Assisted Reproductive Technology Surveillance — United States, 2011

Saswati Sunderam, PhD

Dmitry M. Kissin, MD

Sara B. Crawford, PhD

Suzanne G. Folger, PhD

Denise J. Jamieson, MD

Wanda D. Barfield, MD

Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC

Corresponding author: Saswati Sunderam, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. Telephone: 770-488-6356; E-mail: ms[email protected].

Abstract

Problem/Condition: Since the first U.S. infant conceived with Assisted Reproductive Technology (ART) was born in 1981, both the use of advanced technologies to overcome infertility and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which both eggs and embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely to deliver multiple-birth infants than those who conceive naturally because more than one embryo might be transferred during a procedure. Multiple births pose substantial risks to both mothers and infants, including pregnancy complications, preterm delivery, and low birthweight infants. This report provides state-specific information on U.S. ART procedures performed in 2011 and compares infant outcomes that occurred in 2011 (resulting from procedures performed in 2010 and 2011) with outcomes for all infants born in the United States in 2011.

Reporting Period Covered: 2011.

Description of System: In 1996, CDC began collecting data on all ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web-based data collecting system developed by CDC.

Results: In 2011, a total of 151,923 ART procedures performed in 451 U.S. fertility clinics were reported to CDC. These procedures resulted in 47,818 live-birth deliveries and 61,610 infants. The largest numbers of ART procedures were performed among residents of six states: California (18,808), New York (excluding New York City) (14,576), Massachusetts (10,106), Illinois (9,886), Texas (9,576), and New Jersey (8,698). These six states also had the highest number of live-birth deliveries as a result of ART procedures and together accounted for 47.2% of all ART procedures performed, 45.3% of all infants born from ART, and 45.1% of all multiple live-birth deliveries, but only 34% of all infants born in the United States. Nationally, the average number of ART procedures performed per 1 million women of reproductive age (15–44 years), which is a proxy indicator of ART use, was 2,401. In 11 states (Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Virginia), the District of Columbia, and New York City, this proxy measure was higher than the national rate, and of these, in three states (Massachusetts, New Jersey, and New York) and the District of Columbia, it exceeded twice the national rate. Nationally, among ART cycles with patients using fresh embryos from their own eggs in which at least one embryo was transferred, the average number of embryos transferred increased with increasing age (2.0 among women aged <35 years, 2.3 among women aged 35–40 years, and 2.9 among women aged >40 years). Elective single-embryo transfer (eSET) rates decreased with increasing age (12.2% among women aged <35 years, 4.7% among women aged 35–40 years, and 0.7% among women aged >40 years). Rates of eSET also varied substantially between states (range: 0.7% in Idaho to 53% in Delaware among women aged <35 years).

The number of ART births as a percentage of total infants born in the state is considered as another measure of ART use. Overall, ART contributed to 1.5% of U.S. births (range: 0.2% in Puerto Rico to 4.5% in Massachusetts) with the highest rates (≥3.5% of all infants born) observed in four states (Connecticut, Massachusetts, New Jersey, and New York state), and the District of Columbia. Infants conceived with ART comprised 20% of all multiple-birth infants (range: 4.7% in Puerto Rico to 41.3% in New York state), 19% of all twin infants (range: 4.1% in Mississippi to 39.7% in Massachusetts), and 32% of triplet or higher order infants (range: 0 in several states to 71.4% in Hawaii). Among infants conceived with ART, 45.6% were born in multiple-birth deliveries (range: 23.1% in Delaware to 61.3% in Wyoming), compared with only 3.4% of infants among all births in the general population (range: 1.9% in Puerto Rico to 4.8% in New Jersey). Approximately 43% of ART-conceived infants were twins, and 3% were triplets and higher order infants.

Nationally, infants conceived with ART comprised 5.7% of all low birthweight (<2,500 grams) infants (range: 0.6% in Puerto Rico to 15% in Massachusetts) and 5.9% of all very low birthweight (<1,500 grams) infants (range: 0.8% in Mississippi to 17.3% in Massachusetts). Overall, among ART-conceived infants, 31% were low birthweight (range: 18% in District of Columbia to 44.6% in Puerto Rico), compared with 8.1% among all infants (range: 6% in Alaska to 12.5% in Puerto Rico); 5.7% of ART infants were very low birthweight (range: 0 in North Dakota to 8.5% in Hawaii), compared with 1.4% among all infants (range: 0.9% in Alaska to 2.2% in Mississippi). Finally, ART-conceived infants comprised 4.6% of all infants born preterm (<37 weeks; range: 0.5% in Puerto Rico to 13% in Massachusetts) and 5.2% of all infants born very preterm (<32 weeks; range: 0 in Wyoming to 17.1% in Massachusetts). Overall, among infants conceived with ART, 36.2% were born preterm (range: 12.5% in Vermont to 56.9% in Puerto Rico), compared with 11.8% among all infants born in the general population (range: 8.8% in Vermont to 17.6% in Puerto Rico); 6.7% of ART infants were born very preterm (range: 0 in Wyoming to 12.5% in Alaska), compared with 1.9% among all infants born in the general population (range: 1.3% in Wyoming to 3.0% in Puerto Rico).

