- Email: [email protected]
Evaluating the Clinical Effect of Female Blood Donors of Child-Bearing Age on Maternal and Neonatal Outcomes: A Cohort Study
Journal Pre-proof Evaluating the Clinical Effect of Female Blood Donors of ChildBearing Age on Maternal and Neonatal Outcomes: A Cohort Study
Michaël Chassé, Alan Tinmouth, Mindy Goldman, Sheila O'Brien, Steven Hawken, Malia Murphy, Mark Walker, Ann E. Sprague, Kumanan Wilson, Carl van Walraven, Dean A. Fergusson PII:
S0887-7963(19)30165-8
DOI:
https://doi.org/10.1016/j.tmrv.2019.11.007
Reference:
YTMRV 50601
To appear in:
Transfusion Medicine Reviews
Please cite this article as: M. Chassé, A. Tinmouth, M. Goldman, et al., Evaluating the Clinical Effect of Female Blood Donors of Child-Bearing Age on Maternal and Neonatal Outcomes: A Cohort Study, Transfusion Medicine Reviews(2019), https://doi.org/10.1016/ j.tmrv.2019.11.007
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© 2019 Published by Elsevier.
Journal Pre-proof Evaluating the clinical effect of female blood donors of child-bearing age on maternal and neonatal outcomes: a cohort study Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, Quebec, H2X 0A9, Canada; [email protected]
Alan Tinmouth
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Mindy Goldman
Donor and Clinical Services, Canadian Blood Services, Ottawa, Ontario, K1G 4J5, Canada; [email protected]
Sheila O’Brien
Epidemiology and Surveillance, Canadian Blood Services, Ottawa, Ontario, K1G 4J5, Canada; [email protected]
Steven Hawken
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Malia Murphy
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1Y 4E9, Canada; [email protected]
Mark Walker
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Ann E. Sprague
Better Outcomes Registry & Network, Ottawa, Ontario, Canada, K1H 8L6, Canada; [email protected]
Kumanan Wilson
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1Y 4E9; [email protected]
Carl van Walraven
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
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Dean A. Fergusson
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Michaël Chassé
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Corresponding Author:
Michaël Chassé, MD, PhD Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, Quebec, H2X 0A9, Canada Tel: +1 514 890 8000 x 30816 Email: [email protected]
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Journal Pre-proof Abstract
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Iron deficiency is a global problem in women of child bearing age and is associated with adverse maternal and newborn outcomes. Repeated blood donations deplete iron stores and decrease hemoglobin levels. However, the clinical impact of iatrogenic iron deficiency on mothers and neonates due to blood donation is uncertain. The objective of this study was to assess the association between repeated blood donations in female donors of child-bearing age and the associated risk of adverse maternal and neonatal outcomes. We undertook an observational cohort study of all females who delivered a live or stillborn infant in Ontario, Canada between 1 January 2010 and 31 March 2012 using birth record data from the Better Outcomes Registry & Network, Canadian Blood Services and the Institute of Clinical Evaluative Sciences. Only a woman’s first pregnancy within the study time frame was included for analysis. We excluded women <18 years or >50 years of age at the time of delivery and multiple birth pregnancies. Data on all female donors who made whole blood donations between 1 January 2007 and 31 March 2012 were obtained from Canadian Blood Services. The primary newborn outcome was diagnosis of a small for gestational age neonate (less than 10th centile). Secondary outcomes were preterm birth, stillbirth, APGAR <4 at 5 minutes, cord pH <7, neonatal death, maternal transfusion, infection, pre-eclampsia, gestational hypertension, gestational diabetes, placental abruption and maternal death. Regression models evaluated the effect of repeated donation and the time interval between donations and conception on neonatal and maternal outcomes while adjusting for important clinical and demographic risk factors. A total of 260,037 women delivered live or stillborn singleton infants between 1 January 2010 and 31 March 2012. A total of 7,919 (3.0%) women were blood donors, with a mean of 2.43 ± 2.10 lifetime donations. Mean maternal age at the time of delivery for non-donors and donors was 30.30 ± 5.38yrs and 29.74 ± 4.94yrs, respectively. Small for gestational age occurred in 23,706 (9.4%) of neonates born to non-donors, and 526 (6.6%) born to donors. There was a reduction in the risk of small for gestational age with increasing number of lifetime donations (adjusted OR 0.89 [0.86, 0.92] per additional donation). For the prespecified secondary outcomes, we observed a reduction in the risk of low birthweight (adjusted OR 0.95 [0.91, 0.98] per additional donation). There was no association with other secondary neonatal or maternal outcomes except for maternal hypertension. Proximity of donation to conception had no effect on risk of a small-for-gestational age neonate. Our data suggest that there is no increased risk of deleterious neonatal and maternal outcomes associated with repeated blood donations prior to pregnancy. Although possibly a result of a healthy donor effect, our findings are reassuring to female donors and their children as well as to clinicians and blood system stakeholders seeking to inform policy decisions. Key Words: Blood donation, small-for-gestational age, neonate, mother, iron deficiency.
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Journal Pre-proof Introduction Most blood systems in developed countries are entirely dependent on volunteer blood donors[1]. Sustaining the volunteer donor base is critical to the mission of blood collection agencies of providing a safe and effective blood product to the right place, at the right time. To ensure an adequate number of voluntary donors, blood collection agencies must not only ensure that the donation process is as simple as possible for the donor, but more importantly, is safe and without significant health impacts[2]. Many
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of the donor deferral policies enacted by blood collection agencies are implemented to protect the donor from potential harm, but they can also decrease the number of blood donors and donations.
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It is known that blood donations, especially repeated donations, can deplete iron stores and lead to
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anemia in donors [3]. A pre-donation threshold (125g/L for females and 130g/L for males in Canada)
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has been established to ensure that donors with anemia or those at risk of developing anemia do not
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give blood. Despite these precautions, recent evidence has demonstrated that the blood donation process can lead to depleted iron stores, in the absence of anemia, at time of donation in a significant
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number of donors[4]. Independent risk factors for iron deficient erythropoiesis and deferrals for iron
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deficiency included female sex, younger age (in female donors only), shorter donation intervals, and number of donations in the last 2 years[5]. In most countries, pre-donation screening involves a
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hemoglobin level but no measures of iron stores (e.g. ferritin levels), as such only iron deficiency anemia is detected and iron depletion with a normal hemoglobin, which commonly occurs in repeat female blood donors[6–8] is not detected. The result is that presently many female repeated donors unknowingly donate blood despite iron deficiency, and the repeated blood donation aggravates the iron deficiency, and can result in anemia. The clinical impact of iatrogenic iron deficiency due to blood donation is uncertain and there is growing concern[9–11] that repeated donation in females may be harmful. However, one recent Canadian study in the Province of Quebec conducted in 18,483 female blood donor observed no 3
Journal Pre-proof association between repeated blood donation and the risk of low birthweight, preterm birth and stillbirth[12]. Whether this observation would hold in a different population, or when compared to women who have never donated remains to be studied. Addressing iron deficiency in donors ultimately requires changing the approach to donor management[5,11]. Potential strategies to reduce iron deficiency in female donors would include iron supplementation[7,13,14] , ferritin testing followed by deferral or iron supplementation, and decreasing
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the frequency of donation among the highest risk donor group (i.e. females of child bearing age). Mitigation strategies may result in a potential loss of donations, and additional strategies and resources
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to counterbalance the loss in donor base would be required. In light of the recent accumulating
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evidence of increased iron deficiency in repeat female blood donors, it is critical that we better
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understand the impact of iron deficiency in blood donors on a population level[9]. To better understand
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the clinical impact of repeated blood donation in women, we conducted a cohort study to investigate
Study population
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Materials and Methods
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maternal and neonatal outcomes.
