Assisted Reproductive Technology Surveillance --- United States, 2004

Please note: An erratum has been published for this article. To view the erratum, please click here.

Victoria Clay Wright, MPH, Jeani Chang, MPH, Gary Jeng, PhD,
Michael Chen, PhD, Maurizio Macaluso, MD, DrPH
Division of Reproductive Health
National Center for Chronic Disease Prevention and Health Promotion

Corresponding author: Victoria Clay Wright, MPH, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, 4770 Buford Hwy., N.E., MS K-34, Atlanta, GA 30341. Telephone: 770-488-6384; Fax: 770-488-6391; E-mail: [email protected].

Abstract

Problem/Condition: In 1996, CDC initiated data collection regarding assisted reproductive technology (ART) procedures performed in the United States, as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493 [October 24, 1992]). ART includes fertility treatments in which both eggs and sperm are handled in the laboratory (i.e., in vitro fertilization and related procedures). Patients who undergo ART procedures are more likely to deliver multiple-birth infants than women who conceive naturally. Multiple births are associated with increased risk for mothers and infants (e.g., pregnancy complications, premature delivery, low-birthweight infants, and long-term disability among infants).

Reporting Period Covered: 2004.

Description of System: In 2004, CDC contracted with a statistical survey research organization, Westat, Inc., to obtain data from ART medical centers in the United States. Westat, Inc., maintains CDC's web-based data collection system called the National ART Surveillance System.

Results: In 2004, a total of 127,977 ART procedures were reported to CDC. These procedures resulted in 36,760 live-birth deliveries and 49,458 infants. Nationwide, 74% of ART procedures used freshly fertilized embryos from the patient's eggs, 15% used thawed embryos from the patient's eggs, 8% used freshly fertilized embryos from donor eggs, and 4% used thawed embryos from donor eggs. Overall, 42% of ART transfer procedures resulted in a pregnancy, and 34% resulted in a live-birth delivery (delivery of one or more live-born infants). The highest live-birth rates were observed among ART procedures that used freshly fertilized embryos from donor eggs (51%). The highest numbers of ART procedures were performed among residents of California (17,303), New York (11,123), Illinois (9,306), Massachusetts (8,906), and New Jersey (8,513). These five states also reported the highest number of infants conceived through ART. Of 49,458 infants born through ART, 50% were born in multiple-birth deliveries. The multiple-birth risk was highest for women who underwent ART transfer procedures that used freshly fertilized embryos from either donor eggs (40%) or their own eggs (33%). Approximately 1% of U.S. infants born in 2004 were conceived through ART. Those infants accounted for 18% of multiple births nationwide. Approximately 9% of ART singletons, 56% of ART twins, and 95% of ART triplets or higher-order multiples were low birthweight. The percentages of ART infants born preterm were 15% among singletons, 64% among twins, and 98% among triplets or higher-order multiples.

Interpretation: Whether an ART procedure resulted in a pregnancy and live-birth delivery varied according to different patient and treatment factors. ART poses a major risk for multiple births. This risk varied according to the patient's age, the type of ART procedure performed, the number of embryos transferred, the day of embryo transfer (day 3 or day 5), and embryo availability.

Public Health Actions: ART-related multiple births represent a sizable proportion of all multiple births nationwide and in selected states. To minimize the adverse maternal and child health effects that are associated with multiple pregnancies, ongoing efforts to limit the number of embryos transferred in each ART procedure should be continued and strengthened. Adverse maternal and infant outcomes (e.g., low birthweight and preterm delivery) associated with ART treatment choices should be explained fully when counseling patients who are considering ART.

Introduction

Since 1978, assisted reproductive technology (ART) procedures have been used to overcome infertility. ART procedures include those infertility treatments in which both eggs and sperm are handled in the laboratory for the purpose of establishing a pregnancy (i.e., in vitro fertilization [IVF] and related procedures). Since the birth of the first U.S. infant conceived with ART in 1981, use of these treatments has increased dramatically. Each year, both the number of medical centers providing ART services and the total number of procedures performed have increased notably (1).

In 1992, Congress passed the Fertility Clinic Success Rate and Certification Act (FCSRCA),* which requires each medical center in the United States that performs ART procedures to report data to CDC annually on every ART procedure initiated. CDC uses the data to report medical center--specific pregnancy success rates. In 1997, CDC published the first surveillance report under this mandate (2). That report was based on ART procedures performed in 1995. Since then, CDC has continued to publish a surveillance report annually that details each medical center's success rates. CDC also has used this surveillance data file to perform more in-depth analyses of infant outcomes (e.g., multiple births) (3--10). Multiple-infant births are associated with greater health problems for both mothers and infants, including higher rates of caesarean deliveries, prematurity, low birthweight, and infant death and disability (11,12). In the United States, ART has been associated with a substantial risk for multiple gestation pregnancy and multiple birth (3--10). In addition to the multiple-birth risks, studies suggest an increased risk for low birthweight among singleton infants conceived through ART (13,14). This report is based on ART surveillance data provided to CDC's National Center for Chronic Disease Prevention and Health Promotion, Division of Reproductive Health, regarding procedures performed in 2004. A report of these data, according to the medical center in which the procedure was performed, was published separately (1). In this report, emphasis is on presenting state-specific data and more detailed data regarding risks associated with ART (e.g., multiple birth, low birthweight, and preterm delivery).

Methods

CDC contracted with Westat, Inc., to collect data on ART procedures performed in 2004 from medical centers in the United States and its territories. Data collected include patient demographics, medical history and infertility diagnoses, clinical information pertaining to the ART procedure, and information regarding resultant pregnancies and births. The data file is organized with one record per ART procedure performed. Multiple procedures from a single patient are not linked. Despite the federal mandate, 11% of ART medical centers did not report their 2004 data (1).

