BACKGROUND:

Teenagers aged 16 to 18 are at increased risk for iron deficiency, exacerbated by losses with whole blood (WB) or double red blood cell (2RBC) donations. Required 56-day (WB) or 112-day (2RBC) interdonation intervals (IDIs) are too short for many to replace lost iron without supplements.

METHODS:

Teenagers donating WB or 2RBCs at Vitalant, a national blood provider, had serum ferritin measured at their first and immediately subsequent successful donation from December 2016 to 2018. We modeled postindex log-ferritin as a function of IDI to estimate the shortest intervals that corresponded with 50% to 95% prevalence of adequate donor iron stores (ferritin ≥20 ng/mL female donors, ≥30 ng/mL male donors) at the subsequent donation.

RESULTS:

Among 30 806 teenagers, 11.4% of female and 9.7% of male donors had inadequate iron stores at index donation. Overall, 92.6% had follow-up ferritin values within 13 months. Approximately 12 months after WB index donations, >60% of female and >80% of male donors had adequate iron stores (>50% and >70% after 2RBC donations). Follow-up–donation iron stores were highly dependent on index ferritin. Less than half of WB donors with low ferritin at index achieved adequate stores within 12 months. Achieving a ≥90% prevalence of adequate ferritin at 12 months required index values >50 ng/mL.

CONCLUSIONS:

These findings suggest that postdonation low-dose iron supplements should be strongly encouraged in teenagers with borderline or low iron stores to permit donation without increased risk for symptoms of mild iron depletion. Increasing the minimum recommended IDI to allow time for replacing donation-related iron losses may be desirable for teenagers.

What’s Known on This Subject:

Young blood donors are at elevated risk for iron depletion due to iron losses with whole blood (250 mg) or double red blood cells (425 mg). Frequent donation can result in significant iron depletion and/or iron deficiency anemia.

What This Study Adds:

The time course of postdonation iron store recovery is not well known. Our observational study of >30 000 returning teen-aged blood donors suggests that a substantial fraction remain iron depleted a year after donation.

Iron deficiency in the US population has been monitored in surveillance studies such as NHANES.1,2  Among 16- to 19-year-old Americans, <1% of male and 11% to 16% of female individuals have absent iron stores (ferritin <12 ng/mL, transferrin saturation <15%, and/or erythrocyte protoporphyrin >1.24 μmol/L).1,2  By using a less-stringent cutoff (ferritin <26 ng/mL), in similar-aged female individuals, the prevalence of iron deficiency may be as high as 39%.3  Mild iron deficiency can result in bothersome symptoms like pica and has been associated with subtle deleterious cognitive effects.4 

In the United States, there is an emphasis on collecting blood from 16- to 18-year-old (teen-aged) donors because of their general good health and ready accessibility in school settings.5  More recent assessments of iron status in teenage blood donors revealed high rates of mild iron depletion and/or absent stores (10%–15% in male donors, 49%–58% in female donors).6,7  The hematocrit-dependent loss of ∼250 mg of iron with whole blood (WB) and ∼425 mg during double red blood cell (2RBC) donation may be difficult to replace on an average Western diet, from which an estimated maximum of 4 mg is absorbed per day.8  An AABB working group, using a risk-based decision-making framework for blood safety,9  concluded that precautionary mitigation efforts beyond donor education and hemoglobin (Hb) testing are appropriate in light of accumulating evidence.10  The group’s preferred risk management options include iron supplementation, use of postdonation ferritin testing to motivate donor action, and/or increasing the interdonation interval (IDI) to allow more time for iron store recovery. IDI prolongation was acknowledged as likely to have the greatest negative impact on blood availability.10  Although many European blood operators had implemented one or more of these interventions in some of their donors, Vitalant, the second largest nonprofit North American blood collector, was the first to introduce ferritin testing for its teen-aged donors in 2016.7,1114  All North American blood collectors obtain blood samples through the donation venipuncture. In the absence of a US Food and Drug Administration–approved point-of-care assay, nonobligatory ferritin testing is conducted on donation samples that reflect predonation iron status.

