The challenge of choosing in cardiovascular risk management.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have broadened the options for state-of-the-art CV risk management (CVRM). In the majority of patients with CVD, risk lowering can be achieved by utilising standard preventive medication combined with lifestyle modifications. In a minority of patients, add-on therapies should be considered to further reduce the large residual CV risk. However, the choice of which drug combination to prescribe and in which patients has become increasingly complicated, and is dependent on both the absolute CV risk and the reason for the high risk. In this review, we discuss therapeutic decisions in CVRM, focusing on (1) the absolute CV risk of the patient and (2) the pros and cons of novel treatment options.

Major threats to early safety after transcatheter aortic valve implantation in a contemporary cohort of real-world patients.

INTRODUCTION: Despite considerable advances in the last decade, major adverse events remain a concern after transcatheter aortic valve implantation (TAVI). The aim of this study was to provide a detailed overview of their underlying causes and contributing factors in order to identify key domains for quality improvement. METHODS: This observational, prospective registry included all patients undergoing TAVI between 31 December 2015 and 1 January 2020 at the St. Antonius Hospital in Nieuwegein and the University Medical Centre in Utrecht. Outcomes of interest were all-cause mortality, stroke, major bleeding, life-threatening or disabling bleeding, major vascular complications, myocardial infarction, severe acute kidney injury and conduction disturbances requiring permanent pacemaker implantation within 30 days after TAVI, according to the Valve Academic Research Consortium­2 criteria. RESULTS: Of the 1250 patients who underwent TAVI in the evaluated period, 146 (11.7%) developed a major complication. In 54 (4.3%) patients a thromboembolic event occurred, leading to stroke in 36 (2.9%), myocardial infarction in 13 (1.0%) and lower limb ischaemia in 11 (0.9%). Major bleeding occurred in 65 (5.2%) patients, most frequently consisting of acute cardiac tamponade (n = 25; 2.0%) and major access-site bleeding (n = 21; 1.7%). Most complications occurred within 1 day of the procedure. Within 30 days a total of 54 (4.3%) patients died, the cause being directly TAVI-related in 30 (2.4%). Of the patients who died from causes that were not directly TAVI-related, 14 (1.1%) had multiple hospital-acquired complications. CONCLUSION: A variety of underlying mechanisms and causes form a wide spectrum of major threats affecting early safety in 11.7% of patients undergoing TAVI in a contemporary cohort of real-world patients.

Transcatheter aortic valve replacement: impact of pre-procedural FEops HEARTguide assessment on device size selection in borderline annulus size cases.

OBJECTIVES: The aim of this study is to evaluate device size selection in patients within the borderline annulus size range undergoing transcatheter aortic valve replacement (TAVR) and to assess if pre-procedural patient-specific computer simulation will lead to the selection of a different device size than standard of care. BACKGROUND: In TAVR, appropriate device sizing is imperative. In borderline annulus size cases no standardised technique for tailored device size selection is currently available. Pre-procedural patient-specific computer simulation can be used, predicting the risk for paravalvular leakage (PVL) and need for permanent pacemaker implantation (PPI). METHODS: In this multicentre retrospective study, 140 patients in the borderline annulus size range were included. Hereafter, device size selection was left to the discretion of the operator. After TAVR, in 24 of the 140 patients, patient-specific computer simulation calculated the most appropriate device size expected to give the lowest risk for PVL and need for PPI. In these 24 patients, device size selection based on patient-specific computer simulation was compared with standard-of-care device size selection relying on a standardised matrix (Medtronic). RESULTS: In a significant proportion of the 140 patients (26.4%) a different device size than recommended by the matrix was implanted. In 10 of the 24 patients (41.7%) in whom a computer simulation was performed, a different device size was recommended than by means of the matrix. CONCLUSIONS: Device size selection in patients within the borderline annulus size range is still ambiguous. In these patients, patient-specific computer simulation is feasible and can contribute to a more tailored device size selection.

Gamification of health professions education: a systematic review.