The percentage of infants conceived with ART who were low birthweight varied from 8.8% (range: 3.9% in the District of Columbia to 17.9% in Puerto Rico) among singletons, to 56.4% (range: 34.6% in Vermont to 70.4% in Mississippi) among twins, and 95.7% (range: 79.5% in North Carolina to 100% in several states) among triplets or higher-order multiples; comparable percentages for all infants were 6.4% (range: 4.5% in Idaho and Oregon to 11.3% in Puerto Rico), 56.3% (range: 47.7% in Vermont to 72.1% in Puerto Rico), and 93.9% (range: 50% in Wyoming to 100% in several states), respectively. The percentage of ART infants who were preterm varied from 13.2% (range: 7.3% in the District of Columbia to 28.6% in Puerto Rico) among singletons, to 61.8% (range: 46% in the District of Columbia to 82.7% in Oklahoma) among twins, and 97.1% (range: 76.9% in Iowa to 100% in several states) among triplets or higher-order multiples; comparable percentages for all infants were 10.1% (range:7.5% in Oregon to 16.6% in Puerto Rico), 57.3% (range: 46.8% in New Hampshire to 68.8% in Louisiana), and 93.4% (range: 73.3% in Rhode Island to 100% in several states), respectively. Only nonsuppressed values from reporting areas are provided to protect confidentiality.

Interpretation: The percentage of infants conceived with ART varied considerably by state (range: 0.2% to 4.5%). In most states, multiples from ART comprised a substantial proportion of all twin, triplet, and higher-order infants born in the state, and the rates of low birthweight and preterm infants were disproportionately higher among ART infants than in the birth population overall. Even among women aged <35 years, for whom elective single embryo transfers should be considered (particularly in patients with a favorable prognosis), on average, two embryos were transferred per cycle in ART procedures, influencing the overall multiple infant rates in the United States. Compared with ART singletons, ART twins were approximately 5 times more likely to be born preterm, and approximately six times more likely to be low birthweight. Singleton infants conceived with ART had slightly higher rates of preterm delivery and low birthweight than among all singleton infants born in the United States. However, all multiple-birth infants, regardless of whether they were ART-conceived or not, were more likely to be preterm and low birthweight compared with singletons. Further, ART use per population unit was distributed disproportionately in the United States, with 11 states showing ART use above the national rate. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (e.g., coverage for at least four cycles of in vitro fertilization, three states (Illinois, Massachusetts, and New Jersey) also had rates of ART use >1.5 times the national level. This type of mandated insurance has been associated with greater use of ART and might account for the differences in per capita ART use observed among states.

Public Health Actions: Reducing the number of embryos transferred per ART procedure and promoting eSET procedures, when clinically appropriate, are needed to reduce multiple births and related adverse consequences of ART. Improved patient education and counseling on the health risks of having twins might be useful in reducing twin births given that twins account for the majority of ART-conceived multiple births. Although ART contributes to increasing rates of multiple births, it does not explain all of the increases, and therefore other explanations for multiple births not investigated in this report, such as the possible role of non-ART fertility treatments, warrants further study.

Introduction

Since the birth of the first U.S. infant conceived with Assisted Reproductive Technology (ART) in 1981, use of advanced technologies to overcome infertility has increased steadily, as has the number of fertility clinics providing ART services and procedures in the United States (1). In 1992, Congress passed the Fertility Clinic Success Rate and Certification Act (FCSRCA; Public Law 102-493), which requires that all U.S. fertility clinics performing ART procedures report data to CDC annually on every ART procedure performed. In 1997, CDC published the first annual ART Success Rates Report under FCSRCA, which reported on ART procedures performed in 1995 (2). CDC uses the data it receives to report pregnancy success rates for all ART programs and clinics in the annual ART Success Rates Report (1). Several measures of success for ART are presented in the annual report including the percentage of ART cycles that result in a pregnancy, live-birth deliveries, and singleton live births. Since 2010, ART Fertility Clinic Success Rates Reports are published in two separate reports: a Fertility Clinic Success Rates Report and a National Summary Report (1,3).

ART is associated with potential risks to the mother and fetus. Because multiple embryos are transferred in the majority of ART procedures, ART has been associated with a substantial risk for multiple-gestation pregnancy and multiple births (4–11). Multiple births are associated with greater health problems for mothers and infants, including higher rates of caesarean deliveries, prematurity, low birthweight, infant death, elevated risk for birth defects, and disability (4–15). Further, even singleton infants conceived with ART have a higher risk of low birthweight (16,17).

This report is based on ART surveillance data reported to CDC's Division of Reproductive Health for procedures performed in 2011. Data are presented regarding the use of ART in each U.S. state, the District of Columbia, and the Commonwealth of Puerto Rico as well as infant outcomes in 2011 resulting from procedures performed in 2010 and 2011. Additionally, the report examines the contribution of ART to selected adverse outcomes (e.g., multiple birth, low birthweight, and preterm delivery) and compares 2011 ART infant outcomes to outcomes among all infants born in the United States in 2011.

Methods

National ART Surveillance System

In 1996, CDC initiated data collection of ART procedures performed in the United States. ART data for 1995–2003 were obtained from the Society of Assisted Reproductive Technology (SART). Since 2004, CDC has contracted with Westat, Inc., a statistical survey research organization, to obtain data from fertility clinics in the United States through the National ART Surveillance System (NASS), a web-based data collection system developed by CDC (http://www.cdc.gov/art/NASS.htm). Clinics enter their data into NASS and verify the data's accuracy before sending the data to Westat. The data then are compiled by Westat and reviewed by both CDC and Westat. A few clinics (6.0%) did not report their data to CDC and are listed as nonreporting programs in the Fertility Clinic Success Rates Report, as required by FCSRCA. Because nonreporting clinics tend to be smaller than reporting clinics, NASS is estimated to contain information on >97.0% of all ART cycles in the United States (1).

Data collected include patient demographics, medical history, and infertility diagnoses; clinical information pertaining to the ART procedure type; and information regarding resultant pregnancies and births. The data file is organized with one record per ART procedure (or cycle of treatment) performed. Multiple procedures from individual patients are not linked. Because ART providers typically do not provide continued prenatal care after a pregnancy is established, information on live births for all procedures is collected by ART clinics either directly from their patients (83.0%) or from their patients' obstetric providers (17.0%).