ART data and outcomes from ART procedures are presented by patient's state of residence at time of treatment. If the patient's state of residency was missing, the state of residency was assigned as the state in which the ART procedure was performed. In addition, data regarding the number of ART procedures in relation to the total population for each state are indicated.^† Data regarding number of procedures also are presented by treatment type and stage of treatment. ART procedures are classified into four groups according to whether a woman used her own eggs or received eggs from a donor and whether the embryos transferred were freshly fertilized or previously frozen and thawed. Because both live-birth rates and multiple-birth risk vary substantially among these four treatment groups, data are presented separately for each type.

In addition to treatment types, within a given treatment procedure, different stages of treatment exist. A typical ART procedure begins when a woman starts taking drugs to stimulate egg production or has her ovaries monitored with the intent of having embryos transferred. If eggs are produced, the procedure progresses to the egg-retrieval stage. After the eggs are retrieved, they are combined with sperm in the laboratory, and if fertilization is successful, the resulting embryos are selected for transfer. If the embryo implants in the uterus, the procedure progresses to a clinical pregnancy (i.e., the presence of a gestational sac detectable by ultrasound). The resulting pregnancy might progress to a live-birth delivery, which is defined as the delivery of one or more live-born infants. Only ART procedures involving freshly fertilized eggs include an egg-retrieval stage; ART procedures using thawed eggs do not include egg retrieval because eggs were fertilized during a previous procedure and the resulting embryos were frozen until the current procedure. An ART procedure can be discontinued at any step for medical reasons or by the patient's choice.

Variations in a typical ART procedure are noteworthy. Although a typical ART procedure includes IVF of gametes, culture for >2 days, and embryo transfer into the uterus (i.e., transcervical embryo transfer), in certain cases, unfertilized gametes (eggs and sperm) or zygotes (early embryos [i.e., a cell that results from fertilization of the egg by a sperm]) are transferred into the fallopian tubes within 1--2 days of retrieval. These are known as gamete and zygote intrafallopian transfer (GIFT and ZIFT). Another adaptation is intracytoplasmic sperm injection (ICSI), in which fertilization is still in vitro but is accomplished by selection of a single sperm that is injected directly into the egg. This technique was developed originally for couples with male factor infertility but now is commonly used for an array of diagnostic groups.

Data are presented in this report for each of the four treatment types: freshly fertilized embryos from the patient's eggs, freshly fertilized embryos from donor eggs, thawed embryos from the patient's eggs, and thawed embryos from donor eggs. In addition, detailed data are presented for the most common treatment type, those using freshly fertilized embryos from the patient's eggs. These procedures account for >70% of the total number of ART procedures performed each year. For those procedures that progressed to the embryo-transfer stage, the percentage distribution of selected patient and treatment factors were calculated. In addition, success rates, defined as live-birth deliveries per ART-transfer procedure, were calculated according to the same patient and treatment characteristics.

Patient factors included the age of the woman undergoing ART, whether she had previously given birth, the number of previous ART attempts, and the infertility diagnosis of both the female and male partners. The patient's age at the time of the ART procedure was grouped into five age groups: age <35 years, 35--37 years, 38--40 years, 41--42 years, and >42 years. Infertility diagnoses ranged from one factor in one partner to multiple factors in one or both partners and were categorized as follows:

• tubal factor --- the woman's fallopian tubes are blocked or damaged, causing difficulty for the egg to be fertilized or for an embryo to travel to the uterus;
• ovulatory dysfunction --- the ovaries are not producing eggs normally; such dysfunctions include polycystic ovarian syndrome and multiple ovarian cysts;
• diminished ovarian reserve --- the ability of the ovary to produce eggs is reduced; reasons include congenital, medical, or surgical causes or advanced age;
• endometriosis --- involves the presence of tissue similar to the uterine lining in abnormal locations; this condition can affect both fertilization of the egg and embryo implantation;
• uterine factor --- a structural or functional disorder of the uterus that results in reduced fertility;
• male factor --- a low sperm count or problems with sperm function that cause difficulty for a sperm to fertilize an egg under normal conditions;
• other causes of infertility --- immunological problems or chromosomal abnormalities, cancer chemotherapy, or serious illnesses;
• unexplained cause --- no cause of infertility was detected in either partner;
• multiple factors, female --- diagnosis of one or more female cause; or
• multiple factors, male and female --- diagnosis of one or more female cause and male factor infertility.

Treatment factos included the following:

• the number of days the embryo was cultured;
• the number of embryos that were transferred;
• whether the procedure was IVF-transfer only, IVF with ICSI, GIFT, ZIFT, or a combination of IVF with or without ICSI and either GIFT or ZIFT;
• whether extra embryos were available and cryopreserved; and
• whether a gestational carrier (i.e., surrogate) received the transferred embryos with the expectation of gestating the pregnancy.

The number of embryos transferred in an ART procedure was categorized as 1, 2, 3, 4, or >5. The number of days of embryo culture was calculated using dates of egg retrieval and embryo transfer and was categorized as 1, 2, 3, 4, 5, or 6. However, because of limited sample sizes, live-birth rates are presented only for the two most common days, day 3 and day 5. For the same reason, live-birth rates are presented for IVF with and without ICSI and not for GIFT and ZIFT. ICSI was subdivided as to whether it was used among couples receiving a diagnosis involving male factor (the original indication for ICSI treatment).

Chi-square tests were run to evaluate differences in live-birth rates by select patient and treatment factors within each age group. Multivariable logistic regression also was performed to evaluate the independent effects of patient factors (diagnosis, number of previous ART procedures, and number of previous births) on the chance to have a live birth as a result of an ART treatment. Because patient age is known to be a strong predictor for live birth, separate models were constructed for each age group; these models provide an indication of the variability in live births based on patient factors within each age strata. For these analyses, the referent groups included patients with a tubal factor diagnosis, no previous ART procedures, and no previous births. Multivariable models did not include treatment factors because of multicollinearity between certain treatment factors and multiple potential effect modifications. Rather, detailed stratified analyses were performed to elucidate additional detail related to associations among different treatment factors and the likelihood of live birth.

