Effectiveness of ferritin-guided donation intervals in whole-blood donors in the Netherlands (FIND'EM): a stepped-wedge cluster-randomised trial.

BACKGROUND: Whole-blood donors are at increased risk for iron deficiency and anaemia. The current standard of haemoglobin monitoring is insufficient to ensure the maintenance of proper iron reserves and donor health. We aimed to determine the effects of ferritin-guided donation intervals for blood donor health and blood supply in the Netherlands. METHODS: In this stepped-wedge cluster-randomised trial (FIND'EM), the 138 fixed and mobile donation centres in the Netherlands are organised into 29 geographical clusters and the clusters were randomly assigned to four treatment groups, with two groups being further split into two per a protocol amendment. Eligible donors were whole-blood donors who consented for use of their leftover material in the study. Each group was sequentially crossed over from the existing policy (haemoglobin-based screening; control) to a ferritin-guided donation interval policy over a 3-year period. In the intervention groups, in addition to the existing haemoglobin screening, ferritin was measured in all new donors and at every fifth donation in repeat donors. Subsequent donation intervals were extended to 6 months if ferritin concentrations were 15-30 ng/mL and to 12 months if they were less than 15 ng/mL. Outcomes were measured cross-sectionally across all donation centres at four timepoints. Primary outcomes were ferritin and haemoglobin concentrations, iron deficiency, and haemoglobin-based deferrals. We assessed all outcomes by sex and menopausal status and significance for primary outcomes was indicated by a p value of less than 0·0125. This trial is registered in the Dutch trial registry, NTR6738, and is complete. FINDINGS: Between Sept 11, 2017, and Nov 27, 2020, 412 888 whole-blood donors visited a donation centre, and we did measurements on samples from 37 621 donations from 36 099 donors. Over 38 months, ferritin-guided donation intervals increased mean ferritin concentrations (by 0·18 log10 ng/mL [95% CI 0·15-0·22; p<0·0001] in male donors, 0·10 log10 ng/mL [0·06-0·15; p<0·0001] in premenopausal female donors, and 0·17 log10 ng/mL [0·12-0·21; p<0·0001] in postmenopausal female donors) and mean haemoglobin concentrations (by 0·30 g/dL [95% CI 0·22-0·38; p<0·0001] in male donors, 0·12 g/dL [0·03-0·20; p<0·0074] in premenopausal female donors, and 0·16 g/dL [0·05-0·27; p<0·0044] in postmenopausal female donors). Iron deficiency decreased by 36-38 months (odds ratio [OR] 0·24 [95% CI 0·18-0·31; p<0·0001] for male donors, 0·49 [0·37-0·64; p<0·0001] for premenopausal female donors, and 0·24 [0·15-0·37; p<0·0001] for postmenopausal female donors). At 36-38 months, haemoglobin-based deferral decreased significantly in male donors (OR at 36-38 months 0·21 [95% CI 0·10-0·40, p<0·0001]) but not significantly in premenopausal or postmenopausal female donors (0·81 [0·54-1·20; p=0·29] and 0·50 [95% CI 0·25-0·98; p=0·051], respectively). INTERPRETATION: Ferritin-guided donation intervals significantly improved haemoglobin and ferritin concentrations and significantly decreased iron deficiency over the study period. Haemoglobin-based deferrals decreased significantly for male donors, but not female donors. Although this intervention is overall beneficial for maintenance of iron and haemoglobin concentrations in donors, increased efforts are needed to recruit and retain donors. FUNDING: The Sanquin Research Programming Committee.

Balancing non-discriminatory donor selection and blood safety in the Netherlands: Evaluation of an individual risk assessment of sexual behavior.