ART Procedures

ART includes fertility treatments in which both eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). ART does not include treatments in which only sperm are handled (i.e., intrauterine insemination) or procedures in which a woman takes drugs only to stimulate egg production without the intention of having eggs retrieved. Because an ART procedure consists of several steps over an interval of approximately 2 weeks, a procedure often is referred to as a cycle of treatment. An ART cycle generally begins with drug-induced ovarian stimulation. If eggs are produced, the cycle progresses to the egg-retrieval stage. After the eggs are retrieved, they are combined with sperm in the laboratory through IVF. If this is successful, the most viable embryos (i.e., those that are morphologically most likely to develop and implant) are selected for transfer by clinicians. If an embryo implants in the uterus, a clinical pregnancy is diagnosed by the presence of a gestational sac detectable by ultrasound. Most pregnancy losses occur within the first 12 weeks. Beyond 12 weeks of gestation, the pregnancy usually progresses to a live-birth delivery (with survival probabilities ranging from 95.0% at 16 weeks to 98.0% at 20 weeks), which is defined as the delivery of one or more live-born infants (18).

ART procedures are classified into four types on the basis of the source of the egg (patient or donor) and the status of the embryos (fresh or thawed). Both fresh and thawed embryos can result from either the patient's eggs or from the donor's eggs. ART procedures involving fresh embryos include an egg-retrieval stage. ART procedures that use thawed embryos do not include egg retrieval because the 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 patient choice.

Variables and Definitions

ART data and outcomes from ART procedures are presented by the patient's state of residence at the time of treatment. If this information was missing, the state of residence was assigned as the state in which the procedure was performed. Cycles among non-U.S. residents are included in NASS data but might be excluded from some calculations for which the exact denominators were not known. To protect confidentiality in the presentation of data in tables, cells with values between 1 and 4 are suppressed, as are data that can be used to derive cell values of 1–4.* These values are included in totals. ART data for territories (with the exception of Puerto Rico) are not included in this report to protect data confidentiality.

This report presents data on all cycles initiated; however, outcomes are determined on the basis of cycles that involved embryo transfer. The number of ART procedures performed per 1 million women of reproductive age (15–44 years) was calculated, and the resulting ratio approximates the proportion of women of reproductive age who used ART in each state. However, this proxy measure of ART use is only an approximation because some women who used ART might fall outside the age range of 15–44 years, and some women might have had more than one procedure during the reporting period.

Live-birth delivery was defined as birth of one or more live-born infants, with delivery of multiple infants counted as one live-birth delivery. A singleton live-birth was defined as a birth of one live-born infant from a single gestation pregnancy. A multiple birth was defined as a birth of two or more infants, at least one of whom was live-born.

Elective single-embryo transfer (eSET) is a procedure in which one embryo, selected from a larger number of available embryos, is placed in the uterus, with extra embryos cryopreserved. This procedure does not include cycles in which only one embryo is available. Transfer procedures in which only one embryo was transferred but no embryos were cryopreserved also are excluded from this definition. The embryo selected for eSET might be from a previous IVF cycle (e.g., cryopreserved [frozen] embryos) or from the current fresh IVF cycle that yielded more than one embryo. The remaining embryos might be set aside for future use through cryopreservation. In this report, both eSET procedures and the average number of embryos transferred were calculated for fresh, nondonor cycles in which at least one embryo was transferred.

The average number of embryos transferred for three age groups (<35 years, 35–40 years, and >40 years) was calculated by dividing the total number of embryos transferred by the total number of embryo-transfer procedures performed in that age group. The percentage of eSET was calculated by dividing the total number of transfer procedures in which only one embryo was transferred and one or more embryos were cryopreserved, by the sum of this numerator (total number of single embryo transfer procedures where extra embryos were available for cryopreservation) and the total number of transfer procedures in which more than one embryo were transferred.

The contribution of ART to an outcome was calculated by dividing the total number of outcomes among ART-conceived pregnancies by the total number of overall outcomes. The contribution of ART to all infants born was calculated by plurality (singleton, multiples, twins, and triplets or higher order births) and by adverse perinatal outcomes (low birthweight and prematurity). The contribution of ART to total infants born in the state was used as a second measure of ART use. The number and percentage of infants (ART-conceived and all infants) born in the state were calculated for singleton, multiple, twin, and triplet or higher order births and for different categories of birthweight and gestational age. Additionally, the percentages of infants with low birthweight and preterm delivery were calculated for each group of plurality (singleton, twins, and triplets and higher order births) for both ART-conceived infants and all infants, by dividing the number of low birthweight or preterm infants in each group of plurality by the total number of infants in that group.

Low birthweight was defined as <2,500 grams, very low birthweight as <1,500 grams, and extremely low birthweight as <1,000 grams. For comparability with births to women who did not undergo ART, for which gestational age is determined on the basis of the date of the last menstrual period (LMP), gestational age was calculated for fresh ART cycles by subtracting the date of egg retrieval from the birth date and adding 14 days. For frozen embryo cycles, and for fresh ART cycles for which the date of retrieval was not available, gestational age was calculated by subtracting the date of embryo transfer from the birth date and adding 17 days (to account for an average of 3 days in embryo culture). Preterm delivery was defined as gestational age <37 weeks, very preterm delivery as gestational age <32 weeks, and extremely preterm delivery as gestational age <28 weeks (19).

