STUDY QUESTION: Is air pollution associated with IVF treatment outcomes in the USA? SUMMARY ANSWER: We did not find clear evidence of a meaningful association between reproductive outcomes and average daily concentrations of particulate matter with an aerodynamic diameter ≤2.5 μm (PM2.5) and ozone (O3). WHAT IS KNOWN ALREADY: Maternal exposure to air pollution such as PM2.5, nitrogen oxides, carbon monoxide or O3 may increase risks for adverse perinatal outcomes. Findings from the few studies using data from IVF populations to investigate associations between specific pollutants and treatment outcomes are inconclusive. STUDY DESIGN, SIZE AND DURATION: Retrospective cohort study of 253 528 non-cancelled fresh, autologous IVF cycles including 230 243 fresh, autologous IVF cycles with a transfer of ≥1 embryo was performed between 2010 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: We linked 2010-2012 National ART Surveillance System data for fresh, autologous IVF cycles with the ambient air pollution data generated using a Bayesian fusion model available through the Centers for Disease Control and Prevention's Environmental Public Health Tracking Network. We calculated county-level average daily PM2.5 and O3 concentrations for three time periods: cycle start to oocyte retrieval (T1), oocyte retrieval to embryo transfer (T2) and embryo transfer +14 days (T3). Multivariable predicted marginal proportions from logistic and log-linear regression models were used to estimate adjusted risk ratios (aRR) and 95% CI for the association between reproductive outcomes (implantation rate, pregnancy and live birth) and interquartile increases in PM2.5 and O3. The multipollutant models were also adjusted for patients and treatment characteristics and accounted for clustering by clinic and county of residence. MAIN RESULTS AND THE ROLE OF CHANCE: For all exposure periods, O3 was weakly positively associated with implantation (aRR 1.01, 95% CI 1.001-1.02 for T1; aRR 1.01, 95% CI 1.001-1.02 for T2 and aRR 1.01, 95% CI 1.001-1.02 for T3) and live birth (aRR 1.01, 95% CI 1.002-1.02 for T1; aRR 1.01, 95% CI 1.004-1.02 for T2 and aRR 1.02, 95% CI 1.004-1.03 for T3). PM2.5 was not associated with any of the reproductive outcomes assessed. LIMITATIONS, REASONS FOR CAUTION: The main limitation of this study is the use of aggregated air pollution data as proxies for individual exposure. The weak positive associations found in this study might be related to confounding by factors that we were unable to assess and may not reflect clinically meaningful differences. WIDER IMPLICATIONS OF THE FINDINGS: More research is needed to assess the impact of air pollution on reproductive function. STUDY FUNDING/COMPETING INTEREST(S): None.
STUDY QUESTION: Is the use of donor oocytes in women <35 years of age associated with an increased risk of adverse perinatal outcomes compared to use of autologous oocytes? SUMMARY ANSWER: Among fresh assisted reproductive technology (ART) cycles performed in women under age 35, donor oocyte use is associated with a higher risk of preterm birth, low birth weight and stillbirth (when zero embryos were cryopreserved) as compared to autologous oocytes. WHAT IS KNOWN ALREADY: Previous studies demonstrated elevated risk of poor perinatal outcomes with donor versus autologous oocytes during ART, primarily among older women. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study using data reported to Centers for Disease Control and Prevention's National ART Surveillance System (NASS) during the period from 2010 to 2015 in order to best reflect advances in clinical practice. Approximately 98% of all US ART cycles are reported to NASS, and discrepancy rates were <6% for all fields evaluated in 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included all non-banking fresh and frozen ART cycles performed between 2010 and 2015 in women under age 35 using autologous or donor eggs. Cycles using cryopreserved eggs, donated embryos or a gestational carrier were excluded. Among fresh embryo transfer cycles, we calculated predicted marginal proportions to estimate the unadjusted and adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for the association between donor versus autologous oocyte use and stillbirth, spontaneous abortion, preterm delivery and low birth weight among singleton pregnancies or births. Stillbirth models were stratified by number of embryos cryopreserved. All models were adjusted for patient and treatment characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 71 720 singleton pregnancies occurring during 2010-2015, singletons resulting from donor oocytes were more likely to be preterm (15.6% versus 11.0%; aRRs 1.39: CI 1.20-1.61) and have low birth weight (11.8% versus 8.8%; aRRs 1.34; CI 1.16-1.55) than those resulting from autologous oocytes. With zero embryos cryopreserved, donor versus autologous oocyte use was associated with increased risk for stillbirth (2.1% versus 0.6%; aRRs 3.73; CI 1.96-7.11); no association with stillbirth was found when ≥1 embryo was cryopreserved (0.54% versus 0.56%; aRR 1.15; CI 0.59-2.25). LIMITATIONS, REASONS FOR CAUTION: The data come from a national surveillance system and is thus limited by the accuracy of the data entered by individual providers and clinics. There may be unmeasured differences between women using donor eggs versus their own eggs that could be contributing to the reported associations. Given the large sample size, statistically significant findings may not reflect clinically important variations. WIDER IMPLICATIONS OF THE FINDINGS: Risks of preterm birth, low birth weight and stillbirth among singleton pregnancies using donor oocytes were increased compared to those using autologous oocytes. Further study regarding the pathophysiology of the potentially increased risks among donor oocyte recipient pregnancy is warranted. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.
OBJECTIVE: To assess trends of tubal factor infertility and to evaluate risk of miscarriage and delivery of preterm or low birth weight (LBW) neonates among women with tubal factor infertility using assisted reproductive technology (ART). METHODS: We assessed trends of tubal factor infertility among all fresh and frozen, donor, and nondonor ART cycles performed annually in the United States between 2000 and 2010 (N=1,418,774) using the National ART Surveillance System. The data set was then limited to fresh, nondonor in vitro fertilization cycles resulting in pregnancy to compare perinatal outcomes for cycles associated with tubal compared with male factor infertility. We performed bivariate and multivariable analyses controlling for maternal characteristics and calculated adjusted risk ratios (RRs) and 95% confidence intervals (CI). RESULTS: The percentage of ART cycles associated with tubal factor infertility diagnoses decreased from 2000 to 2010 (26.02-14.81%). Compared with male factor infertility, tubal factor portended an increased risk of miscarriage (14.0% compared with 12.7%, adjusted RR 1.08, 95% CI 1.04-1.12); risk was increased for both early and late miscarriage. Singleton neonates born to women with tubal factor infertility had an increased risk of preterm birth (15.8% compared with 11.6%, adjusted RR 1.27, 95% CI 1.20-1.34) and LBW (10.9% compared with 8.5%, adjusted RR 1.28, 95% CI 1.20-1.36). Significant increases in risk persisted for early and late preterm delivery and very low and moderately LBW delivery. A significantly elevated risk was also detected for twin, but not triplet, pregnancies. CONCLUSION: Tubal factor infertility, which is decreasing in prevalence in the United States, is associated with an increased risk of miscarriage, preterm birth, and LBW delivery as compared with couples with male factor infertility using ART.