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the association between blood donations in female donors of child-bearing age and risk of adverse
We conducted a longitudinal cohort study to assess the association between repeated blood donations in female donors of child-bearing age and the risk of adverse maternal and neonatal outcomes. Donor data were obtained from Canadian Blood Services (CBS), the blood system operator for Canada, except for the province of Quebec. Data on baseline characteristics, and maternal and neonatal outcomes were obtained from the Institute for Clinical Evaluative Sciences (ICES), a provincial repository of recordlevel, linkable health and administrative datasets as well as the Better Outcomes Registry & Network (BORN). This study was approved by the Ottawa Health Science Network and Canadian Blood 4
Journal Pre-proof Services Research Ethics Boards (#20150566-01H and #2016.023, respectively). All Ontario women who delivered a live or stillborn infant between 1 January 2010 and 31 March 2012 were eligible. We included only the woman’s first pregnancy that occurred during the study timeframe; any subsequent pregnancy was excluded from analysis. Women under 18 years of age, or over 50 years of age at the time of delivery were excluded, as were those whose index pregnancy was a multiple birth pregnancy (delivery of twins, triplets etc.). Women were considered donors if they gave at least one whole blood
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donation between January 1 st 2007 and the index pregnancy. Donors who donated through platelet or
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CBS does not perform any double red cell collections.
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plasma apheresis programs without any whole blood donation events were classified as non-donors;
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Data Collection
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Donor data was probabilistically linked using name, date of birth, and postal code to administrative registries in ICES to identify donors that delivered a live or stillborn infant during the study timeframe.
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Cohort characteristics and study outcomes were obtained from datasets held at ICES. Births were
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identified through the Better Outcomes Registry & Network (BORN) registry. BORN is a provincial registry of Ontario’s pregnancy, birth and childhood data stored at ICES. Maternal, pregnancy and
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neonatal characteristics and outcomes were determined from the BORN registry. Red cell transfusion was ascertained through the Canadian Institute for Health Information Discharge Abstract Database. Maternal death was confirmed through examination of The Ministry of Health and Long-term Care registered persons database. Pre-pregnancy maternal hypertension and diabetes were determined by the Ontario Hypertension and Diabetes Datasets, respectively. The Ontario Marginalization Index[15] dataset was used to derive material deprivation and ethnic concentration indices. Study Exposures and outcomes
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Journal Pre-proof Our primary exposure was the occurrence and number of whole blood donations prior to pregnancy. Our primary outcome was diagnosis of small for gestational age dichotomized as the presence or absence of <10th percentile for birthweight for any given gestational age. Secondary outcomes were preterm birth (gestational age <37 weeks), low birthweight <2500g, APGAR <4 at 5 min, cord pH <7, microcephaly, hypoglycemia, hyperbilirubinemia, stillbirth (delivery after 20 weeks’ gestation) and neonatal death. Also included as secondary outcomes, any blood product transfusion and red blood cell
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transfusion, infection, pre-eclampsia, gestational hypertension, gestational diabetes, placental abruption
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and maternal death. Outcome definitions are provided in eTable 1.
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Statistical Analysis
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Baseline characteristics of women at the time of first pregnancy within the study period are presented
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using frequency distributions and univariate descriptive statistics, including measures of central tendency and dispersion, and categorized by blood donor status (yes or no). The primary analysis was a
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logistic model fitting the number of whole blood donations prior to pregnancy as a continuous variable
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using small for gestational age as a binary outcome. We adjusted for known and potential risk factors associated with maternal and neonatal outcome: maternal age at delivery, maternal body mass index,
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maternal alcohol dependence syndrome and drug use (prescription or illegal), pre-existing maternal diabetes and hypertension, use of assisted reproduction technologies, parity, time since previous delivery. Socioeconomic status and ethnicity are also known risk factors for low birth weight and preterm delivery[16,17]. To adjust for these confounders we derived the material deprivation and ethnic concentration indexes obtained from the Ontario Marginalization Index (On-Marg)[15] and included them as covariates in our models. This index is obtained from the postal codes of patients, and using Statistic Canada census data, derives from 42 census variables an estimation of the socioeconomic status. On-Marg has been used for many other research projects to estimate socioeconomic status, 6
Journal Pre-proof including at ICES[18,19]. To assess the effect of the timing of the last donation on outcome, we introduced time between conception and last donation as a covariate in the model. Effect modification of time between conception and last donation and the total number of donations prior to pregnancy was tested using an interaction term between the total number of previous donations and time from conception. The effect of the timing of donations and pregnancy were further assessed by categorizing the exposure by number of donations 2 to 3 years, 1 to 2 years, 6 months to 1 years and less than 6
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months before conception. After linkage, we identified a number of women that gave blood in a time window likely after conception but before delivery. These donations were considered as an additional
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exposure category. For each reported outcome, we reported estimated the 95% confidence interval.
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Management of missing values
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We did not anticipate missing data related to our exposure as all blood donors in Ontario must be registered through CBS as they are the sole blood collection agency. Therefore, all women who gave
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blood during the study period are included in CBS donor databases. Regarding the birth cohort, all
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pregnancies were selected from the BORN dataset. For the study timeframe, when compared to the Canadian Institute of Health Information, BORN captures more than 99% of births in Ontario[20].
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Thus, it is possible that a very minimal number of pregnancies or deliveries will be missed at time of inclusion and, as this data is not available anywhere else, no further analysis can be performed on this small number of pregnancies. We believe that this very low number of missed pregnancies is unlikely to affect results. For included patients, the outcome measures of birth weight and gestational age (for pre-term delivery) is systematically collected for all deliveries in Ontario and expected that less than 1% birth weight or gestational age would be missing and that it would be unlikely to affect our analyses[21,22]. Nevertheless, we report the number of missing outcome and covariate values. Because
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Journal Pre-proof the missing covariate values were unlikely to be missing at random, missing observations were coded as “missing” and included in each model. All statistical analyses were conducted using SAS 9.4.
Sample size calculations Approximately 144,000 pregnancies are captured into BORN registry each year[23]. Over the period of
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our study, we estimated around 260,000 women with singleton pregnancies. From CBS data between 2007 and 2012, approximately 230,000 females gave at least one whole blood donation in Ontario
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(60% donated 2 or more), with an average 1.5 blood donations per year, representing more than 8,000
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women. As stated a priori in our protocol, the estimated number of included women provides a power
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of 99.9% to detect a 1% absolute increased risk for small for gestational age birth weight (with a
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Results
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baseline risk of 10% in the general population).
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From January 1 2010 to March 31, 2012, a total of 260,037 women delivered live or stillborn singleton infants and were eligible for this study of which 7,919 (3.0%) women were blood donors (Figure 1).
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Mean maternal age at the time of delivery for non-donors and donors was 30.3 ± 5.4yrs and 29.7 ± 4.9yrs, respectively. Blood donors had a lower number of previous pregnancies, and had a lower prevalence of diabetes, smoking and alcohol dependence syndrome. They were also more likely to be in the lower quintiles of deprivation index and ethnicity concentration (Table 1). The included women donated a mean of 2.4 ± 2.1 lifetime donations. The women who donated in the last 3 years prior to their delivery donated on average 2.4 times. A total of 498 (6.2%) women donated blood in a time window that would occur after conception. (eTable 2). Crude neonatal and maternal outcomes are presented in Table 2. 8
Journal Pre-proof Overall, small for gestational age occurred in 23,706 (9.4%) of neonates born to non-donors, and 526 (6.6%) born to donors. There was a reduction of the risk of small for gestational age with increasing number of lifetime donations (adjusted OR 0.89 [0.86, 0.92] per additional donation). This association was observed when donations occurred more than 1 year prior to conception, with no association when the donations occurred less than one year prior to conception (Table 3). The interaction between time and the number of donations was not significant (data not shown). For the prespecified secondary
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outcomes, we observed a reduction in the risk of low birthweight (adjusted OR 0.95 [0.91, 0.98] per additional donation). There was no association with other secondary neonatal outcomes (Table 4).
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Because of very low event rates and the number of potential risk factors in our model, no analyses were
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possible for microcephaly (events =54), stillbirth (events=58) and maternal death (events=15).
