A pediatric virtual care evaluation framework and its evolution using consensus methods.

BACKGROUND: The use of virtual care has increased dramatically in response to the COVID-19 pandemic, yet evidence is lacking regarding the impact of virtual care on patient outcomes, particularly in pediatrics. A standardized evaluation approach is required to support the integration of virtual care into pediatric health care delivery programs. The objective of this work was to develop a comprehensive and structured framework for pediatric virtual care evaluation. This framework is intended to engage and guide care providers, health centres, and stakeholders towards the development of a standardized approach to the evaluation of pediatric virtual care. METHODS: We brought together a diverse multidisciplinary team, including pediatric clinicians, researchers, digital health leads and analysts, program leaders, a human factors engineer, a family advisor and our manager of health equity and diversity. The team reviewed the literature, including published evaluation frameworks, and used a consensus-based method to develop a virtual care evaluation framework applicable to a broad spectrum of pediatric virtual care programs. We used an iterative process to develop framework components, including domains and sub-domains, examples of evaluation questions, measures, and data sources. Team members met repeatedly over seven months to generate and provide feedback on all components of the framework, making revision as needed until consensus was reached. The framework was then applied to an existing virtual care program. RESULTS: The resulting framework includes four domains (health outcomes, health delivery, individual experience, and program implementation) and 19 sub-domains designed to support the development and evaluation of pediatric virtual care programs. We also developed guidance on how to use the framework and illustrate its utility by applying it to an existing pediatric virtual care program. CONCLUSIONS: This virtual care evaluation framework expands on previously developed frameworks by providing additional detail and a structure that supports practical application. It can be used to evaluate a wide range of pediatric virtual care programs in a standardized manner. Use of this comprehensive yet easy to use evaluation framework will inform appropriate implementation and integration of virtual care into routine practice and support its sustainability and continuous improvement.

First and second trimester maternal serum markers for prenatal aneuploidy screening: An update on the adjustment factors for race, smoking, and insulin dependent diabetes mellitus.

OBJECTIVES: The concentrations of maternal serum markers for aneuploidy screening are influenced by maternal characteristics such as race, smoking, insulin dependent diabetes mellitus (IDDM), and in vitro fertilization (IVF). Accurate risk estimation requires adjustment of initial values for these characteristics. This study aims to update and validate adjustment factors for race, smoking, and IDDM. METHODS: The study included singleton pregnancies that received multiple marker screening in Ontario, Canada between January 2012, and December 2018, and had their information collected in the Better Outcomes Registry & Network (BORN) Ontario. Serum markers assessed included first trimester pregnancy-associated plasma protein A (PAPP-A), free ß and total human chorionic gonadotropin (hCG), placental growth factor (PlGF) and αlpha-fetoprotein (AFP); second trimester AFP, unconjugated estriol (uE3), total hCG and inhibin A. The Mann-Whitney U test was used to assess the differences in the median multiple of the median (MoM) of serum markers between study and reference groups. New adjustment factors were generated by dividing the median MoM of a particular race, individuals who smoke tobacco, or have IDDM by those of the reference groups. RESULTS: The study included 624,789 pregnancies. There were statistically significant differences in serum marker concentrations among pregnant individuals who were Black, Asian, or First Nations compared to a White group, those who smoked compared to Non-smoking individuals, and those with IDDM compared to Non-IDDM group. New adjustment factors for race, smoking, and IDDM were validated by comparing median MoM of serum markers corrected using the current adjustment factors and new adjustment factors generated in this study. CONCLUSION: The adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

Genetic and metabolic investigations for neurodevelopmental disorders: position statement of the Canadian College of Medical Geneticists (CCMG).