In addition to presenting live-birth rates as a measure of success, a second measure of success based on singleton live births also is presented according to patient age. Singleton live births are a key measure of ART success because they have a much lower risk than multiple-infant births for adverse health outcomes, including prematurity, low birthweight, disability, and death.

Multiple birth as a separate outcome measure also was assessed in two ways. First, each multiple-birth delivery was defined as a single event. A multiple-birth delivery was defined as the delivery of two or more infants, at least one of which was live-born. The multiple-birth risk thus was calculated as the proportion of multiple-birth deliveries among total live-birth deliveries. Multiple birth also was assessed according to the proportion of infants from multiple deliveries among total infants (i.e., each infant was considered separately in this calculation). The proportion of live-born infants who were multiples (twins and triplets or higher-order multiples) then was calculated.^§ Each of these measures represents a different focus. The multiple-birth risk, which is based on the number of deliveries or infant sets, provides an estimate of the individual risk posed by ART to the woman for multiple birth. The proportion of infants born in a multiple-birth delivery provides a measure of the effect of ART procedures on children in the population. Both measures are presented by type of ART procedure and by maternal age for births conceived with the patient's eggs. Multiple-birth risk is presented further by patient's age, number of embryos transferred, and whether additional embryos were available and cryopreserved for future use. Embryo availability (an indicator of embryo quality) has been demonstrated to be an independent predictor of the number of embryos transferred (3,6). In addition, multiple-birth risk is presented for embryos cultured on day 3 and day 5 by patient's age, number of embryos transferred, and whether additional embryos were available and cryopreserved for future use. The proportion of infants born in a multiple-birth delivery is presented separately by patient's state of residency at the time of ART treatment.

To assess the impact of ART procedures on total births in the United States in 2004, additional analyses, including all ART infants born in 2004, are presented. Because the goal of the analysis was to assess the effect of ART on the 2004 U.S. birth cohort and the ART surveillance system is organized according to the date of the ART procedure rather than the infant's date of birth, a separate ART data file was created for these analyses. This data file was drawn from two different ART reporting years and was composed of 1) infants conceived from ART procedures performed in 2003 and born in 2004 (approximately two of every three live-birth deliveries reported to the ART surveillance system for 2003); and 2) infants conceived from ART procedures performed in 2004 and born in 2004 (approximately one of every three live-birth deliveries reported to the ART surveillance system for 2004). Data regarding the total number of live births and multiple births in the United States in 2004 were obtained from birth certificate data (U.S. natality files) from CDC's National Center for Heath Statistics (16). These data represent all births registered in the United States in 2004. Data are presented in relation to the total number of infants born in the United States in 2004 by plurality of birth.

Adverse infant health outcomes, including low birthweight, very low birthweight, and preterm delivery also were evaluated. Because ART providers do not provide continued prenatal care after a pregnancy is established, birthweight and date of birth were collected via active follow-up with ART patients (85%) or their obstetric providers (15%). Although ART clinic staff collect limited information on infant outcomes, maternal health outcomes are not investigated systematically. Low birthweight and very low birthweight were defined as <2,500 grams and <1,500 grams, respectively. Gestational age was calculated as date of birth minus date of egg retrieval (and fertilization). If the date of retrieval was missing, and for procedures that used frozen embryos, gestational age was calculated as date of birth minus date of embryo transfer. For comparability with the general population, date of theoretical last menstrual period (LMP) was adjusted by adding 14 days to the gestational age estimate. Preterm delivery was defined as gestational age <37 weeks. Preterm low birthweight was defined as gestational age <37 weeks and birthweight <2,500 grams. Term low birthweight was defined as gestational age >37 weeks and birthweight <2,500 grams. The rates for low birthweight, very low birthweight, preterm low birthweight, and term low birthweight among ART infants born in 2004 are presented by plurality of birth. In addition, data for each of the five outcomes are presented for ART singletons born in 2004 by type of procedure. For the most common procedure type, those using freshly fertilized embryos from the patient's eggs, the rates for each outcome also are presented according to maternal age and number of previous live births. Chi-square tests were run separately to evaluate differences in the five outcomes by type of ART procedure, maternal age, and number of previous births. All analyses were performed using the SAS^® software system (17).

Results

Of 461 medical centers in the United States and surrounding territories that performed ART procedures in 2004, a total of 411 (89%) provided data to CDC (Figure 1). The majority of medical centers that performed ART procedures were in the eastern United States, in or near major cities. Within states, the number of medical centers performing ART procedures varied. States with the largest number of ART medical centers that reported data in 2004 were California (55), New York (35), Texas (30), Illinois (28), and Florida (27). Four states (Alaska, Maine, Montana, and Wyoming) and two U.S. territories (Guam and U.S. Virgin Islands) had no ART medical centers.

Number and Type of ART Procedures

A total of 127,977 ART procedures performed in 2004 were reported to CDC (Table 1). This number excludes <1% (n = 239) of ART procedures performed in 2004 that involved the evaluation of a new treatment procedure. The largest number of ART procedures occurred among patients who used their own freshly fertilized embryos (94,242 [74%]). Of the 127,977 procedures started, 107,050 (84%) progressed to embryo transfer. Overall, 42% of ART procedures that progressed to the transfer stage resulted in a pregnancy; 34% resulted in a live-birth delivery; and 23% resulted in a singleton live birth. Pregnancy rates, live-birth rates, and singleton live-birth rates varied according to type of ART. The highest success rates were observed among ART procedures that used donor eggs and freshly fertilized embryos (59% pregnancy rate, 51% live-birth rate, and 30% singleton live-birth rate). The lowest rates were observed among procedures using the patient's eggs and thawed embryos (35% pregnancy rate, 28% live-birth rate, and 21% singleton live-birth rate).

The 36,760 live-birth deliveries from ART procedures performed in 2004 resulted in 49,458 infants (Table 1); the number of infants born was higher than the number of live-birth deliveries because of multiple-infant births. A total of 24,921 singleton infants were born as a result of ART. The largest proportion of infants born (71% [35,191]) were from ART procedures in which patients used freshly fertilized embryos from their own eggs.