Gamification refers to using game attributes in a non-gaming context. Health professions educators increasingly turn to gamification to optimize students' learning outcomes. However, little is known about the concept of gamification and its possible working mechanisms. This review focused on empirical evidence for the effectiveness of gamification approaches and theoretical rationales for applying the chosen game attributes. We systematically searched multiple databases, and included all empirical studies evaluating the use of game attributes in health professions education. Of 5044 articles initially identified, 44 met the inclusion criteria. Negative outcomes for using gamification were not reported. Almost all studies included assessment attributes (n = 40), mostly in combination with conflict/challenge attributes (n = 27). Eight studies revealed that this specific combination had increased the use of the learning material, sometimes leading to improved learning outcomes. A relatively small number of studies was performed to explain mechanisms underlying the use of game attributes (n = 7). Our findings suggest that it is possible to improve learning outcomes in health professions education by using gamification, especially when employing game attributes that improve learning behaviours and attitudes towards learning. However, most studies lacked well-defined control groups and did not apply and/or report theory to understand underlying processes. Future research should clarify mechanisms underlying gamified educational interventions and explore theories that could explain the effects of these interventions on learning outcomes, using well-defined control groups, in a longitudinal way. In doing so, we can build on existing theories and gain a practical and comprehensive understanding of how to select the right game elements for the right educational context and the right type of student.

Incidence and outcome of prosthetic valve endocarditis after transcatheter aortic valve replacement in the Netherlands.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is increasingly being used as an alternative to conventional surgical valve replacement. Prosthetic valve endocarditis (PVE) is a rare but feared complication after TAVR, with reported first-year incidences varying from 0.57 to 3.1%. This study was performed to gain insight into the incidence and outcome of PVE after TAVR in the Netherlands. METHODS: A multicentre retrospective registry study was performed. All patients who underwent TAVR in the period 2010-2017 were screened for the diagnosis of infective endocarditis in the insurance database and checked for the presence of PVE before analysis of general characteristics, PVE parameters and outcome. RESULTS: A total of 3968 patients who underwent TAVR were screened for PVE. During a median follow-up of 33.5 months (interquartile range (IQR) 22.8-45.8), 16 patients suffered from PVE (0.4%), with a median time to onset of 177 days (IQR 67.8-721.3). First-year incidence was 0.24%, and the overall incidence rate was 0.14 events per 1000 person-years. Overall mortality during follow-up in our study was 31%, of which 25% occurred in hospital. All patients were treated conservatively with intravenous antibiotics alone, and none underwent a re-intervention. Other complications of PVE occurred in 5 patients (31%) and included aortic abscess (2), decompensated heart failure (2) and cerebral embolisation (1). CONCLUSION: PVE in patients receiving TAVR is a relatively rare complication and has a high mortality rate.

Sex differences in characteristics and outcome in acute coronary syndrome patients in the Netherlands.

BACKGROUND: Sex differences in acute coronary syndrome (ACS) have been reported, but little is known about the situation in the Netherlands. METHODS: This registry is a merge of available data on ACS patients in the electronic data capture systems of 11 centres with 24/7 interventional cardiology services. We included patients >18 years undergoing a cardiac catheterisation between 2010-2012. We evaluated sex differences in clinical and procedural characteristics and 1­year mortality. RESULTS: A total of 29,265 ACS patients (8,720 women and 20,545 men) were registered. Women were on average 4.5 years older (68.5 vs 63.0 years, p < 0.001) and had a higher prevalence of hypertension (62.7 vs 49.8%, p < 0.001) and insulin-dependent diabetes mellitus (9.6 vs 6.8%, p < 0.001) than men. Women less often presented with ST-elevation myocardial infarction (43.7% vs 47.6%, p < 0.001) and appeared to have less extensive coronary artery disease than men. Women less often underwent coronary angiography by radial access (52.5 vs 55.9%, p < 0.001). One-year mortality was higher in women than in men (7.3% and 5.6%, p < 0.001). More specific, the relationship between sex and mortality was age-dependent and showed higher mortality in women ≤71 years, but lower mortality in older women compared with men (p-interaction <0.001). CONCLUSION: We found differences in clinical and procedural characteristics and outcome between women and men admitted for ACS, which are in line with other Western countries. The limitations of our registry, based on existing local databases, can be overcome by the use of the prospective Netherlands Heart Registry that is currently in development.