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Repeated donations were not associated with any adverse maternal outcomes except for gestational
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hypertension (adjusted OR 1.03 [1.001 1.07] per additional donation, n=206 women). This effect was
Discussion
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not significant when considering time between donation to conception (Table 4).
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In a large observational cohort, we did not observe an increased risk of adverse neonatal or maternal
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outcomes in women who donated blood before their pregnancy in the Canadian context. The risk was not increased compared to woman who never donated, nor was it increased with an increased frequency of donations prior to pregnancy. Our results from a large population cohort are consistent with previous findings in Canada[12,24]. A reduced time from donation to conception was also not associated with any adverse maternal or perinatal outcomes. For one secondary maternal outcome, we observed a small statistically significant increase in the risk of maternal hypertension. This finding must be interpreted with caution given the multiplicity of secondary outcomes measured, the small observed effect size (possibly not clinically significant), and the absence of adverse effects for other outcomes. In fact, we observed a generally protective effect of blood donation prior to pregnancy. This 9
Journal Pre-proof observation is most likely related to the healthy-donor effect1. This bias is related to the fact that one must be in a relatively good state of health to consider donating or to be permitted to donate blood. Potential blood donors undergo a screening questionnaire that can lead to donation deferral. For example, at CBS donors are deferred for underlying conditions such as insulin dependent diabetes, systemic lupus erythematosus, renal dysfunction, and lifestyle behaviors such as intranasal cocaine use and illicit drug use. Also, donors who are unwell are less likely to give blood. Our results do not
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suggest that donating blood improves neonatal outcome, but rather that given our current selection processes, such practice is not associated with higher risks compared to women who never donated.
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Our results may be surprising given the known association between blood donation and iron deficiency,
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and iron deficiency anemia and neonatal outcome[26,27]. Although in our study we did not know if the
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donors were iron deficient, recent evidence suggest that iron deficiency prevalence is high in this
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population. In a large national study of over 12,000 donors, 32% of first time and 65% of repeat female donors had low or absent iron stores[28]. This data is similar to a large U.S. cohort study for 2,524
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blood donors, which showed evidence of iron deficient erythropoiesis in 50% of female donors and
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62% of frequent female donors. Importantly, iron deficiency itself, as well as the resulting anemia have been associated with negative maternal and neonatal outcomes[26]. A recent systematic review found
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a significant association between anemia in pregnancy and the risk of increased adverse perinatal outcomes with an increased risk of low birth weight (OR 1.25 95% CI; 1.08 to 1.45), preterm birth (OR 1.28 95% CI; 1.12 to 1.47) and stillbirth (OR 1.19 95% CI; 1.09 to 1.29)[27]. Despite these findings in the anemic pregnant female population, we observed no association with adverse effects in our population of female blood donors despite the evidence that these women are at high risk of being iron deficient. We can propose a few hypothetical explanations for these findings. First, we do not know the actual status of the iron stores in previous blood donors during their pregnancies. In Canada, some but not all 10
Journal Pre-proof women are screened for iron deficiency in pregnancy and advised to take supplements. If taken a few months before conception or even if started at the time of conception, the supplements could reduce any impact of donation[27]. Second, the iron deficiency in female blood donors is likely different than iron deficiency due to the blood /iron loss associated with repeat blood donations as suggested in previous populational studies where anemia may be associated with lower socioeconomic status, malnutrition or other illnesses[27]. These other factors may by themselves increase the risk of poorer
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neonatal outcome. In blood donors who are self- selected based partially on good health and who are screened for anemia, any unmeasured iron deficiency would be partly due to blood donation and not
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necessarily other unmeasured confounders. Conversely, it is possible that the potential deleterious
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effects of anemia and iron deficiency are counterbalanced by the selection of a healthy donor
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population , and potentially the benefits of universal health care coverage and routine prenatal care,
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thus preventing us from detecting harm associated with repeated blood donation. In other words, because of the inherent characteristics of our population, neonatal and maternal outcomes could be
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more favorable independent of blood donation or not and would therefore obfuscate the potential harms
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of iron deficiency in this population. Finally, there is a possibility of Type 2 error in which we are incorrectly concluding that there is no harm associated with blood donation. This could be due to
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incomplete adjustment for measured confounding factors, unmeasured confounding factors, incorrect statistical modelling or insufficient power. Our study has strengths and limitations. We conducted a large, population-level study of all pregnancies in our jurisdiction using high quality data sources. We were able to consider numerous potential confounding factors known to be associated with neonatal and maternal outcomes, including smoking status, alcohol consumption, sociodemographic factors and comorbidities and despite these facts, we did not observe evidence of risks of blood donation in our female blood donor population. Although the included women gave blood an average of 2.43 times, 3,661 (46.2%) of women donated 11
Journal Pre-proof blood only once during the study timeframe which may be insufficient to cause a significant enough iron deficiency to affect outcome. We however had 664 (8.4%) women who donated at least once in the 6 months prior to conception, thus were less likely to be improving their iron status leading up to the pregnancy. Also, the data pertaining to previous donations was available only for the specified study timeframe. It is therefore possible that some women donated blood before the 3-year observation window in both groups. However, it seems unlikely that more remote donation would affect
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significantly our results given our observed lack of effect in the 3 years prior to the pregnancy. Finally, ferritin and hemoglobin levels were not available to strengthen the analysis. It is therefore possible that
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a proportion of blood donors did not have iron deficiency, and thus diluting a potential deleterious
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association. However, given the high prevalence of iron deficiency among blood donors in our previous
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studies[4] and our large sample size, we hypothesize that we should have been able to detect an effect
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should it be present.
In summary, while there is evidence that repeated blood donations may result in iron deficiency and
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anemia in female donors, our data suggest that there is no increased risk of repeated blood donations
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prior to pregnancy on neonatal and maternal outcomes in the Canadian context. However, given the evidence of the impact of confirmed maternal iron deficiency on neonatal outcomes, when such
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deficiency is confirmed, blood donation deferral should be implemented, a thorough investigation for the cause of iron deficiency should be conducted and iron supplementation should be offered when appropriate. Although possibly a result of a healthy donor effect, our findings are reassuring to female donors as well as clinical and blood organization stakeholders seeking to inform policy decisions.
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Journal Pre-proof Disclosures This study is based in part on data provided by the Better Outcomes Registry and Network (“BORN”), part of the Children’s Hospital of Eastern Ontario. The interpretation and conclusions contained herein do not necessarily represent those of BORN Ontario. Part of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI. The ONMARG dataset was created at the Institute for Clinical Evaluative Sciences using data directly from Toronto Community Health Profiles, applying algorithms detailed in Matheson et al. “Development of the Canadian Marginalization Index: a new tool for the study of inequality.” Canadian Journal of Public Health, 2012;103(suppl.2):S12-S16.
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Funding
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This work was supported by a CBS/011R Partnership in Transfusion Science Spring 2015 Award [funding reference number: CHIR-101507-AT-342028].
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Acknowledgements
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We would like to thank Glenys Smith analyst at the Institute for Clinical Evaluative Sciences for her contribution to the analysis of this project. This work was made possible because of the extensive collaboration of Canadian Blood Services and the Ontario Institute for Clinical Evaluative Science and the Better Outcomes Registry and Network (“BORN”).
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[24] Rigas AS, Pedersen OB, Rostgaard K, Sørensen E, Erikstrup C, Hjalgrim H, et al. Frequent
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blood donation and offspring scholastic attainment: an assessment of long‐term consequences of prenatal iron deficiency. Transfusion 2019;59:1717–22. https://doi.org/10.1111/trf.15193. [25] Atsma F, Veldhuizen I, Verbeek A, de Kort W, de Vegt F. Healthy donor effect: its magnitude in health research among blood donors. Transfusion 2011;51:1820–8. https://doi.org/10.1111/j.1537-2995.2010.03055.x. [26] Sifakis S, Pharmakides G. Anemia in pregnancy. Ann N Y Acad Sci 2000;900:125–36. [27] Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ 16
Journal Pre-proof 2013;346:f3443. https://doi.org/10.1136/bmj.f3443. [28] Goldman M, Uzicanin S, Osmond L, Scalia V, O’Brien SF. A large national study of ferritin testing in Canadian blood donors. Transfusion 2017;57:564–70.