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist. METHODS OF STATEMENT DEVELOPMENT: A multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and to the Canadian Pediatric Society (Mental Health and Developmental Disabilities Committee); following incorporation of feedback, it was approved by the CCMG Board of Directors on 1 September 2022. RESULTS AND CONCLUSIONS: Chromosomal microarray is recommended as a first-tier test for patients with GDD, ID or ASD. Fragile X testing should also be done as a first-tier test when there are suggestive clinical features or family history. Metabolic investigations should be done if there are clinical features suggestive of an inherited metabolic disease, while the patient awaits consultation with a metabolic physician. Exome sequencing or a comprehensive gene panel is recommended as a second-tier test for patients with GDD or ID. Genetic testing is not recommended for patients with NDDs in the absence of GDD, ID or ASD, unless accompanied by clinical features suggestive of a syndromic aetiology or inherited metabolic disease.

Cytogenetic outcomes following a failed cell-free DNA screen: a population-based retrospective cohort study of 35,146 singleton pregnancies.

BACKGROUND: Cell-free fetal DNA screening is routinely offered to pregnant individuals to screen for aneuploidies. Although cell-free DNA screening is consistently more accurate than multiple-marker screening, it sometimes fails to yield a result. These test failures and their clinical implications are poorly described in the literature. Some studies suggest that a failed cell-free DNA screening result is associated with increased likelihood of cytogenetic abnormalities. OBJECTIVE: This study aimed to assess the association between a failed cell-free DNA test and common aneuploidies. The objectives were to determine: (1) the proportion of test failures on first and subsequent attempts, and (2) whether a failed cell-free DNA screen on first attempt is associated with increased likelihood of common aneuploidies (trisomies 21, 18, and 13, and sex chromosome aneuploidies). STUDY DESIGN: This was a population-based retrospective cohort study using data from Ontario's prescribed maternal and child registry, Better Outcomes Registry and Network Ontario. The study included all singleton pregnancies in Ontario with an estimated date of delivery from September 1, 2016 to March 31, 2019 that had a cell-free DNA screening record in the registry. Specific outcomes (trisomies 21, 18, and 13, and sex chromosome aneuploidies) of pregnancies with a failed cell-free DNA screen on first attempt were compared with those of pregnancies with low-risk cell-free DNA-screening results using modified Poisson regression adjusted for funding status (publicly funded vs self-paid), gestational age at screening, method of conception, and maternal age for autosomal aneuploidies. RESULTS: Our cohort included 35,146 pregnancies that had cell-free DNA screening during the study period. The overall cell-free DNA screening failure rate was 4.8% on first attempt and 2.2% after multiple attempts. An abnormal cytogenetic result for trisomies 21, 18, and 13, or sex chromosome aneuploidies was identified in 19.4% of pregnancies with a failed cell-free DNA screening for which cytogenetic testing was performed. Pregnancies with a failed cell-free DNA screen on first attempt had a relative risk of 130.3 (95% confidence interval, 64.7-262.6) for trisomy 21, trisomy 18, or trisomy 13, and a risk difference of 5.4% (95% confidence interval, 2.6-8.3), compared with pregnancies with a low-risk result. The risk of sex chromosome aneuploidies was not significantly greater in pregnancies with a failed result compared with pregnancies with a low-risk result (relative risk, 2.7; 95% confidence interval, 0.9-7.9; relative difference, 1.2%; 95% confidence interval, -0.9 to 3.2). CONCLUSION: Cell-free DNA screening test failures are relatively common. Although repeated testing improves the likelihood of an informative result, pregnancies with a failed cell-free DNA screen upon first attempt remain at increased risk for common autosomal aneuploidies, but not sex chromosome aneuploidies.

Care4Rare Canada: Outcomes from a decade of network science for rare disease gene discovery.

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs. We achieved a diagnostic yield of 34% (623/1,806 of participating families), including the discovery of deleterious variants in 121 genes not previously associated with disease, and we continue to study candidate variants in novel genes for 145 families. The Consortium has made significant contributions to RD research, including development of platforms for data collection and sharing and instigating a Canadian network to catalyze functional characterization research of novel genes. The Consortium was instrumental to implementing genome-wide sequencing as a publicly funded test for RD diagnosis in Canada. Despite the successes of the past decade, the challenge of solving all RDs remains enormous, and the work is far from over. We must leverage clinical and 'omic data for secondary use, develop tools and policies to support safe data sharing, continue to explore the utility of new and emerging technologies, and optimize research protocols to delineate complex disease mechanisms. Successful approaches in each of these realms is required to offer diagnostic clarity to all families with RDs.

