The Role of Multiple Birth and Birth Complications in the Association Between Assisted Reproductive Technology Conception and Autism Diagnosis.

In recent decades, the use of assisted reproductive technology (ART) has increased rapidly. To assess the relationship between ART and autism diagnosis, we linked California birth records from 2000 through 2016 with contemporaneous records from the National ART Surveillance System (NASS) and autism caseload records from California's Department of Developmental Services from 2000 through November 2019. All 95,149 birth records that were successfully linked to a NASS record, indicating an ART birth, were matched 1:1 using propensity scores to non-ART births. We calculated the hazard risk ratio (HRR) for autism diagnosis and the proportions of the relationship between ART conception and autism diagnosis mediated by multiple birth pregnancy and related birth complications. The HRR for autism diagnosis following ART compared with non-ART conception is 1.26 (95% CI, 1.17-1.35). Multiple birth, preterm birth, and Cesarean delivery jointly mediate 77.9% of the relationship between ART conception and autism diagnosis. Thus, increased use of single embryo transfer in the United States to reduce multiple births and related birth complications may be a strategy to address the risk of autism diagnosis among ART-conceived children.

Multiple Imputation of Missing Race/Ethnicity Information in the National Assisted Reproductive Technology Surveillance System.

Background: Missing race/ethnicity data are common in many surveillance systems and registries, which may limit complete and accurate assessments of racial and ethnic disparities. Centers for Disease Control and Prevention's National Assisted Reproductive Technology (ART) Surveillance System (NASS) has a congressional mandate to collect data on all ART cycles performed by fertility clinics in the United States and provides valuable information on ART utilization and treatment outcomes. However, race/ethnicity data are missing for many ART cycles in NASS. Materials and Methods: We multiply imputed missing race/ethnicity data using variables from NASS and additional zip code-level race/ethnicity information in U.S. Census data. To evaluate imputed data quality, we generated training data by imposing missing values on known race/ethnicity under missing at random assumption, imputed, and examined the relationship between race/ethnicity and the rate of stillbirth per pregnancy. Results: The distribution of imputed race/ethnicity was comparable to the reported one with the largest difference of 0.53% for non-Hispanic Asian. Our imputation procedure was well calibrated and correctly identified that 89.91% (standard error = 0.18) of known race/ethnicity values on average in training data. Compared to complete-case analysis, using multiply imputed data reduced bias of parameter estimates (the range of bias for stillbirth per pregnancy across race/ethnicity groups is 0.02%-0.18% for imputed data analysis, versus 0.04%-0.66% for complete-case analysis) and yielded narrower confidence intervals. Conclusions: Our results underscore the importance of collecting complete race/ethnicity information for ART surveillance. However, when the missingness exists, multiply imputed race/ethnicity can improve the accuracy and precision of health outcomes estimated across racial/ethnic groups.

Association of state insurance coverage mandates with assisted reproductive technology care discontinuation.

BACKGROUND: Insurance coverage for fertility services may reduce the financial burden of high-cost fertility care such as assisted reproductive technology and improve its utilization. Patients who exit care after failing to reach their reproductive goals report higher rates of mental health problems and a lower sense of well-being. It is important to understand the relationship between state-mandated insurance coverage for fertility services and assisted reproductive technology care discontinuation. OBJECTIVE: This study aimed to assess whether state-mandated insurance coverage for fertility services is associated with lower rates of care discontinuation after an initial assisted reproductive technology cycle that did not result in a live birth. STUDY DESIGN: This is a retrospective, population-based cohort study using data from United States fertility clinics reporting to the National Assisted Reproductive Technology Surveillance System during 2016 and 2018. Patients who began their first autologous assisted reproductive technology cycle during 2016 and 2017 and did not have a live birth were included. We describe the rate of assisted reproductive technology care discontinuation (no additional cycle within 12 months of the previous cycle's date of failure). Multivariable analyses were conducted to evaluate factors independently associated with care discontinuation, including the scope of fertility services included in state coverage mandate at assisted reproductive technology cycle initiation that were as follows: comprehensive (≥3 assisted reproductive technology cycles), limited (1, 2, or an unspecified number of assisted reproductive technology cycles), mandate not including assisted reproductive technology, and no mandate. RESULTS: Among 91,324 patients who underwent their first autologous assisted reproductive technology cycle that did not result in live birth, 24,072 (26.4%) discontinued care. Compared with patients who lived in states with mandates for comprehensive assisted reproductive technology coverage, those in states with mandates for fertility services coverage that did not include assisted reproductive technology or states with no mandate were 46% (adjusted relative risk, 1.46; 95% confidence interval, 1.31-1.63) and 26% (adjusted relative risk, 1.26; 95% confidence interval, 1.15-1.39) more likely to discontinue care, respectively, after controlling for patient and cycle characteristics. Increasing patient age, distance from clinic ≥50 miles, previous live birth, fewer oocytes retrieved, and not having embryos cryopreserved were also associated with higher rates of discontinuation. Non-Hispanic Black, non-Hispanic Asian, and Hispanic patients had higher rates of care discontinuation than non-Hispanic White patients regardless of the existence or scope of state-mandated assisted reproductive technology coverage. CONCLUSION: Comprehensive state-mandated insurance coverage for assisted reproductive technology is associated with lower rates of assisted reproductive technology care discontinuation.

