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Infertility treatments that include ovulation stimulation, both assisted reproductive technologies (ARTs) and non-ART ovulation stimulation, are associated with increased risks of multiple birth and concomitant sequelae and adverse outcomes, even among singletons. While a US surveillance system for ART-induced births is ongoing, no population-based tracking system exists for births resulting from non-ART treatments. The authors developed a multistage model to estimate the uncertain proportion of US infants born in 2005 who were conceived by using non-ART ovulation treatments. Using published surveillance data, they estimated proportions of US multiple births conceived naturally and by ART and assumed that the remainder were conceived with non-ART treatments. They used Bayesian meta-analyses to summarize published clinical studies on the multiple-gestation risk associated with non-ART ovulation treatments, applied a fetal survival factor, and used this multiple-birth risk estimate and their own estimate of the proportion of US multiple births attributable to non-ART ovulation stimulation to estimate the total (and, through subtraction, singleton) proportion of infants conceived with such treatments. On the basis of the model, the authors estimate that 4.6% of US infants born in 2005 (95% uncertainty range: 2.8%-7.1%) resulted from non-ART ovulation treatments. Notably, this figure is 4 times greater than the ART contribution. [ABSTRACT FROM AUTHOR]

Problem/Condition: In 1996, CDC initiated data collection regarding assisted reproductive technology (ART) procedures performed in the United States, as mandated by the Fertility Clinic Success Rate and Certification Act (FCSRCA) (Public Law 102-493, October 24, 1992). ART includes fertility treatments in which both eggs and sperm are handled in the laboratory (i.e., in vitro fertilization and related procedures). Patients who undergo ART treatments are more likely to deliver multiple-birth infants than women who conceive naturally. Multiple births are associated with increased risk for mothers and infants (e.g., pregnancy complications, premature delivery, low-birthweight infants, and long-term disability among infants).Reporting Period Covered: 2002.Description of System: CDC contracts with the Society for Assisted Reproductive Technology (SART) to obtain data from ART medical centers located in the United States. Since 1997, CDC has compiled data related to ART procedures.Results: In 2002, a total of 115,392 ART procedures were reported to CDC. These procedures resulted in 33,141 live-birth deliveries and 45,751 infants. Nationally, 74% of ART procedures used freshly fertilized embryos from the patient's eggs; 14% used thawed embryos from the patient's eggs; 8% used freshly fertilized embryos from donor eggs; and 3% used thawed embryos from donor eggs. Overall, 42% of ART transfer procedures resulted in a pregnancy, and 34% resulted in a live-birth delivery (delivery of one or more live-born infants). The highest live-birth rates were observed among ART procedures using freshly fertilized embryos from donor eggs (50%). The highest numbers of ART procedures were performed among residents of California (15,117), New York (13,276), Massachusetts (8,631), New Jersey (7,744), and Illinois (7,492). These five states also reported the highest number of infants conceived through ART. Of 45,751 infants born through ART, 53% were born in multiple-birth deliveries. The multiple-birth risk was highest for women who underwent ART transfer procedures using freshly fertilized embryos from either donor eggs (42%) or their own eggs (35%). Number of embryos transferred, embryo availability (an indicator of embryo quality), and patient's age were also strong predictors of multiple-birth risk. Approximately 1% of U.S. infants born in 2002 were conceived through ART. Those infants accounted for 17% of multiple births nationally. The percentage of ART infants who were low birth rate ranged from 9% among singletons to 95% among triplets or higher order multiples. The percentage of ART infants born preterm ranged from 15% among singletons to 97% among triplets or higher order multiples.Interpretation: Whether an ART procedure resulted in a pregnancy and live-birth delivery varied according to different patient and treatment factors. ART poses a major risk for multiple births. This risk varied according to the patient's age, the type of ART procedure performed, the number of embryos transferred, and embryo availability (an indicator of embryo quality).Public Health Actions: ART-related multiple births represent a sizable proportion of all multiple births nationally and in selected states. Efforts should be made to limit the number of embryos transferred for patients undergoing ART. In addition, adverse infant health outcomes (e.g., low birthweight and preterm delivery) should be considered when assessing the efficacy and safety of ART. [ABSTRACT FROM AUTHOR]

Problem/Condition: In 1996, CDC initiated data collection regarding assisted reproductive technology (ART) procedures performed in the United States to determine medical center-specific pregnancy success rates, as mandated by the Fertility Clinic Success Rate and Certification Act (FCSRCA) (Public Law 102-493, October 24, 1992). ART includes fertility treatments in which both eggs and sperm are handled in the laboratory (i.e., in vitro fertilization and related procedures). Patients who undergo ART treatments are more likely to deliver multiple-birth infants than women who conceive naturally. Multiple births are associated with increased risk for mothers and infants (e.g., pregnancy complications, premature delivery, low-birthweight infants, and long-term disability among infants). Reporting Period Covered: 2001. Description of System: CDC contracts with a professional society, the Society for Assisted Reproductive Technology (SART), to obtain data from fertility medical centers located in the United States. Since 1997, CDC has compiled data related to ART procedures. The Assisted Reproductive Technology Surveillance System was initiated by CDC in collaboration with the American Society for Reproductive Medicine, the Society for Assisted Reproductive Technology, and RESOLVE: The National Infertility Association. Results: In 2001, a total of 29,344 live-birth deliveries and 40,687 infants resulting from 107,587 ART procedures were reported from 384 medical centers in the United States and U.S. territories. Nationally, 80,864 (75%) of ART treatments used freshly fertilized embryos from the patient's eggs; 14,705 (14%) used thawed embryos from the patient's eggs; 8,592 (8%) used freshly fertilized embryos from donor eggs; and 3,426 (3%) used thawed embryos from donor eggs. Overall, 40% of ART procedures that progressed to the transfer stage resulted in a pregnancy; 33% resulted in a live-birth delivery (delivery of >1 infant); and 21% resulted in a singleton live birth. The highest live-birth rates were observed among ART procedures using freshly fertilized embryos from donor eggs (47%). The greatest numbers of ART procedures were performed among residents of California (13,124), New York (12,379), Massachusetts (8,151), Illinois (7,933), and New Jersey (6,011). These five states also reported the highest number of live-birth deliveries and infants born as a result of ART. The ratio of number of ART procedures per million population ranged from 74 in Idaho to 1,273 in Massachusetts, with a national average of 371 ART procedures started per million persons. Among ART treatments in which freshly fertilized embryos from the patient's eggs were used, substantial variation in live birth rates by patient (e.g., women aged <40 years) and treatment characteristics (e.g., ovulatory dysfunction, endometriosis, or unexplained infertility) was observed. The risk for a multiple-birth delivery was highest for women who underwent ART transfer procedures using freshly fertilized embryos from either donor eggs (42%) or from their own eggs (36%). Among ART transfer procedures in which the patient's own eggs were used, an inverse relation existed between multiple-birth risk and patient age. Number of embryos transferred and embryo availability (an indicator of embryo quality) were also strong predictors of multiple-birth risk. Of the 40,687 infants born, 46% were twins, and 8% were triplet and higher order multiples. The total multiple-infant birth rate was 53%. Approximately 1% of U.S. infants born in 2001 were conceived through ART. Those infants accounted for 16% of multiple births nationally. Interpretation: Whether an ART procedure resulted in a pregnancy and live-birth delivery varied according to different patient and treatment factors. ART poses a major risk for multiple births. This risk varied according to the patient's age, the type of ART procedure performed, the number of embryos transferred, and embryo availability (an indicator of embryo quality). Public Health Actions: ART-related multiple births represent a sizable proportion of all multiple births nationally and in selected states. Efforts should be made to limit the number of embryos transferred for patients undergoing ART. [ABSTRACT FROM AUTHOR]