Performance of a universal prenatal screening program incorporating cell-free fetal DNA analysis in Ontario, Canada.

BACKGROUND: The emergence of cell-free fetal DNA (cfDNA) testing technology has disrupted the landscape of prenatal screening for trisomies 21 (T21) and 18 (T18). Publicly funded systems around the world are grappling with how to best integrate this more accurate but costly technology, as there is limited evidence about its incremental value in real-world conditions. The objectives of this study were to describe the population-based performance of Ontario's prenatal screening program, which incorporates publicly funded cfDNA screening for specific indications, and the effect of cfDNA testing on the screening and diagnostic choices made by pregnant people. METHODS: We conducted a retrospective, descriptive cohort study using routinely collected data from Better Outcomes & Registry Network (BORN) Ontario, which captures linked population data for prenatal and neonatal health encounters across Ontario. We included all singleton pregnancies with an estimated due date between Sept. 1, 2016, and Mar. 31, 2019, that underwent publicly funded prenatal screening in Ontario, and a comparison cohort from Apr. 1, 2012, and Mar. 31, 2013. We assessed performance of the screening program for the detection of T21 or T18 by calculating sensitivity, specificity, positive predictive value and negative predictive value against diagnostic cytogenetic results or birth outcomes. We assessed the impact of the program by calculating the proportion of T21 screen-positive pregnancies undergoing subsequent cfDNA screening and invasive prenatal diagnostic testing. RESULTS: The study cohort included 373 682 pregnancies. The prenatal screening program had an uptake of 69.9%, a screen-positive rate and sensitivity of 1.6% and 89.9% for T21, and 0.2% and 80.5% for T18, respectively. The test failure rate for cfDNA screening was 2.2%. Invasive prenatal diagnostic testing decreased from 4.4% in 2012-2013 to 2.4% over the study period; 65.2% of pregnant people who received a screen-positive result from cfDNA testing went on to have invasive prenatal diagnostic testing. INTERPRETATION: This publicly funded screening program, incorporating cfDNA analysis for common aneuploidies, showed robust performance, a substantial reduction in invasive prenatal diagnostic testing and that pregnant people exercise autonomy in their choices about prenatal screening and diagnosis.

New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases.

Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale.

The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms.

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs). The Network is built around a registry of more than 500 Canadian MO scientists, representing expertise for over 7,500 human genes. RDMM uses a committee process to identify and evaluate clinician-MO scientist collaborations and approve 25,000 Canadian dollars in catalyst funding. To date, we have made 85 clinician-MO scientist connections and funded 105 projects. These collaborations help confirm variant pathogenicity and unravel the molecular mechanisms of RD, and also test novel therapies and lead to long-term collaborations. To expand the impact and reach of this model, we made the RDMM Registry open-source, portable, and customizable, and we freely share our committee structures and processes. We are currently working with emerging networks in Europe, Australia, and Japan to link international RDMM networks and registries and enable matches across borders. We will continue to create meaningful collaborations, generate knowledge, and advance RD research locally and globally for the benefit of patients and families living with RD.

Direct health-care costs for children diagnosed with genetic diseases are significantly higher than for children with other chronic diseases.

PURPOSE: We aimed to estimate direct health-care costs and physician utilization for a cohort of children diagnosed with genetic diseases. METHODS: Retrospective cohort study using population-based provincial health administrative data for children with genetic diseases (n = 255) compared with three matched cohorts (asthma n = 1275, diabetes n = 255, general population n = 1275). We estimated direct health-care costs and resource use 5 years after diagnosis in five categories: physician billing, same day surgery, emergency, inpatient hospitalizations, and home care. RESULTS: During the postdiagnostic period, annual mean total costs for the genetic disease cohort were significantly higher than all other cohorts. Annual mean total costs for all cohorts were highest in the year after diagnosis with costs for the genetic disease cohort between 4.54 and 19.76 times higher during the 5 years. Inpatient hospitalizations and physician billing accounted for the majority of costs. The genetic disease cohort received more care from specialists, whereas the chronic disease cohorts received more care from general practitioners. CONCLUSION: Direct health-care costs for children with genetic diseases are significantly higher than children with/without a chronic disease, particularly in the year after diagnosis. These findings are important when considering resource allocation and funding prioritization for children with genetic diseases.