The two states that had the most ART medical centers (California and New York) also reported the highest numbers of ART procedures performed (Table 2). The greatest numbers of ART procedures performed in 2004 were among residents of California (17,303), New York (11,123), Illinois (9,306), Massachusetts (8,906), and New Jersey (8,513). The five states with the largest number of ART procedures performed also ranked highest for numbers of live-birth deliveries and infants born. ART procedures were performed for residents of certain states and territories without an ART medical center (Alaska, Maine, Montana, Guam, Wyoming, and U.S. Virgin Islands); however, each accounted for a limited percentage of total ART usage in the United States. Non-U.S. residents accounted for <1% of ART procedures, live-birth deliveries, and infants born. The ratio of number of ART procedures per 1 million population ranged from 17 in Puerto Rico to 1,384 in Massachusetts, with an overall average of 436 ART procedures started per 1 million persons.

Characteristics of Patients and ART Treatments Among Women Who Used Freshly Fertilized Embryos from Their Own Eggs

Forty-six percent of ART transfer procedures that used freshly fertilized embryos from the patient's eggs were performed on women aged <35 years, 23% on women aged 35--37 years, 19% on women aged 38--40 years, 8% on women aged 41--42 years, and 4% on women aged >42 years. Patient and treatment characteristics of these women varied by age (Table 3). Tubal factor and male factor were reported more commonly for ART procedures in women aged <35 years than for women in older age categories. In contrast, diminished ovarian reserve, reported for only 2% of women aged <35 years, was reported for 19% of women aged 41--42 years and 31% of women aged >42 years. Among all women, 8%--14% of ART transfer procedures were reported as involving unexplained infertility, 9%--18% as multiple female factors, and 18%--19% as both male and female factors.

Approximately 64% of women aged <35 years were undergoing their first ART procedure. The percentage of women who had undergone at least one previous ART procedure increased with age: only 42% of women aged >42 years were undergoing their first ART procedure. The percentage of women who had had a previous birth followed similar patterns: 21% of women aged <35 years reported at least one previous birth, a proportion that increased steadily with age, and 37% of women in the oldest age group had had a previous birth.^¶

The majority of ART procedures used IVF with or without ICSI. Less than 1% of ART procedures used GIFT or ZIFT. ICSI use among couples with and without a diagnosis of male factor infertility varied by patient age. Despite variation among all age groups, the total proportion of ICSI use (i.e., combined ICSI for male factor and ICSI for other diagnoses) was greater than the proportion of in vitro fertilization with transcervical embryo transfer (IVF-ET) without ICSI.

Among all age groups, the majority of procedures included embryo culture for 3 days; the next most common procedure involved embryo culture to day 5. Culture to day 5 coincides with development of the embryo to the blastocyst stage; this technique was used more frequently among younger women, possibly because ART procedures performed in younger women yielded more embryos that can survive in culture through day 5.

The majority of ART procedures involved transfer of more than one embryo. Among women aged <35 years, 94% of procedures involved transfer of two or more embryos, and 41% involved transfer of three or more embryos. For women aged >42 years, 82% involved transfer of two or more embryos, and 62% involved transfer of three or more embryos. The availability of extra embryos (an indicator of overall embryo quality) decreased with age. Extra embryos were available and cryopreserved for 43% of women aged <35 years, whereas only 4% of women aged >42 years had extra embryos available and cryopreserved. Data were not available regarding extra embryos that were not cryopreserved for future use. Overall, 1% of ART transfer procedures used a gestational carrier or surrogate. Limited variation existed by patient age.

Live-Birth Rates Among Women Who Used Freshly Fertilized Embryos from Their Own Eggs

Live-birth rates for women who underwent ART procedures that used freshly fertilized embryos from their own eggs also varied by patient age and selected patient and treatment factors (Table 4). Although the average live-birth rate for ART-transfer procedures performed among women who used their own freshly fertilized eggs was 34%, live-birth rates ranged from 43% among women aged <35 years to 6% among women aged >42 years. Couples in which the woman was aged <40 years whose infertility diagnosis was classified as ovulatory dysfunction or male factor infertility had higher than average live-birth rates. Women aged <40 years with an infertility diagnosis of diminished ovarian reserve tended to have lower-than-average--live-birth rates. In addition, women aged >40 years with an infertility diagnosis of endometriosis or uterine factor experienced higher-than-average--live-birth rates; however, the variation in success rates across diagnostic categories was not statistically significant. Across all age groups, women who had undergone a previous ART procedure had lower live-birth rates than women who had undergone their first ART procedure. However, the number of previous ART procedures cannot be subdivided by whether they were successful because data were not available. The variation in success rates by number of previous ART procedures was not statistically significant for women aged >40 years. Women who had one or more previous births had higher live-birth rates than those with no previous births. However, the difference in live-birth rates for the number of previous births was not statistically significant for women aged >40 years. Multivariable adjustment for patient factors within each age strata demonstrated similar patterns to those described above (data not presented).

Among women aged <42 years, live-birth rates were higher among women who had ART procedures that used IVF-ET without ICSI, in comparison with procedures that used ICSI, regardless of whether male factor was reported (Table 4). In all age groups, live-birth rates were lowest among couples who used ICSI in the absence of male factor infertility; however, the variation in live-birth rates was not statistically significant for women aged >42 years. In all age groups, live-birth rates were increased among women who had extended embryo culture to day 5, transferred two or more embryos, and had extra embryos available and cryopreserved for future use. Variations in live-birth rates were statistically significant for these treatment factors within all age groups, except for women aged >42 years who had extra embryos available and cryopreserved for future use. Although live-birth rates also appeared to increase across all age groups when a gestational carrier was used, these results did not reach statistical significance in any age group. All of the results for treatment factors need to be considered cautiously because treatment was not randomized but rather based on medical center assessment and patient choice.