Problem/Condition: In 1996, CDC initiated data collection regarding assisted reproductive technology (ART) procedures performed in the United States to determine medical center-specific pregnancy success rates, as mandated by the Fertility Clinic Success Rate and Certification Act (FCSRCA) (Public Law 102-493, October 24, 1992). ART includes fertility treatments in which both eggs and sperm are handled in the laboratory (i.e., in vitro fertilization and related procedures). Patients who undergo ART treatments are more likely to deliver multiple-birth infants than women who conceive naturally. Multiple births are associated with increased risk for mothers and infants (e.g., pregnancy complications, premature delivery, low-birthweight infants, and long-term disability among infants).Reporting Period Covered: 2000.Description of System: CDC contracts with a professional society, the Society for Assisted Reproductive Technology (SART), to obtain data from fertility medical centers located in the United States. Since 1997, CDC has compiled data related to ART procedures. The Assisted Reproductive Technology Surveillance System was initiated by CDC in collaboration with the American Society for Reproductive Medicine, the Society for Assisted Reproductive Technology, and RESOLVE: The National Infertility Association.Results: In 2000, a total of 25,228 live-birth deliveries and 35,025 infants resulting from 99,629 ART procedures were reported to CDC from 383 medical centers that performed ART in the United States and U.S. territories. Nationally, 75,516 (76%) of ART treatments were freshly fertilized embryos using the patient's eggs; 13,312 (13%) were thawed embryos using the patient's eggs; 7,919 (8%) were freshly fertilized embryos from donor eggs; and 2,882 (3%) were thawed embryos from donor eggs. The national live-birth delivery per transfer rate was 30.8%. The five states that reported the highest number of ART procedures were California (13,194), New York (11,239), Massachusetts (8,041), Illinois (7,323), and New Jersey (5,506). These five states also reported the highest number of live-birth deliveries and infants born as a result of ART. Overall, 47% of women undergoing ART transfer procedures using freshly fertilized embryos from their own eggs were aged <35 years; 23% were aged 35-37 years; 19% were aged 38-40 years; 7% were aged 41-42 years; and 4% were aged >42 years. Among ART treatments in which freshly fertilized embryos from the patient's eggs were used, substantial variation in patient age, infertility diagnoses, history of past infertility treatment, and past births was observed. Nationally, live-birth rates were highest for women aged <35 years (38%). The risk for a multiple-birth delivery was highest for women who underwent ART transfer procedures using freshly fertilized embryos from either donor eggs (40%) or from their own eggs (35%). Among women who underwent ART transfer procedures using freshly fertilized embryos from their own eggs, further variation by patient age and number of embryos transferred was observed. Of the 35,025 infants born, 44% were twins, and 9% were triplet and higher order multiples, for a total multiple-infant birth rate of 53%. Patient's residing in states with the highest number of live-birth deliveries also reported the highest number of infants born in multiple-birth deliveries.Interpretation: Whether an ART procedure was successful (defined as resulting in a pregnancy and live-birth delivery) varied according to different patient and treatment factors. Patient factors included the age of the woman undergoing ART, whether she had previously given birth, whether she had previously undergone ART, and the infertility diagnosis of both the female and male partners. Treatment factors included whether eggs were from the patient or a woman serving as an egg donor, whether the embryos were freshly fertilized or previously frozen and thawed, how long the embryos were kept in culture, how many embryos were transferred, and whether various specialized treatment procedures were used in conjunction with ART. ART poses a major risk for multiple births. This risk varied according to the patient's age, the type of ART procedure performed, and the number of embryos transferred. In addition, the increased risk for multiple births has a notable population impact in certain states.Public Health Actions: As use of ART and ART success rates continue to increase, ART-related multiple births are an increasingly important public health problem nationally and in many states. The proportion of infants born through ART in 2000 that were multiple births (53%) was substantially higher than in the general U.S. population during the same period. Data in this report indicate a need to reduce multiple births associated with ART. Efforts should be made to limit the number of embryos transferred for patients undergoing ART. In addition, continued research and surveillance is key to understanding the effect of ART on maternal and child health. [ABSTRACT FROM AUTHOR]

Multiple birth, which is associated with adverse fetal, infant, and maternal outcomes, is increasingly related to the use of in vitro fertilization (IVF). Among women undergoing IVF who use their own eggs, greater maternal age is associated with decreased risk of multiple birth; using donor eggs from younger women may negate this age effect. Data from 6,936 IVF procedures performed in the United States in 1996-1997 on women aged 35-54 years who used donor eggs were analyzed to assess the effect of maternal age, number of embryos transferred, and cryopreservation of extra, nontransferred embryos (an indicator of higher embryo quality) on risk of multiple birth. Greater maternal age did not decrease multiple-birth risk. Rates of multiple birth were related to number of embryos transferred and whether extra embryos had been cryopreserved, and they were high compared with those of IVF patients the same age who had used their own eggs. Among women who had extra embryos cryopreserved, transferring more than two embryos increased multiple-birth risk, with no corresponding increase in the chance for a livebirth. These results highlight the need to consider the age of the donor and embryo quality when making embryo transfer decisions involving use of donor eggs. [ABSTRACT FROM AUTHOR]

Problem/condition: Sickle cell disease (SCD), an inherited blood disorder affecting an estimated 100,000 persons in the United States, is associated with multiple complications and reduced life expectancy. Complications of SCD can include anemia, debilitating acute and chronic pain, infection, acute chest syndrome, stroke, and progressive organ damage, including decreased cognitive function and renal failure. Early diagnosis, screenings and preventive interventions, and access to specialist health care can decrease illness and death. Population-based public health surveillance is critical to understanding the course and outcomes of SCD as well as the health care use, unmet health care needs, and gaps in essential services of the population affected by SCD., Period Covered: 2004-2018., Description of the Program: In 2015, CDC established the Sickle Cell Data Collection (SCDC) program to characterize the epidemiology of SCD in two states (California and Georgia). Previously, surveillance for SCD was conducted by two short-term projects: Registry and Surveillance System for Hemoglobinopathies (RuSH), which was conducted during 2010-2012 and included 2004-2008 data, and Public Health Research, Epidemiology, and Surveillance for Hemoglobinopathies (PHRESH), which was conducted during 2012-2014 and included 2004-2008 data. Both California and Georgia participated in RuSH and PHRESH, which guided the development of the SCDC methods and case definitions. SCDC is a population-based tracking system that uses comprehensive data linkages in state health systems. These linkages serve to synthesize and disseminate population-based, longitudinal data for persons identified with SCD from multiple sources using selected International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision codes and laboratory results confirmed through state newborn screening (NBS) programs or clinic case reporting. Administrative and clinical data sources include state Medicaid and Children's Health Insurance Program databases, death certificates, NBS programs, hospital discharge and emergency department records, and clinical records or case reports. Data from multiple sources and years are linked and deduplicated so that states can analyze and report on SCD population prevalence, demographic characteristics, health care access and use, and health outcomes. The SCD case definition is based on an algorithm that classifies cases with laboratory confirmation as confirmed cases and those with a reported clinical diagnosis or three or more diagnostic codes over a 5-year period from an administrative data source as probable cases. In 2019, nine states (Alabama, California, Georgia, Indiana, Michigan, Minnesota, North Carolina, Tennessee, and Virginia) were funded as part of an SCDC capacity-building initiative. The newly funded states developed strategies for SCD case identification and data linkage similar to those used by California and Georgia. As of 2021, the SCDC program had expanded to 11 states with the addition of Colorado and Wisconsin., Results: During 2004-2018, the cumulative prevalence of confirmed and probable SCD cases identified in California and Georgia was 9,875 and 14,777 cases, respectively. The 2018 annual prevalence count was 6,027 cases for California and 9,141 for Georgia. Examination of prevalence counts by contributing data source during 2014-2018 revealed that each data source captured 16%-71% of cases in California and 17%-87% in Georgia; therefore, no individual source is sufficient to estimate statewide population prevalence. The proportion of pediatric SCD patients (children aged 0-18 years) was 27% in California and 40% in Georgia. The percentage of females with SCD in California and Georgia was 58% and 57%, respectively. Of the cases with SCD genotyping data available (n = 5,856), 63% of patients had sickle cell anemia. SCDC data have been used to directly apprise health care providers and policymakers about health care needs and gaps for patients with SCD. For example, an SCDC Georgia assessment indicated that 10% of babies born during 2004-2016 with SCD lived more than a 1-hour drive from any SCD specialty care option, and another 14% lived within a 1-hour drive of a periodic SCD specialty clinic only. Likewise, an SCDC California assessment indicated that during 2016-2018, most patients with SCD in Los Angeles County lived approximately 15-60 miles from hematologists experienced in SCD care. A surveillance capacity and performance assessment of all 11 SCDC states during 2020-2021 indicated that states differed in the availability of data sources used for SCD surveillance and the time frames for accessing each state data source. Nonetheless, methods for standardizing reporting were developed across all participating states., Interpretation: This report is the first comprehensive description of CDC's efforts in collaboration with participating states to establish, maintain, and expand SCD surveillance through the SCDC program to improve health outcomes for persons living with SCD. Findings from California and Georgia analyses highlighted a need for additional SCD specialty clinics. Despite different approaches, expansion of SCDC to multiple states was possible using standardized, rigorous methods developed across all participating states for reporting on disease prevalence, health care needs and use, and deaths., Public Health Action: Findings from surveillance can be used to improve and monitor care and outcomes for persons with SCD. These and other SCDC analyses have had a role in opening new SCD clinics, educating health care providers, developing state health care policies, and guiding new research initiatives. Public health officials can use this report as a guiding framework to plan or implement surveillance programs for persons with SCD. Both data-related activities (data sources; patient identifiers; and obtaining, transferring, and linking data) and the administrative considerations (stakeholder engagement, costs and resources, and long-term sustainability) are crucial to the success of these programs., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Introduction: Sickle cell disease (SCD), a group of inherited blood cell disorders that primarily affects Black or African American persons, is associated with severe complications and a >20-year reduction in life expectancy. In 2014, an expert panel convened by the National Heart, Lung, and Blood Institute issued recommendations to prevent or reduce complications in children and adolescents with the most severe SCD subtypes, known as sickle cell anemia (SCA); recommendations included 1) annual screening of children and adolescents aged 2-16 years with transcranial Doppler (TCD) ultrasound to identify those at risk for stroke and 2) offering hydroxyurea therapy to children and adolescents aged ≥9 months to reduce the risk for several life-threatening complications., Methods: Data from the IBM MarketScan Multi-State Medicaid Database were analyzed. TCD screening and hydroxyurea use were examined for 3,352 children and adolescents with SCA aged 2-16 years and continuously enrolled in Medicaid during 2019. Percentage change during 2014-2019 and variation by health subgroups were assessed. Analyses were stratified by age., Results: During 2014-2019, TCD screening increased 27% among children and adolescents aged 10-16 years; hydroxyurea use increased 27% among children aged 2-9 years and 23% among children and adolescents aged 10-16 years. However, in 2019, only 47% and 38% of children and adolescents aged 2-9 and 10-16 years, respectively, had received TCD screening and 38% and 53% of children and adolescents aged 2-9 years and 10-16 years, respectively, used hydroxyurea. For both prevention strategies, usage was highest among children and adolescents with high levels of health care utilization and evidence of previous complications indicative of severe disease., Conclusion and Implications for Public Health Practice: Despite increases since 2014, TCD screening and hydroxyurea use remain low among children and adolescents with SCA. Health care providers should implement quality care strategies within their clinics and partner with patients, families, and community-based organizations to address barriers to delivering and receiving recommended care., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Lewis L. Hsu reports institutional support from the Health Resources and Services Administration, the National Institutes of Health (NIH), the European Commission, the Illinois Department of Public Health, the Joy in Childhood Foundation, Global Blood Therapeutics, Forma Therapeutics, Imara, Baxalta, Cyclerion, and Eli Lilly; consulting fees from DuPont Nemours Children’s Hospital, Hoffman-LaRoche, DisperSol, Guidepoint, Magellan, Deerfield, and Kuwait University; speaker honoraria from the Foundation for Sickle Cell Disease Research, Bridgeport Hospital, and Tova Health Center; participation on an Aruvant Data Safety Monitoring Board and service as a scientific advisor or member of an expert advisory board for the NIH Sickle Cell Disease Advisory Committee, Hilton Publishing, and the Illinois Universal Newborn Screening Advisory Committee; and unpaid memberships in the Sickle Cell Disease Association of America, the Sickle Cell Disease Association of Illinois, and the National Alliance of Sickle Cell Centers. No other potential conflicts of interest were disclosed.

