatments were available). Publicly available data on births from 1971 through 211 were used to determine national multiple birth rates, and data on in vitro fertilization (IVF) from 1997 through 211 were used to estimate the annual proportion of multiple births that were attributable to IVF and to non-ivf fertility treatments, after adjustment for maternal age. Trends in multiple births were examined starting from 1998, the year when clinical practice guidelines for IVF were developed with an aim toward reducing the incidence of multiple births. Results We estimated that by 211, a total of 36% of twin births and 77% of triplet and higher-order births resulted from conception assisted by fertility treatments. The observed incidence of twin births increased by a factor of 1.9 from 1971 to 29. The incidence of triplet and higher-order births increased by a factor of 6.7 from 1971 to 1998 and decreased by 29% from 1998 to 211. This decrease coincided with a 7% reduction in the transfer of three or more embryos during IVF (P<.1) and a 33% decrease in the proportion of triplet and higher-order births attributable to IVF (P<.1). Conclusions Over the past four decades, the increased use of fertility treatments in the United States has been associated with a substantial rise in the rate of multiple births. The rate of triplet and higher-order births has declined over the past decade in the context of a reduction in the transfer of three or more embryos during IVF. (Funded by the Centers for Disease Control and Prevention.) 2218 n engl j med 369;23 nejm.org december 5, 213

2 fertility Treatments and Multiple Births In vitro fertilization (IVF) and non-ivf fertility treatments (i.e., ovulation induction and ovarian stimulation) constitute major risk factors for the genesis of multiple births (twin, triplet, and higher-order births). 1 IVF procedures, which are defined as procedures in which eggs and sperm are manipulated with the purpose of establishing a pregnancy, represent the overwhelming majority of procedures for assisted reproductive technology. Ovulation induction and ovarian stimulation, which are often included as part of the IVF process, are also coupled with timed intercourse or intrauterine insemination to establish a pregnancy independently of IVF. In ovulation induction, drugs are administered to induce ovulation in women who are otherwise anovulatory. 2 In contrast, ovarian stimulation is a process in which drugs are used to promote multifollicular ovarian development and ovulation in women who are subfertile. 2 Multiple births resulting from fertility treatments are associated with increased health risks for women and their offspring, 3-6 as well as substantial financial costs to families and society. 7,8 Limiting the number of embryos transferred during IVF cycles is important for reducing multiple births. 9,1 Although the practice of transferring three or more embryos in a single cycle has declined steadily, several factors may constrain efforts at further reduction. First, competition among fertility clinics may result in an intense focus on per-cycle pregnancy rates. 11 Second, financial exigencies encountered by patients may drive up the number of embryos transferred in the hope of maximizing per-cycle pregnancy rates. 12 Finally, patient acceptance of multiple births and the risks thereof may contribute to the transfer of more embryos. 13 Whereas the use of IVF is documented in a congressionally mandated national registry in the United States, the use of non-ivf fertility treatments is not and thus is not directly ascertainable. Nevertheless, non-ivf fertility treatments are associated with a substantial proportion of multiple births and have been shown to account for more multiple births than IVF. 17,18 In this study, we expanded on these earlier observations by conducting a longitudinal analysis to determine the trends in and magnitude of the contribution of fertility treatments to multiple births. Methods Estimation of the Rate of Multiple Births This study was approved by the institutional review board at the Centers for Disease Control and Prevention (CDC). We used publicly available birth data from the National Center for Health Statistics (NCHS) of the CDC to determine the annual national rates of multiple births over the course of the four decades (1971 through 211) during which fertility treatments have been available in the United States. 19 To correct for the effect of maternal age on multiple births, rates of twin births and of triplet and higher-order births, adjusted for maternal age, were calculated with the use of direct standardization, with the distribution of maternal age (<3, 3 to 34, 35 to 39, and 4 years) in 1971 used for the standard population. 