BACKGROUND: To better balance the safety of the blood supply and the inclusion of men who have sex with men (MSM), further improvements are needed to the risk management strategy employed in the Netherlands to reduce transfusion-transmissible infections (TTIs). A gender-neutral individual risk assessment could provide a solution by determining donor eligibility based on sexual behaviors known to increase the risk of TTIs. Our objective is to estimate the proportion of blood donors that would be deferred by such an assessment, as well as their discomfort answering such questions. STUDY DESIGN AND METHODS: Two surveys were distributed in May 2020 to assess sexual behavior in blood donors in the last 4, 6, and 12 months, as well as their discomfort reporting such information. A combination of both surveys measured the extent to which discomfort was associated with reporting sexual behavior. A high-risk sexual behavior pattern was defined as having had multiple sexual partners and having engaged in anal sex, without consistent condom use. RESULTS: Of all 2177 participating whole blood donors, 0.8% report engaging in high-risk sexual behaviors over the last 4 months and would therefore be ineligible to donate. When accounting for the additional proportion of donors that reported such questions would stop them from donating, 2.0% and 3.2% of female and male donors, respectively, would be lost. DISCUSSION: Gender-neutral eligibility criteria based on high-risk sexual behaviors may reduce the overall number of eligible donors in the Netherlands, but could make blood donation more accessible to a broader group of donors.

Donation-induced iron depletion is significantly associated with low hemoglobin at subsequent donations.

BACKGROUND: Blood donation is associated with a loss of hemoglobin (Hb)-bound iron. Hb levels recover relatively fast by using stored iron. However, it takes more time to replenish iron stores, potentially resulting in iron deficiency. STUDY DESIGN: Hb and ferritin levels were measured in 5056 new, first-time, and repeat whole blood donors. We investigated whether increasing numbers of donations are associated with lower ferritin levels. Furthermore, we tested whether low ferritin levels are associated with low-Hb deferral at the subsequent donation attempt by performing logistic regression adjusted for age and stratified by sex. RESULTS: Whereas mean Hb levels are relatively stable, ferritin levels significantly decrease with increasing numbers of donations and were approximately 50% lower for donors with >50 donations compared with those with 2-10 donations. Despite the poor correlation of ferritin and Hb levels, cross-sectional, iron-deficient donors (ferritin <15 ng/ml) had 21.8 (8.5-55.6) higher odds in men, 10.1 (6.1-16.5) in premenopausal women, and 11.7 (5.2-26.4) in postmenopausal women for Hb deferral at a subsequent visit. DISCUSSION: To conclude, repeated donations may induce iron deficiency, which corresponds with an over tenfold increased risk of having insufficiently restored Hb levels at a subsequent donation attempt. Longer donation intervals and/or higher dietary or supplemental iron intake are warranted to prevent accumulated iron depletion and subsequent low-Hb deferral in whole blood donors.

New blood donors in times of crisis: Increased donation willingness, particularly among people at high risk for attracting SARS-CoV-2.

BACKGROUND: Traditionally, during crises the number of new blood donors increases. However, the current coronavirus disease 2019 (COVID-19) pandemic created additional barriers to donate due to governmental prevention measures and increased personal health risks. In this report, we examined how the pandemic affected new donor registrations in the Netherlands, especially among groups with higher risk profiles for severe COVID-19. Additionally, we explored the role of media for blood donation and new donor registrations. STUDY DESIGN AND METHODS: We analyzed new donor registrations and attention for blood donation in newspapers and on social media from January until May 2020, in comparison to the same period in 2017 to 2019. RESULTS: After the introduction of nationwide prevention measures, several peaks in new donor registrations occurred, which coincided with peaks in media attention. Interestingly, people with a higher risk profile for COVID-19 (e.g., due to age or region of residence) were overrepresented among new registrants. DISCUSSION: In sum, the first peak of the current pandemic has led to increased new blood donor registrations, despite the associated increased health risks. Time and future studies will have to tell whether these new donors are one-off 'pandemic' donors or if they will become regular, loyal donors.

Dietary intake of heme iron is associated with ferritin and hemoglobin levels in Dutch blood donors: results from Donor InSight.