Despite an understanding of the magnitude of iron depletion in teenage (and adult) donors, knowledge of the time course of iron recovery is limited. In the REDS-III CHILL study, researchers enrolled 4265 donors in high school, 551 over age 18. The CHILL researchers demonstrated that all individuals donating at intervals of 24 to 52 weeks were twice as likely to have low ferritin values as those with donations separated by at least a year.6  Researchers on the REDS-III HEIRS study of 215 donors 18 to 79 years old concluded that in the absence of iron supplements, ∼13 weeks are required for recovery of mean ferritin to ≥26 ng/mL in groups with predonation values above this level.15  In those with low baseline ferritin, mean values had not recovered to at least 26 ng/mL by 24 weeks.

In this article, we report findings of a voluntary donor safety initiative introduced by Vitalant. Using ∼2 years of testing data, we analyzed the impact of an initial (index) WB or 2RBC donation on iron stores using ferritin levels at the first subsequent successful blood donation to estimate the shortest IDIs that correspond with 50% to 95% prevalence of adequate iron stores. We also report these IDI estimates by donor- and donation-related characteristics.

Vitalant implemented serum ferritin testing of tube specimens from every successful donation (with qualifying history and screening examination and adequate unit volume) by 16- to 18-year-old donors, beginning December 19, 2016.7  All donors and legal guardians acknowledge that additional testing may be performed to enhance donor or patient safety. Broad consent is obtained for review of anonymized data provided through a blood operations honest broker. Data were available from this safety initiative through December 31, 2018. Vitalant collects ∼14% of the US blood supply in 27 states, predominantly west of Ohio but also in the mid-Atlantic region. Donations included in this study were obtained from 24 of the 27 states in which Vitalant collects blood.

In healthy individuals, ferritin is the single most practical and cost-effective measure of body iron stores.16  Although chronic inflammation and obesity can elevate ferritin values in mildly iron-deficient individuals, this is of lesser concern among teenagers in whom low values indicate the presence of iron deficiency. There is no US Food and Drug Administration–approved point-of-care ferritin assay, so predonation sample tubes from successful collections are tested using an AU680 assay (Beckman-Coulter, Inc, Brea, CA) linear from 8 to 450 ng/mL, available through Creative Testing Solutions (headquartered in Scottsdale, AZ). Creative Testing Solutions, a nonprofit blood donor testing laboratory, performs ABO and Rh typing, infectious disease screening, and other relevant tests on ∼75% of the US blood supply. We defined “inadequate iron stores” by low ferritin values (ie, <20 ng/mL in female donors and <30 ng/mL in male donors). All WB donors are deferred from red blood cell (RBC) but not apheresis donation for 56 days, and 2RBC donors are deferred from any donation type for 112 days, but teenagers with low ferritin at index or subsequent donation were deferred longer (12 months for female teenagers, 6 months for male teenagers) and counseled by letter to take low-dose (18–28 mg) iron for 60 days. We examined >2 years of data from these donors to estimate the mean shortest IDI after index WB and 2RBC donations by which substantial percentages of subsequent-donation ferritin results exceeded values considered low.

Ferritin values and donation dates were available from Vitalant centers using the eProgesa (MAK System, Paris, France) blood establishment computer system. Teen-aged donor values were obtained from their first (index) ferritin-tested WB or 2RBC donation and the next successful donation of any type with an available ferritin value. To assess only WB and 2RBC donations, concurrent RBC donations during plateletpheresis and/or plasmapheresis were not included at index. Repeat donors who had donated only platelets or plasma in the 2 years before their first ferritin-tested donation were excluded to limit effects to RBC donation. Deferred donors did not have specimens drawn in the absence of a blood donation. Thus, individuals deferred for low finger-stick Hb (female donors <12.5 g/dL; male donors <13.0 g/dL), unacceptable history or examination findings, or without a successful follow-up donation before reaching age 19 were not included in the data set.

