Embryo transfer practices and multiple births resulting from assisted reproductive technology: an opportunity for prevention

Problem/condition Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Although the majority of infants conceived through ART are singletons, women who undergo ART procedures are more likely than women who conceive naturally to have multiple-birth infants because multiple embryos may be transferred. Multiple births can pose substantial risks for both mothers and infants, including obstetric complications, preterm birth ( Period covered 2017. Description of system In 1995, CDC began collecting data on ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102-493 [October 24, 1992]). Data are collected through the National ART Surveillance System (NASS), a web-based data collection system developed by CDC. This report includes data from the 50 states, the District of Columbia, and Puerto Rico. Results In 2017, a total of 196,454 ART procedures (range: 162 in Alaska to 24,179 in California) with at least one embryo transferred were performed in 448 U.S. fertility clinics and reported to CDC. These procedures resulted in 68,908 live-birth deliveries (range: 67 in Puerto Rico to 8,852 in California) and 78,052 infants born (range: 85 in Puerto Rico to 9,926 in California). Nationally, the number of ART procedures performed per 1 million women of reproductive age (15-44 years) was 3,040. ART use rates exceeded the national rate in 14 states (Connecticut, Delaware, District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Utah, Vermont, and Virginia). ART use exceeded 1.5 times the national rate in seven states (Connecticut, the District of Columbia, Illinois, Maryland, Massachusetts, New Jersey, and New York). Nationally, among all ART transfer procedures, the average number of embryos transferred increased slightly with increasing age (1.3 among women aged 37 years). This year, single-embryo transfer (SET) rates among all embryo-transfer procedures are presented instead of elective single-embryo transfer procedures previously reported. Nationally, SET rates were 67.3% (range: 38.9% in South Dakota to 90.4% in Delaware), 65.0% (range: 23.6% in Puerto Rico to 89.4% in Delaware), and 60.0% (range: 28.6% in Puerto Rico to 83.1% in Delaware) among women aged 37 years, respectively. In 2017, ART contributed to 1.9% of all infants born in the United States (range: 0.4% in Puerto Rico to 5.0% in Massachusetts). Approximately 73.6% of ART-conceived infants were singleton infants. Overall, ART contributed to 14.7% of all multiple births, including 14.7% of all twin infants and 17.3% of all triplets and higher-order infants. ART-conceived twins accounted for approximately 96.5% (18,890 of 19,570) of all ART-conceived infants born in multiple deliveries. The percentage of multiple births was higher among infants conceived with ART (26.4%) than among all infants born in the total birth population (3.4%). Approximately 25.5% of ART-conceived infants were twins, and 0.9% were triplets and higher-order infants. Nationally, infants conceived with ART contributed to 4.5% of all low birthweight ( Interpretation Although singleton infants accounted for the majority of ART-conceived infants, multiple births from ART still contributed to a substantial proportion of all twins, triplets, and higher-order infants born in the United States. Variations in SET rates among states and territories were noted, reflecting variations in embryo-transfer practices among fertility clinics, which might in part account for higher multiple birth from ART observed in some states and territories. Public health action Reducing the number of embryos transferred and increasing use of SET, when clinically appropriate, can help reduce multiple births and related adverse health consequences for both mothers and infants. Because infants from multiple births are at increased risk for numerous adverse sequelae that cannot be ascertained from the data collected through NASS alone, long-term follow-up for ART infants through integration of existing maternal and infant health surveillance systems and registries with data available from NASS might be useful for monitoring adverse outcomes on a population basis.

Reducing the number of embryos transferred per ART procedure and increasing use of eSET, when clinically appropriate (typically for women aged <35 years), could help reduce multiple births, particularly ART-conceived twin infants, and related adverse consequences of ART. Because twins account for the majority of ART-conceived multiple births, improved patient education and counseling on the maternal and infant health risks of having twins is needed. Although ART contributes to high rates of multiple births, other factors not investigated in this report (e.g., delayed childbearing and non-ART fertility treatments) also contribute to multiple births and warrant further study.