Objective: To describe the prevalence and treatment characteristics of assisted reproductive technology (ART) cycles involving specific male factor infertility diagnoses in the United States. Design: Cross-sectional analysis of ART cycles in the National ART Surveillance System (NASS). Setting: Clinics that reported patient ART cycles performed in 2017 and 2018. Patient(s): Patients who visited an ART clinic and the cycles were reported in the NASS. The ART cycles included all autologous and donor cycles that used fresh or frozen embryos. Intervention(s): Not applicable. Main Outcome Measures: Analyses used new, detailed reporting of male factor infertility subcategories, treatment characteristics, and male partner demographics available in the NASS. Result(s): Among 399,573 cycles started with intent to transfer an embryo, 30.4% (n = 121,287) included a male factor infertility diagnosis as a reason for using ART. Of these, male factor only was reported in 16.5% of cycles, and both male and female factors were reported in 13.9% of cycles; 21.8% of male factor cycles had >1 male factor. Abnormal sperm parameters were the most commonly reported diagnoses (79.7%), followed by medical condition (5.3%) and genetic or chromosomal abnormalities (1.0%). Males aged ≤40 years comprised 59.6% of cycles with male factor infertility. Intracytoplasmic sperm injection was the primary method of fertilization (81.7%). Preimplantation genetic testing was used in 26.8%, and single embryo transfer was used in 66.8% of cycles with male factor infertility diagnosis. Conclusion(s): Male factor infertility is a substantial contributor to infertility treatments in the United States. Continued assessment of the prevalence and characteristics of ART cycles with male factor infertility may inform treatment options and improve ART outcomes. Future studies are necessary to further evaluate male factor infertility.
Objectives: To assess trends, predictors, and perinatal outcomes of ovarian hyperstimulation syndrome (OHSS) associated with in vitro fertilization (IVF) cycles in the United States. Design: Retrospective cohort study using National Assisted Reproductive Technology Surveillance System (NASS) data. Setting: Not applicable. Patient(s): Fresh autologous and embryo-banking cycles performed from 2000 to 2015. Interventions(s): None. Main Outcome Measure(s): OHSS, first-trimester loss, second-trimester loss, stillbirth, low birth weight, and preterm delivery. Result(s): The proportion of IVF cycles complicated by OHSS increased from 10.0 to 14.3 cases per 1,000 from 2000 to 2006, and decreased to 5.3 per 1,000 from 2006 to 2015. The risk of OHSS was highest for cycles with more than 30 oocytes retrieved (adjusted risk ratio [aRR] 3.85). OHSS was associated with a diagnosis of ovulatory disorder (aRR 2.61), tubal factor (aRR 1.14), uterine factor (aRR 1.17) and cycles resulting in pregnancy (aRR 3.12). In singleton pregnancies, OHSS was associated with increased risk of low birth weight (aRR 1.29) and preterm delivery (aRR 1.32). In twin pregnancies, OHSS was associated with an increased risk of second-trimester loss (aRR 1.81), low birth weight (aRR 1.06), and preterm delivery (aRR 1.16). Conclusion(s): Modifiable predictive factors for OHSS include number of oocytes retrieved, pregnancy following fresh embryo transfer, and the type of medication used for pituitary suppression during controlled ovarian hyperstimulation. Patients affected by OHSS had a higher risk of preterm delivery and low birth weight. Clinicians should take measures to reduce the risk of OHSS whenever possible.
Objective To compare characteristics, explore predictors, and compare assisted reproductive technology (ART) cycle, transfer, and pregnancy outcomes of autologous and donor cryopreserved oocyte cycles with fresh oocyte cycles. Design Retrospective cohort study from the National ART Surveillance System. Setting Fertility treatment centers. Patient(s) Fresh embryo cycles initiated in 2013 utilizing embryos created with fresh and cryopreserved, autologous and donor oocytes. Intervention(s) Cryopreservation of oocytes versus fresh. Main Outcomes Measure(s) Cancellation, implantation, pregnancy, miscarriage, and live birth rates per cycle, transfer, and/or pregnancy. Result(s) There was no evidence of differences in cancellation, implantation, pregnancy, miscarriage, or live birth rates between autologous fresh and cryopreserved oocyte cycles. Donor cryopreserved oocyte cycles had a decreased risk of cancellation before transfer (adjusted risk ratio [aRR] 0.74, 95% confidence interval [CI] 0.57–0.96) as well as decreased likelihood of pregnancy (aRR 0.88, 95% CI 0.81–0.95) and live birth (aRR 0.87, 95% CI 0.80–0.95); however, there was no evidence of differences in implantation, pregnancy, or live birth rates when cycles were restricted to those proceeding to transfer. Donor cryopreserved oocyte cycles proceeding to pregnancy had a decreased risk of miscarriage (aRR 0.75, 95% CI 0.58–0.97) and higher live birth rate (aRR 1.05, 95% CI 1.01–1.09) with the transfer of one embryo, but higher miscarriage rate (aRR 1.28, 95% CI 1.07–1.54) and lower live birth rate (aRR 0.95, 95% CI 0.92–0.99) with the transfer of two or more. Conclusion(s) There was no evidence of differences in ART outcomes between autologous fresh and cryopreserved oocyte cycles. There was evidence of differences in per-cycle and per-pregnancy outcomes between donor cryopreserved and fresh oocyte cycles, but not in per-transfer outcomes.