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https://doi.org/10.1111/trf.13956.
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Figure 1. Flowchart of cohort creation.
BORN: Better Outcomes Registry and Network
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Journal Pre-proof Table 1. Maternal Baseline Characteristics
29.74 ± 4.94 1,523 (19.2%) 5,429 (68.6%) 964 (12.2%) 3 (0.0%)
26.29 ± 18.81 212,688 (84.4%) 1,679 (0.7%) 18,951 (7.5%) 10,227 (4.1%) 8,573 (3.4%)
27.62 ± 13.00 6,685 (84.4%) 14 (0.2%) 527 (6.7%) 363 (4.6%) 330 (4.2%)
2,360 (0.9%)
88 (1.1%)
2,559 (1.0%)
127,569 (50.6%)
3032 (38.3%)
3,500 (1.4%)
119 (1.5%)
229,591 (91.1%)
7,486 (94.5%)
19,027 (7.5%)
314 (4.0%)
0 (0-2) 159,503 (63.3%) 581 (0.2%) 23,144 (9.2%) 38,092 (15.1%) 20,888 (8.3%) 9,910 (3.9%)
0 (0-2) 5,589 (70.6%) 14 (0.2%) 586 (7.4%) 1,007 (12.7%) 492 (6.2%) 231 (2.9%)
42,481 (16.8%) 204,626 (81.2%) 5,011 (2.0%)
1,241 (15.7%) 6,496 (82.0%) 182 (2.3%)
245,505 (97.4%) 6,613 (2.6%)
7,713 (97.4%) 206 (2.6%)
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No Yes Time since previous delivery, years Median (IQR) <6 months 6 months – <1 year 1 – <2 years 2 – < 3 years 3 – <4 years ≥4 years Use of assisted reproductive therapy for current pregnancy Missing No Yes Hypertension No Yes
4,792 (60.5%)
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Missing
95 (1.2%)
121,990 (48.4%)
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No Yes Previous preterm delivery
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Missing
4,595 (58.0%) 3,236 (40.9%)
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108,923 (43.2%) 140,835 (55.9%)
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30.30 ± 5.38 48,460 (19.2%) 160,865 (63.8%) 42,522 (16.9%) 271 (0.1%)
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Missing Nulliparous Parous Previous term delivery
Donors n=7,919
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Age at Delivery, yrs Mean ± SD 18 - 25 26 - 35 36 - 45 45+ Pre-pregnancy BMI, kg/m2 Mean ± SD Missing <18.5 18.5-24.9 25.0-29.9 ≥30 Parity
Non-Donors n=252,118
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Journal Pre-proof 7,805 (98.6%) 114 (1.4%)
13,925 (5.5%) 211,992 (84.1%) 26,201 (10.4%)
426 (5.4%) 7,019 (88.6%) 474 (6.0%)
10,027 (4.0%) 241,839 (95.9%) 252 (0.1%)
480 (6.1%) 7,432 (93.9%) 7 (0.1%)
10,027 (4.0%) 229,584 (91.1%) 12,507 (5.0%)
480 (6.1%) 6,966 (88.0%) 473 (6.0%)
4,234 (1.7%) 59,778 (23.7%) 44,500 (17.7%) 44,609 (17.7%) 44,267 (17.6%) 54,730 (21.7%)
74 (0.9%) 2,102 (26.5%) 1,628 (20.6%) 1,591 (20.1%) 1,341 (16.9%) 1,183 (14.9%)
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246,918 (97.9%) 5,200 (2.1%)
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4,234 (1.7%) 30,392 (12.1%) 33,487 (13.3%) 40,415 (16.0%) 53,854 (21.4%) 89,736 (35.6%)
74 (0.9%) 1,500 (18.9%) 1,642 (20.7%) 1,638 (20.7%) 1,822 (23.0%) 1,243 (15.7%)
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Diabetes No Yes Smoking Missing No Yes Alcohol dependence syndrome Missing No Yes History of drug use (prescribed or illicit) Missing No Yes Deprivation Quintile Missing 1 (lowest) 2 3 4 5 (highest) Ethnic Concentration Quintile Missing 1 (lowest) 2 3 4 5 (highest)
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Journal Pre-proof Table 2. Neonatal and Maternal outcomes
38.89 ± 1.77 39 (38-40) 236,910 (94.0%) 11,745 (4.7%) 1,611 (0.6%) 1,126 (0.4%) 726 (0.3%)
39.08 ± 1.78 39 (38-40) 7,469 (94.3%) 352 (4.4%) 43 (0.5%) 31 (0.4%) 24 (0.3%)
3,372.29 ± 544.62 3,384 (3,060-3,710) 193 (0.1%) 27,259 (10.8%) 212,643 (84.3%) 10,362 (4.1%) 941 (0.4%) 720 (0.3%)
3,456.24 ± 538.21 3,472 (3,158-3,787) 10 (0.1%) 1,081 (13.7%) 6,530 (82.5%) 248 (3.1%) 28 (0.4%) 22 (0.3%)
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Donors
42 (0.5%) 7,351 (92.8%) 526 (6.6%)
2,494 (1.0%) 248,968 (98.8%) 656 (0.3%)
100 (1.3%) 7,800 (98.5%) 19 (0.2%)
76,853 (30.5%) 174,247 (69.1%) 1,018 (0.4%)
2,400 (30.3%) 5,495 (69.4%) 24 (0.3%)
8 (0.0%) 246,961 (98.0%) 5,149 (2.0%)
1 (0.0%) 7,769 (98.1%) 149 (1.9%)
8 (0.0%) 228,927 (90.8%) 23,183 (9.2%)
1 (0.0%) 7,168 (90.5%) 750 (9.5%)
391 (0.2%) 251,485 (99.7%) 242 (0.1%)
21 (0.3%) 7,892 (99.7%) 6 (0.1%)
5,172 (2.1%) 241,878 (95.9%)
198 (2.5%) 7,532 (95.1%)
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834 (0.3%) 227,578 (90.3%) 23,706 (9.4%)
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Neonatal Outcomes Gestational age at birth, weeks Mean ± SD Median (IQR) Term, ≥37 Late Preterm, 34 - 37 Moderate Preterm, 32 - 33 Very Preterm, 28 - 32 Extremely Preterm, < 28 Birthweight Mean ± SD Median (IQR) Missing ≥4,000g ≥2,500-3999g ≥1500g - <2,499g ≥1000g - <1499g <1000g SGA (less than 10th centile) Missing No Yes APGAR <4 at 5 min Missing No Yes Arterial cord pH <7 Missing No Yes Hypoglycemia Missing No Yes Hyperbilirubinemia Missing No Yes Death at Birth Missing No Yes Maternal Outcomes Preeclampsia Missing No
Non-Donors
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Journal Pre-proof 189 (2.4%)
5,479 (2.2%) 245,245 (97.3%) 1,394 (0.6%)
210 (2.7%) 7,664 (96.8%) 45 (0.6%)
7,136 (2.8%) 236,548 (93.8%) 8,434 (3.3%)
270 (3.4%) 7,305 (92.2%) 344 (4.3%)
7,136 (2.8%) 232,556 (92.2%) 12,426 (4.9%)
270 (3.4%) 7,409 (93.6%) 240 (3.0%)
0 (0.0%) 250,725 (99.4%) 1,393 (0.6%)