2,21 The unit of analysis for a live birth was the live-born infant, not the delivery that resulted in a live-born infant. A live-born infant delivered from a multiplegestation pregnancy was included in the category of multiple birth. Rates of twin births and of triplet and higher-order births were calculated per 1 live births (i.e., per 1 live-born infants). Although NCHS birth data include all live births in the United States, we included only live births for which the mother resided in 1 of the 5 states or the District of Columbia. Estimation of Proportion of Multiple Births Resulting from Medically Assisted Conception Currently, the characterization of births as resulting from medically assisted conception versus natural conception is not included in data on vital statistics; hence, we had to estimate the relative contributions of births from these types of conception from the national incidence of multiple births. Medically assisted conceptions were defined as those that resulted from IVF or other fertility treatments, whereas natural conceptions were defined as those that were not assisted by fertility treatment. Since data on births resulting from IVF are available only from 1997 on, multiple births resulting from medically assisted versus natural conception were estimated for the period from 1997 through 211. Using a method similar to the method for estimating maternal age adjusted national rates of multiple births, we estimated the proportion of multiple births resulting from natural conception and the propor- n engl j med 369;23 nejm.org december 5,

3 The new england journal of medicine tion resulting from medically assisted conception using direct standardization, with the distribution of maternal age (<3, 3 to 34, 35 to 39, and 4 years) in 1997 used for the standard population. Direct standardization allowed us to account for the effect of maternal age in order to make the proportions comparable across years. Because the years 1962 through 1966 predated the availability of fertility treatments, we assumed that the distribution of the plurality of all births (singletons, twins, and triplets and higher-order multiples) during this period would approximate the distribution of the plurality of births from natural conceptions in the period from 1997 through 211. With this assumption, we estimated the annual occurrence of twin births and of triplet and higherorder births from natural conception. Next, we estimated the annual proportions of twin births and of triplet and higher-order births attributable to medically assisted conceptions by calculating the differences between the national numbers of multiple births and the estimated numbers of multiple births from natural conception. Estimation of Proportion of Multiple Births Resulting from IVF Using data from the National ART [Assisted Reproductive Technology] Surveillance System (NASS) of the CDC, we estimated the annual proportion of multiple births from medically assisted conceptions that involved IVF. We included in this category multiple births from all assisted reproductive technology procedures namely, IVF, gamete intrafallopian transfer, and zygote intrafallopian transfer with IVF accounting for an overwhelming majority of these procedures (>99% currently). The remaining births from medically assisted conceptions were classified as multiple births resulting from non-ivf fertility treatments. Clinics are federally mandated to report to the CDC information on their IVF procedures and the outcomes. 22 Currently, the NASS captures data on more than 95% of IVF procedures performed annually in the United States. IVF data have been available since Since there is no national registry for non-ivf fertility treatments, we estimated the proportion of multiple births from non-ivf fertility treatments by calculating the difference between the total number of medically assisted multiple births and the corresponding number of multiple births from IVF. NASS data were also used to describe the secular changes in the rates of live births resulting from IVF-assisted conception and in the number of embryos transferred during IVF, including the use of elective and nonelective single-embryo transfers during procedures in which fresh rather than frozen embryos were transferred. Singleembryo transfers during IVF were classified as elective if one embryo was transferred and at least one embryo was cryopreserved. The remaining single-embryo transfers, in which no embryos were cryopreserved during the procedure, were classified as nonelective single-embryo transfers. Guidelines for Reducing Multiple Births Resulting from IVF The Society for Assisted Reproductive Technology first developed practice guidelines aimed at reducing multiple births in The guidelines focused on limiting the number of embryos transferred during an IVF procedure. Revised guidelines have been published multiple times since Because we expected the 1998 guidelines to effect a change in the proportion of multiple births resulting from IVF in the years after 1998, we performed a test for trend for the overall period from 1998 through 211. We used linear regression, in which the outcome was the proportion of twin or triplet and higher-order