Content of This Report

This report provides information on U.S. ART procedures performed in 2011 and compares infant outcomes that occurred in 2011 (resulting from procedures performed in 2010 and 2011) with outcomes for all infants born in the United States in 2011. Specifically, this report provides data on the number and outcomes of all ART procedures performed in the 50 states, the District of Columbia, and the Commonwealth of Puerto Rico in 2011. Live-birth delivery rates, the number of live-born infants, live singleton and multiple birth deliveries, and data regarding the number of ART procedures in relation to the number of women in the reproductive age group (15–44 years) are reported (20).† Data also are presented on the number of embryo-transfer procedures performed, the average number of embryos transferred, and the percentage of eSET procedures performed among women who used fresh embryos from their own eggs, by age group, for each state.

For each state, the proportions of singleton, multiple, twin, and triplet or higher order infants resulting from ART are compared with their respective ratios among all infants born in that state in 2011. Infants born in the state during that year include those that were conceived naturally as well as those resulting from ART and other infertility treatments. To accurately assess the proportion of ART births among overall U.S. births in 2011, ART births were aggregated from 2 reporting years: 1) infants conceived from ART procedures performed in 2010 and born in 2011 (approximately 69% of the live-birth deliveries reported to the ART surveillance system for 2011), and 2) infants conceived from ART procedures performed in 2011 and born in 2011 (approximately 31% of the live-birth deliveries reported to the ART surveillance system for 2011). Data on the total number of live-birth and multiple birth infants in each state in 2011 were obtained from U.S. natality files (21). The report presents the number and percentage of select adverse perinatal outcomes (low birthweight, very low birthweight, preterm delivery, and very preterm delivery) among ART-conceived infants and all infants, as well as the contribution of ART to these outcomes. Additionally, the percentages of adverse perinatal outcomes are reported for singleton, twin, and triplet and higher order infants for ART-conceived infants and all infants. Finally, results for New York City are presented separately from the rest of the state because New York City is an independent vital registration reporting area (21). Therefore, unless otherwise specified, references in this report to New York include only New York State and exclude New York City.

Results

Overview of Fertility Clinics

Of 481 fertility clinics in the United States that performed ART procedures in 2011, a total of 451 (94.0%) provided data to CDC (Figure 1) with the majority located in or near major cities in the eastern United States. The number of fertility clinics performing ART procedures varied by state. States with the largest number of fertility clinics reporting data for 2011 were California (64), Texas (39), New York (including New York City) (38), Florida (28), Illinois (26), and New Jersey (21).

Number and Type of ART Procedures

The number, type, and outcome of ART procedures performed in 2011 are provided for the 50 states, the District of Columbia, New York City, and Puerto Rico (Table 1). State residency data were missing for approximately 3.8% of procedures performed and 4.1% of live-birth deliveries but are included in the total. Approximately 16.0% of ART cycles were conducted among out-of-state residents. Non-U.S. residents accounted for approximately 2.0% of ART procedures, live-birth deliveries, and infants born.

Nationally, a total of 151,923 ART procedures performed in 2011 were reported to CDC (Table 1). Of the 151,923 procedures performed, 129,355 (85.2%) progressed to embryo transfer (Table 1). Overall, 45.7% (59,132 of 129,355) of ART procedures that progressed to the transfer stage resulted in a pregnancy, 37.0% (47,818 of 129,355) resulted in a live-birth delivery, 26.6% (34,464 of 129,355) resulted in a singleton live-birth delivery, and 10.3% (13,354 of 129,355) resulted in a multiple live-birth delivery. The 47,818 live-birth deliveries from ART procedures performed in 2011 resulted in 61,610 infants (34,464 singleton live-birth deliveries and 13,354 multiple live-birth deliveries) (Table 1; Figure 2).

Six states (California, Illinois, Massachusetts, New Jersey, New York (excluding New York City), and Texas) accounted for 47.2% (71,650 of 151,923) of ART procedures performed, 47.3% (61,202 of 129,355) of all embryo transfer procedures, 45.3% (27,936 of 61,610) of all infants born from ART in the United States, and 45.1% (6,024/13,354) of all ART multiple live-birth deliveries; however, these six states only accounted for 34% of all U.S. births (21) (Table 1).

The number of ART procedures per million women of reproductive age varied from 313 in Puerto Rico to 7,502 in Massachusetts, with an overall national ratio of 2,401 procedures per 1 million women of reproductive age. Eleven states (Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Virginia), New York City, and the District of Columbia had ratios higher than the national ratio. Three states (Massachusetts (7,502), New York (excluding New York City) (6,860), and New Jersey (5,038)) and the District of Columbia (6,563) had ratios exceeding twice the national level, and three states (Connecticut, Illinois, and Maryland) had ratios exceeding one and half times the national level (4,708, 3,769, and 4,729, respectively) (Figure 3).

Embryo Transfer and Patient's Age

The number of embryo-transfer procedures performed, the average number of embryos transferred per procedure, and the percentage of eSET procedures performed among women who used fresh embryos from their own eggs are provided by age group (Table 2). Overall, the highest number of embryo-transfer procedures performed was among women aged <35 years and lowest among women aged >40 years. Nationally, the average number of embryos transferred per procedure varied from 2.0 among women aged <35 years (range: 1.5 to 2.2) to 2.3 among women aged 35–40 years (range: 1.8 to 2.8), and 2.9 among women aged >40 years (range: 2.1 to 4.0). In 10 states (California, Connecticut, Hawaii, Maine, Maryland, Massachusetts, New Hampshire, New York, Vermont, and Virginia), the District of Columbia, New York City, and Puerto Rico, more embryo-transfer procedures were performed among women aged 35–40 years than among younger women. Nationally, rates of eSET ranged from 12.2% among women aged <35 years (range: 0.7% in Idaho to 52.9% in Delaware) to 4.7% among women aged 35–40 years (range: 0 in several states to 37.0% in Delaware) and 0.7% among women aged >40 years (range: 0 in most states to 16.7% in Mississippi). Among women aged <35 years, eSET rates exceeded the national rate in 18 states (Arkansas, California, Connecticut, Delaware, Georgia, Iowa, Maine, Maryland, Massachusetts, Montana, New Hampshire, South Dakota, Vermont, Virginia, Washington, West Virginia, Wisconsin and Wyoming), and the District of Columbia.