0 (0.0%) 7,873 (99.4%) 46 (0.6%)
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0 (0.0%) 251,223 (99.6%) 895 (0.4%)
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Yes Placental Abruption Missing No Yes Gestational Hypertension Missing No Yes Gestational Diabetes Missing No Yes Transfusion Missing No Yes RBC transfusion Missing No Yes Infection during pregnancy Missing No Yes
225 (2.8%) 7,648 (96.6%) 46 (0.6%)
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5,818 (2.3%) 244,686 (97.1%) 1,614 (0.6%)
0 (0.0%) 7,896 (99.7%) 23 (0.3%)
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Journal Pre-proof Table 3. Association between number of donations and risk of Small for Gestational Age Unadjusted Odds Ratio (95%CI) 0.89 (0.86, 0.92) 1.04 (0.74, 1.46) 0.92 (0.81,1.04) 0.87 (0.76, 0.995) 0.87 (0.79, 0.94) 0.89 (0.82, 0.97)
Number of donations After Conception Conception-6months >6months-1yr >1yr-2yr >2yr-3yr
Adjusted Odds Ratio (95%CI)* 0.91 (0.88, 0.94) 1.14 (0.81, 1.61) 0.98 (0.86, 1.11) 0.91 (0.79, 1.04) 0.86 (0.79, 0.94) 0.91 (0.83, 0.99)
*
Adjusted for maternal age at delivery, maternal BMI, maternal alcohol dependence syndrome and drug use, pre-existing maternal diabetes and hypertension, use of assisted reproduction technologies, maternal deprivation quintile, ethnic concentration quintile, parity, time since previous delivery. Table 4. Association between number of donations and risk of secondary outcomes After Conception
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Adjusted Odds Ratio (95%CI)* Conception- >6months>1yr-2yr >2yr-3yr 6months 1yr
Neonatal outcomes
Cord pH <7 Hypoglycemia Hyperbilirubinemia Maternal outcomes Gestational hypertension Gestational Diabetes Pre-eclampsia
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APGAR <4 at 5 minutes
0.83 (0.49, 1.41) 0.67 (0.09, 5.01) 0.52(0.07, 3.84) 1.12 (0.59, 2.13) 1.14 (0.84, 1.55) 1.35 (0.89, 2.07) 1.33 (0.83, 2.13) 0.81 (0.41, 1.60)
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Birthweight <2,500
Placental Abruption
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Infection during pregnancy Maternal Transfusion Maternal RBC transfusion
0.96 (0.30, 3.09) 2.19 (0.95, 5.04) 2.22 (0.69, 7.12)
0.98 (0.90, 1.18) 1.14 (0.61, 2.12) 0.97 (0.88, 1.08) 1.02 (0.72, 1.45) 0.58 (0.34, 0.97) 0.94 (0.81, 1.10) 1.04 (0.97, 1.11)
1.01 (0.93, 1.10) 0.83 (0.38, 1.81) 0.95 (0.85, 1.06) 1.06 (0.75, 1.50) 0.65 (0.39, 1.09) 0.93 (0.79, 1.08) 0.99 (0.92, 1.06)
0.99 (0.96, 1.02) 0.98 (0.77, 1.25) 0.95 (0.91, 0.98) 1.03 (0.91, 1.16) 0.88 (0.75, 1.02) 0.97 (0.92, 1.03) 0.99 (0.97, 1.01)
1.05 (0.89, 1.23) 0.80 (0.65, 0.98) 1.00 (0.81, 1.24) 1.27 (0.84, 1.92) 0.89 (0.58, 1.37) 1.59 (1.15, 2.21) 1.32 (0.73, 1.48)
1.05 (0.95, 1.15) 0.95 (0.84, 1.07) 0.99 (0.88, 1.12) 1.17 (0.90, 1.50) 1.02 (0.80, 1.32) 1.04 (0.82, 1.33) 1.04 (0.73, 1.48)
0.99 (0.89, 1.09) 0.91 (0.80, 1.03) 1.05 (0.93, 1.19) 0.79 (0.56, 1.11) 0.89 (0.67, 1.17) 0.76 (0.55, 1.05) 0.57 (0.31, 1.02)
1.03 (1.001, 1.07) 0.91 (0.87, 0.95) 1.01 (0.97, 1.06) 0.96 (0.86, 1.07) 0.99 (0.91, 1.09) 1.01 (0.93, 1.10) 0.93 (0.81, 1.08)
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1.03 (0.90, 1.18) 0.65 (0.17, 2.50) 0.88 (0.73, 1.05) 0.89 (0.47, 1.68) 1.65 (1.07, 2.55) 1.25 (1.01, 1.55) 0.96 (0.86, 1.08)
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Infant Death
0.96 (0.83, 1.10) 1.54 (0.67, 3.56) 0.98 (0.83, 1.16) 1.21 (0.71, 2.07) 1.08 (0.66, 1.77) 0.82 (0.64, 1.06) 0.90 (0.80, 1.00)
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0.90 (0.60, 1.37)
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Preterm Birth
1.05 (0.90, 1.22) 0.88 (0.72, 1.06) 1.04 (0.85, 1.28) 0.66 (0.37, 1.16) 1.24 (0.87, 1.77) 0.68 (0.43, 1.09) 0.74 (0.39, 1.42)
Overall
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Adjusted for maternal age at delivery, maternal BMI, maternal alcohol dependence syndrome and drug use, pre-existing maternal diabetes and hypertension, use of assisted reproduction technologies, maternal deprivation quintile, ethnic concentration quintile, parity, time since previous delivery. 23
Journal Pre-proof Highlights
1. We observed a reduction in the risk of small for gestational age birth with increasing number of lifetime whole blood donations.
2. We observed no other association between repeated blood donation and other neonatal and maternal outcomes.
3. Our findings are reassuring to female donors and their children as well as to clinicians and blood
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system stakeholders seeking to inform policy decisions.
24
Michaël Chassé, Alan Tinmouth, Mindy Goldman, Sheila O'Brien, Steven Hawken, Malia Murphy, Mark Walker, Ann E. Sprague, Kumanan Wilson, Carl van Walraven, Dean A. Fergusson PII:
S0887-7963(19)30165-8
DOI:
https://doi.org/10.1016/j.tmrv.2019.11.007
Reference:
YTMRV 50601
To appear in:
Transfusion Medicine Reviews
Please cite this article as: M. Chassé, A. Tinmouth, M. Goldman, et al., Evaluating the Clinical Effect of Female Blood Donors of Child-Bearing Age on Maternal and Neonatal Outcomes: A Cohort Study, Transfusion Medicine Reviews(2019), https://doi.org/10.1016/ j.tmrv.2019.11.007
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Published by Elsevier.