Whole blood donors, especially frequently donating donors, have a risk of iron deficiency and low hemoglobin levels, which may affect their health and eligibility to donate. Lifestyle behaviors, such as dietary iron intake and physical activity, may influence iron stores and thereby hemoglobin levels. We aimed to investigate whether dietary iron intake and questionnaire-based moderate-to-vigorous physical activity were associated with hemoglobin levels, and whether ferritin levels mediated these associations. In Donor InSight-III, a Dutch cohort study of blood and plasma donors, data on heme and non-heme iron intake (mg/day), moderate-to-vigorous physical activity (10 minutes/day), hemoglobin levels (mmol/L) and ferritin levels (µg/L) were available in 2,323 donors (1,074 male). Donors with higher heme iron intakes (regression coefficients (ß) in men and women: 0.160 and 0.065 mmol/L higher hemoglobin per 1 mg of heme iron, respectively) and lower non-heme iron intakes (ß: -0.014 and -0.017, respectively) had higher hemoglobin levels, adjusted for relevant confounders. Ferritin levels mediated these associations (indirect effect (95% confidence interval) in men and women respectively: 0.074 (0.045; 0.111) and 0.061 (0.030; 0.096) for heme and -0.003 (-0.008;0.001) and -0.008 (-0.013;-0.003) for non-heme). Moderate-to-vigorous physical activity was negatively associated with hemoglobin levels in men only (ß: -0.005), but not mediated by ferritin levels. In conclusion, higher heme and lower non-heme iron intake were associated with higher hemoglobin levels in donors, via higher ferritin levels. This indicates that donors with high heme iron intake may be more capable of maintaining iron stores to recover hemoglobin levels after blood donation.

Variations in hemoglobin measurement and eligibility criteria across blood donation services are associated with differing low-hemoglobin deferral rates: a BEST Collaborative study.

BACKGROUND: Determination of blood donor hemoglobin (Hb) levels is a pre-requisite to ensure donor safety and blood product quality. We aimed to identify Hb measurement practices across blood donation services and to what extent differences associate with low-Hb deferral rates. METHODS: An online survey was performed among Biomedical Excellence for Safer Transfusion (BEST) Collaborative members, extended with published data. Multivariable negative-binomial regression models were built to estimate adjusted associations of minimum donation intervals, Hb cut-offs (high, ≥13.5 g/dL in men or ≥ 12.5 g/dL in women, vs. lower values), iron monitoring (yes/no), providing or prescribing iron supplementation (yes/no), post-versus pre-donation Hb measurement and geographical location (Asian vs. rest), with low-Hb deferral rates. RESULTS: Data were included from 38 blood services. Low-Hb deferral rates varied from 0.11% to 8.81% among men and 0.84% to 31.85% among women. Services with longer minimum donation intervals had significantly lower deferral rates among both women (rate ratio, RR 0.53, 95%CI 0.33-0.84) and men (RR 0.53, 95%CI 0.31-0.90). In women, iron supplementation was associated with lower Hb deferral rates (RR 0.47, 95%CI 0.23-0.94). Finally, being located in Asia was associated with higher low-Hb deferral rates; RR 9.10 (95%CI 3.89-21.27) for women and 6.76 (95%CI 2.45-18.68) for men. CONCLUSION: Differences in Hb measurement and eligibility criteria, particularly longer donation intervals and iron supplementation in women, are associated with variations in low-Hb deferral rates. These insights could help improve both blood donation service efficiency and donor care.

No increased risk of transfusion-transmissible infections after tattooing, body piercing, or acupuncture among blood donors in the Netherlands.

BACKGROUND: In the Netherlands, needle-related events (NREs) including tattoos, piercings, and acupuncture are a reason for temporary blood donor deferral. This study aims to evaluate whether donors with recent NREs had a higher risk of transfusion-transmissible infections (TTIs) compared to donors without recent NREs. STUDY DESIGN AND METHODS: Data from 2006 through 2015 on all blood donation attempts in the Netherlands were collected. Multivariate regression models (for repeated measurements) were used to assess the associations between recent NREs and the acquisition of TTIs. Posttest counseling data were used to determine the most likely risk factor in TTI-positive new and repeat donors. RESULTS: Recent NREs were documented in 97,518 out of 9,266,036 (1.1%) donation attempts; 14,097 (14.5%) NREs resulted in NRE-based donor deferral. Recent NREs reported pre-donation were not associated with an increased risk for TTIs. A total of 29 out of 287 TTI-positive donors (11 repeat donors, 18 new donors) reported a recent NRE pre- and/or post-donation. Recent NREs, all needle-stick injuries, were the likely route of transmission in 12 out of 287 (4.2%) of TTI-positive donors. The donor health questionnaire (DHQ) identified only 1 out of 12 TTI-linked NREs. Non-return after NRE deferral, any deferral, or no deferral was 24, 15, and 5%, respectively. DISCUSSION: Recent tattoos, body piercings, or acupuncture were not associated with an increased risk for TTIs in Dutch donors. Given the lower return rates of donors following a temporary NRE-based deferral, we advocate ending blood donor deferral policies for acupuncture, tattooing, and body piercings, but not needle-stick injuries, in countries where these practices can be considered safe.