Singleton and Multiple Births

Among 3,994,670 infants born in the United States and Puerto Rico in 2011 (21), a total of 59,631 (1.5%) were conceived with ART procedures performed in 2010 and 2011 (Tables 3 and 4). California, Texas, and Florida ranked among the three highest states in total number of U.S. births. ART-conceived births were highest in California, followed by New York (excluding New York City), and Texas. Approximately 0.2% (in Puerto Rico) to 4.5% (in Massachusetts) of infants were born as a result of ART. The contribution of ART to all infants born in the state was highest in Massachusetts, followed by New York (excluding New York City) (4%), New Jersey (3.6%), Connecticut (3.5%), and the District of Columbia (3.7%) (Table 3). Although singletons accounted for 96.6% of total infants born in 2011 (range: 95.2% in New Jersey to 97.4% in New Mexico), singletons accounted for only 54.4% of all ART infants (range: 38.7% in Wyoming to 76.9% in Delaware). Nationwide, 45.6% (range: 23.1% in Delaware to 61.3% in Wyoming) of ART infants were multiples compared with only 3.4% (range: 1.9% in Puerto Rico to 4.8% in New Jersey) of all infants (Table 4). ART multiple-birth infants represent 19.8% (range: 4.9% in Mississippi to 41.3% in New York (excluding New York City)) of total multiple-birth infants. Approximately 42.7% (range: 31.6% in Rhode Island to 61.3% in Wyoming) of all ART-conceived infants were twins compared with only 3.3% (range: 1.9% in Puerto Rico to 4.6% in New Jersey) of all infants. ART-conceived twin infants accounted for 19.3% (range: 4.1% in Mississippi to 39.7% in Massachusetts) of all twins born in 2011. Finally, 2.9% of ART-conceived infants were triplets or higher order multiples (range: 0 in several states to 8.7% in Mississippi) compared with 0.1% (with very little variation by state) of all infants. ART triplet or higher order multiple infants contributed to 32.2% (range: 0 in several states to 71.4% in Hawaii) of all triplet or higher order infants born in 2011.

Adverse Perinatal Outcomes

Nationally, ART infants represented approximately 5.7% of all low birthweight and 5.9% of very low birthweight infants (Table 5). The contribution of ART to low birthweight infants ranged from 0.6% in Puerto Rico to 15% in Massachusetts. The contribution of ART to very low birthweight infants ranged from 0.8% in Mississippi to 17.3% in Massachusetts. In three states (Connecticut, Massachusetts, and New Jersey) >10% of all low birthweight infants born were conceived with ART. In four states (Connecticut, Hawaii, Massachusetts, and New Jersey) >10% of all very low birthweight infants were conceived with ART.

In all states, rates of low birthweight and very low birthweight infants were higher among infants conceived with ART than among all infants (Table 5). Among ART infants, 31% were low birthweight infants (range: 18% in the District of Columbia to 44.6% in Puerto Rico), compared with 8.1% among all infants (range: 6% in Alaska to 12.5% in Puerto Rico). Approximately 5.7% of ART infants were very low birthweight infants (range: 0 in North Dakota to 8.5% in Hawaii), compared with 1.4% among all infants (range: 0.9% in Alaska to 2.2% in Mississippi) (Table 5). Additional analyses show that among very low birthweight (<1,500 g) ART-conceived infants, 40.5% were born with extremely low birthweight of <1,000g. Nationally, infants conceived with ART contributed approximately 4.6% and 5.2%, respectively, to all preterm and very preterm infants (Table 6). The contribution of ART to preterm infants ranged from 0.5% in Puerto Rico to 13% in Massachusetts. The contribution of ART to very preterm infants ranged from 0 in Wyoming to 17.1% in Massachusetts. In three states (Connecticut, Massachusetts, and New Jersey), >10% of all preterm and very preterm infants in the state were conceived with ART.

As with low birthweight, rates of preterm and very preterm infants were higher among ART infants than in the general birth population (Table 6). Among ART infants, 36.2% were born preterm (range: 12.5% in Vermont to 56.9% in Puerto Rico), compared with 11.8% among all infants (range: 8.8% in Vermont to 17.6% in Puerto Rico). Approximately 6.7% of ART infants were very preterm (range: 0 in Wyoming to 12.5% in Alaska), compared with 2% among all infants (range: 1.3% in Wyoming to 3% in Puerto Rico) (Table 6). Additional analyses show that among all ART-conceived infants born very preterm (<32 weeks), 45.7% were born extremely preterm (<28 weeks of gestation).

The percentage of ART infants who were low birthweight varied from 8.8% (range: 3.9% in District of Columbia to 17.9% in Puerto Rico) among singletons, to 56.4% (range: 34.6% in Vermont to 70.4% in Mississippi) among twins, and 95.7% (range: 79.5% in North Carolina to 100% in several states) among triplets or higher-order multiples; comparable percentages among all infants born were 6.4% (range: 4.5% in Idaho to 11.3% in Puerto Rico), 56.3% (range: 47.7% in Vermont to 72.1% in Puerto Rico), and 93.9% (range: 50% in Wyoming to 100% in several states), respectively (Table 7).