Increasing evidence exists for an association between early life fine particulate matter (PM 2.5 ) exposure and several neurodevelopmental outcomes, including autism spectrum disorder (ASD); however, the association between PM 2.5 and adaptive and cognitive function remains poorly understood. Participants included 658 children with ASD, 771 with a non-ASD developmental disorder, and 849 population controls from the Study to Explore Early Development. Adaptive functioning was assessed in ASD cases using the Vineland Adaptive Behavior Scales (VABS); cognitive functioning was assessed in all groups using the Mullen Scales of Early Learning (MSEL). A satellite-based model was used to assign PM 2.5 exposure averages during pregnancy, each trimester, and the first year of life. Linear regression was used to estimate beta coefficients and 95% confidence intervals, adjusting for maternal age, education, prenatal tobacco use, race-ethnicity, study site, and season of birth. PM 2.5 exposure was associated with poorer VABS scores for several domains, including daily living skills and socialization. Associations were present between prenatal PM 2.5 and lower MSEL scores for all groups combined; results were most prominent for population controls in stratified analyses. These data suggest that early life PM 2.5 exposure is associated with specific aspects of cognitive and adaptive functioning in children with and without ASD.

Background: Population-based data about cerebral venous sinus thrombosis (CVST) are limited., Objectives: To investigate the epidemiology of CVST in the United States., Patients/methods: Three administrative data systems were analyzed: the 2018 Healthcare Cost and Utilization Project National Inpatient Sample (NIS) the 2019 IBM MarketScan Commercial and Medicare Supplemental Claims Database, and the 2019 IBM MarketScan Multi-state Medicaid Database. CVST, thrombocytopenia, and numerous comorbidities were identified using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. Incidence rates of CVST and CVST with thrombocytopenia were estimated (per 100,000 total US population [NIS] and per 100,000 population aged 0 to 64 years covered by relevant contributing health plans [MarketScan samples]). Comorbidity prevalence was estimated among CVST cases versus total inpatients in the NIS sample. Recent pregnancy prevalence was estimated for the Commercial sample., Results: Incidence rates of CVST in NIS, Commercial, and Medicaid samples were 2.85, 2.45, and 3.16, respectively. Incidence rates of CVST with thrombocytopenia were 0.21, 0.22, and 0.16, respectively. In all samples, CVST incidence increased with age; however, peak incidence was reached at younger ages in females than males. Compared with the general inpatient population, persons with CVST had higher prevalences of hemorrhagic stroke, ischemic stroke, other venous thromboembolism (VTE), central nervous system infection, head or neck infection, prior VTE, thrombophilia, malignancy, head injury, hemorrhagic disorder, and connective tissue disorders. Women aged 18 to 49 years with CVST had a higher pregnancy prevalence than the same-aged general population., Conclusions: Our findings provide recent and comprehensive data on the epidemiology of CVST and CVST with thrombocytopenia., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Sickle cell disease (SCD) is associated with increased risk of poor health outcomes from respiratory infections, including COVID-19 illness. We used US death data to investigate changes in SCD-related mortality before and during the COVID-19 pandemic. We estimated annual age- and quarter-adjusted SCD-related mortality rates for 2014-2020. We estimated the number of excess deaths in 2020 compared with 2019 using the standardized mortality ratio (SMR). We found 1023 SCD-related deaths reported in the United States during 2020, of which 86 (8.4%) were associated with COVID-19. SCD-related deaths, both associated and not associated with COVID-19, occurred most frequently among adults aged 25-59 years. The SCD-related mortality rate changed <5% year to year from 2014 to 2019 but increased 12% in 2020; the sharpest increase was among adults aged ≥60 years. The SMR comparing 2020 with 2019 was 1.12 (95% CI, 1.06-1.19). Overall, 113 (95% CI, 54-166) excess SCD-related deaths occurred in 2020.

Objective: Maternal prepregnancy BMI and gestational weight gain (GWG) are examined in relation to autism spectrum disorder (ASD) and other developmental disorders (DD) in offspring in a multisite case-control study., Methods: Maternal prepregnancy BMI, obtained from medical records or self-report, was categorized as underweight, normal weight, overweight, obesity Class 1, or obesity Class 2/3. GWG was standardized for gestational age (GWG z score), and the rate (pounds/week) was categorized per adherence with clinical recommendations. Logistic regression models, adjusting for demographic factors, were used to assess associations with ASD (n = 1,159) and DD (n = 1,617), versus control children (n = 1,633)., Results: Maternal obesity Class 2/3 was associated with ASD (adjusted odds ratio [AOR] = 1.87, 95% CI: 1.40-2.51) and DD (AOR = 1.61, 95% CI: 1.22-2.13). GWG z score was not associated with DD (AOR = 1.14, 95% CI: 0.95-1.36), but the GWG z score highest tertile was associated with higher odds of ASD, particularly among male children (AOR = 1.47, 95% CI: 1.15-1.88)., Conclusions: Results indicate that maternal prepregnancy severe obesity increases risk of ASD and DD in children and suggest high gestational-age-adjusted GWG is a risk factor for ASD in male children. Because maternal BMI and GWG are routinely measured and potentially modifiable, these findings could inform early interventions for high-risk mother-child dyads., (© 2021 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Sickle cell disease (SCD) disproportionately affects Black or African American persons in the United States and can cause multisystem organ damage and reduced lifespan. Among 178 persons with SCD in the United States who were reported to an SCD-coronavirus disease case registry, 122 (69%) were hospitalized and 13 (7%) died.

