Attitudes and Knowledge of Maternal-Fetal Medicine Fellows Regarding Noninvasive Prenatal Testing.

Using cell-free DNA in maternal serum to detect fetal aneuploidy has been shown to have high sensitivity and specificity. The purpose of this study was to assess attitudes and knowledge of Maternal-Fetal Medicine (MFM) fellows regarding noninvasive prenatal testing (NIPT). A 13 question survey was sent via listserv to US-based MFM fellows. One hundred sixteen fellows responded, a 42.3% response rate, with >75% reporting they are comfortable ordering NIPT. Most (82%) preferred that a patient discuss options with a provider or genetic counselor. Three common methods used to learn about NIPT were: formal educational activities (n = 78, 69%), self-review of the literature (n = 76, 67%), and discussions with peers (n = 73, 65%). On questions related to trisomy 21, accuracy was >70%. However, accuracy was lower regarding use in twin pregnancies (42%) and monosomy X screening (50%).

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.

Optimizing preconception care and interventions for improved population health.

There is growing literature indicating that optimal preconception health is associated with improved reproductive, perinatal, and pediatric outcomes. Given that preconception care is recommended for all individuals planning a pregnancy, medical providers and public health practitioners have a unique opportunity to optimize care and improve health outcomes for reproductive-aged individuals. Knowledge of the determinants of preconception health is important for all types of health professionals, including policy makers. Although some evidence-based recommendations have already been implemented, additional research is needed to identify factors associated with favorable health outcomes and to ensure that effective interventions are made in a timely fashion. Given the largely clinical readership of this journal, this piece is primarily focused on clinical care. However, we acknowledge that optimizing preconception health for the entire population at risk of pregnancy requires broadening our strategies to include population-health interventions that consider the larger social systems, structures, and policies that shape individual health outcomes.

A Rare Case of Obstructive Shock due to Cardiac Tamponade in a Term Pregnancy.

Obstructive shock due to cardiac tamponade is a rare, life-threatening occurrence in the peripartum period. Etiologies include preeclampsia, infection, autoimmune conditions, and malignancy. Early recognition of the underlying disease process allows for multidisciplinary treatment and a favorable outcome. A 33-year-old presented for cardiac tamponade identified in the peripartum period. She was diagnosed with preeclampsia with severe features immediately prior to her repeat cesarean delivery and received magnesium prophylaxis. Postoperatively, she developed hypotension, tachycardia, and shortness of breath and was found to have a pericardial effusion with tamponade physiology. She underwent pericardial drain placement which was initially successful. However, she had recurrent symptomatic tamponade and thus a pericardial window was performed resulting in improvement of her symptoms. Workup revealed pericardial inflammation possibly secondary to a viral source, and she was successfully treated with anti-inflammatory therapy. We hypothesize that this patient's cardiac tamponade was caused by inflammatory pericarditis exacerbated by severe preeclampsia. Preeclampsia is a disease characterized by cardiovascular remodeling and fluid shifts in other compartments and thus is theorized to have contributed to this patient's effusion. Cardiac tamponade should be considered in the differential for any parturient presenting with hypotension and shortness of breath.

Angiogenic Function of Human Placental Endothelial Cells in Severe Fetal Growth Restriction Is Not Rescued by Individual Extracellular Matrix Proteins.

Severe fetal growth restriction (FGR) is characterized by increased placental vascular resistance resulting from aberrant angiogenesis. Interactions between endothelial cells (ECs) and the extracellular matrix (ECM) are critical to the complex process of angiogenesis. We have previously found that placental stromal abnormalities contribute to impaired angiogenesis in severe FGR. The objective of this research is to better characterize the effect of individual ECM proteins on placental angiogenic properties in the setting of severe FGR. ECs were isolated from human placentae, either control or affected by severe FGR, and subjected to a series of experiments to interrogate the role of ECM proteins on adhesion, proliferation, migration, and apoptosis. We found impaired proliferation and migration of growth-restricted ECs. Although individual substrates did not substantially impact migratory capacity, collagens I, III, and IV partially mitigated proliferative defects seen in FGR ECs. Differences in adhesion and apoptosis between control and FGR ECs were not evident. Our findings demonstrate that placental angiogenic defects that characterize severe FGR cannot be explained by a singular ECM protein, but rather, the placental stroma as a whole. Further investigation of the effects of stromal composition, architecture, stiffness, growth factor sequestration, and capacity for remodeling is essential to better understand the role of ECM in impaired angiogenesis in severe FGR.

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.

Contemporary Understanding of Ebola and Zika Virus in Pregnancy.

Understanding the pathophysiology, management, and prevention of emerging infectious diseases among pregnant women is imperative to achieve a successful response from the medical community. Ebola and Zika viruses represent infections with profound public health implications. In particular, Ebola virus is associated with high case fatality and pregnancy and neonatal loss rates, while Zika virus has been associated with multiple congenital anomalies; these features present critical clinical dilemmas for management of pregnant and reproductive aged women. The objective of this article is to summarize key background information and best practices for management of Ebola and Zika virus in pregnancy.

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.

Tocolysis: A Review of the Literature.