births resulting from IVF and non-ivf treatments and the explanatory variable was the year. Similarly, we performed a test for trend for national multiple birth rates and the number of embryos transferred during IVF for the period from 1998 through 211, to evaluate the effects of the 1998 guidelines. Results Observed Rates of Multiple Births The observed national rates of twin births and of triplet and higher-order births from 1971 through 211 are shown in Figure 1. The observed rate of twin births (Fig. 1A) increased by a factor of 1.9 from 1971 to 29, the year in which the highest rate was observed, whereas the observed rate of triplet and higher-order births (Fig. 1C) increased by a factor of 6.7, with the highest rate seen in From 1998 to 211, the rate of triplet and higher-order births declined by 29%, from 1.94 to 1.37 per 1 live births (P<.1 for trend). The overall proportion of total national births that 222 n engl j med 369;23 nejm.org december 5, 213

4 fertility Treatments and Multiple Births A Observed and Maternal Age Adjusted Rates of Twin Births 35 Observed 3 National Twin Births (no. per 1 live births) Age-adjusted B Observed Maternal Age Pattern for Twin Births Maternal Age (% of national twin births) <3 Yr Yr Yr 4 Yr C Observed and Maternal Age Adjusted Rates of Triplet and Higher-Order Births National Triplet and Higher-Order Births (no. per 1 live births) Observed Age-adjusted D Observed Maternal Age Pattern for Triplet and Higher-Order Births Maternal Age (% of national triplet and higher-order births) 9 8 <3 Yr Yr Yr 1 4 Yr Figure 1. Rates of Multiple Births, Shown are observed national rates of twin births (Panel A) and triplet and higher-order births (Panel C), as well as the rates adjusted for maternal age, for the period from 1971 to 211. Also shown are observed maternal age patterns for twin births (Panel B) and triplet and higher-order births (Panel D) during the same period. were multiple births grew from 1.8% in 1971 to 3.5% in 211. Given the effect of maternal age on multiple births, we plotted the observed maternal age patterns for twin births (Fig. 1B) and triplet and higher-order births (Fig. 1D) from 1971 through 211. Over the course of this period, the proportion of twin births and of triplet and higher-order births among women younger than 3 years of age declined by 39% and 6%, respectively. In contrast, the proportion of all multiple births among women older than 3 years of age more than doubled, from 24% to 54% (a 125% increase). After adjustment for maternal age, the national rate of twin births (Fig. 1A) increased by a factor of 1.6 from 1971 to 29, the year in which the highest rate was observed, and the national rate of triplet and higher-order births (Fig. 1C) increased by a factor of 4.8 from 1971 to 1998, the year in which the highest rate was observed. Estimated Proportions of Multiple Births According to Method of Conception Figure 2 shows the estimated national proportions, adjusted for maternal age, of twin births and of triplet and higher-order births resulting from natural conception, medically assisted conception, IVF, and non-ivf fertility treatments from 1997 to 211. We estimated that the proportion of twin births resulting from medically assisted conceptions rose from 27% in 1998 to 36% in 211 n engl j med 369;23 nejm.org december 5,

5 The new england journal of medicine A Twin Births 9 Method of Conception (% of national twin births) B Triplet and Higher-Order Births 9 Method of Conception (% of national triplet and higher-order births) IVF Natural conception Natural conception Medically assisted conception Non-IVF treatments Medically assisted conception Non-IVF treatments Figure 2. Multiple Births, According to Method of Conception, Shown are the estimated national proportions, adjusted for maternal age, of twin births (Panel A) and triplet and higher-order births (Panel B) that resulted from natural conception, medically assisted conception, in vitro fertilization (IVF), and non-ivf fertility treatments during the period from 1997 through 211. (P<.1 for trend). In contrast, we estimated that the proportion of triplet and higher-order births from medically assisted conceptions declined from 84% in 1998 to 77% in 211 (P<.1 for trend). From 1998 to 211, the estimated proportion of twin births that were attributable to IVF increased from 1% to 17% (a 7% increase, P<.1 for trend), and the proportion of triplet and higher-order births attributable to IVF declined from 48% to 32% (a 33% decrease, P<.1 IVF for trend). The estimated proportion of twin births that were attributable to non-ivf fertility treatments increased from 16% in 1998 to 19% in 211 (P =.8 for trend), and the estimated proportion of triplet and higher-order births attributable to non-ivf fertility treatments increased from 36% in 1998 to 45% in 211 (P<.1 for trend). IVF Birth Cohort The trends from 1997 through 211 for singleton, twin, and triplet and higher-order birth rates within the IVF birth