Journal Pre-proof Evaluating the clinical effect of female blood donors of child-bearing age on maternal and neonatal outcomes: a cohort study Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, Quebec, H2X 0A9, Canada; [email protected]
Alan Tinmouth
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Mindy Goldman
Donor and Clinical Services, Canadian Blood Services, Ottawa, Ontario, K1G 4J5, Canada; [email protected]
Sheila O’Brien
Epidemiology and Surveillance, Canadian Blood Services, Ottawa, Ontario, K1G 4J5, Canada; [email protected]
Steven Hawken
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Malia Murphy
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1Y 4E9, Canada; [email protected]
Mark Walker
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Ann E. Sprague
Better Outcomes Registry & Network, Ottawa, Ontario, Canada, K1H 8L6, Canada; [email protected]
Kumanan Wilson
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1Y 4E9; [email protected]
Carl van Walraven
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
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Dean A. Fergusson
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Michaël Chassé
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H 8L6, Canada; [email protected]
Corresponding Author:
Michaël Chassé, MD, PhD Centre de recherche du Centre hospitalier de l’Université de Montréal, Montréal, Quebec, H2X 0A9, Canada Tel: +1 514 890 8000 x 30816 Email: [email protected]
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Journal Pre-proof Abstract
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Iron deficiency is a global problem in women of child bearing age and is associated with adverse maternal and newborn outcomes. Repeated blood donations deplete iron stores and decrease hemoglobin levels. However, the clinical impact of iatrogenic iron deficiency on mothers and neonates due to blood donation is uncertain. The objective of this study was to assess the association between repeated blood donations in female donors of child-bearing age and the associated risk of adverse maternal and neonatal outcomes. We undertook an observational cohort study of all females who delivered a live or stillborn infant in Ontario, Canada between 1 January 2010 and 31 March 2012 using birth record data from the Better Outcomes Registry & Network, Canadian Blood Services and the Institute of Clinical Evaluative Sciences. Only a woman’s first pregnancy within the study time frame was included for analysis. We excluded women <18 years or >50 years of age at the time of delivery and multiple birth pregnancies. Data on all female donors who made whole blood donations between 1 January 2007 and 31 March 2012 were obtained from Canadian Blood Services. The primary newborn outcome was diagnosis of a small for gestational age neonate (less than 10th centile). Secondary outcomes were preterm birth, stillbirth, APGAR <4 at 5 minutes, cord pH <7, neonatal death, maternal transfusion, infection, pre-eclampsia, gestational hypertension, gestational diabetes, placental abruption and maternal death. Regression models evaluated the effect of repeated donation and the time interval between donations and conception on neonatal and maternal outcomes while adjusting for important clinical and demographic risk factors. A total of 260,037 women delivered live or stillborn singleton infants between 1 January 2010 and 31 March 2012. A total of 7,919 (3.0%) women were blood donors, with a mean of 2.43 ± 2.10 lifetime donations. Mean maternal age at the time of delivery for non-donors and donors was 30.30 ± 5.38yrs and 29.74 ± 4.94yrs, respectively. Small for gestational age occurred in 23,706 (9.4%) of neonates born to non-donors, and 526 (6.6%) born to donors. There was a reduction in the risk of small for gestational age with increasing number of lifetime donations (adjusted OR 0.89 [0.86, 0.92] per additional donation). For the prespecified secondary outcomes, we observed a reduction in the risk of low birthweight (adjusted OR 0.95 [0.91, 0.98] per additional donation). There was no association with other secondary neonatal or maternal outcomes except for maternal hypertension. Proximity of donation to conception had no effect on risk of a small-for-gestational age neonate. Our data suggest that there is no increased risk of deleterious neonatal and maternal outcomes associated with repeated blood donations prior to pregnancy. Although possibly a result of a healthy donor effect, our findings are reassuring to female donors and their children as well as to clinicians and blood system stakeholders seeking to inform policy decisions. Key Words: Blood donation, small-for-gestational age, neonate, mother, iron deficiency.
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Journal Pre-proof Introduction Most blood systems in developed countries are entirely dependent on volunteer blood donors[1]. Sustaining the volunteer donor base is critical to the mission of blood collection agencies of providing a safe and effective blood product to the right place, at the right time. To ensure an adequate number of voluntary donors, blood collection agencies must not only ensure that the donation process is as simple as possible for the donor, but more importantly, is safe and without significant health impacts[2]. Many
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of the donor deferral policies enacted by blood collection agencies are implemented to protect the donor from potential harm, but they can also decrease the number of blood donors and donations.
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It is known that blood donations, especially repeated donations, can deplete iron stores and lead to
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anemia in donors [3]. A pre-donation threshold (125g/L for females and 130g/L for males in Canada)
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has been established to ensure that donors with anemia or those at risk of developing anemia do not
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give blood. Despite these precautions, recent evidence has demonstrated that the blood donation process can lead to depleted iron stores, in the absence of anemia, at time of donation in a significant
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number of donors[4]. Independent risk factors for iron deficient erythropoiesis and deferrals for iron
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deficiency included female sex, younger age (in female donors only), shorter donation intervals, and number of donations in the last 2 years[5]. In most countries, pre-donation screening involves a
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hemoglobin level but no measures of iron stores (e.g. ferritin levels), as such only iron deficiency anemia is detected and iron depletion with a normal hemoglobin, which commonly occurs in repeat female blood donors[6–8] is not detected. The result is that presently many female repeated donors unknowingly donate blood despite iron deficiency, and the repeated blood donation aggravates the iron deficiency, and can result in anemia. The clinical impact of iatrogenic iron deficiency due to blood donation is uncertain and there is growing concern[9–11] that repeated donation in females may be harmful. However, one recent Canadian study in the Province of Quebec conducted in 18,483 female blood donor observed no 3
Journal Pre-proof association between repeated blood donation and the risk of low birthweight, preterm birth and stillbirth[12]. Whether this observation would hold in a different population, or when compared to women who have never donated remains to be studied. Addressing iron deficiency in donors ultimately requires changing the approach to donor management[5,11]. Potential strategies to reduce iron deficiency in female donors would include iron supplementation[7,13,14] , ferritin testing followed by deferral or iron supplementation, and decreasing
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the frequency of donation among the highest risk donor group (i.e. females of child bearing age). Mitigation strategies may result in a potential loss of donations, and additional strategies and resources
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to counterbalance the loss in donor base would be required. In light of the recent accumulating
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evidence of increased iron deficiency in repeat female blood donors, it is critical that we better
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understand the impact of iron deficiency in blood donors on a population level[9]. To better understand
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the clinical impact of repeated blood donation in women, we conducted a cohort study to investigate
Study population
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Materials and Methods
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maternal and neonatal outcomes.
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the association between blood donations in female donors of child-bearing age and risk of adverse
We conducted a longitudinal cohort study to assess the association between repeated blood donations in female donors of child-bearing age and the risk of adverse maternal and neonatal outcomes. Donor data were obtained from Canadian Blood Services (CBS), the blood system operator for Canada, except for the province of Quebec. Data on baseline characteristics, and maternal and neonatal outcomes were obtained from the Institute for Clinical Evaluative Sciences (ICES), a provincial repository of recordlevel, linkable health and administrative datasets as well as the Better Outcomes Registry & Network (BORN). This study was approved by the Ottawa Health Science Network and Canadian Blood 4
Journal Pre-proof Services Research Ethics Boards (#20150566-01H and #2016.023, respectively). All Ontario women who delivered a live or stillborn infant between 1 January 2010 and 31 March 2012 were eligible. We included only the woman’s first pregnancy that occurred during the study timeframe; any subsequent pregnancy was excluded from analysis. Women under 18 years of age, or over 50 years of age at the time of delivery were excluded, as were those whose index pregnancy was a multiple birth pregnancy (delivery of twins, triplets etc.). Women were considered donors if they gave at least one whole blood
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donation between January 1 st 2007 and the index pregnancy. Donors who donated through platelet or
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CBS does not perform any double red cell collections.
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plasma apheresis programs without any whole blood donation events were classified as non-donors;
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Data Collection
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Donor data was probabilistically linked using name, date of birth, and postal code to administrative registries in ICES to identify donors that delivered a live or stillborn infant during the study timeframe.
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Cohort characteristics and study outcomes were obtained from datasets held at ICES. Births were
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identified through the Better Outcomes Registry & Network (BORN) registry. BORN is a provincial registry of Ontario’s pregnancy, birth and childhood data stored at ICES. Maternal, pregnancy and
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neonatal characteristics and outcomes were determined from the BORN registry. Red cell transfusion was ascertained through the Canadian Institute for Health Information Discharge Abstract Database. Maternal death was confirmed through examination of The Ministry of Health and Long-term Care registered persons database. Pre-pregnancy maternal hypertension and diabetes were determined by the Ontario Hypertension and Diabetes Datasets, respectively. The Ontario Marginalization Index[15] dataset was used to derive material deprivation and ethnic concentration indices. Study Exposures and outcomes
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Journal Pre-proof Our primary exposure was the occurrence and number of whole blood donations prior to pregnancy. Our primary outcome was diagnosis of small for gestational age dichotomized as the presence or absence of <10th percentile for birthweight for any given gestational age. Secondary outcomes were preterm birth (gestational age <37 weeks), low birthweight <2500g, APGAR <4 at 5 min, cord pH <7, microcephaly, hypoglycemia, hyperbilirubinemia, stillbirth (delivery after 20 weeks’ gestation) and neonatal death. Also included as secondary outcomes, any blood product transfusion and red blood cell
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transfusion, infection, pre-eclampsia, gestational hypertension, gestational diabetes, placental abruption
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and maternal death. Outcome definitions are provided in eTable 1.