The percentage of ART infants who were very low birthweight varied from 1.7% (range: 0 in several states to 3.5% in North Carolina) among singletons, to 8.9% (range: 0 in several states to 16.4% in Kansas) among twins, and 36.9% (range: 0 in several states to 60% in Hawaii) among triplets or higher-order multiples; comparable percentages among all infants were 1.2% (range: 0.7% in several states to 1.8% in District of Columbia), 9.8% (range: 6.5% in Maine to 14.4% in Vermont), and 36.9% (range: 9.5% in Hawaii to 100% in Vermont), respectively. The percentage of ART infants who were preterm varied from 13.2% (range: 7.3% in the District of Columbia to 28.6% in Puerto Rico) among singletons, to 61.8% (range: 46% in the District of Columbia to 82.7% in Oklahoma) among twins, and 97.1% (range: 76.9% in Iowa to 100% in several states) for triplets or higher-order multiples; comparable percentages among all infants were 10.1% (range:7.5% in Oregon to 16.6% in Puerto Rico), 57.3% (range: 46.8% in New Hampshire to 68.8% in Louisiana), and 93.4% (range: 73.3% in Rhode Island to 100% in several states), respectively (Table 8). The percentage of ART infants who were very preterm varied from 2.2% (range: 0 in several states to 3.8% in Louisiana, North Carolina, and South Carolina) among singletons, to 10.5% (range: 0 in Vermont and Wyoming to 23.8% in Nebraska) among twins, and 38.2% (range: 0 in several states to 75% in Idaho and Tennessee) among triplets or higher-order multiples; comparable percentages among all infants were 1.6% (range: 1% in Idaho and Oregon to 2.8% in Puerto Rico), 11.3% (range: 6.3% in Maine to 17.1% in Louisiana), and 38% (range: 0 in Alaska and Vermont to 77.8% in District of Columbia), respectively.

Discussion

Overview

The use of ART has increased substantially in the United States since the beginning of ART surveillance. In 1996 (the first full year for which ART data were reported to CDC), 20,597 infants were born from 64,036 ART cycles (22). Since then, the number of cycles reported to CDC has more than doubled and the number of infants born from ART procedures has approximately tripled. The impact of ART on rates of multiple-birth infants and poor birth outcomes is substantial because almost half of ART infants (46%) were born in multiple births (compared with only 3% of infants among the general birth population). On average, two embryos were transferred among women aged <35 years. National rates of eSET procedures were low, even among women aged <35 years. Rates of low birthweight and preterm births were substantially higher among ART infants (31% and 36%, respectively) than among all infants (8% and 12%, respectively). Compared with ART singletons, ART twins and triplet or higher order infants were five and seven times more likely to be preterm. Although infants conceived with ART accounted for approximately 1.5% of total births in the United States in 2011, the proportion of twin and triplet or higher order infants attributed to ART were 19% and 32%, respectively, which is similar to the rates for previous years.

Variations by State

ART use varied widely by state, especially after controlling for the size of the population of women of reproductive age. Residents of California, Illinois, Massachusetts, New York (excluding New York City), New Jersey, and Texas had 45.0% of all ART infants but accounted for only 34.0% of all infants born in the United States. Rates of ART use were not correspondingly high in all six states. ART use exceeded twice the national average in only three of these six states (Massachusetts, New Jersey, and New York, excluding New York City) (as measured by the number of ART procedures performed per 1 million women of reproductive age). By this measure, Massachusetts ranked highest in ART use whereas California, despite having the highest overall number of ART procedures and the highest number of ART infants, ranked 15th nationally, with a rate of ART use that was lower than the national rate. Furthermore, the contribution of ART to all infants born in the state was 4.5% in Massachusetts compared with 1.5% in California, which also indicates higher ART use in Massachusetts. Similarly, residents of Connecticut, Delaware, District of Columbia, Hawaii, Illinois, Maryland, New Hampshire, New Jersey, New York, and New York City, Rhode Island, and Virginia had higher rates of ART use than the national average as reflected by the high number of ART procedures performed per 1 million women of reproductive age in those states.

This divergence might be explained in part by variations in state health insurance coverage. Currently, 15 states (Arkansas, California, Connecticut, Hawaii, Illinois, Louisiana, Maryland, Massachusetts, Montana, New Jersey, New York, Ohio, Rhode Island, Texas, and West Virginia) have passed legislation mandating insurance coverage for infertility treatments; four of these states (Illinois, Massachusetts, New Jersey, and Rhode Island) also have mandated comprehensive insurance coverage that must cover at least four cycles of IVF.§ Three out of the four states with mandates (Illinois, Massachusetts, and New Jersey) also had rates of ART use >1.5 times the national level. This type of mandated insurance has been associated with greater use of ART (23–25).

Elective Single-Embryo Transfer Rates

Typically, younger women are better candidates for eSET procedures because they might have more than one embryo available for transfer and better prognosis. Data on eSET rates varied by age group and by state. Rates of eSET procedures were higher among women aged <35 years than other age groups but varied widely among states (range: 0.7% to 53%). Although many factors (e.g., patient's age and diagnostic factors) influence eSET rates, research shows that broad insurance mandates for IVF might result not only in large increases in access to ART services but also in substantially fewer aggressive treatments, with fewer embryos transferred within a procedure (24,26). In the four states with mandatory insurance for ART, among women aged <35 years, eSET rates were higher than the national average of 12.2% only in Massachusetts (22.9%) but lower in Illinois (11.5%), New Jersey (9.9%) and Rhode Island (8.6%). Because ART procedures are expensive, attempts to reduce out-of-pocket costs might result in higher number of embryo transfers per attempt for patients who do not have insurance coverage for ART (24,26). In the United States, approximately 20.0% of all ART costs are covered by state mandate of private insurers and/or by private insurers. Even where mandated, coverage for infertility treatment often varies in scope (23). The higher use of eSET in Massachusetts is consistent with previous research linking insurance with embryo transfer practices that might promote eSET. Such a pattern is not evident in Illinois, New Jersey and Rhode Island, all of which had state-mandated insurance for ART but lower-than-national rates of eSET procedures performed. ESET rates also exceeded the national rate in a number of states that do not have mandated insurance coverage for ART, especially among women aged <35 years, suggesting provider compliance with American Society for Reproductive Medicine (ASRM)/SART recommendations on eSET even in the absence of mandated insurance (27).