Problem/condition Since the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Although the majority of infants conceived through ART are singletons, women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks for both mothers and infants, including obstetric complications, preterm delivery ( Period covered 2016. Description of system In 1995, CDC began collecting data on 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 [October 24, 1992]). Data are collected through the National ART Surveillance System (NASS), a web-based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia, and Puerto Rico). Results In 2016, a total of 197,706 ART procedures (range: 162 in Wyoming to 24,030 in California) with the intent to transfer at least one embryo were performed in 463 U.S. fertility clinics and reported to CDC. These procedures resulted in 65,964 live-birth deliveries (range: 57 in Puerto Rico to 8,638 in California) and 76,892 infants born (range: 74 in Alaska to 9,885 in California). Nationally, the number of ART procedures performed per 1 million women of reproductive age (15-44 years), a proxy measure of the ART use rate, was 3,075. ART use rates exceeded the national rate in 14 reporting areas (Connecticut, Delaware, the District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Pennsylvania, Rhode Island, Utah, and Virginia). ART use exceeded 1.5 times the national rate in nine states, including three (Illinois, Massachusetts, and New Jersey) that also had comprehensive mandated health insurance coverage for ART procedures (i.e., coverage for at least four oocyte retrievals). Nationally, among ART transfer procedures for patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age (1.5 among women aged 37 years). Among women aged Interpretation Multiple births from ART contributed to a substantial proportion of all twins, triplets, and higher-order infants born in the United States. For women aged 1.5 times the national average. Although other factors might influence ART use, insurance coverage for infertility treatments accounts for some of the difference in per capita ART use observed among states because most states do not mandate any coverage for ART treatment. Public health action Twins account for almost all of ART-conceived multiple births born in multiple deliveries. Reducing the number of embryos transferred and increasing use of eSET, when clinically appropriate, could help reduce multiple births and related adverse health consequences for both mothers and infants. Because multiple-birth infants are at increased risk for numerous adverse sequelae that cannot be ascertained from the data collected through NASS alone, long-term follow-up of ART infants through integration of existing maternal and infant health surveillance systems and registries with data available from NASS might be useful for monitoring adverse outcomes.

The decreased rates of triplet births: Temporal trends and biologic speculations

Continuous quality improvement and assisted reproductive technology multiple gestations: some progress, some answers, more questions

Assisted reproductive technology use, embryo transfer practices, and birth outcomes after infertility insurance mandates: New Jersey and Connecticut

Problem/ConditionSince the first U.S. infant conceived with assisted reproductive technology (ART) was born in 1981, both the use of ART and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Although the majority of infants conceived through ART are singletons, women who undergo ART procedures are more likely than women who conceive naturally to deliver multiple-birth infants. Multiple births pose substantial risks for both mothers and infants, including obstetric complications, preterm delivery (<37 weeks), and low birthweight (<2,500 g) infants. This report provides state-specific information for the United States (including the District of Columbia and Puerto Rico) on ART procedures performed in 2015 and compares birth outcomes that occurred in 2015 (resulting from ART procedures performed in 2014 and 2015) with outcomes for all infants born in the United States in 2015.Period Covered2015.Description of SystemIn 1995, CDC began collecting data on 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 [October 24, 1992]). Data are collected through the National ART Surveillance System, a web-based data collection system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia, and Puerto Rico).ResultsIn 2015, a total of 182,111 ART procedures (range: 135 in Alaska to 23,198 in California) with the intent to transfer at least one embryo were performed in 464 U.S. fertility clinics and reported to CDC. These procedures resulted in 59,334 live-birth deliveries (range: 55 in Wyoming to 7,802 in California) and 71,152 infants born (range: 68 in Wyoming to 9,176 in California). Nationally, the number of ART procedures performed per 1 million women of reproductive age (15–44 years), a proxy measure of the ART utilization rate, was 2,832. ART use exceeded the national rate in 13 reporting areas (California, Connecticut, Delaware, the District of Columbia, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Virginia).Nationally, among ART transfer procedures in patients using fresh embryos from their own eggs, the average number of embryos transferred increased with increasing age of the woman (1.6 among women aged <35 years, 1.8 among women aged 35–37 years, and 2.3 among women aged >37 years). Among women aged <35 years, the national elective single-embryo transfer (eSET) rate was 34.7% (range: 11.3% in Puerto Rico to 88.1% in Delaware).In 2015, ART contributed to 1.7% of all infants born in the United States (range: 0.3% in Puerto Rico to 4.5% in Massachusetts). ART also contributed to 17.0% of all multiple-birth infants, 16.8% of all twin infants, and 22.2% of all triplets and higher-order infants. The percentage of multiple-birth infants was higher among infants conceived with ART (35.3%) than among all infants born in the total birth population (3.4%). Approximately 34.0% of ART-conceived infants were twins and 1.0% were triplets and higher-order infants.Nationally, infants conceived with ART contributed to 5.1% of all low birthweight infants. Among ART-conceived infants, 25.5% had low birthweight, compared with 8.1% among all infants. ART-conceived infants contributed to 5.3% of all preterm (gestational age <37 weeks) infants. The percentage of preterm births was higher among infants conceived with ART (31.2%) than among all infants born in the total birth population (9.7%). Among singletons, the percentage of ART-conceived infants who had low birthweight was 8.7% compared with 6.4% among all infants born. The percentage of ART-conceived infants who were born preterm was 13.4% among singletons compared with 7.9% among all infants.InterpretationMultiple births from ART contributed to a substantial proportion of all twins, triplets, and higher-order infants born in the United States. For women aged <35 years, who are typically considered good candidates for eSET, the national average of 1.6 embryos was transferred per ART procedure. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive mandated health insurance coverage for ART procedures (i.e., coverage for at least four cycles of IVF), three (Illinois, Massachusetts, and New Jersey) had rates of ART use exceeding 1.5 times the national rate. This type of mandated insurance coverage has been associated with greater use of ART and likely accounts for some of the difference in per capita ART use observed among states.Public Health ActionTwins account for the majority of ART-conceived multiple births. Reducing the number of embryos transferred and increasing use of eSET when clinically appropriate could help reduce multiple births and related adverse health consequences for both mothers and infants. State-based surveillance of ART might be useful for monitoring and evaluating maternal and infant health outcomes of ART in states with high ART use.