The significance of refuge heterogeneity for lowland stream caddisfly larvae to escape from drift.

The process of macroinvertebrate drift in freshwater lowland streams is characterized by dislodgement, drift distance and subsequent return to the bottom. Refuges are important to all drift phases, since they may help larvae to avoid dislodgement and to escape from drift, even more so if the refuge structure is complex and heterogeneous. The aim of the present study was therefore to determine the influence of refuge heterogeneity on the ability of caddisfly larvae to return to the bottom from drift and to avoid secondary dislodgement. To this purpose a series of indoor flume experiments were undertaken, testing six Limnephilidae (Trichoptera) species, that occur on a gradient from lotic to lentic environments. Bed morphology (plain, refuges with or without leaf patches) and flow velocity (low (0.1 m/s), intermediate (0.3 m/s) and high (0.5 m/s) were manipulated. We showed that all species were favoured by refuges and that especially for species on the lentic end of the gradient (L. lunatus, L. rhombicus and A. nervosa), the ability to escape from drift and to avoid secondary dislodgement was increased. Moreover, we showed that all species spent more time in refuges than in open channel parts and more time in heterogeneous refuges (leaf patches) than in bare refuges, the latter being especially the case for larvae of the lotic species. For lentic species, not well adapted to high flow velocity, refuges are thus crucial to escape from drift, while for the lotic species, better adapted to high flow velocity, the structure of the refuge becomes increasingly important. It is concluded that refuges may play a crucial role in restoring and maintaining biodiversity in widened, channelized and flashy lowland streams.

Biodegradation and mechanical behavior of an advanced bioceramic-containing Mg matrix composite synthesized through in-situ solid-state oxidation.

Recent studies have shown great potential of Mg matrix composites for biodegradable orthopedic devices. However, the poor structural integrity of these composites, which results in excessive localized corrosion and premature mechanical failure, has hindered their widespread applications. In this research, an in-situ Powder Metallurgy (PM) method was used to fabricate a novel biodegradable Mg-bredigite composite and to achieve enhanced chemical interfacial locking between the constituents by triggering a solid-state thermochemical reaction between Mg and bredigite particles. The reaction resulted in a highly densified and integrated microstructure, which prevented corrosion pits from propagating when the composite was immersed in a physiological solution. In addition, chemical interlocking between the constituents prohibited interparticle fracture and subsequent surface delamination during compression testing, enabling the composite to withstand larger plastic deformation before mechanical failure. Furthermore, the composite was proven to be biocompatible and capable of maintaining its ultimate compressive strength in the strength range of cortical bone after 25-day immersion in DMEM. The research provided the necessary information to guide further research towards the development of a next generation of biodegradable Mg matrix composites with enhanced chemical interlocking.

How the concept of biochemical response influenced the management of primary biliary cholangitis over time.

BACKGROUND: Criteria assessing biochemical response to ursodeoxycholic acid (UDCA) are established risk stratification tools in primary biliary cholangitis (PBC). We aimed to evaluate to what extent liver tests influenced patient management during a three decade period, and whether this changed over time. METHODS: 851 Dutch PBC patients diagnosed between 1988 and 2012 were reviewed to assess patient management in relation to liver test results during UDCA treatment. To do so, biochemical response at one year was analysed retrospectively according to Paris-1 criteria. RESULTS: Response was assessable for 687/851 (81%) patients; 157/687 non-responders. During a follow-up of 8.8 years (IQR 4.8-13.9), 141 died and 30 underwent liver transplantation. Transplant-free survival of non-responders (60%) was significantly worse compared with responders (87%) (p < 0.0001). Management was modified in 46/157 (29%) non-responders. The most frequent change observed, noted in 26/46 patients, was an increase in UDCA dosage. Subsequently, 9/26 (35%) non-responders became responders within the next two years. Steroid treatment was started in one patient; 19 patients were referred to a tertiary centre. No trend towards more frequent changes in management over time was observed (p = 0.10). CONCLUSION: Changes in medical management occurred in a minority of non-responders. This can largely be explained by the lack of accepted response criteria and of established second-line treatments for PBC. Nevertheless, the observation that response-guided management did not increase over time suggests that awareness of the concept of biochemical response requires further attention,particularly since new treatment options for PBC will soon become available.

Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax.

The mitochondrial pathway of apoptosis is initiated by Bcl-2 homology region 3 (BH3)-only members of the Bcl-2 protein family. On upregulation or activation, certain BH3-only proteins can directly bind and activate Bak and Bax to induce conformation change, oligomerization and pore formation in mitochondria. BH3-only proteins, with the exception of Bid, are intrinsically disordered and therefore, functional studies often utilize peptides based on just their BH3 domains. However, these reagents do not possess the hydrophobic membrane targeting domains found on the native BH3-only molecule. To generate each BH3-only protein as a recombinant protein that could efficiently target mitochondria, we developed recombinant Bid chimeras in which the BH3 domain was replaced with that of other BH3-only proteins (Bim, Puma, Noxa, Bad, Bmf, Bik and Hrk). The chimeras were stable following purification, and each immunoprecipitated with full-length Bcl-xL according to the specificity reported for the related BH3 peptide. When tested for activation of Bak and Bax in mitochondrial permeabilization assays, Bid chimeras were ~1000-fold more effective than the related BH3 peptides. BH3 sequences from Bid and Bim were the strongest activators, followed by Puma, Hrk, Bmf and Bik, while Bad and Noxa were not activators. Notably, chimeras and peptides showed no apparent preference for activating Bak or Bax. In addition, within the BH3 domain, the h0 position recently found to be important for Bax activation, was important also for Bak activation. Together, our data with full-length proteins indicate that most BH3-only proteins can directly activate both Bak and Bax.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Dutch guidance for the treatment of chronic hepatitis C virus infection in a new therapeutic era.

BACKGROUND: A new era for the treatment of chronic hepatitis C is about to transpire. With the introduction of the first-generation protease inhibitors the efficacy of hepatitis C treatment improved significantly. Since then, the therapeutic agenda has moved further forward with the recent approval of sofosbuvir and the expected approval of agents such as simeprevir and daclatasvir. This paper, developed parallel to the approval of sofosbuvir, is to serve as a guidance for the therapeutic management of chronic hepatitis C. METHODS: We performed a formal search through PubMed, Web of Science and ClinicalTrials.gov to identify all clinical trials that have been conducted with EMA-approved new agents in hepatitis C; for this version (April 2014) we focused on sofosbuvir. For each disease category, the evidence was reviewed and recommendations are based on GRADE. RESULTS: We identified 11 clinical trials with sofosbuvir and for each disease category recommendations for treatment are made. Not all disease categories were studied extensively and therefore in some cases we were unable to provide recommendations. CONCLUSION: The recent approval of sofosbuvir will most likely change the therapeutic landscape of chronic hepatitis C. The use of sofosbuvir-containing regimens can shorten the duration of therapy, increase efficacy and result in less side effects, compared with standard of care. The efficacy relative to standard of care needs to be weighed against the increased costs of sofosbuvir. With future approval of the other direct-acting antivirals, the outcome of hepatitis C treatment will likely improve further and this guidance will be updated.

Everolimus- and sirolimus-eluting stents in patients with and without ST-segment elevation myocardial infarction.