We developed a 2-stage statistical model. The first stage used linear regression to estimate mean follow-up ferritin (log-transformed to meet normality assumptions) as a function of IDI, using a 3-knot cubic spline to allow for nonlinear changes in the trajectory of the mean. We estimated the lower bounds of 50%, 60%, 70%, 80%, 90%, and 95% prediction intervals at IDIs up to 20 months (in 0.5-month intervals, selected to balance precision and computer run-time). Across the IDI range, a specific prediction boundary (eg, 60%) traces ferritin values above which 60% of donors’ follow-up values lie. Assuming ferritin levels increase over time after the postdonation nadir (at ∼30 days),17  the earliest IDI at which 60% of the population has adequate iron stores, IDI60%, occurs when the rising 60% prediction boundary first exceeds the low-ferritin threshold. The lower prediction boundary and the threshold marking adequate iron stores can be shown on a scatterplot of individual donors’ postindex ferritin levels and IDIs (Supplemental Fig 6).

The second analysis stage used bootstrapping to quantify uncertainty in IDI estimates. We repeated our modeling procedure in each of 250 bootstrap samples of IDIX%, where X = 50% to 95%. We summarized results via means and 95% confidence intervals (CIs), with CIs based on the percentile method.

Analyses were stratified by sex, collection type (WB, 2RBC), donor status (first-time, repeat), and index ferritin level. Donor status was defined as “repeat” if at least 1 RBC donation in the last 2 years was documented in our computer system and was presumed “first-time” otherwise. For each sex, we classified index ferritin values in 5 categories: inadequate iron stores (low ferritin) and by quartiles of higher ferritin levels. Summary plots were created to display mean (95% CI) IDIs beyond which specified proportions of teenagers to have adequate iron stores.

During 24.5 months of surveillance, 125 384 unique teenagers successfully donated WB or 2RBCs at least once (Fig 1). However, 75.4% failed to return or to donate successfully; among these donors, 38.8% of female individuals and 12.3% of male individuals had a low index ferritin. In contrast, among the 30 806 teenagers (15 376 female and 15 430 male) who returned and successfully donated within 24.5 months, 11.4% of female and 9.7% of male donors had a low index ferritin. At index donation in the 30 806 observational cohort, 78.9% of female and 75.4% of male individuals were first-time donors. Furthermore, most index donations were WB: 96.2% of female donors (WB n = 14 791; 2RBC n = 585) and 73.9% of male donors (WB n = 11 403; 2RBC n = 4027).

Donation intervals were donor determined but also reflect blood drive scheduling. Overall, 92.6% of postindex ferritin values were obtained within 13 months of index donation, with a second peak in the 13th month reflecting annual blood drives (Fig 2). Consequently, IDI 95% CIs are much narrower before 12 to 13 months of follow-up than after. Most teenage allogeneic donations occur at high school or college blood drives held 1 to 4 times per year; in our 2017 sample, these accounted for 84%, 82%, and 70% of donations at ages 16, 17, and 18, respectively.

The mean IDIs required for 50% to 95% of donors’ ferritins to exceed values considered low are shorter for male than female individuals and for WB than 2RBC donations (Fig 3A). Twelve months after their first WB donation, 80% to 90% of male WB donors but only 60% to 70% of female WB donors had adequate iron stores. These proportions were ∼10% lower for 2RBC donors of both sexes (ie, 70% to 80% for male and 50% to 60% for female donors 12 months after index donation). Among donors with adequate index donation iron stores, modest improvements are seen in the proportions of donors with iron stores above low values at subsequent donation: 90% of male and 70% to 80% of female donors one year after WB donation (Fig 3B).

By donation experience, first-time donors may exceed low ferritin values slightly earlier than repeat donors in the first year after donation of WB or 2RBCs (Fig 4).

Among WB donors of each sex, the proportion exceeding low values at their follow-up donation is highly dependent on index ferritin (Fig 5). For 90% to maintain or rebuild adequate iron stores within 3 to 9 months of index donation, index ferritin values had to be ≥47 ng/mL for male donors or ≥53 ng/mL for female donors.