Problem/condition: Hemophilia is an X-linked genetic disorder that primarily affects males and results in deficiencies in blood-clotting proteins. Hemophilia A is a deficiency in factor VIII, and hemophilia B is a deficiency in factor IX. Approximately one in 5,000 males are born with hemophilia, and hemophilia A is about four times as common as hemophilia B. Both disorders are characterized by spontaneous internal bleeding and excessive bleeding after injuries or surgery. Hemophilia can lead to repeated bleeding into the joints and associated chronic joint disease, neurologic damage, damage to other organ systems, and death. Although no precise national U.S. prevalence estimates for hemophilia exist because of the difficulty identifying cases among persons who receive care from various types of health care providers, two previous state-based studies estimated hemophilia prevalence at 13.4 and 19.4 per 100,000 males. In addition, these studies showed that 67% and 82% of persons with hemophilia received care in a federally funded hemophilia treatment center (HTC), and 86% and 94% of those with the most severe cases of hemophilia (i.e., those with the lowest levels of clotting factor activity in the circulating blood) received care in a federally funded HTC. As of January 2020, the United States had 144 HTCs., Period Covered: 1998-2019., Description of the System: Surveillance for hemophilia, which is a complex, chronic condition, is challenging because of its low prevalence, the difficulty in ascertaining cases uniformly, and the challenges in routinely characterizing and tracking associated health complications. Over time, two systems involving many stakeholders have been used to conduct ongoing hemophilia surveillance. During 1998-2011, CDC and the HTCs collaborated to establish the Universal Data Collection (UDC) surveillance system. The purposes of the UDC surveillance system were to monitor human immunodeficiency virus (HIV) and bloodborne viral hepatitis in persons with hemophilia, thereby tracking blood safety, and to track the prevalence of and trends in complications associated with hemophilia. HTC staff collected clinical data and blood specimens from UDC participants and submitted them to CDC. CDC tested specimens for viral hepatitis and HIV. In 2011, the UDC surveillance system was replaced by a new hemophilia surveillance system called Community Counts. CDC and the HTCs established Community Counts to expand laboratory testing and the collection of clinical data to better identify and track emerging health issues in persons with hemophilia., Results: This report is the first comprehensive summary of CDC's hemophilia surveillance program, which comprises both UDC and Community Counts. Data generated from these surveillance systems have been used in the development of public health and clinical guidelines and practices to improve the safety of U.S. blood products and either prevent hemophilia-related complications or identify complications early. Several factors have played a role in the effectiveness of the UDC and Community Counts systems, including 1) a stable data collection design that was developed and is continually reviewed in close partnership with HTC regional leaders and providers to ensure surveillance activities are focused on maximizing the scientific and clinical impact; 2) flexibility to respond to emerging health priorities through periodic updates to data collection elements and special studies; 3) high data quality for many clinical indicators and state-of-the-art laboratory testing methods for hemophilia treatment product inhibitors (developed and refined in part based on CDC research); 4) timely data and specimen collection and submission, laboratory specimen testing, analysis, and reporting; and 5) the largest and most representative sample of persons with hemophilia in the United States and one of the largest and most comprehensive data collection systems on hemophilia worldwide., Interpretation: CDC has successfully developed, implemented, and maintained a surveillance system for hemophilia. The program can serve as an example of how to conduct surveillance for a complex chronic disease by involving stakeholders, improving and building new infrastructure, expanding data collection (e.g., new diagnostic assays), providing testing guidance, establishing a registry with specimen collection, and integrating laboratory findings in clinical practice for the individual patient., Public Health Action: Hemophilia is associated with substantial lifelong morbidity, excess premature deaths, and extensive health care needs throughout life. Through monitoring data from Community Counts, CDC will continue to characterize the benefits and adverse events associated with existing or new hemophilia treatment products, thereby contributing to maximizing the health and longevity of persons with hemophilia., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

In the Seattle, Washington metropolitan area, where the first case of novel coronavirus 2019 disease (COVID-19) in the United States was reported (1), a community-level outbreak is ongoing with evidence of rapid spread and high morbidity and mortality among older adults in long-term care skilled nursing facilities (SNFs) (2,3). However, COVID-19 morbidity among residents of senior independent and assisted living communities, in which residents do not live as closely together as do residents in SNFs and do not require skilled nursing services, has not been described. During March 5-9, 2020, two residents of a senior independent and assisted living community in Seattle (facility 1) were hospitalized with confirmed COVID-19 infection; on March 6, social distancing and other preventive measures were implemented in the community. UW Medicine (the health system linked to the University of Washington), Public Health - Seattle & King County, and CDC conducted an investigation at the facility. On March 10, all residents and staff members at facility 1 were tested for SARS-CoV-2, the virus that causes COVID-19, and asked to complete a questionnaire about their symptoms; all residents were tested again 7 days later. Among 142 residents and staff members tested during the initial phase, three of 80 residents (3.8%) and two of 62 staff members (3.2%) had positive test results. The three residents had no symptoms at the time of testing, although one reported an earlier cough that had resolved. A fourth resident, who had negative test results in the initial phase, had positive test results 7 days later. This resident was asymptomatic on both days. Possible explanations for so few cases of COVID-19 in this residential community compared with those in several Seattle SNFs with high morbidity and mortality include more social distancing among residents and less contact with health care providers. In addition, early implementation of stringent isolation and protective measures after identification of two COVID-19 cases might have been effective in minimizing spread of the virus in this type of setting. When investigating a potential outbreak of COVID-19 in senior independent and assisted living communities, symptom screening is unlikely to be sufficient to identify all persons infected with SARS-CoV-2. Adherence to CDC guidance to prevent COVID-19 transmission in senior independent and assisted living communities (4) could be instrumental in preventing a facility outbreak., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Alexander L. Greninger reports personal fees from Abbott Molecular outside the submitted work. No other potential conflicts of interest were disclosed.

Background: To examine whether neighborhood deprivation modifies the association between early life air pollution exposure and autism spectrum disorder (ASD), we used resources from a multisite case-control study, the Study to Explore Early Development., Methods: Cases were 674 children with confirmed ASD born in 2003-2006; controls were 855 randomly sampled children born during the same time period and residents of the same geographic areas as cases. Air pollution was assessed by roadway proximity and particulate matter <2.5 μm (PM 2.5 ) exposure during pregnancy and first year of life. To characterize neighborhood deprivation, an index was created based on eight census tract-level socioeconomic status-related parameters. The continuous index was categorized into tertiles, representing low, moderate, and high deprivation. Logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs)., Results: Neighborhood deprivation modified ( P for interaction = 0.08) the association between PM 2.5 exposure during the first year of life and ASD, with a stronger association for those living in high (OR = 2.42, 95% CI = 1.20, 4.86) rather than moderate (OR=1.21, 95% CI = 0.67, 2.17) or low (OR=1.46, 95% CI = 0.80, 2.65) deprivation neighborhoods. Departure from additivity or multiplicativity was not observed for roadway proximity or exposures during pregnancy., Conclusion: These results provide suggestive evidence of interaction between neighborhood deprivation and PM 2.5 exposure during the first year of life in association with ASD., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest.

Background: Participation in epidemiologic studies has declined, raising concerns about selection bias. While estimates derived from epidemiologic studies have been shown to be robust under a wide range of scenarios, additional empiric study is needed. The Georgia Study to Explore Early Development (GA SEED), a population-based case-control study of risk factors for autism spectrum disorder (ASD), provided an opportunity to explore factors associated with non-participation and potential impacts of non-participation on association studies., Methods: GA SEED recruited preschool-aged children residing in metropolitan-Atlanta during 2007-2012. Children with ASD were identified from multiple schools and healthcare providers serving children with disabilities; children from the general population (POP) were randomly sampled from birth records. Recruitment was via mailed invitation letter with follow-up phone calls. Eligibility criteria included birth and current residence in study area and an English-speaking caregiver. Many children identified for potential inclusion could not be contacted. We used data from birth certificates to examine demographic and perinatal factors associated with participation in GA SEED and completion of the data collection protocol. We also compared ASD-risk factor associations for the final sample of children who completed the study with the initial sample of all likely ASD and POP children invited to potentially participate in the study, had they been eligible. Finally, we derived post-stratification sampling weights for participants who completed the study and compared weighted and unweighted associations between ASD and two factors collected via post-enrollment maternal interview: infertility and reproductive stoppage., Results: Maternal age and education were independently associated with participation in the POP group. Maternal education was independently associated with participation in the ASD group. Numerous other demographic and perinatal factors were not associated with participation. Moreover, unadjusted and adjusted odds ratios for associations between ASD and several demographic and perinatal factors were similar between the final sample of study completers and the total invited sample. Odds ratios for associations between ASD and infertility and reproductive stoppage were also similar in unweighted and weighted analyses of the study completion sample., Conclusions: These findings suggest that effect estimates from SEED risk factor analyses, particularly those of non-demographic factors, are likely robust.

Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies., Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample., Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p  < 1.12 × 10 - 7 . Seven CpGs showed differences at p  < 1 × 10 - 5 and 48 at 1 × 10 - 4 . Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance ( r  = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds., Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD., Competing Interests: This study was approved by the institutional review boards at each SEED site: SEED 1 recruitment was approved by the IRBs of each recruitment site: Institutional Review Board (IRB)-C, CDC Human Research Protection Office; Kaiser Foundation Research Institute (KFRI) Kaiser Permanente Northern California IRB, Colorado Multiple IRB, Emory University IRB, Georgia Department of Public Health IRB, Maryland Department of Health and Mental Hygiene IRB, Johns Hopkins Bloomberg School of Public Health Review Board, University of North Carolina IRB and Office of Human Research Ethics, IRB of The Children’s Hospital of Philadelphia, and IRB of the University of Pennsylvania. All enrolled families provided written consent for participation. This methylation substudy was approved as an amendment of the Johns Hopkins Institutional Review Board (IRB) approval. For participants from the Simons simplex collection, parents consented and children assented as required by each local institutional review board, which included a coalition of clinics located at Michigan, Yale, Emory, Columbia, Vanderbilt, McGill Washington, and Harvard Universities (Children’s Hospital of Boston), and at the Universities of Washington, Illinois (Chicago), Missouri, UCLA, and the Baylor College of Medicine. To protect the privacy of participants, Global Unique Identifiers (GUIDs) were constructed from personal information using an algorithm devised in collaboration with scientists at the NIH [66]. Each clinic retained personal identifiers on site and transmitted de-identified GUIDs to a central database, as described previously [37].Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Autism spectrum disorder (ASD) is a prevalent developmental disorder. Studies indicate that while ASD etiology has a genetic component, the risk is polygenic, with gene-environment interactions being likely. The prenatal period is a critical exposure window for nongenetic risk factors. Previous studies have found positive associations between congenital malformations (all types) and ASD; a few also found specific associations between genitourinary system malformations and ASD; and one study found an association between hypospadias and ASD. In the accompanying article, Rotem et al. (Am J Epidemiol. 2018;187(4):656-663) describe how they conducted a comprehensive analysis focusing on the shared risk of ASD with hypospadias or cryptorchidism, using existing data from a large Israeli health services system, which afforded several advantages because of the large sample size and low attrition of the patient population. The authors conducted a careful analysis, including sensitivity analyses, to account for risk factor and case misclassifications that might have occurred had they relied solely on preexisting diagnostic codes to define exposures and outcome. They observed positive associations between both hypospadias and cryptorchidism and ASD that were independent of numerous sociodemographic and pregnancy health factors. This study advances our understanding of ASD etiology and illustrates how existing data might be used to assess some ASD risk factors.

Participant attrition can limit inferences drawn from study results and inflate research costs. We examined factors associated with completion of the Study to Explore Early Development (2007-2011), a multiple-component, case-control study of risk factors for autism spectrum disorder in preschoolers, conducted in California, Colorado, Georgia, Maryland, North Carolina, and Pennsylvania. Participants (n = 3,769) were asked to complete phone interviews, questionnaires, an in-person evaluation, and biologic sampling. We examined whether participant demographic and administrative factors predicted completion using mixed-effects logistic regression models. Completion of individual key study components was generally 70% or higher. However, 58% of families completed all per-protocol data elements (defined a priori as key study components). Per-protocol completion differed according to mother's age, race, educational level, driving distance to clinic, number of contact attempts to enroll, and number of telephone numbers provided (all P < 0.05). Case status was not associated with completion, despite additional data collection for case-confirmation. Analysis of a subset that completed an early interview revealed no differences in completion by household factors of income, primary language spoken, number of adults, or number of children with chronic conditions. Differences in completion by race and education were notable and need to be carefully considered in developing future recruitment and completion strategies.

Objective: Although data on publicly available special education are informative and offer a glimpse of trends in autism spectrum disorder (ASD) and use of educational services, using these data for population-based public health monitoring has drawbacks. Our objective was to evaluate trends in special education eligibility among 8-year-old children with ASD identified in the Autism and Developmental Disabilities Monitoring Network., Methods: We used data from 5 Autism and Developmental Disabilities Monitoring Network sites (Arizona, Colorado, Georgia, Maryland, and North Carolina) during 4 surveillance years (2002, 2006, 2008, and 2010) and compared trends in 12 categories of special education eligibility by sex and race/ethnicity. We used multivariable linear risk regressions to evaluate how the proportion of children with a given eligibility changed over time., Results: Of 6010 children with ASD, more than 36% did not receive an autism eligibility in special education in each surveillance year. From surveillance year 2002 to surveillance year 2010, autism eligibility increased by 3.6 percentage points ( P = .09), and intellectual disability eligibility decreased by 4.6 percentage points ( P < .001). A greater proportion of boys than girls had an autism eligibility in 2002 (56.3% vs 48.8%). Compared with other racial/ethnic groups, Hispanic children had the largest increase in proportion with autism eligibility from 2002 to 2010 (15.4%, P = .005) and the largest decrease in proportion with intellectual disability (-14.3%, P = .004)., Conclusion: Although most children with ASD had autism eligibility, many received special education services under other categories, and racial/ethnic disparities persisted. To monitor trends in ASD prevalence, public health officials need access to comprehensive data collected systematically, not just special education eligibility.

Objectives: To describe the association between indicators of socioeconomic status (SES) and the prevalence of autism spectrum disorder (ASD) in the United States during the period 2002 to 2010, when overall ASD prevalence among children more than doubled, and to determine whether SES disparities account for ongoing racial and ethnic disparities in ASD prevalence., Methods: We computed ASD prevalence and 95% confidence intervals (CIs) from population-based surveillance, census, and survey data. We defined SES categories by using area-level education, income, and poverty indicators. We ascertained ASD in 13 396 of 1 308 641 8-year-old children under surveillance., Results: The prevalence of ASD increased with increasing SES during each surveillance year among White, Black, and Hispanic children. The prevalence difference between high- and low-SES groups was relatively constant over time (3.9/1000 [95% CI = 3.3, 4.5] in 2002 and 4.1/1000 [95% CI = 3.6, 4.6] in the period 2006-2010). Significant racial/ethnic differences in ASD prevalence remained after stratification by SES., Conclusions: A positive SES gradient in ASD prevalence according to US surveillance data prevailed between 2002 and 2010, and racial and ethnic disparities in prevalence persisted during this time among low-SES children.

The risk of autism spectrum disorder varies by maternal race-ethnicity, immigration status, and birth region. In this retrospective cohort study, Western Australian state registries and a study population of 134 204 mothers enabled us to examine the odds of autism spectrum disorder with intellectual disability in children born from 1994 to 2005 by the aforementioned characteristics. We adjusted for maternal age, parity, socioeconomic status, and birth year. Indigenous women were 50% less likely to have a child with autism spectrum disorder with intellectual disability than Caucasian, nonimmigrant women. Overall, immigrant women were 40% less likely to have a child with autism spectrum disorder with intellectual disability than nonimmigrant women. However, Black women from East Africa had more than 3.5 times the odds of autism spectrum disorder with intellectual disability in their children than Caucasian nonimmigrant women. Research is implicated on risk and protective factors for autism spectrum disorder with intellectual disability in the children of immigrant women., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The Autism and Developmental Disabilities Monitoring (ADDM) Network conducts population-based surveillance of autism spectrum disorder (ASD) among 8-year old children in multiple US sites. To classify ASD, trained clinicians review developmental evaluations collected from multiple health and education sources to determine whether the child meets the ASD surveillance case criteria. The number of evaluations collected has dramatically increased since the year 2000, challenging the resources and timeliness of the surveillance system. We developed and evaluated a machine learning approach to classify case status in ADDM using words and phrases contained in children's developmental evaluations. We trained a random forest classifier using data from the 2008 Georgia ADDM site which included 1,162 children with 5,396 evaluations (601 children met ADDM ASD criteria using standard ADDM methods). The classifier used the words and phrases from the evaluations to predict ASD case status. We evaluated its performance on the 2010 Georgia ADDM surveillance data (1,450 children with 9,811 evaluations; 754 children met ADDM ASD criteria). We also estimated ASD prevalence using predictions from the classification algorithm. Overall, the machine learning approach predicted ASD case statuses that were 86.5% concordant with the clinician-determined case statuses (84.0% sensitivity, 89.4% predictive value positive). The area under the resulting receiver-operating characteristic curve was 0.932. Algorithm-derived ASD "prevalence" was 1.46% compared to the published (clinician-determined) estimate of 1.55%. Using only the text contained in developmental evaluations, a machine learning algorithm was able to discriminate between children that do and do not meet ASD surveillance criteria at one surveillance site., Competing Interests: The authors have declared that no competing interests exist.

Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3-5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The developmental disabilities questions in the 2014 National Health Interview Survey (NHIS) were changed from previous years, including question reordering and a new approach to asking about autism spectrum disorder (ASD). This report examines survey-based estimates of the lifetime prevalence of ASD, intellectual disability (ID), and any other developmental delay (other DD) following the inclusion of a standalone ASD question, the inclusion of specific diagnoses in the ASD question, and the ASD question preceding the other DD question, and compares them with estimates from previous years., Methods: In NHIS, one child is randomly selected from each family to be the subject of detailed questions on health conditions, functional limitations, and health care utilization. Parents are asked if a doctor or health professional had ever told them that their child had each of a series of developmental disabilities. Prevalence estimates of ASD, ID, and other DD for children aged 3–17 years were calculated using data collected in 2011–2014., Results: The estimated prevalence of ASD based on 2014 data was 2.24%, a significant increase from the estimated annualized prevalence of 1.25% based on 2011–2013 data. In contrast, the prevalence of other DD declined significantly from 4.84% based on 2011–2013 data to 3.57% based on 2014 data. The prevalence of ID did not significantly change from 2011–2013 (1.27%) to 2014 (1.10%). The prevalence of having any of the three conditions was constant across survey years., Conclusions: The revised question ordering and new approach to asking about developmental disabilities in the 2014 NHIS likely affected the prevalence estimates of these conditions. In previous years, it is likely that some parents of children diagnosed with ASD reported this developmental disability as other DD instead of, or in addition to, ASD. Following these changes, the 2014 ASD estimate was more similar to ASD prevalence estimates from other sources., (All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.)

Objectives: We assessed the association between assisted reproductive technology (ART) and diagnosed autistic disorder in a population-based sample of California births., Methods: We performed an observational cohort study using linked records from the California Birth Master Files for 1997 through 2007, the California Department of Developmental Services autism caseload for 1997 through 2011, and the Centers for Disease Control and Prevention's National ART Surveillance System for live births in 1997 through 2007. Participants were all 5 926 251 live births, including 48 865 ART-originated infants and 32 922 cases of autism diagnosed by the Department of Developmental Services. We compared births originated using ART with births originated without ART for incidence of autism., Results: In the full population, the incidence of diagnosed autism was twice as high for ART as non-ART births. The association was diminished by excluding mothers unlikely to use ART; adjustment for demographic and adverse prenatal and perinatal outcomes reduced the association substantially, although statistical significance persisted for mothers aged 20 to 34 years., Conclusions: The association between ART and autism is primarily explained by adverse prenatal and perinatal outcomes and multiple births.

Objective: Obesity is prevalent among women of reproductive age, and developmental disabilities in children continue to increase. We examined associations between mother's prepregnancy body mass index (BMI) and physical and developmental disabilities, and objective measures of reading and math skills and fine and gross motor function in children., Methods: We used the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n=5200), a cohort of children born in 2001 and followed until kindergarten. Children were classified according to maternal prepregnancy BMI (in kg per m(2)): underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obese class I (BMI 30.0-34.9) and obese class II/III (BMI ≥ 35.0). Parent reports of doctor-diagnosed disabilities were collected up to kindergarten and classified as learning and behavioral or physical. Children's reading and math and fine and gross motor function were assessed at kindergarten according to standardized tests. Linear and modified logistic regression models were adjusted for maternal sociodemographic variables, family enrichment variables, and children's sex, age and year of kindergarten entry. Additional adjustment for current child BMI was performed in separate models. All data are weighted to be nationally representative of the children born in 2001., Results: Compared with children of normal-weight mothers, children born to obese class II/III mothers had an increased risk of learning or behavioral (risk ratio 1.67; 95% confidence interval 1.27, 2.21)), but not physical disabilities (risk ratio 0.57; 95% confidence interval 0.27, 1.22). Gross (P<0.001), but not fine (P=0.06) motor function was significantly associated with maternal BMI, but gross motor function was attenuated after adjustment for current child BMI (P=0.05). Children's reading scores (P=0.01) but not math scores (P=0.11) were significantly associated with maternal BMI., Conclusions: In this nationally representative US cohort, children born to severely obese mothers had an increased risk for diagnosed learning and behavioral but not physical disabilities by kindergarten.

Objectives: This report presents data on the prevalence of diagnosed autism spectrum disorder (ASD) as reported by parents of school-aged children (ages 6-17 years) in 2011-2012. Prevalence changes from 2007 to 2011-2012 were evaluated using cohort analyses that examine the consistency in the 2007 and 2011-2012 estimates for children whose diagnoses could have been reported in both surveys (i.e., those born in 1994-2005 and diagnosed in or before 2007)., Data Sources: Data were drawn from the 2007 and 2011-2012 National Survey of Children's Health (NSCH), which are independent nationally representative telephone surveys of households with children. The surveys were conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics with funding and direction from the Health Resources and Services Administration's Maternal and Child Health Bureau., Results: The prevalence of parent-reported ASD among children aged 6-17 was 2.00% in 2011-2012, a significant increase from 2007 (1.16%). The magnitude of the increase was greatest for boys and for adolescents aged 14-17. Cohort analyses revealed consistent estimates of both the prevalence of parent-reported ASD and autism severity ratings over time. Children who were first diagnosed in or after 2008 accounted for much of the observed prevalence increase among school-aged children (those aged 6-17). School-aged children diagnosed in or after 2008 were more likely to have milder ASD and less likely to have severe ASD than those diagnosed in or before 2007., Conclusions: The results of the cohort analyses increase confidence that differential survey measurement error over time was not a major contributor to observed changes in the prevalence of parent-reported ASD. Rather, much of the prevalence increase from 2007 to 2011-2012 for school-aged children was the result of diagnoses of children with previously unrecognized ASD.

Objective: Both underweight and obese mothers have an increased risk for adverse offspring outcomes. Few studies have examined the association between prepregnancy body mass index (BMI) and children's neurodevelopment., Subjects: We used data from the nationally representative Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n=6850). Children were classified according to their mother's prepregnancy BMI (kg m(-2)) status: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obese class I (BMI 30.0-34.9), and obese class II and III (BMI ≥35.0). Children's age-adjusted mental development index (MDI) and psychomotor development index (PDI) T-scores (mean 50, s.d. 10) were obtained using a validated shortened version of the Bayley Scales of Infant Development-II at approximately 2 years of age. While adjusting for sociodemographics, we estimated the average MDI and PDI scores or the risk of delayed (<-1 s.d. vs >1 s.d.) mental or motor development, relative to children of normal weight mothers., Results: Compared with children of normal weight mothers, MDI scores were lower among children of mothers of all other prepregnancy BMI categories, with the greatest adjusted difference among children of class II and III obese mothers (-2.13 (95% CI -3.32, -0.93)). The adjusted risk of delayed mental development was increased among children of underweight (risk ratio (RR) 1.36 (95% CI 1.04, 1.78)) and class II and III obese (RR 1.38 (95% CI 1.03, 1.84)) mothers. Children's PDI scores or motor delay did not differ by maternal prepregnancy BMI., Conclusion: In this nationally representative sample of 2-year-old US children, low and very-high maternal prepregnancy BMI were associated with increased risk of delayed mental development but not motor development.

There are inconsistencies in the literature regarding the association between gestational weight gain (GWG) and child adiposity. GWG is hypothesized to act on child adiposity directly through intrauterine programming and indirectly through birth weight. It is unclear if the relative importance of these pathways differs by prepregnancy BMI status. We analyzed data from 3600 participants of the nationally representative Early Childhood Longitudinal Study-Birth Cohort. Child BMI Z-score was calculated from height and weight measured at 5 y. Using linear regression, controlling for sociodemographics and family lifestyle, we examined prepregnancy BMI-specific associations between GWG and child BMI Z-score. There was a nonlinear association among normal (P < 0.001) and overweight mothers only (P = 0.013), such that GWG beyond the midpoint of the 2009 Institute of Medicine recommendations was associated with a significant increase in child BMI Z-score. After the addition of birth-weight-for-gestational-age and breastfeeding to the model, the association remained among normal-weight mothers (P = 0.005) and was slightly attenuated among overweight mothers (P = 0.09). No significant association was observed between GWG and child BMI Z-score among underweight or obese mothers. We used path analysis to decompose the total effect into direct and indirect effects. This indicated the presence of a stronger direct than indirect effect. In conclusion, low GWG is not associated with BMI Z-score among any prepregnancy BMI group. Excess GWG is associated with an increase in child BMI Z-score among normal and overweight mothers only. Prevention of excess GWG may be a strategy to prevent childhood obesity.

Objective: Women who conceive with the assistance of fertility treatments are at increased risk for multiple-gestation pregnancies and accompanying adverse pregnancy outcomes. The Pregnancy Risk Assessment Monitoring System (PRAMS) can be used to assess outcomes associated with fertility treatments, but a previous study suggested that PRAMS questions about fertility treatments overestimated use of assisted reproductive technology (ART) by 2.6 times. These PRAMS ART questions were revised in 2004. We compared prevalence estimates based on revised questions with counts from the National ART Surveillance System (NASS), the standard for describing ART prevalence., Methods: We compared weighted PRAMS prevalence estimates of births conceived by using ART with corresponding counts from NASS for three states (Florida, Maryland, and Utah) for 2004. We also compared these data by age, parity, plurality, and infant birthweight., Results: Estimated ART births determined from PRAMS totaled 3,672 (95% confidence interval 2,210, 5,134), compared with 2,939 ART births reported to NASS. PRAMS estimates and NASS counts differed by maternal age (p=0.02) and parity (p<0.01). For example, PRAMS responses from women aged ≥ 40 years overestimated ART use by 70% (27.9% vs. 16.5%, p<0.01)., Conclusions: Revised PRAMS questions better estimate numbers of ART births than earlier PRAMS questions. PRAMS data are useful to describe behaviors and outcomes associated with ART use.