Factors associated with large-for-gestational-age infants born after frozen embryo transfer cycles.

Objective: To examine trends of frozen embryo transfer (FET) proportions and large-for-gestational-age (LGA) incidence and determine risk factors for LGA infants after FET. Design: Retrospective cohort study. Setting: Not applicable. Patients: Frozen embryo transfer cycles. Interventions: None. Main Outcome Measures: Singleton LGA infant. Results: The percentage of FETs increased from 20%-74% of transfers, whereas the rate of LGA among FET singleton births decreased from 18%-12% during 2004-2018. In a subanalysis of 127,525 FET-associated singleton live births during 2016-2018, patient factors associated with LGA were higher-than-normal maternal body mass index (body mass index [BMI], 25.0-29.9 kg/m2; adjusted relative risk [aRR], 1.31; 95% confidence interval [CI], 1.26-1.36; BMI, 30.0-34.9 kg/m2; aRR, 1.48; 95% CI, 1.41-1.55; and BMI, >35 Kg/m2; aRR, 1.68; 95% CI, 1.59-1.77) and ≥1 prior birth vs. none. Low maternal BMI (<18.5 vs. 18.5-24.9 kg/m2) and cycles involving patients who were non-Hispanic (NH) Asian/Native Hawaiian/Pacific Islander, NH Black, or Hispanic (compared with NH White) were at lower risk of LGA infants. Cycle factors associated with LGA included gestational carrier use (aRR, 1.25; 95% CI, 1.16-1.34) and donor sperm (aRR, 1.17; 95% CI, 1.10-1.25). Conclusions: Although the number and proportion of FET cycles increased from 2004-2018, the rate of LGA after FET decreased. Maternal BMI, parity, and race/ethnicity were the strongest risk factors for LGA infants after FET.

Hepatitis C care cascade among persons born 1945-1965: 3 medical centers.

OBJECTIVES: Effective screening, diagnosis, and treatment are needed to reduce chronic hepatitis C virus (HCV) infection-associated morbidity and mortality. In order to successfully increase HCV treatment, it is necessary to identify and understand gaps in linkage of antibody-positive patients with newly identified HCV to subsequent HCV RNA testing, clinical evaluation, and treatment. STUDY DESIGN: To estimate attainment of HCV care cascade steps among antibody-positive patients with newly identified HCV, we conducted chart reviews of patients with a new positive HCV antibody test at 3 academic medical centers participating in the Birth-Cohort Evaluation to Advance Screening and Testing of Hepatitis C (BEST-C) study. METHODS: We tracked receipt of RNA testing, clinical evaluation, treatment initiation, and treatment completion among individuals born between 1945 and 1965 who were newly diagnosed as HCV antibody-positive between December 2012 and October 2015 at 3 BEST-C centers, predominantly from the participating medical centers' primary care practices and emergency departments. RESULTS: Of the 130 HCV-seropositive individuals identified, 118 (91%) had an RNA or genotype test, 75 (58%) were RNA-positive, 73 (56%) were linked to care, 22 (17% overall; 29% among RNA-positive) started treatment, and 21 (16%; 28% among RNA-positive) completed treatment. CONCLUSIONS: This analysis showed that although linkage to care was largely successful in the target birth cohort, the largest gap in the HCV care cascade was seen in initiating treatment. Greater emphasis on linking patients to clinical evaluation and treatment is necessary in order to achieve the public health benefits promised by birth-cohort testing.

Hepatitis C virus testing for case identification in persons born during 1945-1965: Results from three randomized controlled trials.