Although variability in live-birth rates among patients who used different treatment options cannot be adjusted completely, stratified analyses were used to examine associations between treatment factors and live-birth rates among more homogenous groups of patients. To address concerns that, in the absence of male factor infertility, ICSI might be used preferentially for women considered difficult to treat, multiple groups of patients with an indication of being difficult to treat were evaluated separately (data not presented). These groups included women with previously failed ART procedures (i.e., women who underwent previous ARTs but had no previous pregnancies or births), women diagnosed with diminished ovarian reserve, and women with a low number of eggs retrieved (i.e., less than five). Within each of these groups, age-specific live-birth rates for IVF-ET with and without ICSI were examined. In all analyses, except for women aged >42 years with less than five eggs retrieved, women who used IVF with ICSI had lower success rates than women who used IVF without ICSI; the pattern of these results (data not presented) is consistent with the findings presented in this report (Table 4). Data regarding women deemed to have a higher likelihood of success (i.e., women with >10 eggs retrieved, women with diagnoses other than diminished ovarian reserve, and women with extra embryos cryopreserved for future use) were evaluated separately (data not presented) to adjust for the possibility that day 5 embryo transfers might have been used preferentially for women with a presumed better prognosis. Again, within each of these subgroups, age-specific--live-birth rates were lower for embryo transfers on days 1--4 compared with day 5 transfers. Finally, analyses were conducted in which the data were stratified by patient age, number of embryos transferred, day of embryo transfer (day 3 or day 5), and number of embryos available simultaneously. These results are included with the discussion regarding multiple-birth risk.

Total live-birth rates are compared with singleton live-birth rates for women who underwent ART procedures in which freshly fertilized embryos from their own eggs were used (Figure 2). Both live-birth rates and singleton live-birth rates decreased with patient age. Across all age groups, singleton live-birth rates were lower than live-birth rates. However, the magnitude of the difference between these two measures declined with patient age.

Multiple-Birth Risks Associated with ART

Of 11,839 multiple-birth deliveries, 8,478 (72%) were from pregnancies conceived with freshly fertilized embryos from the patient's eggs, 1,129 (10%) were from thawed embryos from the patient's eggs, 1,878 (16%) were from freshly fertilized embryos from a donor's eggs, and 354 (3%) were from thawed embryos from a donor's eggs (Table 5). In comparison with ART procedures that used the patient's eggs and freshly fertilized embryos, the risks for multiple-birth delivery were increased when eggs from a donor were used and decreased when thawed embryos were used. Among ART procedures in which freshly fertilized embryos from the patient's own eggs were used, a strong inverse relation existed between multiple-birth risk and patient age. The average multiple-birth risk for ART procedures in which freshly fertilized embryos from the patient's eggs were used was 33%. The multiple-birth risk varied from 36% among women aged <35 years to 8% among women aged >42 years.

Of 49,458 infants born through ART, 50% (24,537) were born in multiple-birth deliveries (Table 5). The proportion of infants born in a multiple-birth delivery also varied by type of ART procedure and patient age. Among ART transfer procedures in which the patient used freshly fertilized embryos from their own eggs, the proportion of infants born in a multiple-birth delivery ranged from 54% in women aged <35 years to 16% in women aged >42 years. Among ART transfer procedures in which thawed embryos from the patient's eggs were used, the proportion of infants born in a multiple-birth delivery ranged from 42% in women aged <35 years to 30% in women aged >42 years. When thawed embryos from donor eggs were used, the proportion of infants born in a multiple-birth delivery was 42%. The proportion of infants born in a multiple-birth delivery was highest (58%) in women who used freshly fertilized embryos from donor eggs.

A more detailed examination of multiple-birth risk for women who underwent ART procedures in which freshly fertilized embryos from their own eggs were used revealed that number of embryos transferred was a risk factor for multiple-birth delivery, but the magnitude of the risk varied by patient age (Table 6). Among all age groups, transfer of two or more embryos was associated with increased live-birth delivery rates. However, the multiple-birth risk also was increased substantially. Among women aged <40 years, the percentage of triplet or higher order deliveries increased steadily with increasing number of embryos transferred from two to five or more. For women aged 41--42 years, the percentage of twin deliveries increased steadily with two to five or more embryos transferred. For women aged >42 years, the multiple-birth deliveries did not demonstrate a trend by number of embryos (two or more) having been transferred, possibly because women in this age group have embryos with reduced implantation potential and therefore are less likely to have multiple births.

An assessment of multiple-birth risk among patients who used freshly fertilized embryos from their own eggs and set aside extra embryos for future use also is presented (Table 6). These patients can be thought of as those with elective embryo transfer because they chose to transfer fewer embryos than the total number that were available. For women with elective embryo transfer who were aged <35 years, live-birth rates were 45% when only one embryo was transferred and 53% when two embryos were transferred. For women aged 35--37 years, live-birth rates were 35% with elective embryo transfer of a single embryo and 50% when two embryos were transferred. Whereas an increase in live-birth rates was noted among patients with single compared with double elective embryo transfers, transferring two embryos posed a substantial multiple-birth risk for both age groups (38% and 32%, respectively).**

Among patients who used freshly fertilized embryos from their own eggs, the live-birth rates and multiple-birth risks typically were higher for embryo transfers on day 5 than on day 3 (Table 7). Overall, across all age groups, embryo transfers on day 5 were associated with fewer embryos transferred than those on day 3. For example, among day 3 embryo transfers in women aged <35 years, 52% involved the transfer of two or fewer embryos whereas 82% of day 5 embryo transfers in women aged <35 years involved the transfer of two or fewer embryos. Similarly, in women aged <35 years, 62% of day 3 elective embryo transfers and 90% of day 5 elective embryos transfers involved the transfer of two or more embryos. As noted previously for all day of embryo transfers (Table 6), live-birth rates and multiple-birth risks were even higher for patients who had elective embryo transfers. For women with elective embryo transfer on day 5 who were aged <35 years, live birth rates were 52% when one embryo was transferred and 57% when two embryos were transferred. By contrast, the multiple-birth risks in these two groups were 4% and 45%, respectively. Thus, the 5% increase in the live-birth rate was accompanied by a 41% increase in the risk for a multiple delivery. If success is measured in terms of singleton live-birth, the highest success rates for this group were with one embryo transferred. This also was true for women aged 35--37 or 38--40 years with elective single embryo transfer on day 5 (Table 7).