Nablus syndrome: Easy to diagnose yet difficult to solve.

Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.

'Not another safety culture survey': using the Canadian patient safety climate survey (Can-PSCS) to measure provider perceptions of PSC across health settings.

BACKGROUND: The importance of a strong safety culture for enhancing patient safety has been stated for over a decade in healthcare. However, this complex construct continues to face definitional and measurement challenges. Continuing improvements in the measurement of this construct are necessary for enhancing the utility of patient safety climate surveys (PSCS) in research and in practice. This study examines the revised Canadian PSCS (Can-PSCS) for use across a range of care settings. METHODS: Confirmatory factor analytical approaches are used to extensively test the Can-PSCS. Initial and cross-validation samples include 13 126 and 6324 direct care providers from 119 and 35 health settings across Canada, respectively. RESULTS: Results support a parsimonious model of direct care provider perceptions of patient safety climate (PSC) with 19 items in six dimensions: (1) organisational leadership support for safety; (2) incident follow-up; (3) supervisory leadership for safety; (4) unit learning culture; (5) enabling open communication I: judgement-free environment; (6) enabling open communication II: job repercussions of error. Results also support the validity of the Can-PSCS across a range of care settings. CONCLUSIONS: The Can-PSCS has several advantages: (1) it is a theory-based instrument with a small number of actionable dimensions central to the construct of PSC; (2) it has robust psychometric properties; (3) it is validated for use across a range of care settings, therefore suitable for use in regionalised health delivery systems and can help to raise expectations about acceptable levels of PSC across the system; (4) it has been tested in a publicly funded universal health insurance system and may be suitable for similar international systems.

Exploring informed choice in the context of prenatal testing: findings from a qualitative study.

PURPOSE: This study explored whether and how a sample of women made informed choices about prenatal testing for foetal anomalies; its aim was to provide insights for future health policy and service provision. METHODS: We conducted semi-structured interviews with 38 mothers in Ottawa, Ontario, all of whom had been offered prenatal tests in at least one pregnancy. Using the Multi-dimensional Measure of Informed Choice as a general guide to analysis, we explored themes relevant to informed choice, including values and knowledge, and interactions with health professionals. RESULTS: Many, but not all, participants seemed to have made informed decisions about prenatal testing. Values and knowledge were interrelated and important components of informed choice, but the way they were discussed differed from the way they have been presented in scientific literature. In particular, 'values' related to expressions of women's moral views or ideas about 'how life should be lived' and 'knowledge' related to the ways in which women prioritized and interpreted factual information, through their own and others' experiences and in 'thinking through' the personal implications of testing. While some women described non-directive discussions with health professionals, others perceived testing as routine or felt pressured to accept it. CONCLUSIONS: Our findings suggest a need for maternity care providers to be vigilant in promoting active decision making about prenatal testing, particularly around the consideration of personal implications. Further development of measures of informed choice may be necessary to fully evaluate decision support tools and to determine whether prenatal testing programmes are meeting their objectives.

The influence of experiential knowledge on prenatal screening and testing decisions.

Minimal research focuses on the process of decision making in the context of prenatal screening and testing. This paper outlines an important contextual influence on these decisions. Specifically, we propose that experiential knowledge, particularly about pregnancy, screening, and disability, has a significant influence on prenatal screening and testing decisions. Drawing upon 38 semistructured interviews with women, this study explored how women made prenatal screening and testing decisions. Qualitative data analysis revealed two types of experiential knowledge, empathetic and embodied, which played a pivotal role in women's thinking about the value of prenatal tests and whether or not they accepted the offer of screening, testing, or both. We conclude that prenatal genetic counseling could benefit from an exploration of clients' experiential knowledge, both empathetic and embodied forms.