The Centers for Disease Control and Prevention and US Preventive Services Task Force recommend one-time hepatitis C virus (HCV) testing for persons born during 1945-1965 (birth cohort). However, few studies estimate the effect of birth cohort (BC) testing implementation on HCV diagnoses in primary care settings. We aimed to determine the probability of identifying HCV infections in primary care using targeted BC testing compared with usual care at three academic medical centers. From December 2012 to March 2014, each center compared one of three distinct interventions with usual care using an independently designed randomized controlled trial. Across centers, BC patients with no clinical documentation of previous HCV testing or diagnosis were randomly assigned to receive a one-time offering of HCV antibody (anti-HCV) testing via one of three independent implementation strategies (repeated-mailing outreach, electronic medical record-integrated provider best practice alert [BPA], and direct patient solicitation) or assigned to receive usual care. We estimated model-adjusted risk ratios (aRR) of anti-HCV-positive (anti-HCV+) identification using BC testing versus usual care. In the repeated mailing trial, 8992 patients (intervention, n = 2993; control, n = 5999) were included in the analysis. The intervention was eight times as likely to identify anti-HCV+ patients compared with controls (aRR, 8.0; 95% confidence interval [CI], 2.8-23.0; adjusted probabilities: intervention, 0.27%; control, 0.03%). In the BPA trial, data from 14,475 patients (BC, n = 8928; control, n = 5,547) were analyzed. The intervention was 2.6 times as likely to identify anti-HCV+ patients versus controls (aRR, 2.6; 95% CI, 1.1-6.4; adjusted probabilities: intervention, 0.29%; control, 0.11%). In the patient-solicitation trial, 8873 patients (BC, n = 4307; control, n = 4566) were analyzed. The intervention was five times as likely to identify anti-HCV+ patients compared with controls (aRR, 5.3; 95% CI, 2.3-12.3; adjusted probabilities: intervention, 0.68%; control, 0.11%). Conclusion: BC testing was effective in identifying previously undiagnosed HCV infections in primary care settings. (Hepatology 2018;67:524-533).

HIV Infection Status as a Predictor of Hepatitis C Virus RNA Testing in Primary Care.

INTRODUCTION: Receipt of hepatitis C virus (HCV) RNA testing following a positive HCV antibody (anti-HCV+) test result to establish current infection is a quality indicator for HCV-related care. This study examines HIV infection status as a predictor of HCV RNA test receipt after an anti-HCV+ result in the primary care setting. METHODS: Electronic medical records of anti-HCV+ patients from a multisite retrospective study of patients aged ≥18 years who utilized one or more primary care outpatient services during 2005-2010 were analyzed in 2014. A multivariable logistic regression model examined the independent relationships between patient characteristics and receipt of HCV RNA testing. RESULTS: Among 1,115 anti-HCV+ patients, 133 (11.9%) were also HIV-positive. Of these, 77.4% (n=103) underwent HCV RNA testing to determine current infection status. By contrast, 66.7% (n=654/980) of anti-HCV+ patients who were HIV-negative received HCV RNA testing. Following multivariable adjustment, the odds of receiving HCV RNA testing were higher among anti-HCV+ patients who were also HIV-positive (AOR=1.9, 95% CI=1.2, 3.0), compared with their HIV-negative counterparts. Elevated alanine aminotransferase level was also associated with receipt of HCV RNA testing (AOR=1.9, 95% CI=1.4, 2.4). Black race was associated with decreased odds of receiving HCV RNA testing (AOR=0.7, 95% CI=0.5, 1.0). CONCLUSIONS: HIV infection status is independently associated with the likelihood of receiving HCV RNA testing following an anti-HCV+ result. One quarter of anti-HCV+ patients who were also HIV-positive and one third of their HIV-negative counterparts, respectively, did not receive testing to establish active HCV infection, which is imperative for appropriate care and treatment.

Hepatitis C virus antibody positivity and predictors among previously undiagnosed adult primary care outpatients: cross-sectional analysis of a multisite retrospective cohort study.