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Statistical Analysis
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Baseline characteristics of women at the time of first pregnancy within the study period are presented
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using frequency distributions and univariate descriptive statistics, including measures of central tendency and dispersion, and categorized by blood donor status (yes or no). The primary analysis was a
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logistic model fitting the number of whole blood donations prior to pregnancy as a continuous variable
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using small for gestational age as a binary outcome. We adjusted for known and potential risk factors associated with maternal and neonatal outcome: maternal age at delivery, maternal body mass index,
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maternal alcohol dependence syndrome and drug use (prescription or illegal), pre-existing maternal diabetes and hypertension, use of assisted reproduction technologies, parity, time since previous delivery. Socioeconomic status and ethnicity are also known risk factors for low birth weight and preterm delivery[16,17]. To adjust for these confounders we derived the material deprivation and ethnic concentration indexes obtained from the Ontario Marginalization Index (On-Marg)[15] and included them as covariates in our models. This index is obtained from the postal codes of patients, and using Statistic Canada census data, derives from 42 census variables an estimation of the socioeconomic status. On-Marg has been used for many other research projects to estimate socioeconomic status, 6
Journal Pre-proof including at ICES[18,19]. To assess the effect of the timing of the last donation on outcome, we introduced time between conception and last donation as a covariate in the model. Effect modification of time between conception and last donation and the total number of donations prior to pregnancy was tested using an interaction term between the total number of previous donations and time from conception. The effect of the timing of donations and pregnancy were further assessed by categorizing the exposure by number of donations 2 to 3 years, 1 to 2 years, 6 months to 1 years and less than 6
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months before conception. After linkage, we identified a number of women that gave blood in a time window likely after conception but before delivery. These donations were considered as an additional
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exposure category. For each reported outcome, we reported estimated the 95% confidence interval.
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Management of missing values
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We did not anticipate missing data related to our exposure as all blood donors in Ontario must be registered through CBS as they are the sole blood collection agency. Therefore, all women who gave
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blood during the study period are included in CBS donor databases. Regarding the birth cohort, all
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pregnancies were selected from the BORN dataset. For the study timeframe, when compared to the Canadian Institute of Health Information, BORN captures more than 99% of births in Ontario[20].
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Thus, it is possible that a very minimal number of pregnancies or deliveries will be missed at time of inclusion and, as this data is not available anywhere else, no further analysis can be performed on this small number of pregnancies. We believe that this very low number of missed pregnancies is unlikely to affect results. For included patients, the outcome measures of birth weight and gestational age (for pre-term delivery) is systematically collected for all deliveries in Ontario and expected that less than 1% birth weight or gestational age would be missing and that it would be unlikely to affect our analyses[21,22]. Nevertheless, we report the number of missing outcome and covariate values. Because
7
Journal Pre-proof the missing covariate values were unlikely to be missing at random, missing observations were coded as “missing” and included in each model. All statistical analyses were conducted using SAS 9.4.
Sample size calculations Approximately 144,000 pregnancies are captured into BORN registry each year[23]. Over the period of
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our study, we estimated around 260,000 women with singleton pregnancies. From CBS data between 2007 and 2012, approximately 230,000 females gave at least one whole blood donation in Ontario
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(60% donated 2 or more), with an average 1.5 blood donations per year, representing more than 8,000
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women. As stated a priori in our protocol, the estimated number of included women provides a power
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of 99.9% to detect a 1% absolute increased risk for small for gestational age birth weight (with a
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Results
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baseline risk of 10% in the general population).
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From January 1 2010 to March 31, 2012, a total of 260,037 women delivered live or stillborn singleton infants and were eligible for this study of which 7,919 (3.0%) women were blood donors (Figure 1).
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Mean maternal age at the time of delivery for non-donors and donors was 30.3 ± 5.4yrs and 29.7 ± 4.9yrs, respectively. Blood donors had a lower number of previous pregnancies, and had a lower prevalence of diabetes, smoking and alcohol dependence syndrome. They were also more likely to be in the lower quintiles of deprivation index and ethnicity concentration (Table 1). The included women donated a mean of 2.4 ± 2.1 lifetime donations. The women who donated in the last 3 years prior to their delivery donated on average 2.4 times. A total of 498 (6.2%) women donated blood in a time window that would occur after conception. (eTable 2). Crude neonatal and maternal outcomes are presented in Table 2. 8
Journal Pre-proof Overall, small for gestational age occurred in 23,706 (9.4%) of neonates born to non-donors, and 526 (6.6%) born to donors. There was a reduction of the risk of small for gestational age with increasing number of lifetime donations (adjusted OR 0.89 [0.86, 0.92] per additional donation). This association was observed when donations occurred more than 1 year prior to conception, with no association when the donations occurred less than one year prior to conception (Table 3). The interaction between time and the number of donations was not significant (data not shown). For the prespecified secondary
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outcomes, we observed a reduction in the risk of low birthweight (adjusted OR 0.95 [0.91, 0.98] per additional donation). There was no association with other secondary neonatal outcomes (Table 4).
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Because of very low event rates and the number of potential risk factors in our model, no analyses were
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possible for microcephaly (events =54), stillbirth (events=58) and maternal death (events=15).
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Repeated donations were not associated with any adverse maternal outcomes except for gestational
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hypertension (adjusted OR 1.03 [1.001 1.07] per additional donation, n=206 women). This effect was
Discussion
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not significant when considering time between donation to conception (Table 4).
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In a large observational cohort, we did not observe an increased risk of adverse neonatal or maternal
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outcomes in women who donated blood before their pregnancy in the Canadian context. The risk was not increased compared to woman who never donated, nor was it increased with an increased frequency of donations prior to pregnancy. Our results from a large population cohort are consistent with previous findings in Canada[12,24]. A reduced time from donation to conception was also not associated with any adverse maternal or perinatal outcomes. For one secondary maternal outcome, we observed a small statistically significant increase in the risk of maternal hypertension. This finding must be interpreted with caution given the multiplicity of secondary outcomes measured, the small observed effect size (possibly not clinically significant), and the absence of adverse effects for other outcomes. In fact, we observed a generally protective effect of blood donation prior to pregnancy. This 9
Journal Pre-proof observation is most likely related to the healthy-donor effect1. This bias is related to the fact that one must be in a relatively good state of health to consider donating or to be permitted to donate blood. Potential blood donors undergo a screening questionnaire that can lead to donation deferral. For example, at CBS donors are deferred for underlying conditions such as insulin dependent diabetes, systemic lupus erythematosus, renal dysfunction, and lifestyle behaviors such as intranasal cocaine use and illicit drug use. Also, donors who are unwell are less likely to give blood. Our results do not
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suggest that donating blood improves neonatal outcome, but rather that given our current selection processes, such practice is not associated with higher risks compared to women who never donated.