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 (<37 weeks), and low birthweight (<2,500 g). This report provides state-specific information for the United States (including the District of Columbia and Puerto Rico) on ART procedures performed in 2016 and compares birth outcomes that occurred in 2016 (resulting from ART procedures performed in 2015 and 2016) with outcomes for all infants born in the United States in 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 <35 years, 1.7 among women aged 35-37 years, and 2.2 among women aged >37 years). Among women aged <35 years, the national elective single-embryo transfer (eSET) rate was 42.7% (range: 8.3% in North Dakota to 83.9% in Delaware). In 2016, ART contributed to 1.8% of all infants born in the United States (range: 0.3% in Puerto Rico to 4.7% in Massachusetts). ART also contributed to 16.4% of all multiple-birth infants, including 16.2% of all twin infants and 19.4% of all triplets and higher-order infants. ART-conceived twins accounted for approximately 96.5% (21,455 of 22,233) of all ART-conceived infants born in multiple deliveries. The percentage of multiple-birth infants was higher among infants conceived with ART (31.5%) than among all infants born in the total birth population (3.4%). Approximately 30.4% of ART-conceived infants were twins and 1.1% were triplets and higher-order infants. Nationally, infants conceived with ART contributed to 5.0% of all low birthweight (<2,500 g) infants. Among ART-conceived infants, 23.6% had low birthweight compared with 8.2% 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 (29.9%) than among all infants born in the total birth population (9.9%). The percentage of ART-conceived infants who had low birthweight was 8.7% among singletons, 54.9% among twins, and 94.9% among triplets and higher-order multiples; the corresponding percentages among all infants born were 6.2% among singletons, 55.4% among twins, and 94.6% among triplets and higher-order multiples. The percentage of ART-conceived infants who were born preterm was 13.7% among singletons, 64.2% among twins, and 97.0% among triplets and higher-order infants; the corresponding percentages among all infants were 7.8% for singletons, 59.9% for twins, and 97.7% for triplets and higher-order infants.
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 <35 years, who typically are considered good candidates for eSET, on average, 1.5 embryos were transferred per ART procedure, resulting in higher multiple birth rates than could be achieved with single-embryo transfers. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive mandated health insurance coverage, three (Illinois, Massachusetts, and New Jersey) had rates of ART use >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.
Background: Singleton infants conceived using assisted reproductive technology have lower average birthweights than naturally conceived infants and are more likely to be born low birthweight (<2500 gr). Lower birthweights are associated with increased infant and child mortality and poor adult health outcomes, including cardiovascular disease, hypertension, and diabetes. Data from registry and single-center studies suggest that frozen/thawed embryo transfer may be associated with larger birthweights. To date, however, a nationwide, full-population study on United States infants born using frozen/thawed embryo transfer has not been reported.
Objectives: The objective of this study was to compare the effect of frozen/thawed vs fresh embryo transfer on birthweight outcomes for singleton, term infants conceived using in vitro fertilization in the United States between 2007 and 2014, including average birthweight and the risks of both macrosomia (>4000 g) and low birthweight (<2500 g).