A clearer understanding of the time course and not just the magnitude of iron depletion in teen-aged donors can inform blood collectors about appropriate IDIs in the absence of iron supplementation. Our analysis takes advantage of ∼2 years of follow-up in ferritin-tested donors using specimens from successful donations. In this large teen-aged cohort, at least 12 months are required for a sizeable proportion to reach next-donation ferritin values indicative of adequate iron stores. However, donor sex, donation type, first-time versus repeat status, and ferritin level at index were significant determinants of iron stores at the follow-up donation. We observed that among teenagers with already low iron stores, less than half of male donors and substantially fewer female donors have adequate ferritin values within a year of RBC donation, with prolonged recovery for most of the remainder of these donors (>20 months).

In 2015, 13.4% of 12.9 million collected RBC units were donated by 16- to 18-year-olds.18  One of the fastest-growing donor demographics in the United States includes individuals aged 16 to 18 (28% growth 2011–2015).18  The enthusiasm of altruistic, highly motivated young donors makes large high school and college blood drives efficient and productive. However, researchers of recently published studies suggest that school-aged donors are at increased risk for donation-related iron depletion compared with older donors.6,7  Teen-aged donation occurs against the backdrop of the growth spurt, initiation of menses, and less-healthy dietary habits.19  Researchers suggest associations between iron deficiency (particularly with anemia) and impaired attention, concentration, and learning, but there are few rigorous randomized controlled trials.4  Iron-dependent brain maturation continues into the mid-20s.20  The potential for small, difficult-to-measure adverse effects suggests that it is reasonable to take steps to prevent iron depletion in young donors with developing brains. Precautionary interventions to mitigate teenager iron depletion are already in place for over half of the collections from US 16- to 18-year-olds.7,12,13  Researchers of studies in progress, such as the placebo-controlled Neuroimaging of Iron-Deficient Donors Study, which are assessing neurocognitive function and functional MRI activity before and after repletion of iron-deficient adult blood donors, are likely to better inform such efforts.21 

Studies of the time course of donor iron deficiency suffer from design shortcomings. Randomized controlled trials have been small studies (<50 subjects) of male donors over periods <6 months.17,22  The larger REDS-III HEIRS study also had a short 24-week follow-up.15  The means and end point of recovery to predonation values reported in the HEIRS study also preclude characterization of the proportion of donors with iron deficiency. Nearly 6 months after WB donation, mean ferritin values had not reached 15 ng/mL in unsupplemented donors with predonation values <26 ng/mL. Thus, a significant proportion of those already iron depleted or with just-sufficient stores may be unable to replenish their iron loss within even 12 months. Low-ferritin donors who took iron shortened mean recovery to ∼3.5 months. In the longitudinal REDS-III CHILL study, ∼3700 16- to 18-year-olds and ∼550 adult controls were followed for 6.5 to 9 months.6  Postdonation iron status was characterized by odds ratios for low ferritin 2 to 6 times higher after donations <1 year apart compared with those ≥1 year.

Our cohort of >30 000 teen-aged donors is the largest described to date. Vitalant’s donor safety initiative yielded observational data, and findings should be interpreted in this context. Estimated IDIs represent best-case scenarios because successful donation was required for follow-up ferritin testing after index donation. The cohort excluded individuals deferred for low Hb, which in healthy teenagers is most likely the result of iron deficiency. These individuals would be expected to require longer IDIs to replenish postdonation iron stores. Another limitation is the possibility of nonrandom donor return. The ∼27% of teenagers who visit a fixed donation site or nonschool drive may have different health habits (diet, supplements, etc) than those who donate at annual school drives. We also did not assess for intervening pregnancy or abortion, neither likely to be impactful.

Like other investigators, we did not determine how many donors were taking iron or began iron after reading educational materials or index deferral information mailed to 10.5% of this cohort. On the basis of survey data on iron supplement use in high school donors reported by the American Red Cross (employing a similar ferritin testing strategy), we estimate that <20% of our donor cohort would be expected to be taking iron after their index donation.23  The presence of a small but substantial proportion of donors taking iron is likely to shorten IDI estimates. This is further enhanced by the exclusion of follow-up donors with iron-deficient low-Hb deferrals.