A systematic review of perceived risks, psychological and behavioral impacts of genetic testing.

Genetic testing may enable early disease detection, targeted surveillance, and result in effective prevention strategies. Knowledge of genetic risk may also enable behavioral change. However, the impact of carrier status from the psychological, behavior, and perceived risk perspectives is not well understood. We conducted a systematic review to summarize the available literature on these elements. An extensive literature review was performed to identify studies that measured the perceived risk, psychological, and/or behavioral impacts of genetic testing on individuals. The search was not limited to specific diseases but excluded the impacts of testing for single gene disorders. A total of 35 articles and 30 studies were included. The studies evaluated hereditary nonpolyposis colorectal carcinoma, hereditary breast and ovarian cancer, and Alzheimer disease. For affective outcomes, the majority of the studies reported negative effects on carriers but these were short-lived. For behavioral outcomes, an increase in screening behavior of varying rates was demonstrated in carriers but the change in behaviors was less than expected. With respect to perceived risk, there were generally no differences between carriers and noncarriers by 12 months after genetic testing and over time risk perception decreased. Overall, predispositional genetic testing has no significant impact on psychological outcomes, little effect on behavior, and did not change perceived risk. It seems as though better patient education strategies are required. Our data would suggest better knowledge among carriers would not have significant psychological impacts and therefore, it is worth pursuing improved educational strategies.

Clinical management recommendations for surveillance and risk-reduction strategies for hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation.

BACKGROUND: In Canada, there are wide variations in services for patients at risk for hereditary breast and ovarian cancer (HBOC), and clinical interventions and recommendations differ between regions and/or provinces. National strategies for the clinical management of HBOC exist in the United Kingdom, France, and Australia, and clinical programs in Canada would benefit from similar national recommendations and a consistent approach to clinical management. The National Hereditary Cancer Task Force developed recommendations to address the clinical management of patients at high risk of HBOC and related cancers. These recommendations are based on current practice in high-risk cancer clinics that provide care for individuals with known BRCA1 or BRCA2 mutations. METHODS: Canadian consensus recommendations were generated by the National Hereditary Cancer Task Force and compared mainly with two recently published guidance documents on the clinical management of women with increased risk of HBOC, one from the United Kingdom and the other from France. After review of these documents and the associated supporting scientific evidence, the Canadian consensus recommendations were modified and rated using predefined criteria. CONCLUSIONS: These recommendations pertain to (1) surveillance options including breast self-examination, clinical breast examination, breast surveillance by imaging, ovarian cancer surveillance, and surveillance for men; (2) risk-reduction strategies including prophylactic mastectomy, prophylactic salpingo-oophorectomy, and pharmacoprevention; and (3) the use of exogenous hormones. Regular updates should occur as new evidence becomes available.

Pelvic magnetic resonance venography reveals high rate of pelvic vein thrombosis after cesarean section.

In the run-in phase of a thromboprophylactic trial in women at moderate to high risk of deep vein thrombosis postcesarean section, we used magnetic resonance venography and found a surprisingly high rate of pelvic deep vein thrombosis (46% overall). Pelvic magnetic resonance venography may be a useful surrogate outcome in obstetric thromboprophylaxis studies but the clinical significance is not known.

The interobserver reliability of pretest probability assessment in patients with suspected pulmonary embolism.