BACKGROUND: Hepatitis C virus (HCV) testing guidance issued by the Centers for Disease Control and Prevention in 1998 recommends HCV antibody (anti-HCV) testing for persons with specified risk factors. The purpose of this study was to determine the prevalence and predictors of anti-HCV positivity among primary care outpatients and estimate the proportion of unidentified anti-HCV-positive (anti-HCV+) persons using risk-based testing. METHODS: We analyzed electronic medical record data from a 4-site retrospective study. Patients were aged ≥18 years, utilized ≥1 outpatient primary care service(s) between 2005 and 2010, and had no documented evidence of prior HCV diagnosis. Among persons tested for anti-HCV, we fit a multilevel logistic regression model to identify patient-level independent predictors of anti-HCV positivity. We estimated the proportion of unidentified anti-HCV+ persons by using multiple imputation to assign anti-HCV results to untested patients. RESULTS: We observed 209 076 patients for a median of 5 months (interquartile range, 1-23 months). Among 17 464 (8.4%) patients who were tested for anti-HCV, 6.4% (n=1115) were positive. We identified history of injection drug use (adjusted odds ratio [95% confidence interval], 6.3 [5.2-7.6]), 1945-1965 birth cohort (4.4 [3.8-5.1]), and elevated alanine aminotransferase levels (4.8 [4.2-5.6]) as independently associated with anti-HCV positivity. We estimated that 81.5% (n=4890/6005) of anti-HCV+ patients were unidentified using risk-based testing. CONCLUSIONS: In these outpatient primary care settings, risk-based testing may have missed 4 of 5 newly enrolled patients who are anti-HCV+. Without knowing their status, unidentified anti-HCV+ persons cannot receive further clinical evaluation or antiviral treatment, and are unlikely to benefit from secondary prevention recommendations to limit disease progression and mortality.

Comparison of hepatitis C virus testing strategies: birth cohort versus elevated alanine aminotransferase levels.

BACKGROUND: Hepatitis C virus (HCV) infection is unidentified in an estimated 40%-85% of infected adults. Surveillance and modeling data have found significant increases in HCV-associated morbidity and mortality. PURPOSE: To compare two HCV antibody (anti-HCV) testing strategies based on (1) elevated alanine aminotransferase levels (ALT) and (2) a birth cohort approach for people born during 1945-1965. METHODS: Data from 19,055 adults aged 20-70 years who completed the National Health and Nutrition Examination Survey in 1999-2008 were analyzed in 2013. Two independent models were evaluated, based on membership in the 1945-1965 birth cohort or elevated ALT, to compare the number of identified anti-HCV-positive (anti-HCV+) individuals; proportion of total identified cases; and the number of people that would be tested using either strategy. RESULTS: The prevalence of anti-HCV among adults aged 20-70 years was estimated at 2.0% (95% CI=1.8%, 2.3%), representing about 3.6 million people. The birth cohort strategy would result in testing about 85.4 million people and identifying nearly 2.8 million anti-HCV+ people with a sensitivity of 76.6%. The ALT strategy would test about 21.5 million adults and identify approximately 1.8 million anti-HCV+ people with a sensitivity of 50.0%. Implementing both strategies concurrently would identify 87.3% of anti-HCV+ adults. CONCLUSIONS: The birth cohort strategy, which is recommended by both the CDC and the U.S. Preventive Services Task Force, would identify 1 million more anti-HCV+ people than the elevated ALT approach. Concurrent implementation would identify an even larger number of individuals ever infected.

"To share or not to share?" Serosorting by hepatitis C status in the sharing of drug injection equipment among NHBS-IDU2 participants.

BACKGROUND: Persons who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV) infection. The Centers for Disease Control and Prevention estimates there are 17 000 new infections per year, mainly among PWID. This study examines injection equipment serosorting-considering HCV serostatus when deciding whether and with whom to share injection equipment. OBJECTIVE: To examine whether injection equipment serosorting is occurring among PWID in selected cities. METHODS: Using data from the National HIV Behavioral Surveillance System-Injection Drug Users (NHBS-IDU2, 2009), we developed multivariate logistic regression models to examine the extent to which participants' self-reported HCV status is associated with their injection equipment serosorting behavior and knowledge of last injecting partner's HCV status. RESULTS: Participants who knew their HCV status were more likely to know the HCV status of their last injecting partner, compared to those who did not know their status (HCV+: adjusted odds ratio [aOR] 4.1, 95% confidence interval [CI], 3.4-4.9; HCV-: aOR 2.5, 95% CI, 2.0-3.0). Participants who reported being HCV+, relative to those of unknown HCV status, were 5 times more likely to share injection equipment with a partner of HCV-positive status (aOR 4.8, 95% CI, 3.9-6.0). CONCLUSIONS: Our analysis suggests PWID are more likely to share injection equipment with persons of concordant HCV status.