Donor InSight: characteristics and representativeness of a Dutch cohort study on blood and plasma donors.

BACKGROUND AND OBJECTIVES: More insight into donor health and behaviour may contribute to more efficient and focused strategies regarding donor care and management. Donor InSight (DIS) is a Dutch cohort study of blood and plasma donors. We aimed to outline the objectives and methods of DIS, describe the cohort, and compare it to the active Dutch donor population. MATERIALS AND METHODS: In 2007-2009 (DIS-I, n = 31 338) and 2012-2013 (DIS-II, 34 826, of whom 22 132 also participated in DIS-I) questionnaire data on demographics, donation, lifestyle, family composition, health and disease were collected. A second follow-up (DIS-III, n = 3046), including donors with differing haemoglobin trajectories, was completed in 2015-2016. DIS-III includes data on genetic determinants, iron and red cell indices. Representativeness of the DIS-I sample for the entire Dutch donor population was assessed by comparing characteristics of both. RESULTS: Donor InSight was initially set up because of a need for more detailed information and evidence as a basis for decision-making in blood banks. DIS-I sample is comparable to the total Dutch donor population in terms of age, body mass index, haemoglobin level, blood pressure, blood type and donation behaviour. CONCLUSION: Donor InSight is a cohort study representative of the Dutch donor population. It provides evidence to support evidence-based decision making.

The association between population density and blood lipid levels in Dutch blood donors.

BACKGROUND: In low and middle-income countries (LMIC), the total and LDL cholesterol and triglyceride levels of residents of urban areas are reported to be higher than those of rural areas. This may be due to differences in lifestyle behaviors between residents of urban areas and rural areas in LMIC. In this study, our aims were to (1) examine whether or not LDL cholesterol, total/HDL ratios and triglyceride levels of individuals in densely populated areas are higher than those of individuals living in less-densely populated areas in a high-income country (HIC) and (2) investigate the potential mediating roles of physical activity and sedentary behavior. METHODS: We used cross-sectional data from 2547 Dutch blood donors that participated in Donor InSight-III. Linear regression was used to analyze the association between population density and LDL cholesterol, total/HDL cholesterol ratio and HDL cholesterol. The mediating roles of moderate-to-vigorous physical activity (MVPA) and sedentary behavior were investigated in a subsample (n = 740) for which objectively measured MVPA/sedentary behavior data was available. Multiple mediation with linear regression analyses were performed and the product-of-coefficients method was used to calculate direct and indirect effects. RESULTS: Mean LDL cholesterol and median total cholesterol/HDL cholesterol ratio and triglyceride levels were 2.89, 3.43 and 1.29 mmol/L, respectively. Population density was not associated with LDL cholesterol [ß 0.00 (- 0.01; 0.01)], log transformed total/HDL cholesterol ratio [ß 1.00 (1.00; 1.00)] and triglyceride levels [ß 1.00 (0.99; 1.00)]. No statistically significant direct or indirect effects were found. CONCLUSION: Contrary to previous findings in LMIC, no evidence was found that population density is associated with blood lipid levels in blood donors in the Netherlands or that MVPA and sedentary behavior mediate this association. This may be the result of socioeconomic differences and, in part, may be due to the good health of the study population and the relatively high population density in the Netherlands. Also, compared to LMIC, differences in physical activity levels in more versus less populated areas may be less pronounced in HIC.

Low awareness of past SARS-CoV-2 infection in healthy plasma donors.

Awareness of infection with SARS-CoV-2 is crucial for the effectiveness of COVID-19 control measures. Here, we investigate awareness of infection and symptoms in relation to antibodies against SARS-CoV-2 in healthy plasma donors. We asked individuals donating plasma across the Netherlands between May 11th and 18th 2020 to report COVID-19-related symptoms, and we tested for antibodies indicative of a past infection with SARS-CoV-2. Among 3,676 with antibodies, and from questionnaire data, 239 (6.5%) are positive for SARS-CoV-2 antibodies. Of those, 48% suspect no COVID-19, despite the majority reporting symptoms; 11% of seropositive individuals report no symptoms and 27% very mild symptoms at any time during the first peak of the epidemic. Anosmia/ageusia and fever are most strongly associated with seropositivity. Almost half of seropositive individuals do not suspect SARS-CoV-2 infection. Improved recognition of COVID-19 symptoms, in particular, anosmia/ageusia and fever, is needed to reduce widespread SARS-CoV-2 transmission.