AIMS: Everolimus-eluting stents (EES) were superior to sirolimus-eluting stents (SES) in a dedicated myocardial infarction trial, a finding that was not observed in trials with low percentages of ST-elevation myocardial infarction (STEMI). Therefore, this study sought to investigate the influence of clinical presentation on outcome after EES and SES implantation. METHODS: A pooled population of 1602 randomised patients was formed from XAMI (acute MI trial) and APPENDIX-AMI (all-comer trial). Primary outcome was cardiac mortality, MI and target vessel revascularisation at 2 years. Secondary endpoints included definite/probable stent thrombosis (ST). Adjustment was done using Cox regression. RESULTS: In total, 902 EES and 700 SES patients were included, of which 44 % STEMI patients (EES 455; SES 257) and 56 % without STEMI (EES 447; SES 443). In the pooled population, EES and SES showed similar outcomes during follow-up. Moreover, no differences in the endpoints were observed after stratification according to presentation. Although a trend toward reduced early definite/probable ST was observed in EES compared with SES in STEMI patients, long-term ST rates were low and comparable. CONCLUSIONS: EES and SES showed a similar outcome during 2-year follow-up, regardless of clinical presentation. Long-term safety was excellent for both devices, despite wide inclusion criteria and a large sub-population of STEMI patients.

Treatment of hepatitis C monoinfection in adults--Dutch national guidelines.

In this new Dutch guideline for hepatitis C virus infection we provide recommendations for the management of hepatitis C infection. Until 2012 the standard for treatment consisted of pegylated interferon alpha (peg-IFNa) and ribavirin. The advent of first-generation direct antiviral agents such as boceprevir and telaprevir has changed the concept of treatment of adult chronic hepatitis C genotype 1 infected patients. There are three benefits of boceprevir and telaprevir. They increase the likelihood of cure in 1) naive genotype 1 patients and 2) in patients who did not respond to earlier treatment with peg-IFNa and ribavirin, while 3) allowing shortening of treatment duration from 48 weeks to 24 or 28 weeks, which is possible in 40-60% of non-cirrhotic naive (boceprevir and telaprevir) and relapsing patients (telaprevir). The use of boceprevir and telaprevir is associated with multiple side effects and awareness of these side effects is needed to guide the patient through the treatment process. This guideline, formulated on behalf of The Netherlands Association of Hepato-gastroenterologists, The Netherlands Association of Internal Medicine, and The Dutch Association for the Study of Liver Disease, serves as a manual for physicians for the management and treatment of acute and chronic hepatitis C virus monoinfection in adults.

Mitotic catastrophe triggered in human cancer cells by the viral protein apoptin.

Mitotic catastrophe is an oncosuppressive mechanism that senses mitotic failure leading to cell death or senescence. As such, it protects against aneuploidy and genetic instability, and its induction in cancer cells by exogenous agents is currently seen as a promising therapeutic end point. Apoptin, a small protein from Chicken Anemia Virus (CAV), is known for its ability to selectively induce cell death in human tumor cells. Here, we show that apoptin triggers p53-independent abnormal spindle formation in osteosarcoma cells. Approximately 50% of apoptin-positive cells displayed non-bipolar spindles, a 10-fold increase as compared to control cells. Besides, tumor cells expressing apoptin are greatly limited in their progress through anaphase and telophase, and a significant drop in mitotic cells past the meta-to-anaphase transition is observed. Time-lapse microscopy showed that mitotic osteosarcoma cells expressing apoptin displayed aberrant mitotic figures and/or had a prolonged cycling time during mitosis. Importantly, all dividing cells expressing apoptin eventually underwent cell death either during mitosis or during the following interphase. We infer that apoptin can efficiently trigger cell death in dividing human tumor cells through induction of mitotic catastrophe. However, the killing activity of apoptin is not only confined to dividing cells, as the CAV-derived protein is also able to trigger caspase-3 activation and apoptosis in non-mitotic cancer cells.

The 2012 revised Dutch national guidelines for the treatment of chronic hepatitis B virus infection.

In 2008, the Netherlands Association of Gastroenterologists and Hepatologists (Nederlands Vereniging van Maag-Darm-Leverartsen) published the Dutch national guidelines for the treatment of chronic hepatitis B virus infection. New insights into the treatment of chronic hepatitis B with relevance for clinical practice have been adopted in these concise, revised guidelines. The most important changes include the choice of initial antiviral therapy, licensing of tenofovir for the treatment of chronic hepatitis B and the management of antiviral resistance.