The states with the highest number of ART-associated live-birth deliveries also had the highest number of infants born in multiple-birth deliveries (Table 8). These include California (3,313), New York (1,731), New Jersey (1,608), Illinois (1,549), Texas (1,518), and Massachusetts (1,463). Nationwide, the percentage of infants born in multiple-birth deliveries after ART treatment was 50%; the percentage of twins was 44% and that of triplets or higher-order multiples was 6%. The percentage of infants born in multiple-birth deliveries was >50% in the majority of states. The states with the highest proportion of infants born in multiple-birth deliveries were New Mexico (64%), Colorado (58%), Kentucky (58%), Mississippi (55%), Alabama (54%), Oklahoma (53%), Texas (53%), and Utah (53%); however, these findings should be interpreted with caution because of an overall low number of live births resulting from ART in certain states.

Of 4,112,052 infants born in the United States in 2004, a total of 49,376 (1%) were conceived with ART (Table 9). Infants conceived with ART accounted for 0.6% of singleton births and 18% of multiple births nationwide; 17% of all twins and 40% of infants born in triplets or higher order multiples were conceived with ART.

Perinatal Risks Associated with ART

The percentage of infants with low birthweight varied from 9% among singletons to 95% among triplets or higher order multiples. The percentages of very low birthweight, preterm, and preterm low birthweight followed similar patterns (Table 10).

The percentages of ART singletons that were low birthweight, very low birthweight, preterm, preterm low birthweight, and term low birthweight varied by procedure type and selected maternal factors (Table 11). In comparison with singletons born after procedures that used freshly fertilized embryos derived from the patient's eggs, singletons born after procedures that used freshly fertilized embryos derived from donor eggs were at increased risk for three perinatal outcomes: low birthweight, preterm delivery, and preterm low birthweight. Singletons born after procedures that used thawed embryos were at decreased risks for low birthweight; however, they were at increased risk for preterm delivery overall. The variation in risk across procedure types was not statistically significant for very low birthweight and preterm low birthweight.

More detailed analysis of maternal factors among singletons born after procedures that used freshly fertilized embryos derived from the patient's eggs indicated limited variation in risk for very low birth weight, preterm delivery, preterm low birth weight, and term low birthweight according to maternal age. Lower risks for low birthweight, preterm delivery, and preterm low birthweight were observed among mother-infant pairs with one previous birth; the variation in risks was statistically significant (p<0.01) for all five adverse perinatal outcomes.

Discussion

According to the most recent estimates of infertility in the United States, 10% of women of reproductive age (15--44 years) reported a previous infertility-associated health-care visit, and 2% reported a visit during the previous year (18). Among married couples in which the woman was of reproductive age, 7% reported they had not conceived after 12 months of unprotected intercourse. With advances in ARTs, couples are increasingly turning to these treatments to overcome their infertility.

Since the birth of the first infant through ART in the United States in 1981, use of ART has grown substantially. Since 1996, CDC has been monitoring ART procedures performed in the United States. During that time, the use of ART has consistently increased. The increased use of ART, coupled with higher ART success rates, has resulted in dramatic increases in the number of children conceived through ART each year. From 1996 (i.e., the first full year for which CDC collected data) through 2004, the number of ART procedures performed has almost doubled, from 64,681 to 127,977 (1). In addition, during 1996--2004, live-birth rates for all types of ART procedures increased substantially. For the most common type of ART procedure, use of freshly fertilized embryos from the patient's eggs, overall live-birth rates increased from 28% in 1996 to 34% in 2004. The number of infants conceived through ART procedures performed in 2004 (49,458) was more than two times higher than that in 1996 (20,840).

This report documents that in 2004, ART use varied according to the patient's state of residency. Residents of California, New York, Massachusetts, Illinois, and New Jersey reported the highest number of ART procedures. These states also reported the highest number of infants conceived through ART. In 2004, ART use by state of residency was not completely in line with expectations based on the total population within states (15). Whereas Massachusetts had the fourth highest number of ART procedures performed, it ranked fourteenth in total population size.^†† Similarly, residents of District of Columbia, New Jersey, Connecticut, and Rhode Island underwent more ART procedures than would have been expected based on their population sizes. As a result, state-specific ratios of ART procedures by population varied according to state of residency. The highest ratios of the number of ART procedures among state residents per 1 million population were observed in Massachusetts (1,384), District of Columbia (1,227), New Jersey (981), Connecticut (823), and Rhode Island (790). This divergence is not unexpected because, in 2004, Massachusetts, New Jersey, and Rhode Island had statewide mandates for insurance coverage for ART procedures. Variation within states also might be related to availability of ART services within each state. However, the relation between demand for services and availability cannot be disentangled (e.g., increased availability in certain states might reflect the increased demand for ART among state residents).

Among women who used fresh fertilized embryos from their own eggs, patient factors (e.g., infertility diagnoses, history of previous ART procedures, and previous births) varied considerably by age. The proportion of procedures in which the couple received a diagnosis of ovulatory dysfunction, endometriosis, or male factor infertility decreased with the woman's age, while the proportion of procedures in which the couple received a diagnosis of diminished ovarian reserve increased with the woman's age. History of previous ART and previous births were more common among older women. In addition, treatment factors varied considerably by the age of the woman. The proportion of procedures in which embryo transfer occurred on day 5 (i.e., the blastocyst stage) declined with the age of the woman, whereas the proportion of procedures in which three or more embryos were transferred increased steadily with age.