Objectives: To assess the risk of autism spectrum disorders (ASD) in children born after assisted conception compared with children born after natural conception., Design: Population-based follow-up study., Setting: All children born alive in Denmark 1995-2003., Participants: 588,967 children born in Denmark from January 1995 to December 2003. Assisted conception was defined as in vitro fertilisation (IVF) with or without intracytoplasmic sperm injection and ovulation induction (OI) with or without subsequent insemination. Children exposed to IVF or OI were identified in the IVF Register and in the Danish Drug Prescription Register., Main Outcome Measures: A diagnosis of ASD in the Danish Psychiatric Central Register., Results: 33,139 (5.6%) of all children born in Denmark in 1995-2003 resulted from assisted conception, 225 of whom (0.68%) had a diagnosis of ASD. Of the 555,828 children born in this period after natural conception, 3394 (0.61%) had a diagnosis of ASD. The follow-up time was 4-13 years (median 9 years). In crude analyses, children born after assisted conception had an increased risk of a diagnosis of ASD: crude hazard rate ratio (HRR) 1.25 (95% CI 1.09 to 1.43). In analyses adjusting for maternal age, educational level, parity, smoking, birth weight and multiplicity, the risk disappeared: adjusted HRR 1.13. (95% CI 0.97 to 1.31). However, subgroup analyses that suggest possible associations in women who received follicle stimulating hormone indicate the need for further study., Discussion: This population-based follow-up study found no risk of ASD in children born after assisted conception.

Background: Clomiphene citrate (CC) is the first line drug for subfertility treatment. Studies assessing the association between CC and birth defects have been inconclusive., Methods: We used data from the National Birth Defects Prevention Study, a population-based, multi-site case-control study of major birth defects. Women from 10 US regions with deliveries affected by at least one of >30 birth defects (cases) and mothers of live born infants without a major birth defect (controls) who delivered October 1997-December 2005 were interviewed. The exposure of interest was reported CC use in the period from 2 months before conception through the first month of pregnancy. Women who conceived using assisted reproductive technology were excluded. Thirty-six birth defect categories with at least three exposed cases were studied. Multiple logistic regression was used to control for potential confounders., Results: CC use was reported by 1.4% of control mothers (94/6500). Among 36 case-groups assessed, increased adjusted odds ratios (aOR) were found [all: aOR, 95% confidence interval (CI)] for anencephaly (2.3, 1.1-4.7), Dandy-Walker malformation (4.4, 1.7-11.6), septal heart defects (1.6, 1.1-2.2), muscular ventricular septal defect (4.9, 1.4-16.8), coarctation of aorta (1.8, 1.1-3.0), esophageal atresia (2.3, 1.3-4.0), cloacal exstrophy (5.4, 1.6-19.3), craniosynostosis (1.9, 1.2-3.0) and omphalocele (2.2, 1.1-4.5)., Conclusions: Several associations between CC use and birth defects were observed. However, because of the small number of cases, inconsistency of some findings with previous reports, and the fact that we cannot assess the CC effect separately from that of the subfertility, these associations should be interpreted cautiously.

Background: This paper assesses the risk of cerebral palsy (CP) in children born after assisted conception compared with children born after natural conception (NC)., Methods: This population based follow-up study included all 588,967 children born in Denmark from 1995 to 2003. Assisted conception was defined as IVF, with or without ICSI, and ovulation induction (OI), with or without subsequent insemination., Results: There were 33 139 (5.6%) children born in Denmark from 1995 to 2003 as a result of assisted conception and through to June 2009, 1146 (0.19%) children received a CP diagnosis. Children born after assisted conception had an increased risk of a CP diagnosis, crude hazard rate ratio (HRR) 1.90 (95% CI: 1.57-2.31) compared with NC children. Divided into IVF and OI children compared with NC children, the risk was HRR 2.34 (95% CI: 1.81-3.01) and HRR 1.55 (95% CI: 1.17-2.06), respectively. When we included the intermediate factors multiplicity and gestational age in multivariate models, the risk of CP in assisted conception disappeared. In general, children with CP born after assisted conception had similar CP subtypes and co-morbidities as children with CP born after NC., Conclusion: The risk of CP is increased after both IVF and OI. The increased risk of CP in children born after assisted conception, and in particular IVF, is strongly associated with the high proportion of multiplicity and preterm delivery in these pregnancies. A more widespread use of single embryo transfer warrants consideration to enhance the long-term health of children born after IVF.

Background: This study was designed to evaluate the hypothesis that the prevalence of autism spectrum disorder (ASD) among children in the United States is positively associated with socioeconomic status (SES)., Methods: A cross-sectional study was implemented with data from the Autism and Developmental Disabilities Monitoring Network, a multiple source surveillance system that incorporates data from educational and health care sources to determine the number of 8-year-old children with ASD among defined populations. For the years 2002 and 2004, there were 3,680 children with ASD among a population of 557,689 8-year-old children. Area-level census SES indicators were used to compute ASD prevalence by SES tertiles of the population., Results: Prevalence increased with increasing SES in a dose-response manner, with prevalence ratios relative to medium SES of 0.70 (95% confidence interval [CI] 0.64, 0.76) for low SES, and of 1.25 (95% CI 1.16, 1.35) for high SES, (P<0.001). Significant SES gradients were observed for children with and without a pre-existing ASD diagnosis, and in analyses stratified by gender, race/ethnicity, and surveillance data source. The SES gradient was significantly stronger in children with a pre-existing diagnosis than in those meeting criteria for ASD but with no previous record of an ASD diagnosis (p<0.001), and was not present in children with co-occurring ASD and intellectual disability., Conclusions: The stronger SES gradient in ASD prevalence in children with versus without a pre-existing ASD diagnosis points to potential ascertainment or diagnostic bias and to the possibility of SES disparity in access to services for children with autism. Further research is needed to confirm and understand the sources of this disparity so that policy implications can be drawn. Consideration should also be given to the possibility that there may be causal mechanisms or confounding factors associated with both high SES and vulnerability to ASD.

Background: With >1% of US births occurring following use of assisted reproductive technology (ART), it is critical to examine whether ART is associated with birth defects., Methods: We analyzed data from the National Birth Defects Prevention Study, a population-based, multicenter, case-control study of birth defects. We included mothers of fetuses or live-born infants with a major birth defect (case infants) and mothers who had live-born infants who did not have a major birth defect (control infants), delivered during the period October 1997-December 2003. We compared mothers who reported ART use (IVF or ICSI) with those who had unassisted conceptions. Multiple logistic regression was used to adjust for the following confounders: maternal race/ethnicity, maternal age, smoking and parity; we stratified by plurality., Results: ART was reported by 1.1% of all control mothers, and by 4.5% of control mothers 35 years or older. Among singleton births, ART was associated with septal heart defects (adjusted odds ratio [aOR] = 2.1, 95% confidence intervals [CI] 1.1-4.0), cleft lip with or without cleft palate (aOR = 2.4, 95% CI 1.2-5.1), esophageal atresia (aOR = 4.5, 95% CI 1.9-10.5) and anorectal atresia (aOR = 3.7, 95% CI 1.5-9.1). Among multiple births, ART was not significantly associated with any of the birth defects studied., Conclusions: These findings suggest that some birth defects occur more often among infants conceived with ART. Although the mechanism is not clear, couples considering ART should be informed of all potential risks and benefits.

This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention's Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort included 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent's age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age > or =35 vs. 25-29 years = 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age > or =40 years vs. 25-29 years = 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20-34 years and fathers aged <40 years (odds ratio = 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology.

Background: Approximately 18% of multiple births in the USA result from assisted reproduction technology (ART). Although many studies comparing ART and naturally conceived twins report no difference in risks for perinatal outcomes, others report slight to moderate positive or protective associations., Methods: We selected twin deliveries with and without indication of ART from Massachusetts live birth-infant death records from 1997 to 2000 linked to the US ART surveillance system. The sample was restricted to deliveries by mothers with increased socioeconomic status, private health insurance and intermediate/plus prenatal care use. Our final sample included 1446 and 2729 ART and non-ART twin deliveries, respectively. Odds ratios (OR) for associations between ART and perinatal outcomes were adjusted for maternal demographic factors, smoking, prenatal care and hospital care level., Results: ART twin deliveries were less likely than non-ART to be very preterm (adjusted OR 0.75; 95% confidence interval 0.58-0.97) or include a very low birthweight (<1500 g) infant (0.75; 0.58-0.95) or infant death (0.55; 0.35-0.88). In stratified analyses, these findings were observed among primiparous deliveries, but there were no risk differences among multiparous ART and non-ART twin deliveries., Conclusions: ART treatment was not a risk factor for adverse perinatal outcome, and risks for several outcomes were somewhat lower among ART twin deliveries. Nonetheless, ART is strongly associated with twinning and twins remain a high-risk group, relative to singletons. Promoting singleton gestation in assisted conception is an important strategy for reducing adverse outcomes.