Benchmarking patient experiences in colonoscopy using the Global Rating Scale.

INTRODUCTION: The Global Rating Scale (GRS) is a quality assurance program that was developed in England to assess patient-centered care in endoscopy. The aim of the current study was to evaluate patient experiences of colonoscopy using the GRS in order to compare different departments and to provide benchmarks. The study also evaluated factors associated with patient satisfaction. METHODS: A GRS questionnaire was used both before and after the procedure in outpatients undergoing colonoscopy. The questionnaire assessed the processes associated with the colonoscopy, from making the appointment up until discharge. Mean values and ranges of 12 endoscopy departments were calculated together with P values in order to assess heterogeneity. RESULTS: In total, 1904 pre-procedure and 1532 (80 %) post-procedure questionnaires were returned from 12 endoscopy departments. The mean time patients had to wait for their procedure was 4.3 weeks (range 3.1 - 5.8 weeks), and 54 % (range 35 - 64 %; P < 0.001) reported being given a choice of appointment dates/times. Discomfort during colonoscopy was reported by 20 % (range 8 - 40 %; P < 0.001). Recovery room privacy was satisfactory for 76 % of patients (range 66 - 90 %; P < 0.05). The majority of patients reported being sufficiently informed about what to do in case of problems after discharge (79 %, range 43 - 98 %; P < 0.001), and 85 % of individuals stated that they would be willing to repeat the colonoscopy procedure (range 72 - 92 %; P < 0.001). Factors associated with a decreased willingness to return were the burdensome bowel preparation (odds ratio [OR] = 0.25; P < 0.001), "rushing staff" attitude (OR = 0.57; P < 0.05), low acceptance of the procedure (OR = 0.42; P < 0.01), and more discomfort than expected (OR = 0.54; P < 0.05). CONCLUSION: Overall patient experiences with colonoscopy were satisfactory, but they also showed considerable variation. This study shows that use of a GRS patient questionnaire is feasible in the Dutch endoscopy setting for the assessment of patient experience. The significant variability between endoscopy units can be used to benchmark services and enable shortcomings to be identified.

Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study.

OBJECTIVE: To assess the absolute risk of fetal loss associated with hereditary deficiencies of antithrombin (AT), protein C (PC) and protein S (PS), and the contribution of additional thrombophilic defects to this risk. DESIGN: A retrospective family cohort study. SETTING: A tertiary referral teaching hospital. POPULATION: Women from families with hereditary deficiencies of AT, PC and PS, and their non-deficient relatives. METHODS: We assessed the absolute risk of fetal loss, comparing deficient women with non-deficient female relatives. MAIN OUTCOME MEASURES: Early, late and total fetal loss rates; odds ratios of fetal loss. RESULTS: We evaluated 289 women, who had 860 pregnancies. The total fetal loss rates were 23% (AT deficient), 26% (PC deficient), 11% (type-I PS deficient) and 15% (type-III PS deficient), compared with 11, 18, 12 and 13% in non-deficient women, respectively. Odds ratios were 2.3 (95% CI 0.9-6.1), 2.1 (95% CI 0.9-4.7), 0.7 (95% CI 0.2-1.8) and 1.1 (95% CI 0.6-2.0), none of which reached statistical significance. Differences were mainly the result of higher late fetal loss rates in women deficient in AT (OR 11.3, 95% CI 3.0-42.0) and PC (OR 4.7, 95% CI 1.3-17.4). The concomitance of factor-V Leiden and prothrombin G20210A was observed in 19% of women, and did not increase the risk of fetal loss. CONCLUSIONS: Although absolute risks of fetal loss were high, odds ratios of total fetal loss were not statistically significant in deficient versus non-deficient women. However the higher absolute risks appeared to reflect higher late fetal loss rates as opposed to early fetal loss rates. An additional effect of concomitance of factor-V Leiden and prothrombin G20210A was not demonstrated, which may result from the exclusion of women at highest risk of venous thromboembolism, or from the small numbers sampled in the study.