ART Multiple Births

A comparison of findings from this report to the 2000 ART Surveillance Summary report (28) shows that since 2000, the percentage of ART-conceived multiple infants in the United States declined by 13% (from 53% in 2000 to 46% in 2011). A sharp decline was noted in the rate of ART-conceived triplets and higher order infants of 67% (from 9% in 2000 to 3% in 2011) and a lesser decline in ART-conceived twin infant rates of 2% (from 44% in 2000 to 43% in 2011).

Despite the decline, multiple birth rates remain high in the United States. On average, two embryos were transferred per cycle among all age groups, even among younger women, in 2011. To control costs, patients and providers might be willing to transfer multiple embryos to maximize the chance of live-birth delivery in a single procedure (25). The expected association between fewer average number of embryos transferred and availability of mandated insurance coverage for ART is not wholly supported by these data. The average percentage of embryos transferred among women aged <35 years in the four states with universal mandated coverage (Illinois, 2.0%; Massachusetts, 1.8%; New Jersey, 2.0%; Rhode Island, 2.1%) was similar to the national rate (2.0%). However, in three (Illinois: 44.3%; Massachusetts: 39.4%; and Rhode Island: 31.6%) of the four states with mandated insurance, the rate of ART-conceived multiple infants was lower than the national rate of ART multiple infants (45.6%). This rate was higher than the national rate in New Jersey (48.8%), which also had mandated insurance. Thus, rates of ART-conceived multiple infants varied between the four states with mandated insurance, suggesting that the link between insurance and embryo transfer practices (e.g., the number of embryos transferred per procedure) and multiple births is complex.

Evidence suggests that infertile couples might prefer multiple births, especially twins, in their desire to achieve parenthood, and might underestimate the risks for such pregnancies or might consider the potential benefits to outweigh the risks. Infertile women might be more receptive to the idea of a multiple birth than fertile women (29,30). Therefore, understanding the viewpoint of couples undergoing infertility treatments about multiple births is an important consideration. ART providers also can vary widely in their clinical practices, which can affect the outcomes in each state; the extent that clinic practices affect the overall state results shown in this report depends on various factors including patient age and diagnostics, the number of cycles performed, as well as the number and size of the other clinics in the state.

In 2011, approximately half of all ART infants were born in multiple births, most of which were twin infants. During 1980–2009, the overall twin birth rates in the United States, which also comprise the majority of multiple births, increased by 76.2%, from 18.9 to 33.3 per 1,000 births (31). In 2009, one in every 30 babies born in the United States was a twin, compared with one in every 53 babies in 1980 (31). The increased use of infertility treatments, both ART and non-ART fertility treatments (ovulation stimulation medications without ART), likely is associated with this sharp increase (32). Because of the risks associated with multiple-gestation pregnancies, medical experts believe that the best outcome of IVF treatment is a singleton pregnancy followed by a singleton birth (33). Singleton live-birth deliveries have much lower risks than multiple births for adverse birth outcomes such as prematurity, low birthweight, disability, and death. ART twins and higher order multiples were five to seven times more likely to be born preterm than were ART singletons. Similar higher rates of preterm and low birthweight were observed among twins and higher order infants born in the general population, compared with singletons. Because most multiple birth infants in the United States are twins, strategies to reduce multiple births should include efforts to reduce the frequency of IVF-related twin pregnancies.

The economic costs of multiple births also are much higher compared with singleton births. The mean medical cost of delivering a singleton baby was estimated to be $9,329, whereas a set of twins costs $20,318, and triplets costs $153,335 (34). Transferring two embryos is associated with a more than threefold increase in the birth rate and a more than 16-fold increase in the twin birth rate as compared with singletons (35). In 2011, the transfer of two embryos was still a common practice, even among younger patients. To improve the likelihood of optimal birth outcomes, the transfer of fewer numbers of embryos should be encouraged among patients and providers, taking into consideration patient age and prognosis (36). The guidelines on the number of embryos transferred were revised in 2004, 2006, 2008, 2009, and 2012 (37–41). Currently, the guidelines suggest a maximum of 1–2 embryos to be transferred for women aged <35 years who have good prognosis, if the transfer is done on day 2 or 3, and a maximum of one embryo to be transferred for that age group if the transfer is done on day 5. When the female is aged >35 years, the maximum number of embryos allowed increases. At its 2011 annual meeting, the American Society for Reproductive Medicine Practice Committee noted that the most direct way to limit the risk for multiple gestations from ART is to transfer single embryos (27).

ART Low Birthweight Infants and Preterm Births

The rates of low birthweight and very low birthweight infants were disproportionately higher among ART infants than among infants in the general birth population. Three states (Connecticut, Massachusetts, and New Jersey) with high number of ART cycles and births also had high ART contributions (>10%) to both categories of low birthweight and preterm births. The contribution of ART to preterm births in the United States, most of which are also low birthweight, is a key concern. Since 1981, the rate of preterm births in the United States has increased >24% (42). Fertility treatments, both ART and controlled ovarian stimulations, contribute substantially to preterm births among both multiple and singleton pregnancies (42). Preterm births are a leading cause of infant mortality and morbidity, and preterm infants are at increased risk for death and have more health and developmental problems than full-term infants (42–45). Among ART infants, a substantial proportion of very preterm and very low birthweight infants were born extremely preterm at <28 weeks of gestation and with extremely low birthweight at <1,000 grams. The health risks associated with preterm births have contributed to increasing health-care costs. In 2005, the estimated economic cost associated with preterm births in the United States was $26 billion ($51,600 per infant born preterm) (42).

