Demographic and experiential correlates of public attitudes towards cell-free fetal DNA screening.

This study seeks to inform clinical application of cell-free fetal DNA (cffDNA) screening as a novel method for prenatal trisomy detection by investigating public attitudes towards this technology and demographic and experiential characteristics related to these attitudes. Two versions of a 25-item survey assessing interest in cffDNA and existing first-trimester combined screening for either trisomy 13 and 18 or trisomy 21 were distributed among 3,164 members of the United States public. Logistic regression was performed to determine variables predictive of interest in screening options. Approximately 47% of respondents expressed an interest in cffDNA screening for trisomy 13, 18, and 21, with a majority interested in cffDNA screening as a stand-alone technique. A significantly greater percent would consider termination of pregnancy following a diagnosis of trisomy 13 or 18 (52%) over one of trisomy 21 (44%). Willingness to consider abortion of an affected pregnancy was the strongest correlate to interest in both cffDNA and first-trimester combined screening, although markedly more respondents expressed an interest in some form of screening (69% and 71%, respectively) than would consider termination. Greater educational attainment, higher income, and insurance coverage predicted interest in cffDNA screening; stronger religious identification also corresponded to decreased interest. Prior experience with disability and genetic testing was associated with increased interest in cffDNA screening. Several of these factors, in addition to advanced age and Asian race, were, in turn, predictive of respondents' increased willingness to consider post-diagnosis termination of pregnancy. In conclusion, divergent attitudes towards cffDNA screening--and prenatal options more generally--appear correlated with individual socioeconomic and religious backgrounds and experiences with disability and genetic testing. Clinical implementation and counseling for novel prenatal technologies should take these diverse stakeholder values into consideration.

Commercial landscape of noninvasive prenatal testing in the United States.

Cell-free fetal DNA-based noninvasive prenatal testing (NIPT) could significantly change the paradigm of prenatal testing and screening. Intellectual property (IP) and commercialization promise to be important components of the emerging debate about clinical implementation of these technologies. We have assembled information about types of testing, prices, turnaround times, and reimbursement of recently launched commercial tests in the United States from the trade press, news articles, and scientific, legal, and business publications. We also describe the patenting and licensing landscape of technologies underlying these tests and ongoing patent litigation in the United States. Finally, we discuss how IP issues may affect clinical translation of NIPT and their potential implications for stakeholders. Fetal medicine professionals (clinicians and researchers), genetic counselors, insurers, regulators, test developers, and patients may be able to use this information to make informed decisions about clinical implementation of current and emerging noninvasive prenatal tests.

The gestational membrane microbiome in the presence or absence of intraamniotic infection.

BACKGROUND: Data regarding the microbiome of the gestational membranes are emerging and conflicting. Shifts in the microbial communities in the setting of labor, rupture of membranes, and intraamniotic infection are yet to be understood. OBJECTIVE: This study aimed to characterize the microbiome of the gestational membranes of women in labor or with ruptured membranes, including those with and without intraamniotic infection. STUDY DESIGN: Women with a singleton pregnancy at ≥28 weeks' gestation undergoing unscheduled cesarean delivery in the setting of labor or rupture of membranes were included. Demographic and clinical variables were collected. We defined suspected intraamniotic infection by standard clinical criteria; placentae and gestational membranes were also reviewed for histologic evidence of infection. Sterile swabs were collected from membranes at the time of delivery. Bacteria were cultured from the swabs, and the isolates were sequenced. DNA extraction and 16S sequencing of the swabs were also performed. Bacterial taxonomy was assigned to each sequence. Alpha diversity indices and beta-diversity metrics were calculated to test for differences in microbial community diversity and composition between uninfected and infected groups. Differential abundance of bacteria between infected and uninfected groups was tested at the class, family, and genus level. RESULTS: Samples were collected from 34 participants. Clinical intraamniotic infection was diagnosed in 38% of participants, although 50% of placentae and membranes demonstrated histologic signs of infection. Of all samples, 68% grew bacteria on culture; this included 62% of the uninfected samples and 77% of the infected samples (P=.83). Multiple measures of alpha diversity were not significantly different between uninfected and infected groups. Similarly, analysis of beta diversity revealed that the microbial community was not significantly different between the uninfected and infected group. Several bacteria traditionally characterized as pathogenic, including Actinomyces and Streptococcus agalactiae, were identified in both infected and uninfected samples. CONCLUSION: The pathogenesis and clinical implications of intraamniotic infection remain poorly understood. Diverse bacteria are present in both infected and uninfected gestational membranes. A unique microbiologic signature may exist among the gestational membranes following labor or rupture of membranes, and further characterization of the pathogens specifically implicated in intraamniotic infection may allow for targeted therapy.