cohort are shown in Figure 3. The rate of triplet and higher-order births attributable to IVF decreased by 79% from 1998 to 211, to a rate of 3 births per 1 IVF-related births in 211. Concurrently, the IVF singleton birth rate increased by 29%, to a rate of 544 births per 1 IVF-related births in 211. These trends converge to mark 25 as the first year during which multiple births accounted for less than 5% of the IVF birth cohort. Nevertheless, in 211, IVF accounted for 2% of all multiple births nationally. Figure 4 shows the annual proportion of IVF procedures during the years 1997 through 211 in which one, two, or three or more embryos were transferred. From 1998 to 211, the proportion of procedures in which three or more embryos were transferred declined by 7%, from 79% to 24% (P<.1 for trend). In contrast, from 1998 to 211, the proportion of IVF procedures in which two embryos were transferred increased from 16% to 55% (P<.1 for trend), and the proportion in which a single embryo was transferred increased from 6% to 21% (P<.1 for trend). Stratification of the fresh-embryo transfers into elective single transfers (i.e., those in which one embryo was transferred and at least one embryo was cryopreserved) and nonelective single transfers (i.e., those in which no embryos were cryopreserved during the procedure) revealed that the proportion of elective singleembryo transfers crossed the 1% mark in 25, increased by about 1% annually thereafter, and reached a rate of 9% by 211 (Fig. 4B). Discussion The high incidence of multiple births in the United States is a consequence of advanced maternal age at delivery and fertility treatments. 23,24 This conclusion is supported by the calculated observed and maternal-age adjusted national rates of twin births and triplet and higher-order births 2222 n engl j med 369;23 nejm.org december 5, 213

6 fertility Treatments and Multiple Births and the estimated proportions of twin births and triplet and higher-order births from conception assisted by fertility treatments. We estimated that by 211, a total of 36% of twin births and 77% of triplet and higher-order births were attributable to medically assisted conceptions. Despite these trends, several indicators suggest that the incidence of multiple births may be stabilizing. The rate of triplet and higher-order births peaked in 1998 and has been declining since then. This decrease has coincided with a 7% reduction in the transfer of three or more embryos during IVF and a 33% decrease in the proportion of triplet and higher-order births attributable to IVF. During the period from 1997 through 211, the increased reliance on single-embryo and doubleembryo transfers during IVF succeeded in reducing the rate of triplet and higher-order births. The forces underlying the decline in the number of embryos transferred probably include professional societies, which have repeatedly revised practice guidelines to include recommendations for lowering the number of embryos transferred during IVF. 25 Consideration must also be given to the effects of insurance coverage for IVF services, 26 ongoing public reporting, 27 promotion of single-embryo transfers, 28 and technological advances. The feasibility of culturing embryos beyond the early cleavage stage to the highly implantable blastocyst stage has led to the growing acceptance of single-embryo transfers. 29 The trends for non-ivf fertility treatments were less favorable than those observed for IVF, presumably reflecting an increase in multiple births attributed to the non-ivf treatments of ovulation induction and ovarian stimulation. An earlier study by Reynolds and colleagues with the use of data from 1997 through 2 identified non-ivf fertility treatments as the leading contributor to medically assisted multiple births. 18 The methods in that study were similar to the ones in our study (but without direct standardization for adjustment for maternal age), and the investigators used 1971 rates to estimate the number of multiple births from natural conception. Our findings suggesting that ovulation induction and ovarian stimulation are important contributors to the multiple birth rate is consistent with findings from other studies ,3 For example, in a clinical trial by Guzick and colleagues involving women who underwent ovarian superovulation and intrauterine insemination, a large proportion of pregnancies resulted in No. of Births per 1 IVF-related Births multiple births, including quadruplets, triplets, and twins. 31 Major strengths of our study were the use of maternal age distributions predating fertility treatments to estimate the rate of multiple births from natural conceptions and the use of direct standardization to estimate the proportions of multiple births that were attributable to IVF and to non-ivf fertility treatments. Thus, we were able to account for the difference in maternal age distribution between the period before and the period after the use of fertility treatments and to carry out a valid comparison of proportions from 1997 through 211. Our study has a few important limitations. First, because of the unavailability of outcome data according to obesity status, race, and ethnic group, we are unable to adjust for changes in these factors over time. It has previously been shown that obese women have an increased likelihood of delivering dizygotic twins, whereas the likelihood is reduced for Hispanic women. 