Study Design: We used data from the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System to compare birthweight outcomes of live-born singleton, autologous oocyte, term (37-43 weeks) infants. Generalized linear models for all infants and stratified by infant sex were used to assess the relationship between frozen/thawed embryo transfer and birthweight, in grams. Infertility diagnosis, year of treatment, maternal age, maternal obstetric history, maternal and paternal race, and infant gestational age and sex were included in the models. Missing race data were imputed. The adjusted relative risks for macrosomia and low birthweight were evaluated using multivariable predicted marginal proportions from logistic regression models.
Results: In total, 180,184 singleton, term infants were included, with 55,898 (31.02%) having been conceived from frozen/thawed embryos. Frozen/thawed embryo transfer was associated with, on average, a 142 g increase in birthweight compared with infants born after fresh embryo transfer (P <.001). An interaction between infant sex and embryo transfer type was significant (P <.0001), with frozen/thawed embryo transfer having a larger effect on male infants by 16 g. The adjusted risk of a macrosomic infant was 1.70 times higher (95% confidence interval, 1.64–1.76) following frozen/thawed embryo transfer than fresh embryo transfer. However, adjusted risk of low birthweight following frozen/thawed embryo transfer was 0.52 (95% confidence interval, 0.48–0.56) compared with fresh embryo transfer.
Conclusion: Frozen/thawed embryo transfer, in comparison with fresh embryo transfer, was associated with increased average birthweight in singleton, autologous oocytes, term infants born in the United States, with a significant interaction between frozen/thawed embryo transfer and infant sex. The risk of macrosomia following frozen/thawed embryo transfer was greater than that following fresh embryo transfer, but the risk of low birthweight among frozen/thawed embryo transfer infants was significantly decreased in comparison with fresh embryo transfer infants.
Twin births among users of assisted reproductive technology (ART) pose serious risks to both mothers and infants. However, patients may prefer twins and may be unaware of the risks of twin pregnancies. Increasing use of elective single embryo transfers (eSET) through improved patient education could help to reduce twin births and related adverse health consequences. A systematic review of PUBMED and EMBASE databases was conducted to evaluate the effectiveness of patient education among ART users on knowledge of twin pregnancy risks, desire for twins, preference for or use of eSET, and twin pregnancy rates. Of 187 references retrieved, six met the selection criteria. Most focused on patients undergoing their first ART cycle aged < 35 years. Patient education was delivered via written materials, DVDs or discussion. Four studies reporting on knowledge of risks or desire for twins showed significant effects of oral and written descriptions of multiple pregnancy complications, risks of twins versus singletons, and DVDs with factual information. Five studies showed increased eSET use or preference after patients were educated on the risks of multiple pregnancy and success rates associated with different types of ART procedures, when combined with clinic policies that supported single blastocyst transfers or provided options for insurance. In younger ART users, patient education on twin pregnancy risks and success rates of eSET may improve knowledge of twin pregnancy risks and increase use of eSET, and may be important for wider implementation of eSET in countries such as the USA where the use of eSET remains low. Clinic policies of single blastocyst transfers or financial incentives may strengthen these effects.
What is already known about this topic? For HIV-discordant couples (in which the man is HIV-infected and the woman is not HIV-infected) who wish to conceive a biological child, strategies to minimize the risk for sexual transmission are needed. In 1990, CDC recommended against insemination with semen from HIV-infected men. What is added by this report? Recent data regarding the safety of semen processing suggest that such processing is a viable option for HIV discordant couples attempting conception. The risk for transmission from an HIV-infected man to an HIV-negative woman is low if appropriate risk-reduction strategies, such as the use of highly active antiretroviral therapy, antiretroviral preexposure prophylaxis, and sperm washing are implemented. Recent evidence suggests that discordant couples might consider condomless intercourse timed to coincide with ovulation or intrauterine insemination of the woman or in vitro fertilization in combination with sperm washing after discussing the risks and benefits of each option with a medical provider. What are the implications for public health practice? As further data emerge, the risk profile for each treatment option will be further defined. HIV-discordant couples who desire to conceive might wish to discuss treatment options with a medical provider who can explain the risks and benefits of different treatment modalities as they apply to the couple’s specific situation before attempting conception.