INTRODUCTION: Pretest probability assessment and objective testing are combined to appropriately manage patients with suspected pulmonary embolism (PE). However, the interobserver reliability of pretest probability assessment has not been investigated. We sought to determine (for patients with suspected PE) the interobserver reliability of pretest probability assessment (by overall impression (gestalt) versus an explicit clinical model). MATERIALS AND METHODS: A prospective cohort study was conducted at an urban university hospital. For patients referred for ventilation and perfusion (V/Q) scanning for suspected PE, structured assessments (11 history and 4 physical examination parameters) were performed by a referring physician and a designated thrombosis physician. The referring and thrombosis physicians also assigned a pretest probability for PE (low, moderate, or high) by gestalt. An explicit seven-point clinical model for suspected PE was later applied to each structured assessment to determine the pretest probability. Assessments were performed independently and prior to diagnostic test results. Interobserver reliability (two rater unweighted Kappa (kappa) statistic) was determined for each parameter on the structured assessment and the pretest probability assessments (gestalt vs. explicit clinical model). RESULTS: One hundred and ten patients with suspected PE received duplicate assessments. Historical features demonstrated substantial to almost perfect interobserver reliability (kappa=0.60-0.95). For the physical findings, only heart rate had substantial interobserver reliability (kappa=0.60). Pretest probability assessment was not reliable when using physician's gestalt (kappa=0.33), but produced substantial interobserver reliability using the explicit clinical model (kappa=0.62). CONCLUSIONS: Given the inadequate interobserver reliability of pretest probability assessment by overall impression (or gestalt), physicians should use explicit clinical models in the diagnostic management of patients with suspected pulmonary embolism.

A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction.

OBJECTIVE: The purpose of this study was to conduct a systematic review of the literature of studies that examined the association between factor V Leiden and/or prothrombin gene variant and intrauterine growth restriction. STUDY DESIGN: This systematic review of studies assesses the association between factor V Leiden and/or prothrombin gene variant and intrauterine growth restriction. RESULTS: Ten case-control studies fulfilled the selection criteria for inclusion in the meta-analysis. There was a significant association between factor V Leiden and intrauterine growth restriction (odds ratio, 2.7; 95% CI, 1.3-5.5) and prothrombin gene variant and intrauterine growth restriction (odds ratio, 2.5; 95% CI, 1.3-5.0). Five cohort studies were identified in the systematic review; 3 studies were prospective (2 full publications), and 2 studies were retrospective (1 full publication). Combining the 2 full publication prospective studies yields a summary relative risk of 0.99 (95% CI, 0.5-1.9). CONCLUSION: This meta-analysis of case-control studies suggests that the factor V Leiden and prothrombin gene variant both confer an increased risk of giving birth to an intrauterine growth restricted infant, although this may be driven by small, poor-quality studies that demonstrated extreme associations. Large well-conducted prospective cohort studies are required to determine definitively whether an association between thrombophilia and intrauterine growth restriction is present.

The outpatient treatment of deep vein thrombosis delivers cost savings to patients and their families, compared to inpatient therapy.

BACKGROUND: The outpatient treatment of deep vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) has been shown to be cost-effective from the perspective of a third party payer. The aim of this study is to determine if some or all of these cost savings to third party payers are shifted to patients and their families. METHODS: A prospective cohort study with micro-costing of patient/family costs was conducted at the thrombosis units of The Ottawa Hospital. Costs were determined by administering a questionnaire at the end of the patients' heparin therapy. Over a period of 4 months, consecutive patients presenting at the thrombosis units were approached at the initiation of their heparin therapy; 44 patients consented to participate and completed questionnaires were obtained for 41. RESULTS: The mean patient/family costs associated with outpatient therapy were significantly less than those associated with inpatient therapy (219.42 dollars versus 402.93 dollars, p=0.003); a savings of 190.91 dollars per patient. Even when lost income to patients/families was ignored, mean patient/family costs remained significantly less for outpatient therapy (72.00 dollars versus 134.29 dollars, p=0.004); a savings of 62.30 dollars per patient. Furthermore, patients preferred outpatient to inpatient therapy by almost 3:1 (30 versus 11, respectively). INTERPRETATION: The outpatient treatment of DVT does not result in any net shifting of costs to patients and their families, and further, brings about cost savings. Given the cost savings associated with and the preference of patients for outpatient care, this study further supports the shift of DVT therapy from the inpatient unit to the outpatient clinic.