Cell-free fetal DNA testing for fetal aneuploidy and beyond: clinical integration challenges in the US context.

The recent release of new, non-invasive prenatal tests for fetal aneuploidy using cell-free fetal DNA (cffDNA) has been hailed as a revolution in prenatal testing and has triggered significant commercial interest in the field. Ongoing research portends the arrival of a wide range of cffDNA tests. However, it is not yet clear how these tests will be integrated into well-established prenatal testing strategies in the USA, as the timing of such testing and the degree to which new non-invasive tests will supplement or replace existing screening and diagnostic tools remain uncertain. We argue that there is an urgent need for policy-makers, regulators and professional societies to provide guidance on the most efficient and ethical manner for such tests to be introduced into clinical practice in the USA.

Cell-free fetal DNA testing: a pilot study of obstetric healthcare provider attitudes toward clinical implementation.

OBJECTIVE: To provide a preliminary assessment of obstetric healthcare provider opinions surrounding implementation of cell-free fetal DNA testing. METHODS: A 37-question pilot survey was used to address questions around the translation and use of non-invasive prenatal testing using cell-free fetal DNA. The survey was distributed and collected at a Continuing Medical Education course on obstetrics and gynecology. RESULTS: Of 62 survey respondents, 73% were female and 87% held MD/DO degrees. Respondents generally agreed that patients want prenatal diagnostic information to help make decisions about a pregnancy and that cell-free fetal DNA testing would encourage the testing of more patients for more conditions. However, there was an overall lack of knowledge or conviction about using this technology. Genetic counseling and professional society approval were deemed important to implementation, whereas the possibility of direct-to-consumer testing and government regulation produced mixed responses. Respondents indicated that they would be more likely to offer cell-free fetal DNA testing for chromosomal abnormalities and single-gene disorders, but would be cautious with respect to determination of sex and behavioral or late-onset conditions. CONCLUSION: Preliminary assessment indicates uncertainty among obstetric providers about the details of implementing cell-free fetal DNA testing and suggests expanded research on perspectives of this stakeholder group.

Is Early Amniotomy Associated with Higher Likelihood of Vaginal Birth after Cesarean?

Objective The study aims to reduce cesarean rates, eligible women are being offered an option of vaginal birth after cesarean (VBAC). However, little data exist regarding efficacy of amniotomy as a tool in this population. We sought to evaluate the impact of early amniotomy on VBAC success. Study Design This is a secondary analysis case-control study using the MFMU (Maternal-Fetal Medicine Units Network) Cesarean Registry. Women were included if they had a singleton pregnancy, were attempting VBAC, and underwent induction with artificial rupture of membranes. Cases were defined as subjects with successful VBAC; controls were defined as subjects with failed trial of labor after cesarean (TOLAC). Early amniotomy was defined as amniotomy at <4 cm. Demographic and obstetric characteristics were compared and multivariate logistic regression was performed. Results A total of 1,490 women were included. Early amniotomy occurred in 59.5% with VBAC versus 63.2% with failed TOLAC ( p = 0.24). After controlling for body mass index, prior vaginal delivery, African-American race, labor length, gestational age, birthweight, epidural use, Foley catheter balloon ripening, induction method and oxytocin use, early amniotomy was associated with a 34% decrease in VBAC success ( p < 0.01). Women who had early amniotomy did not have higher rates of chorioamnionitis (2.8 vs. 2.9%, p > 0.99). Conclusion Unlike data from nulliparous women, our data suggest that induction with early amniotomy does not increase the likelihood of VBAC.

Identifying sex-specific risk factors for stress fractures in adolescent runners.