Assisted reproductive technology (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). This report presents the most recent national data and state-specific results.2005.In 1996, CDC initiated data collection regarding 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]). Beginning with 2004, CDC has 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 (NASS).In 2005, a total of 134,260 ART procedures were reported to CDC. These procedures resulted in 38,910 live-birth deliveries and 52,041 infants. Nationwide, 73% 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 35% 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 (52%). The highest numbers of ART procedures were performed among residents of California (18,655), New York (12,032), Illinois (9,449), New Jersey (9,325), and Massachusetts (8,571). These five states also reported the highest number of live-birth deliveries. Of 52,041 infants born through ART, 49% 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 (41%) or their own eggs (32%). Approximately 1% of U.S. infants born in 2005 were conceived through ART. Those infants accounted for 17% of multiple births nationwide. Approximately 9% of ART singletons, 57% of ART twins, and 95% of ART triplets or higher-order multiples were low birthweight. Similarly, 15% of ART singletons, 66% of ART twins, and 97% of ART triplets or higher-order multiples were born preterm.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 that are associated with adverse maternal and infant outcomes (e.g., preterm delivery, low birthweight, and infant mortality). This risk varied according to the patient's age, the type of ART procedure performed, the number of embryos available for transfer to the uterus, the number actually transferred, and the day of transfer (day 3 or day 5).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.

Do assisted reproductive technologies cause adverse fetal outcomes?