Ferritin measurement IN Donors-Effectiveness of iron Monitoring to diminish iron deficiency and low haemoglobin in whole blood donors (FIND'EM): study protocol for a stepped wedge cluster randomised trial.

BACKGROUND: Blood donors are at risk for reduced iron stores, because of which donor iron monitoring received increased attention in the last decade. Despite the importance for donor health, international consensus on an appropriate policy for iron monitoring is lacking. Therefore, we conduct a trial to evaluate to what extent ferritin-guided donation intervals are effective in increasing haemoglobin and ferritin levels, decreasing low-haemoglobin deferral, increasing donor return and improving the health of whole blood donors in the Netherlands. METHODS: Sanquin Blood Bank is implementing ferritin-guided donation intervals to prevent donors from increasing iron loss at repeated donations. Using a stepped wedge cluster randomised trial approach, the design involves a random crossover of 29 clusters of blood collection centres from the existing policy without ferritin measurements to a ferritin-guided donation interval policy. This new policy includes ferritin measurements for all new donors and at every 5th whole blood donation, extending donation intervals to 6 months if ferritin is 15-≤ 30 ng/mL and to 12 months if ferritin is < 15 ng/mL. We measure ferritin levels of whole blood donors from stored plasma samples and collect haemoglobin levels and information on low-haemoglobin deferral and donor return from the donor database before, during and after the implementation period. We measure donor health during and after the implementation period using questionnaires, assessing physical and mental wellbeing and iron deficiency- and donation-related symptoms. We use multilevel analyses to investigate differences in ferritin and haemoglobin levels, low-haemoglobin deferral rates, donor return and donor health from whole blood donors, between blood collection centres that have versus those that have not yet implemented the ferritin-guided donation interval policy. DISCUSSION: This stepped wedge cluster randomised trial will provide insight into the effectiveness of ferritin-guided donation intervals in lowering iron deficiency, decreasing donor deferrals due to low haemoglobin and improving donor health. We will evaluate a policy that is implemented nationwide in a real-life setting. Our study is therefore not limited to a small experimental setting and the results will guide policymakers seeking an appropriate policy for iron monitoring. TRIAL REGISTRATION: The Dutch trial registry NTR6738 . Registered on 29 September 2017. Retrospectively registered.

Development and validation of a universal blood donor genotyping platform: a multinational prospective study.

Each year, blood transfusions save millions of lives. However, under current blood-matching practices, sensitization to non-self-antigens is an unavoidable adverse side effect of transfusion. We describe a universal donor typing platform that could be adopted by blood services worldwide to facilitate a universal extended blood-matching policy and reduce sensitization rates. This DNA-based test is capable of simultaneously typing most clinically relevant red blood cell (RBC), human platelet (HPA), and human leukocyte (HLA) antigens. Validation was performed, using samples from 7927 European, 27 South Asian, 21 East Asian, and 9 African blood donors enrolled in 2 national biobanks. We illustrated the usefulness of the platform by analyzing antibody data from patients sensitized with multiple RBC alloantibodies. Genotyping results demonstrated concordance of 99.91%, 99.97%, and 99.03% with RBC, HPA, and HLA clinically validated typing results in 89 371, 3016, and 9289 comparisons, respectively. Genotyping increased the total number of antigen typing results available from 110 980 to >1 200 000. Dense donor typing allowed identification of 2 to 6 times more compatible donors to serve 3146 patients with multiple RBC alloantibodies, providing at least 1 match for 176 individuals for whom previously no blood could be found among the same donors. This genotyping technology is already being used to type thousands of donors taking part in national genotyping studies. Extraction of dense antigen-typing data from these cohorts provides blood supply organizations with the opportunity to implement a policy of genomics-based precision matching of blood.

Health-based risk adjustment: improving the pharmacy-based cost group model by adding diagnostic cost groups.