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 2011, of all singleton infants conceived with ART, 8.8% were low birthweight, compared with 7.3% in the general U.S. population. Approximately 2% of singleton infants conceived from ART were very low birthweight, compared with approximately 1% of singletons conceived in the general U.S. population. The percentage of ART singletons born preterm was 13% in comparison to 10% for the general U.S. population. Therefore, adverse infant health outcomes among singletons (e.g. low birthweight and preterm delivery) also should be considered when assessing the effects of ART.

Limitations

The findings in this report are subject to at least five 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, even within a given year, is difficult. Second, because patients can achieve a successful pregnancy after undergoing multiple procedures, the cycle-specific success rates reported here might underestimate the true per-patient success rates. Third, prematurity and low birthweight could be associated with factors contributing to underlying infertility and not entirely to ART procedures. Fourth, a small percentage of fertility clinics that performed ART in 2011 did not report their data to CDC and might have had results different from clinics that reported their data. Finally, five states had a substantial percentage of residency information missing for procedures performed in 2011 (Maryland [6.8%], Georgia [9.0%], Pennsylvania [9.0%], Hawaii [9.6%], and Massachusetts [33.1%]). Overall, residency data were missing for approximately 4.0% of procedures performed and 3.0% of all live-birth deliveries resulting from ART procedures performed in 2011.

Conclusion

During 1996–2011, the number of ART procedures performed in the United States doubled, and the number of infants born as a result of these procedures nearly tripled. With this increasing use, ART-conceived infants now represent 1.5% of infants born in the United States and had a noticeable impact on the prevalence of low birthweight and preterm deliveries in many states, as nearly half of these infants were born in multiple-gestation pregnancies that resulted in multiple births. Furthermore, among ART-conceived infants, although rates of triplet or higher order infants have declined during the last decade, twin infant rates have remained persistently high. Therefore, the impact of ART on poor birth outcomes remains substantial despite the overall decline in multiple infant rates. This could be attributed to the persistently high rates of ART-conceived twin infants, which have declined very little in the last decade. This report documents the rates and contribution of ART to multiple births, low birthweight, and preterm infants by each state. It also highlights the differences in rates of low birthweight and prematurity between ART-conceived singleton, twin, and triplet and higher order infants compared with infants born in the general population. This allows state health departments to monitor the extent of ART-related adverse perinatal outcomes in their individual states.

Comprehensive insurance coverage of ART might increase access to fertility treatments. The findings in this report indicate that ART use was higher than the national rate in all four states with mandated comprehensive insurance coverage. Three of these four states had utilization rates exceeding 1.5 times national levels. However, embryo transfer practices were similar to the national rates in all four states providing comprehensive insurance coverage. The use of elective single-embryo transfers was higher only in Massachusetts, which had a correspondingly lower rate of ART multiple infants. Further research is needed to ascertain the influence of state insurance mandates on ART use, embryo transfer practices, and infant outcomes, as well as the economic costs of multiple births (23–26), including out-of-pocket costs to patients. Addressing the risk for multiple births also requires understanding the perspectives of couples undergoing infertility treatments who might view a multiple birth, especially twins, as an acceptable or even desired outcome and who might not be aware of the increased risks associated with multiple birth to mother and infants. Clinicians need to be aware of ongoing efforts to limit the number of embryos transferred to single embryo to reduce twin rates, which have remained high, and encourage wider implementation of elective single-embryo transfers, when clinically appropriate, as mechanisms of promoting singleton infant births among ART-conceived pregnancies (27).

CDC is working to extend the use of NASS by linking to data collected by states (i.e., birth certificate, infant deaths, hospital discharge, birth defect registries, and cancer registries) to conduct state-based surveillance of ART, infertility, and related issues. This initiative, the States Monitoring ART (SMART) Collaborative,¶ has been determined to be feasible and useful, especially for monitoring long-term outcomes of ART (46). Data from NASS have been linked with vital records from three states (Florida, Massachusetts, and Michigan). The overarching purpose of the SMART Collaborative is to strengthen the capacity of states to evaluate maternal and perinatal outcomes and programs through state-based public health surveillance systems (47).

Further efforts also are needed to monitor the use of non-ART fertility treatments and their role in the rising number of multiple births (32,42). Despite its substantial impact on adverse birth outcomes, ART only partially explains the overall prevalence of these adverse outcomes in the United States. Preterm births resulting from controlled ovarian stimulation (superovulation-intrauterine insemination and conventional ovulation induction) also might contribute to multiple gestations (42). More research is needed to identify the causes and consequences of preterm births that occur because of infertility treatments and to institute guidelines to reduce the number of multiple gestations (42). The risk for multiple gestations associated with non-ART fertility treatments is less well documented, as clinics are not mandated to report data on their use. Recent studies have demonstrated that singleton infants conceived with ovulation stimulation are more likely than naturally conceived infants to be small for gestational age (48). CDC is monitoring the prevalence of non-ART fertility treatment use among women who had live births and their resultant outcomes in several states through the Pregnancy Risk Assessment Monitoring System (49). The most recent ART Surveillance Summary was published by CDC in 2013 (50). CDC will continue to provide updates of ART use in the United States as data become available.

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