To the Editor: Dr Adashi and Senator Wyden (D-OR) commented on the Centers for Disease Control and Prevention’s (CDC’s) National Assisted Reproductive Technology Surveillance System (NASS). The Society for Assisted Reproductive Technology started collecting assisted reproductive technology (ART) data from member-clinics in 1986; the CDC has been collecting detailed information on all ART procedures performed annually in the United States since 1995 and has been monitoring ART effectiveness and safety. Several factors contribute to the high quality of surveillance data, including support of professional societies and consumer organizations, as well as annual data validation of a sample of ART programs. However, there are areas for improvement. Currently, ART programs submit their data to the CDC 1 year after the end of the reporting year to allow collection of complete information about births following successful ART procedures. Another year is needed for statistical analyses, preparation, and publication of the ART Success Rates Report. Thus, the report describing ART procedures performed in 2009 is published at the end of 2011. To improve the timeliness of publishing clinic-specific success rates, the CDC plans to release these rates in advance of the aggregate national data beginning in 2012. Outreach to the few nonreporting ART clinics, which tend to be smaller and may not belong to the relevant professional societies, could improve completeness of the NASS. The quality of reported data can be further improved by prospective reporting, ie, initial reporting of ART procedure (cycle start date and patient’s demographic information) within 4 days of procedure initiation, and complete reporting when the outcome of the procedure is known. All member-clinics of the Society for Assisted Reproductive Technology are now required to report prospectively. Extension of prospective reporting to non–member-clinics (approximately 15% of ART clinics) could further improve data quality and accountability. The growing population of ART-conceived children and the contribution of ART to multiple and preterm births makes ART an important public health issue, which the NASS can help to address. However, the NASS only contains limited pregnancy outcome information. Linking ART surveillance data with other surveillance systems could be an efficient approach to monitor long-term outcomes of ART. In collaboration with the health departments of Massachusetts, Michigan, and Florida, NASS data are being linked to vital records, hospital discharge data, birth defects’ registries, cancer registries, and other surveillance systems. This project, the States Monitoring ART Collaborative, provides an opportunity to establish state-based patientfocused (vs cycle-focused) public health surveillance of ART, infertility, and related issues. Dmitry M. Kissin, MD, MPH Denise J. Jamieson, MD, MPH Wanda D. Barfield, MD, MPH

Multiple pregnancies: a call for action

After completing this article, readers should be able to: 1. Describe the outcomes of assisted reproductive technologies (ART) for singleton, twin, and other multiple births. 2. Describe the role of fertility in adverse outcomes seen with ART births. 3. Review the association of birth defects with ART. 4. Delineate the association of disease of genomic imprinting with ART. 5. Describe the relationship between ART and the subsequent incidence of neurodevelopmental sequelae. In the 1977 ruling “Carey v. Population Services International,” the United States Supreme Court ruled that the decision to bear children is constitutionally protected. (1) Significant interest already had been shown in the development and improvements of in vitro fertilization (IVF) for infertile couples. The first human pregnancy and human birth using IVF were reported by Steptoe and Edwards in the United Kingdom. (2) Their work resulted in the first baby born via reproductive technologies, Louise Brown, born on July 25, 1978, at Oldham General Hospital in Oldham, United Kingdom. (3) She was born via a planned cesarean section, and her birthweight was 2.61 kg. The first successful viable IVF in the United States was performed by Jones and Seager-Jones in 1981 in Norfolk, Virginia. (4) Assisted reproductive technologies (ART) have seen a recent surge in popularity. The Centers for Disease Control and Prevention (CDC) reported that 122,872 cycles of ART were initiated in 2003, resulting in the delivery of 48,756 neonates, (5) accounting for approximately 1% of all neonates delivered in the United States. The percentage is higher in many countries, including Denmark, where it is estimated that 5% of all deliveries are with the assistance of ART. (6) Couples pursue ART for myriad reasons, including tubal transport factors, ovulatory dysfunction, uterine factors, endometriosis, male- and female-specific factors, and when a cause of infertility is unknown. (5) It would be very …

Comparison of the offspring sex ratio between fresh and vitrification-thawed blastocyst transfer

When Darine El-Chaar began her residency in obstetrics and gynecology at the University of Ottawa five years ago, she grew curious about the potential health repercussions of assisted reproductive technologies (ART), the catchall term for procedures used to help couples artificially conceive a child. ART involves surgically removing eggs from a woman’s ovaries, combining them with sperm in the laboratory, and returning them to the womb.1 Women undergoing ART take “fertility drugs” such as clomiphene citrate and gonadotropins to stimulate the production of many eggs rather than the single egg that would normally grow during their monthly menstrual cycle.2 El-Chaar wondered about the influence that ART procedures, as well as the underlying infertility itself, might have on the health of children conceived. She is one of many researchers working to answer the fundamental question of whether introducing fertility drugs and manipulating eggs and sperm in a laboratory setting—in essence, altering the primal environment—sets the stage for adverse health effects in children. Artist’s rendering of intracytoplasmic sperm injection, in which a single sperm is inserted into an egg. Although some research indicates such a risk exists, there haven’t been enough large-scale studies to ascertain if the potential effects are severe enough over the long term to deter couples from seeking infertility treatments. Meanwhile, some findings are pointing the way toward possible refinements to improve health outcomes for ART babies.

Ovarian stimulation and intrauterine insemination at the quarter centennial: implications for the multiple births epidemic