IMPORTANCE: Preterm delivery represents an important cause of infant morbidity and mortality. Various tocolytics have been studied with the objective of stopping preterm labor, increasing gestational age at delivery, and preventing complications related to preterm birth. OBJECTIVE: This review aims to summarize the major classes of tocolytics and review the evidence regarding use of each. EVIDENCE ACQUISITION: A PubMed search of the following terms was performed to gather relevant data: "tocolytic," "preterm labor," "preterm delivery," "PPROM," "magnesium," "indomethacin," "nifedipine," and "betamimetics." RESULTS: The benefits and risks of nonsteroid anti-inflammatory drugs, calcium channel blockers, magnesium, and betamimetics are reviewed. Calcium channel blockers afford superior outcomes in terms of prolonging gestation and decreasing neonatal morbidity and mortality with the fewest adverse effects. CONCLUSIONS AND RELEVANCE: Tocolytics, particularly calcium channel blockers, may provide benefit to pregnant women and their infants. Their use should be tailored to the particular clinical circumstances of the patient and used in conjunction with other management strategies (e.g., administration of corticosteroids for fetal lung maturation or magnesium for neuroprotection and transfer to a tertiary medical center). Further research and professional guidelines are needed on optimal use of these agents.

Participation in ball sports may represent a prehabilitation strategy to prevent future stress fractures and promote bone health in young athletes.

Sports participation has many benefits for the young athlete, including improved bone health. However, a subset of athletes may attain suboptimal bone health and be at increased risk for stress fractures. This risk is greater for female than for male athletes. In healthy children, high-impact physical activity has been shown to improve bone health during growth and development. We offer our perspective on the importance of promoting high-impact, multidirectional loading activities, including ball sports, as a method of enhancing bone quality and fracture prevention based on collective research. Ball sports have been associated with greater bone mineral density and enhanced bone geometric properties compared with participation in repetitive, low-impact sports such as distance running or nonimpact sports such as swimming. Runners and infantry who participated in ball sports during childhood were at decreased risk of future stress fractures. Gender-specific differences, including the coexistence of female athlete triad, may negate the benefits of previous ball sports on fracture prevention. Ball sports involve multidirectional loading with high ground reaction forces that may result in stiffer and more fracture-resistant bones. Encouraging young athletes to participate in ball sports may optimize bone health in the setting of adequate nutrition and in female athletes, eumenorrhea. Future research to determine timing, frequency, and type of loading activity could result in a primary prevention program for stress fracture injuries and improved life-long bone health.

"Don't Want No Risk and Don't Want No Problems": Public Understandings of the Risks and Benefits of Non-Invasive Prenatal Testing in the United States.

BACKGROUND: The recent availability of new non-invasive prenatal genetic tests for fetal aneuploidy has raised questions concerning whether and how these new tests will be integrated into prenatal medical care. Among the many factors to be considered are public understandings and preferences about prenatal testing mechanisms and the prospect of fetal aneuploidy. METHODS: To address these issues, we conducted a nation-wide mixed-method survey of 2,960 adults in the United States to explore justifications for choices among prenatal testing mechanisms. Open responses were qualitatively coded and grouped by theme. RESULTS: Respondents cited accuracy, followed by cost, as the most significant aspects of prenatal testing. Acceptance of testing was predicated on differing valuations of knowledge and on personal and religious beliefs. Trust in the medical establishment, attitudes towards risk, and beliefs about health and illness were also considered relevant. CONCLUSIONS: Although a significant portion of the sample population valued the additional accuracy provided by the new non-invasive tests, they nevertheless expressed concerns over high costs. Furthermore, participants continued to express reservations about the value of prenatal genetic information per se, regardless of how it was obtained.

Identifying sex-specific risk factors for low bone mineral density in adolescent runners.

BACKGROUND: Adolescent runners may be at risk for low bone mineral density (BMD) associated with sports participation. Few prior investigations have evaluated bone health in young runners, particularly males. PURPOSE: To characterize sex-specific risk factors for low BMD in adolescent runners. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Training characteristics, fracture history, eating behaviors and attitudes, and menstrual history were measured using online questionnaires. A food frequency questionnaire was used to identify dietary patterns and measure calcium intake. Runners (female: n = 94, male: n = 42) completed dual-energy x-ray absorptiometry (DXA) to measure lumbar spine (LS) and total body less head (TBLH) BMD and body composition values, including android-to-gynoid (A:G) fat mass ratio. The BMD was standardized to Z-scores using age, sex, and race/ethnicity reference values. Questionnaire values were combined with DXA values to determine risk factors associated with differences in BMD Z-scores in LS and TBLH and low bone mass (defined as BMD Z-score ≤-1). RESULTS: In multivariable analyses, risk factors for lower LS BMD Z-scores in girls included lower A:G ratio, being shorter, and the combination of (interaction between) current menstrual irregularity and a history of fracture (all P < .01). Later age of menarche, lower A:G ratio, lower lean mass, and drinking less milk were associated with lower TBLH BMD Z-scores (P < .01). In boys, lower body mass index (BMI) Z-scores and the belief that being thinner improves performance were associated with lower LS and TBLH BMD Z-scores (all P < .05); lower A:G ratio was additionally associated with lower TBLH Z-scores (P < .01). Thirteen girls (14%) and 9 boys (21%) had low bone mass. Girls with a BMI ≤17.5 kg/m(2) or both menstrual irregularity and a history of fracture were significantly more likely to have low bone mass. Boys with a BMI ≤17.5 kg/m(2) and belief that thinness improves performance were significantly more likely to have low bone mass. CONCLUSION: This study identified sex-specific risk factors for impaired bone mass in adolescent runners. These risk factors can be helpful to guide sports medicine professionals in evaluation and management of young runners at risk for impaired bone health.

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.