We also found that >90% of teenagers with predonation ferritin values ≥50 ng/mL have adequate iron stores within 3 to 9 months of donation. These data support observations in a supplemental analysis of HEIRS data.24  The investigators observed that without iron supplements, only donors with predonation ferritin values >50 ng/mL had mean postdonation values consistently >26 ng/mL. In individuals uninterested in taking iron supplements, maintenance of healthy iron stores by prolonging IDIs may be guided by serum ferritin levels at the preceding donation and/or point-of-care ferritin determination, once available, at subsequent donations. The effect of altering the current minimum postdonation deferral periods has been modeled within our system.25  Once-annual teenager donations would decrease RBC availability by 4.6%. Less-drastic IDI lengthening, guided by ferritin values, would reduce this negative impact on the blood supply.

Teen-aged blood donors, particularly female donors, appear to be at significant risk for prolonged iron deficiency. Pediatricians should consider blood donation as a cause of borderline or low Hb in the ≥16-year-old age group. It has been estimated that up to 24% of blood donors are either anemic before donation (eg, some male individuals with Hb 13.0–13.4 g/dL) or develop anemia that persists for some time after donation.10  As more blood centers test teen-aged donor ferritin, pediatricians may be asked by donors or parents for advice regarding postdonation iron repletion and optimal timing of future blood donations. In studies, researchers have demonstrated that postdonation low-dose iron supplements (19–38 mg for 60 days) can replace iron losses more rapidly than absorption-limited dietary strategies, mitigating risk for iron deficiency with subsequent donation.26,27  The data from the current study in donors with a low likelihood of iron supplement use provide conservative IDIs (by predonation ferritin values) for those who might prefer not to take iron supplements. Although teenagers are a generally healthy population, higher therapeutic doses of iron should be prescribed by a primary care provider only after assessment of individualized risk for other remediable causes of iron deficiency (eg, gastrointestinal blood loss or celiac disease).

Our results show that in a cohort of female teenagers, ∼11% of whom donated with already low iron stores, approximately one-third had low ferritin one year after WB donation. Perhaps as many as 15% of male teenagers are iron depleted 12 months after single RBC donation (more than the ∼10% iron depleted at index), and more than a quarter donating 2RBCs had iron deficiency. Our findings also support the strong encouragement of postdonation low-dose iron supplements, at least in teenagers with already low or borderline iron stores. In these individuals, studies of older donors suggest a significant reduction in time to iron recovery.15  Iron-deficient blood donors may erode their peak exercise performance, develop pica, or deliver lower birth weight infants, even at nonanemic Hb levels.4,28  Researchers of placebo-controlled studies of iron supplementation in nonanemic iron-deficient adults demonstrate improvements in endurance and energetic efficiency in nondonor high-performance athletes and in fatigue among otherwise healthy premenopausal women.4  The maintenance of adequate iron stores allows blood donation without concerns about these sequelae. As the neurocognitive effects of mild iron deficiency are elucidated, more evidence-based iron depletion mitigation efforts, all of which negatively impact the availability of an already-strained blood supply, may need to be enacted. Our data suggest that an increase in the minimum IDI to allow more time for body iron store repletion requires further consideration in teen-aged donors.

Drs Vassallo, Hilton, Kamel, and Custer conceptualized and designed the study, conducted the analyses, interpreted study data, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Bravo and Vittinghoff conducted the analyses, interpreted study data, and critically reviewed the manuscript for important intellectual content; all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2020-1318.

CI

confidence interval

Hb

hemoglobin

IDI

interdonation interval

RBC

red blood cell

WB

whole blood

2RBC

double red blood cell

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: Dr Vassallo reported scientific advisory board membership for Fresenius Kabi and HemaStrat; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Vassallo reported remunerated scientific advisory board membership for Fresenius Kabi and HemaStrat; the other authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data