PURPOSE: Adolescent females and males participating in running represent a population at high risk of stress fracture. Few investigators have evaluated risk factors for prospective stress fracture in this population. METHODS: To better characterize risk factors for and incidence of stress fractures in this population, we collected baseline risk factor data on 748 competitive high school runners (442 girls and 306 boys) using an online survey. We then followed them prospectively for the development of stress fractures for a mean ± SD of 2.3 ± 1.2 total seasons of cross-country and track and field; follow-up data were available for 428 girls and 273 boys. RESULTS: We identified prospective stress fractures in 5.4% of girls (n = 23) and 4.0% of boys (n = 11). Tibial stress fractures were most common in girls, and the metatarsus was most frequently fractured in boys. Multivariate regression identified four independent risk factors for stress fractures in girls: prior fracture, body mass index < 19, late menarche (age menarche ≥15 yr), and previous participation in gymnastics or dance. For boys, prior fracture and increased number of seasons were associated with an increased rate of stress fractures, whereas prior participation in basketball was associated with a decreased risk of stress fractures. CONCLUSIONS: Prior fracture represents the most robust predictor of stress fractures in both sexes. Low body mass index, late menarche, and prior participation in gymnastics and dance are identifiable risk factors for stress fractures in girls. Participation in basketball appears protective in boys and may represent a modifiable risk factor for stress fractures. These findings may help guide future translational research and clinical care in the management and prevention of stress fractures in young runners.

Integrating stakeholder perspectives into the translation of cell-free fetal DNA testing for aneuploidy.

BACKGROUND: The translation of novel genomic technologies from bench to bedside enjoins the comprehensive consideration of the perspectives of all stakeholders who stand to influence, or be influenced by, the translational course. Non-invasive prenatal aneuploidy testing that utilizes cell-free fetal DNA (cffDNA) circulating in maternal blood is one example of an innovative technology that promises significant benefits for its intended end users; however, it is currently uncertain whether it will achieve widespread clinical implementation. We conducted qualitative interviews with 18 diverse stakeholders in this domain, including prospective users of the technology and healthcare personnel, researchers and developers, and experts in social, legal, and regulatory aspects of genetic technology, and a pilot survey of 62 obstetric healthcare providers. Analysis of interview and survey data was combined with a review of the proceedings of a full-day, multidisciplinary conference on the topic and published scientific and ethics literature surrounding this and other relevant technologies. DISCUSSION: We constructed potential pathways for technological implementation, identified broad stakeholder classes party to these translational processes, and performed a preliminary assessment of the viewpoints and interrelations among these diverse stakeholders. Some of the stakeholders whose priorities are critical to understand and integrate into translation include pregnant women and their families; healthcare providers; scientists, their institutions or companies, and the funding agencies that support them; regulatory and judicial bodies; third-party payers; professional societies; educational systems; disability rights communities; and other representatives from civil society. Stakeholder interviews, survey findings, and conference proceedings add complexity to these envisioned pathways and also demonstrate a paramount need to incorporate an iterative stakeholder analysis early and throughout the translational endeavor. We believe that the translational framework that we have developed will help guide crucial future stakeholder mapping and engagement activities for cffDNA aneuploidy testing and inform novel methods of technology assessment for other developments in the growing field of genomic medicine. SUMMARY: Mapping potential pathways for implementation and exploring the attitudes and interrelations of diverse stakeholders may lead to more effective translation of a novel method of prenatal aneuploidy testing.

In the public interest?

Restrictive patenting and licensing for cell-free fetal DNA testing has serious consequences for technology advances and benefits to public health.

Cell-free fetal nucleic acid testing: a review of the technology and its applications.

UNLABELLED: Cell-free fetal nucleic acids circulating in the blood of pregnant women afford the opportunity for early, noninvasive prenatal genetic testing. The predominance of admixed maternal genetic material in circulation demands innovative means for identification and analysis of cell-free fetal DNA and RNA. Techniques using polymerase chain reaction, mass spectrometry, and sequencing have been developed for the purposes of detecting fetal-specific sequences, such as paternally inherited or de novo mutations, or determining allelic balance or chromosome dosage. Clinical applications of these methods include fetal sex determination and blood group typing, which are currently available commercially although not offered routinely in the United States. Other uses of cell-free fetal DNA and RNA being explored are the detection of single-gene disorders, chromosomal abnormalities, and inheritance of parental polymorphisms across the whole fetal genome. The concentration of cell-free fetal DNA may also provide predictive capabilities for pregnancy-associated complications. The roles that cell-free fetal nucleic acid testing assume in the existing framework of prenatal screening and invasive diagnostic testing will depend on factors such as costs, clinical validity and utility, and perceived benefit-risk ratios for different applications. As cell-free fetal DNA and RNA testing continues to be developed and translated, significant ethical, legal, and social questions will arise that will need to be addressed by those with a stake in the use of this technology. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians Learning Objectives: After participating in this activity, physicians should be better able to evaluate techniques and tools for analyzing cell-free fetal nucleic acids, assess clinical applications of prenatal testing, using cell-free fetal nucleic acids and barriers to implementation, and distinguish between relevant clinical features of cell-free fetal nucleic acid testing and existing prenatal genetic screening and diagnostic procedures.