Approximately 30% of pregnancies in the United States may end in miscarriage or stillbirth. Whether pregnancies conceived through assisted reproductive technology (ART) are at an increased risk of loss is inconclusive, and data on maternal age-, ART type-, and gestational age-specific risk of loss are limited. Data on 148,494 ART pregnancies conceived from 1999 through 2002 were analyzed by use of the Kaplan-Meier method to estimate risks of pregnancy loss after specified gestational ages (conditional risk) for 14 groups stratified by maternal age and ART procedure. Births, maternal deaths, and induced abortions were censored. The Kaplan-Meier estimate of total risk of pregnancy loss was 29% but ranged from 22% to 63% depending on patient age and ART procedure. By 6 weeks' gestation, 58% of all pregnancy losses occurred. Conditional risk of pregnancy loss ranged from 10% to 45% at 6 weeks' gestation and from 2% to 7% at the first trimester; it was less than 2% after 20 weeks' gestation. Results can be used to counsel ART patients and inform future research on the etiology of pregnancy loss.

Assisted reproductive technology (ART) treatments, such as in vitro fertilization, have benefited many couples worldwide. However, ART as currently practiced, with the usual transfer of at least two embryos, poses sizable risks for multiple-gestation pregnancy and accompanying serious maternal and child health sequelae. While limiting the number of embryos transferred would appear a straightforward solution, treatments with single-embryo transfer are rare. Likely reasons for this include patient and provider desires to maximize the chance for success in a single treatment given the high cost and lack of insurance coverage, the (sometimes mistaken) belief that transferring more embryos will increase the chance for pregnancy, and the preference for multiple births among some women undergoing ART. Although recent population-based data in the USA and Europe suggest the number of embryos transferred is decreasing, the ART multiple-birth rate remains high. Comprehensive patient-education efforts and continued research on the efficacy of single-embryo transfer are needed.

Objective: To compare the risk for adverse outcomes of pregnancies between heterotopic (defined as a simultaneous intrauterine and ectopic pregnancy) and intrauterine-only pregnancies achieved through assisted reproductive technologies (ARTs)., Design: Retrospective cohort study., Setting: ART centers in the United States., Patient(s): Patients were studied in terms of cycles reported to the population-based United States ART Registry, which included 207 heterotopic and 132,660 intrauterine-only pregnancies reported from 1999 to 2002., Intervention(s): None., Main Outcome Measure(s): Outcomes of heterotopic and intrauterine-only pregnancies and deliveries (spontaneous abortion, induced abortion, still birth, and live birth). Perinatal outcomes (preterm, low birth weight [LBW], preterm LBW, and term LBW) for live-birth deliveries were also assessed., Result(s): Heterotopic pregnancies were more likely to end in spontaneous (relative risk = 2.05; 95% confidence interval, 1.67-2.51) or induced (relative risk = 10.28, 95% confidence interval, 6.76-15.65) abortions than were intrauterine-only pregnancies. There was no significant difference in perinatal outcomes studied, regardless of adjustment for maternal age, infertility diagnosis, previous live births, and type of ART procedure., Conclusion(s): Heterotopic pregnancies were more likely to result in spontaneous or induced abortions than were intrauterine-only pregnancies. There was no difference in perinatal outcomes between heterotopic and intrauterine-only pregnancies progressing to live birth.

Background: Increasing use of IVF in the USA has been a major contributor to the rising national multiple birth rate. Many have advocated that reducing the number of embryos transferred is essential for addressing the IVF-associated multiple birth problem., Methods: A population-based sample of 506 072 IVF transfers performed in the USA in 1996-2002 was used to investigate trends in embryo transfer practices and to determine whether any changes in practice patterns have impacted the multiple gestation risk associated with IVF., Results: The proportion of procedures in which >or=3 embryos were transferred declined significantly for most patient groups between 1996 and 2002. However, declines for some groups were not sizeable (from 79 to 73% and from 76 to 71% for fresh, non-donor procedures among women aged 38-40 and 41-42 years respectively) and transferring >or=3 embryos remained the norm for all groups. As of 2002, single embryo transfer had not increased for most groups and remained uncommon. Some declines in overall multiple gestation rates were observed, although multiple gestation risk associated with 2 embryos transferred increased significantly for all groups., Conclusions: Despite changes in embryo transfer practices, multiple gestation risk remains high, in part due to increased multiple gestation rates associated with the transfer of two embryos.

Background: The association between excessive gestational weight gain and preterm delivery is unclear, as is the association between low gestational weight gain and preterm delivery among overweight and obese women., Methods: Using data from the Pregnancy Risk Assessment Monitoring System in 21 states, we estimated the risk of very (20-31 weeks) and moderately (32-36 weeks) preterm delivery associated with a combination of prepregnancy body mass index (BMI) and gestational weight gain among 113,019 women who delivered a singleton infant during 1996-2001. We categorized average weight gain (kilograms per week) as very low (<0.12), low (0.12-0.22), moderate (0.23-0.68), high (0.69-0.79), or very high (>0.79). We categorized prepregnancy BMI (kg/m) as underweight (<19.8), normal (19.8-26.0), overweight (26.1-28.9), obese (29.0-34.9), or very obese (>or=35.0). We examined associations for all women and for all women with no complications adjusting for covariates., Results: There was a strong association between very low weight gain and very preterm delivery that varied by prepregnancy BMI, with the strongest association among underweight women (adjusted odds ratio = 9.8; 95% confidence interval = 7.0-13.8) and the weakest among very obese women (2.3; 1.8-3.1). Very low weight gain was not associated with moderately preterm delivery for overweight or obese women. Women with very high weight gain had approximately twice the odds of very preterm delivery, regardless of prepregnancy BMI., Conclusions: This study supports concerns about very low weight gain during pregnancy, even among overweight and obese women, and also suggests that high weight gain, regardless of prepregnancy BMI, deserves further investigation.

Studies of assisted reproductive technology (ART) and birth defects must be scrutinized and appropriately interpreted in the context of their limitations. The recent findings reported by Klemetti et al. are compelling, given the study's many strengths, and add to the accumulating evidence suggestive of an association between ART and birth defects.

Background: Multiple births are associated with serious adverse infant and maternal outcomes. The objective of this study was to assess the multiple-birth risk (MBR) associated with IVF and determine whether the risk is impacted by stage of embryo development at transfer., Methods: A population-based sample of 50 819 IVF transfers utilizing day 3 or day 5 embryos performed in the USA in 2001 on women aged 20-40 years was used to assess MBR and live-birth rate (LBR), stratified by patient age, supernumerary embryo availability, and number of embryos transferred., Results: Although significantly more day 5 than day 3 transfers used < or =2 embryos (69.2 versus 27.7%), the former were not associated with decreased MBR. MBR was high when >1 embryo was transferred, irrespective of embryo development stage. LBR were generally maximized with 2 embryos transferred, and for some (day 5 transfers, patients aged 35-37 years) with one embryo. Electing to transfer a single day 5 embryo appeared efficacious for some patients: women aged 20-37 years with supernumerary embryos cryopreserved had LBR of 31.6-39.5%., Conclusions: MBR is high when > or =2 embryos are transferred. Single embryo transfer is the only way to prevent many multiple births and associated adverse health outcomes.

Research aimed at the empirical evaluation of infertility treatment including assisted reproductive technologies (ART) on child health and development is hampered by investigators' inability to methodologically separate possible treatment effects from underlying fecundity impairments. While the literature continues to identify ART as a risk factor for many child health outcomes, less attention has been paid to the methodologic rigor needed to answer this question. We identify aspects of fecundity and the nuances of medical practice that need to be considered and captured when designing epidemiologic investigations aimed at assessing ART and child health. These include: (i) the use of prospective study designs in which the unit of analysis (cycle versus individual versus couple) is defined; (ii) data collection on relevant time-varying covariates at, before and during treatment; and (iii) the use of statistical techniques appropriate for hierarchical data and correlated exposures. While none of these issues in and by itself is unique to ART research, attention to these issues has been lacking in much of the published research limiting our ability to evaluate health consequences for children. Longitudinal studies of children conceived with ART will benefit from attention to these issues and, hopefully, produce answers to lingering questions about safety.