32,33 A family history of twins, prior pregnancies, maternal height, and improved perinatal care are other factors that may confound our estimates. Second, our analysis may have overestimated the contribution of non-ivf fertility treatments. Some multiple births attributed to this type of treatment could represent unreported IVF births originating in nonreporting fertility clinics. Since 1997, an estimated 6.1 to 11.8% of fertility clinics have chosen to forgo public reporting. 22 Alternatively, some multiple births attributed to Singleton Twin Triplet and higher-order Figure 3. National Rates of Singleton, Twin, and Triplet and Higher-Order Live Births Resulting from IVF, n engl j med 369;23 nejm.org december 5,

7 The new england journal of medicine A No. of Embryos Transferred (% of total embryo transfers) B Category of Single-Embryo Transfer (% of fresh embryo transfers) or more Nonelective single Double Single Elective single Figure 4. Embryo Transfer during IVF, Panel A shows data on the transfer of one, two, or three or more embryos as a percentage of the total number of embryo-transfer procedures during the period from 1997 through 211. Panel B shows data on elective and nonelective single-embryo transfers as a percentage of the total number of procedures involving fresh-embryo transfers during the same period. Singleembryo transfers during IVF were defined as elective when one embryo was transferred and at least one embryo was cryopreserved. Single-embryo transfers in which no embryos were cryopreserved during the procedure were classified as nonelective. non-ivf treatments could reflect IVF births that have been lost to follow-up. However, these relative shortcomings are unlikely to have materially affected our findings because nonreporting clinics are typically small, 34 and validation of the reporting of births by clinics has been shown to be accurate. 35 Because of the lack of national birth data to distinguish between natural conception and non-ivf fertility treatments, our related estimates might be underestimated or overestimated to some extent. Finally, the reliance of this study on birth data probably resulted in an underestimation of the true extent of gestational plurality because it did not take into account spontaneous fetal loss and procedures for reducing multifetal gestation Reducing the rate of multiple births will require sustained efforts. Multiple births resulting from IVF are largely preventable by limiting the number of embryos transferred. Increased acceptance of elective single-embryo transfers is likely to require a shift in clinical emphasis from a cross-sectional cycle-centered mindset (i.e., pregnancy rate per cycle) to a longitudinal patient-centered outlook (i.e., cumulative pregnancy rate per patient). 39 It is much more difficult to prevent multiple births resulting from ovulation induction and ovarian stimulation because of unpredictable follicular growth dynamics. 4 Monitoring notwithstanding, the number of oocytes destined to ovulate and fertilize cannot be reliably predicted. 2,41 However, adherence to prudent practice patterns, including the use of low-dose gonadotropins, could reduce the rate of multiple births while maintaining acceptable per-cycle pregnancy rates. 42 The Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation study (AMIGOS; ClinicalTrials.gov number, NCT144862), which is currently being conducted by the Reproductive Medicine Network, may provide a better understanding of how rates of multiple gestations might be reduced among women undergoing ovulation induction and ovarian stimulation. Consideration should also be given to expanding current public reporting to include ovulation induction and ovarian stimulation. Finally, valid and complete implementation of changes to birth certificates to capture births resulting from various fertility treatments could prove to be helpful. In conclusion, the rate of triplet and higherorder births has declined over the past decade in the context of a reduction in the transfer of three or more embryos during IVF. Increased awareness of multiple births resulting from non-ivf fertility treatments may lead to improved medical practice patterns and a decrease in the rate of multiple births. Supported by the Centers for Disease Control and Prevention. Dr. Adashi reports receiving fees for board membership from and holding stock in Alere. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org n engl j med 369;23 nejm.org december 5, 213

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