Overuse injuries in high school runners: lifetime prevalence and prevention strategies.

OBJECTIVE: To evaluate lifetime prevalence and risk factors for overuse injuries in high school athletes currently participating in long-distance running and provide recommendations for injury prevention strategies. DESIGN: Retrospective study design. SETTING: Twenty-eight high schools in the San Francisco Bay Area. PARTICIPANTS: A total of 442 female and 306 male athletes, ages 13-18 years, who are on cross-country and track and field teams. METHODS: Online survey with questions that detailed previous injuries sustained and risk factors for injury. MAIN OUTCOME MEASUREMENTS: Previous overuse injuries and association of risk factors to injury (including training variables, dietary patterns, and, in girls, menstrual irregularities). RESULTS: Previous injuries were reported by 68% of female subjects and 59% of male subjects. More injury types were seen in girls (1.2 ± 1.1 versus 1.0 ± 1.0, P < .01). Both genders had similar participation in running (2.5 ± 2.2 versus 2.3 ± 2.1 years), and previous injury prevalence followed a similar pattern: tibial stress injury (girls, 41%; boys, 34%), ankle sprain (girls, 32%; boys, 28%), patellofemoral pain (girls, 21%; boys, 16%), Achilles tendonitis (girls, 9%; boys, 6%), iliotibial band syndrome (girls, 7%; boys, 5%), and plantar fasciitis (girls, 5%; boys, 3%). Higher weekly mileage was associated with previous injuries in boys, (17.1 ± 11.9 versus 14.1 ± 11.5, P < .05) but not in girls (14.4 ± 10.2 versus 12.6 ± 11.8, not significant). A strong association between higher mileage and faster performances was seen in both groups. No association between previous injury and current dietary patterns (including disordered eating and calcium intake) or menstrual irregularities was seen. CONCLUSIONS: The majority of athletes currently participating in high school cross-country and track and field have a history of sustaining an overuse injury, with girls having a higher prevalence of injury. A modest mileage reduction may represent a modifiable risk factor for injury reduction. Future research is needed to evaluate the effects of incorporating a comprehensive strength training program on the prospective development of overuse injury and performance in this population.

Evaluating the relationship of calcium and vitamin D in the prevention of stress fracture injuries in the young athlete: a review of the literature.

Calcium and vitamin D are recognized as 2 components of nutrition needed to achieve and maintain bone health. Calcium and vitamin D have been clearly shown to improve bone density and prevent fractures at all ages. However, the literature is conflicting as to the role of these nutrients in young athletes ages 18 to 35 years, both for bone development and for the prevention of bone overuse injuries. Differences in findings may relate to study design. Although retrospective and cross-sectional studies have had mixed results, the authors of prospective studies have consistently demonstrated a relationship of increased calcium intake with an improvement in bone density and a decrease in fracture risk. A randomized trial in female military recruits demonstrated that calcium/vitamin D supplementation reduced the incidence of stress fractures. A prospective study in young female runners demonstrated reduced incidence of stress fractures and increased bone mineral density with increased dietary calcium intake. Findings from both studies suggest female athletes and military recruits who consumed greater than 1500 mg of calcium daily exhibited the largest reduction in stress fracture injuries. To date, no prospective studies have been conducted in male athletes or in adolescent athletes. In most studies, males and nonwhite participants were poorly represented. Evidence regarding the relationship of vitamin D intake with the prevention of fractures in athletes is also limited. More prospective studies are needed to evaluate the role of calcium and vitamin D intake in prevention of stress fracture injuries in both male and female adolescent athletes, particularly those participating in sports with greater incidences of stress fracture injury.