Since 1991, risk-adjusted premium subsidies have existed in the Dutch social health insurance sector, which covered about two-thirds of the population until 2006. In 2002, pharmacy-based cost groups (PCGs) were included in the demographic risk adjustment model, which improved the goodness-of-fit, as measured by the R2, to 11.5%. The model's R2 reached 22.8% in 2004, when inpatient diagnostic information was added in the form of diagnostic cost groups (DCGs). PCGs and DCGs appear to be complementary in their ability to predict future costs. PCGs particularly improve the R2 for outpatient expenses, whereas DCGs improve the R2 for inpatient expenses. In 2006, this system of risk-adjusted premium subsidies was extended to cover the entire population.

Associations of health status with subsequent blood donor behavior-An alternative perspective on the Healthy Donor Effect from Donor InSight.

INTRODUCTION: In donor health research, the 'Healthy Donor Effect' (HDE) often biases study results and hampers their interpretation. This refers to the fact that donors are a selected 'healthier' subset of a population due to both donor selection procedures and self-selection. Donors with long versus short donor careers, or with high versus low donation intensities are often compared to avoid this HDE, but underlying health differences might also cause these differences in behaviour. Our aim was to estimate to what extent a donor´s perceived health status associates with donation cessation and intensity. METHODS: All active whole blood donors participating in Donor InSight (2007-2009; 11,107 male; 12,616 female) were included in this prospective cohort study. We performed Cox survival and Poisson regression analyses to assess whether self-reported health status, medication use, disease diagnosed by a physician and recently having consulted a general practitioner (GP) or specialist were associated with (time to) donation cessation and donation intensity. RESULTS: At the end of 2013, 44% of the donors in this study had stopped donating. Donors in self-rated good health had a 15% lower risk to stop donating compared to donors in perceived poorer health. Medication use, disease diagnoses and consulting a GP were associated with a 20-40% increased risk to stop donating and a lower donation intensity, when adjusting for age, number of donations and new donor status. Both men and women reporting good health made on average 10% more donations. CONCLUSION: Donors with a "good" health status were less likely to stop donating blood and tended to donate blood more often than donors with perceived poorer health status. This implies that the HDE is an important source of selection bias in studies on donor health and this includes studies where comparisons within donors are made. This HDE should be adjusted for appropriately when assessing health effects of donation and donors' health status may provide estimates of future donation behavior.

Changes in the incidence of occupational disability as a result of back and neck pain in the Netherlands.

BACKGROUND: Back pain (including neck pain) is one of the most prevalent health problems for which physicians are consulted. Back pain can decrease the quality of life considerably during a great part of the lives of those who suffer from it. At the same time it has an enormous economic impact, mainly through sickness absence and long-term disability. The objective of this paper is to compare the incidence of occupational disability as a result of back and neck pain in 1980-1985 to 1999-2000 and to explain the findings. METHODS: A descriptive study was performed at population level of changes in incidence of occupational disability as a result of back and neck pain. Statistics from the National Institute of Social Insurance in the Netherlands are used to calculate age and gender specific incidence rates for back pain diagnoses based on the ICD-classification. Incidence rate ratios stratified according to gender and adjusted for age were calculated to indicate changes over time. RESULTS: The incidence of occupational disability as a result of back pain decreased significantly by 37% (95% CI 37%-38%) in men and with 21% (95% CI 20%-24%) in women, after adjustment for age. For overall occupational disability as a result of all diagnoses this was 18% (95% CI 18%-19%) and 34% (95% CI 33%-35%) respectively. Changes were not homogeneous over diagnostic subcategories and age groups. Spondylosis decreased most in men by 59% (95% CI 57%-61%). The incidence of non-specific back pain and neck pain increased most by 196% (95% CI 164%-215%). Post-laminectomy syndrome increased over all age categories both for men (85%, 95% CI 61%-113%) and women (113%, 95% CI 65%-179%). CONCLUSION: The decrease in occupational disability as a result of back pain was larger than the decrease in occupational disability over all diagnoses. However, time trends were not homogeneous over age-, nor over sex- nor back pain categories. Most of this decrease was due to general changes such as legal and economic changes. One of several additional explanations for a decrease is the changed view on management of back pain.