Because ART success rates are affected by multiple patient and treatment factors, using a single measure of success is not sufficient to evaluate ART efficacy. At a minimum, ART procedures should be subdivided on the basis of the source of the egg (patient or donor) and the status of the embryos (freshly fertilized or thawed) because success rates vary substantially across these types. Within the type of ART procedure, further variation exists in success rates by patient and treatment factors, most notably patient age. Other factors to consider when assessing success rates are infertility diagnosis, number of previous ART procedures, number of previous births, method of embryo fertilization and transfer, number of days of embryo culture, number of embryos transferred, availability of extra embryos, and use of a gestational carrier (i.e., surrogate). Variation exists in success rates according to each of these factors.

CDC's primary focus in collecting ART data has been on live-birth deliveries as an indicator of success because ART surveillance activities were developed in response to a federal mandate to report ART success rate data. This mandate requires that CDC collect data from all ART medical centers and report success rates, defined as all live births per ovarian stimulation procedures or ART procedures, for each ART medical center. Therefore, a key role for CDC has been to publish standardized data related to ART success rates, including information regarding factors that affect these rates. With these data, persons and couples can make informed decisions regarding whether to undergo this time-consuming and expensive treatment (19).^§§ However, success-rate data also should be balanced with consideration of effects on maternal and infant health. CDC receives data on pregnancy outcomes of public health significance, which enables CDC to monitor multiple-birth rates, preterm delivery, and low birthweight associated with ART.

In the United States, multiple births have increased substantially since the 1980s (16,20). The increase in multiple births has been attributed to an increased use of ART and delayed childbearing (5,21,22). Although infants conceived with ART accounted for 1% of the total births in the United States in 2004, the proportion of twins and triplets or higher order multiples attributed to ART were 17% and 40%, respectively. In 1999, the Society for Assisted Reproductive Technology and the American Society for Reproductive Medicine issued voluntary guidelines (23) on the number of embryos transferred; these guidelines were revised in 2004 (24) and 2006 (25).

In certain states, ART procedures are not covered by insurance carriers, and patients might feel pressured to maximize the opportunity for live-birth delivery. In addition, if success is defined solely as total live-birth delivery, anecdotal evidence suggests that certain ART providers might feel pressure to transfer multiple embryos to maximize their publicly reported success rates (26). In the United States, multiple embryo transfer was still a common practice in 2004; approximately 52% of ART procedures that used fresh, nondonor eggs or embryos and progressed to the embryo-transfer stage involved the transfer of three or more embryos; approximately 21% of procedures involved the transfer of four or more; and 7% of procedures involved the transfer of five or more embryos (1). Among women aged <35 years, the proportion of ART procedures that involved four or more embryos transferred was approximately 10%, as women in this age category typically experience higher success rates with fewer embryos transferred. Multiple scientific reports have advocated that singleton live-birth rates be presented as a distinct indicator of ART success (27--33). This report includes this measure (Figure 2) and presents it with total live-birth rates. Success rates based on singleton live-birth deliveries will provide patients with a measure that more directly highlights infant outcomes with the optimal short- and long-term prognosis. Twins, albeit to a lesser extent than triplets or higher-order multiples, have substantially increased risks for infant morbidity and mortality. The risks for low birthweight and preterm birth both exceed 56% for twins, and the risk for very low birthweight is 10% (16). In addition, because twins are at substantially increased risk for perinatal and infant mortality (11,20), singleton live-birth rates are a valid measure of success.

Data regarding multiple-birth deliveries and proportion of multiple-birth infants as distinct outcomes also are provided. Data in this report indicate that 50% of infants born through ART in 2004 were multiple births, compared with 3% in the general U.S. population (16). The twin rate was 44%, approximately 15 times higher than that in the general U.S. population (3%); the rate for triplets and higher-order multiples was 6%, approximately 42 times higher than the general U.S. population (0.2%). Regarding the specific type of ART procedure, multiple-birth rates were among the highest for women who underwent ART procedures that used freshly fertilized embryos from their own eggs (53%) or from donor eggs (60%).

In 23 states and Puerto Rico, >50% of infants conceived through ART were born in multiple-birth deliveries. Multiple births resulting from ART are an increasing public health concern, nationwide and for the majority of states.

For women who underwent ART procedures using freshly fertilized embryos from their own eggs, the multiple-birth risk increased when multiple embryos were transferred. Embryo availability, an indicator of embryo quality, also was a strong predictor of multiple-birth risk independent from the number of embryos transferred. In analyses stratified by patient age, number of embryos transferred, day of embryo culture (day 3 or 5), and embryo availability, high live-birth rates and singleton live-birth rates were achieved, particularly among younger women as transfer of a single embryo was efficacious. Among the majority of groups, multiple-birth risk likely can be minimized without compromising success rates by limiting the number of embryos transferred.

In addition to the known multiple-birth risks associated with ART, singleton infants conceived from ART procedures are at increased risk for low birthweight and preterm delivery. In 2004, of all singleton infants conceived with ART, 9% were low birthweight, compared with 6% in the general U.S. population (16). The percentage of singleton infants conceived from ART that were very low birthweight was twice that of singletons conceived in the general U.S. population (2% and 1%, respectively), and the percentage of ART singletons born preterm also was higher than the general U.S. population (15% and 11%, respectively). Thus, adverse infant health outcomes among singletons (e.g., low birthweight and preterm delivery) also should be considered when assessing the efficacy and safety of ART.

A comparison of perinatal outcomes among ART twins and triplets or higher-order multiples with their counterparts in the general population is not useful for at least two reasons. First, both ART and non-ART infertility treatments are estimated to account for a substantial proportion of multiple births in the United States, and distinguishing naturally conceived from iatrogenic multiple births is not possible. ART accounts for only 1% of the total U.S. births; however, it accounts for 17% of twins and 40% of triplets or higher-order multiples. Second, the majority of multiple births conceived after ART treatment are likely dizygotic from multiple embryo transfer. Among natural conceptions, approximately one third to one half of twins might be monozygotic, depending on maternal age (34). Monozygotic twins are at increased risk for adverse outcomes in comparison with dizygotic twins (35).

Multiple births are associated with an increased health risk for both mothers and infants (11,12,20,22). Women with multiple-gestation pregnancies are at increased risk for maternal complications (e.g., hemorrhage and hypertension). Infants born in a multiple-birth delivery are at increased risk for prematurity, low birthweight, infant mortality, and long-term disability.

The contribution of ARTs to preterm births in the United States also is a key concern. This report documents that approximately 42% of ART infants born in 2004 were preterm (Table 10), compared with approximately 13% of preterm births in the general U.S. population (16). Preterm infants have increased risk of death and have more health and developmental problems than full-term infants (36--39). The health risks associated with preterm births have contributed to rising health-care costs. The economic burden associated with preterm births in the United States in 2005 has been estimated to be $26 billion ($51,600 per infant born preterm) (39). ART infants born preterm accounted for approximately 4% of all preterm births in the United States in 2004, for a total economic burden estimated at $1 billion. ASRM and SART guidelines on the number of embryos transferred in an ART cycle might help in further reducing the incidence of preterms, the majority of which are multiples.

The findings in this report are subject to several limitations. First, ART surveillance data were reported for each ART procedure performed rather than for each patient who used ART. Linking procedures among patients who underwent more than one ART procedure in a given year is not possible. Because patients who underwent more than one procedure in a given year were most likely to include those in which a pregnancy was not achieved, the success rates reported might underestimate the true per-patient success rate. In addition, ratios of ART procedures per population might be higher than the unknown ratio of the number of persons undergoing ART per population. Second, these data represent couples who sought ART services in 2004; therefore, success rates do not represent all couples with infertility who were potential ART users in 2004. Third, because treatment was not randomized but rather based on medical center assessment and patient choice, results for treatment factors must be considered with caution. Finally, approximately 11% of medical centers that performed ART in 2004 did not report their data to CDC as required.

ART data are reported to CDC by the ART medical center in which the procedure was performed rather than by the state in where the patient resided. In this report, ART data are presented by the female patient's state of residence. In 2004, residency data were missing for approximately 8% of all live-birth deliveries reported to CDC. In cases of missing residency data, residency was assigned as the state in which the ART procedure was performed. Thus, the number of procedures performed among state residents, number of infants, and number of multiple-birth infants might have been overestimated for certain states. Concurrently, the numbers might be underestimated in states that border states with missing residency data, particularly states in the Northeast region of the United States. Nonetheless, the effects of missing residency data were not substantial. Statistics were evaluated separately according to the location of the ART medical center rather than the patient's state of residence. The rankings of the ART medical center location by total number of infants and multiple-birth infants were similar to the rankings based on patient's state of residence (data not presented).

The patient's state of residence was reported at the time of ART treatment. The possibility of migration during the interval between ART treatment and birth exists. U.S. Census Bureau data indicate that approximately 3% of the U.S. population moves between states annually; this rate is even higher for persons aged 20--34 years (40).

Members of the U.S. armed forces have a high potential for migration. Therefore, ART procedures performed among patients who attended military medical centers were evaluated separately. In 2004, a total of 799 (0.6%) ART procedures were performed in four military medical centers (California, District of Columbia, Hawaii, and Texas). In certain facilities, a substantial number of distinct states were listed for patient's state of residence. States and territories for which >1% of ART procedures among residents were performed in a military medical center were Alaska, District of Columbia, Hawaii, Kansas, Louisiana, Maryland, North Carolina, North Dakota, Oklahoma, South Carolina, Texas, Virginia, and Wyoming. States for which >5% of ART procedures among state residents were performed in a military medical center were Alaska and District of Columbia.

Despite these limitations, findings from national surveillance of ART procedures performed in the United States provide useful information for patients contemplating ART, ART providers, and health-care policy makers. ART surveillance data can be used to monitor trends in ART use and outcomes from ART procedures. Data from ART surveillance can be used to assess patient and treatment factors that contribute to higher success rates. Ongoing surveillance data can be used to assess the risk for multiple births and adverse perinatal outcomes among singleton births. Surveillance data provide information to assess changes in clinical practice related to ART treatment.

Increased use of ART procedures and the practice of transferring multiple embryos during ART treatments have led to high multiple-birth rates in the United States (5,10). Balancing the chance of success of ART against the risk for multiple births is challenging. Implementation of approaches to limit the number of embryos transferred for patients undergoing ART should reduce the occurrence of multiple births resulting from ART. Such efforts ultimately might lead ART patients and providers to view treatment success in terms of singleton pregnancies and births. In addition, continued research is needed to understand the adverse effects of ART on maternal and child health. CDC will continue to provide updates of ART use in the United States as data become available.

References

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35. Derom R, Vlietinck R, Derom C, Thiery M, Van Maele G, Van den Berg H. Perinatal mortality in the East Flanders Prospective Twin Survey: preliminary results. Eur J Obstet Gynecol Reprod Biol 1991;41:25--6.
36. Callaghan WM, MacDorman MF, Rasmussen SA, Qin C, Lackritz EM. The contribution of preterm birth to infant mortality rates in the United States. Pediatrics 2006;118:1566--73.
37. Tanner K, Sabrine N, Wren C. Cardiovascular malformations among preterm infants. Pediatrics 2005;116:e833--8.
38. Rasmussen SA, Moore CA, Paulozzi LJ, Rhodenhiser EP. Risk for birth defects among premature infants: a population-based study. J Pediatr 2001;138:668--73.
39. Behrman RE, Stith Butler A, eds. Preterm birth: causes, consequences, and prevention. Washington, DC: National Academies Press; 2006.
40. US Census Bureau. Annual geographical mobility rates, by type of movement: 1947--2005 (Table A-1). Washington, DC: US Census Bureau; 2006. Available at http://www.census.gov/population/www/socdemo/migrate.html.

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Date last reviewed: 5/9/2007