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Our results may be surprising given the known association between blood donation and iron deficiency,
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and iron deficiency anemia and neonatal outcome[26,27]. Although in our study we did not know if the
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donors were iron deficient, recent evidence suggest that iron deficiency prevalence is high in this
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population. In a large national study of over 12,000 donors, 32% of first time and 65% of repeat female donors had low or absent iron stores[28]. This data is similar to a large U.S. cohort study for 2,524
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blood donors, which showed evidence of iron deficient erythropoiesis in 50% of female donors and
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62% of frequent female donors. Importantly, iron deficiency itself, as well as the resulting anemia have been associated with negative maternal and neonatal outcomes[26]. A recent systematic review found
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a significant association between anemia in pregnancy and the risk of increased adverse perinatal outcomes with an increased risk of low birth weight (OR 1.25 95% CI; 1.08 to 1.45), preterm birth (OR 1.28 95% CI; 1.12 to 1.47) and stillbirth (OR 1.19 95% CI; 1.09 to 1.29)[27]. Despite these findings in the anemic pregnant female population, we observed no association with adverse effects in our population of female blood donors despite the evidence that these women are at high risk of being iron deficient. We can propose a few hypothetical explanations for these findings. First, we do not know the actual status of the iron stores in previous blood donors during their pregnancies. In Canada, some but not all 10
Journal Pre-proof women are screened for iron deficiency in pregnancy and advised to take supplements. If taken a few months before conception or even if started at the time of conception, the supplements could reduce any impact of donation[27]. Second, the iron deficiency in female blood donors is likely different than iron deficiency due to the blood /iron loss associated with repeat blood donations as suggested in previous populational studies where anemia may be associated with lower socioeconomic status, malnutrition or other illnesses[27]. These other factors may by themselves increase the risk of poorer
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neonatal outcome. In blood donors who are self- selected based partially on good health and who are screened for anemia, any unmeasured iron deficiency would be partly due to blood donation and not
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necessarily other unmeasured confounders. Conversely, it is possible that the potential deleterious
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effects of anemia and iron deficiency are counterbalanced by the selection of a healthy donor
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population , and potentially the benefits of universal health care coverage and routine prenatal care,
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thus preventing us from detecting harm associated with repeated blood donation. In other words, because of the inherent characteristics of our population, neonatal and maternal outcomes could be
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more favorable independent of blood donation or not and would therefore obfuscate the potential harms
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of iron deficiency in this population. Finally, there is a possibility of Type 2 error in which we are incorrectly concluding that there is no harm associated with blood donation. This could be due to
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incomplete adjustment for measured confounding factors, unmeasured confounding factors, incorrect statistical modelling or insufficient power. Our study has strengths and limitations. We conducted a large, population-level study of all pregnancies in our jurisdiction using high quality data sources. We were able to consider numerous potential confounding factors known to be associated with neonatal and maternal outcomes, including smoking status, alcohol consumption, sociodemographic factors and comorbidities and despite these facts, we did not observe evidence of risks of blood donation in our female blood donor population. Although the included women gave blood an average of 2.43 times, 3,661 (46.2%) of women donated 11
Journal Pre-proof blood only once during the study timeframe which may be insufficient to cause a significant enough iron deficiency to affect outcome. We however had 664 (8.4%) women who donated at least once in the 6 months prior to conception, thus were less likely to be improving their iron status leading up to the pregnancy. Also, the data pertaining to previous donations was available only for the specified study timeframe. It is therefore possible that some women donated blood before the 3-year observation window in both groups. However, it seems unlikely that more remote donation would affect
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significantly our results given our observed lack of effect in the 3 years prior to the pregnancy. Finally, ferritin and hemoglobin levels were not available to strengthen the analysis. It is therefore possible that
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a proportion of blood donors did not have iron deficiency, and thus diluting a potential deleterious
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association. However, given the high prevalence of iron deficiency among blood donors in our previous
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studies[4] and our large sample size, we hypothesize that we should have been able to detect an effect
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should it be present.
In summary, while there is evidence that repeated blood donations may result in iron deficiency and
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anemia in female donors, our data suggest that there is no increased risk of repeated blood donations
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prior to pregnancy on neonatal and maternal outcomes in the Canadian context. However, given the evidence of the impact of confirmed maternal iron deficiency on neonatal outcomes, when such
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deficiency is confirmed, blood donation deferral should be implemented, a thorough investigation for the cause of iron deficiency should be conducted and iron supplementation should be offered when appropriate. Although possibly a result of a healthy donor effect, our findings are reassuring to female donors as well as clinical and blood organization stakeholders seeking to inform policy decisions.
12
Journal Pre-proof Disclosures This study is based in part on data provided by the Better Outcomes Registry and Network (“BORN”), part of the Children’s Hospital of Eastern Ontario. The interpretation and conclusions contained herein do not necessarily represent those of BORN Ontario. Part of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI. The ONMARG dataset was created at the Institute for Clinical Evaluative Sciences using data directly from Toronto Community Health Profiles, applying algorithms detailed in Matheson et al. “Development of the Canadian Marginalization Index: a new tool for the study of inequality.” Canadian Journal of Public Health, 2012;103(suppl.2):S12-S16.
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Funding
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This work was supported by a CBS/011R Partnership in Transfusion Science Spring 2015 Award [funding reference number: CHIR-101507-AT-342028].
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Acknowledgements
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We would like to thank Glenys Smith analyst at the Institute for Clinical Evaluative Sciences for her contribution to the analysis of this project. This work was made possible because of the extensive collaboration of Canadian Blood Services and the Ontario Institute for Clinical Evaluative Science and the Better Outcomes Registry and Network (“BORN”).
13
Journal Pre-proof References [1]
CBS. Blood: Canadian Blood Services 2014. https://www.blood.ca/en/blood (accessed February 14, 2015).
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ISBT. A CODE OF ETHICS FOR BLOOD DONATION AND TRANSFUSION 2006:1. http://www.isbtweb.org/fileadmin/user_upload/Code_of_Ethics/ISBT_Code_of_Ethics_update__feb_2011.pdf (accessed October 31, 2019). Simon TL, Garry PJ, Hooper EM. Iron stores in blood donors. JAMA 1981;245:2038–43.
[4]
Goldman M, Uzicanin S, Scalia V, O’Brien SF. Iron deficiency in Canadian blood donors.
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Cable RG, Glynn SA, Kiss JE, Mast AE, Steele WR, Murphy EL, et al. Iron deficiency in blood
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Transfusion 2014;54:775–9. https://doi.org/10.1111/trf.12380.
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Rigas AS, Sørensen CJ, Pedersen OB, Petersen MS, Thørner LW, Kotzé S, et al. Predictors of
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iron levels in 14,737 Danish blood donors: Results from the Danish Blood Donor Study.
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Transfusion 2014;54:789-796. https://doi.org/10.1111/trf.12518. Smith GA, Fisher SA, Doree C, Di Angelantonio E, Roberts DJ. Oral or parenteral iron
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supplementation to reduce deferral, iron deficiency and/or anaemia in blood donors. Cochrane Database Syst Rev 2014;(7):CD009532. https://doi.org/10.1002/14651858.CD009532.pub2. [8]
Bialkowski W, Bryant BJ, Schlumpf KS, Wright DJ, Birch R, Kiss JE, et al. The strategies to reduce iron deficiency in blood donors randomized trial: design, enrolment and early retention. Vox Sang 2015;108:178–85. https://doi.org/10.1111/vox.12210.
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Popovsky MA. Anemia, iron depletion, and the blood donor: It’s time to work on the donor’s behalf. Transfusion 2012;52:688–92. https://doi.org/10.1111/j.1537-2995.2012.03562.x.
[10] Bianco C, Brittenham G, Gilcher RO, Gordeuk VR, Kushner JP, Sayers M, et al. Maintaining 14
Journal Pre-proof iron balance in women blood donors of childbearing age: summary of a workshop. Transfusion 2002;42:798–805. [11] Brittenham GM. Iron deficiency in whole blood donors. Transfusion 2011;51:458–61. https://doi.org/10.1111/j.1537-2995.2011.03062.x. [12] Germain M, Delage G, Robillard P, Katz LM, Grégoire Y. The association between frequency of blood donation and the occurrence of low birthweight, preterm delivery, and stillbirth: a
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retrospective cohort study. Transfusion 2016;56:2760–7. https://doi.org/10.1111/trf.13762. [13] Kiss JE, Brambilla D, Glynn SA, Mast AE, Spencer BR, Stone M, et al. Oral Iron
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Supplementation After Blood Donation. JAMA 2015;313:575.
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[14] Recipient Epidemiology and Donor Evaluation Study-III. Natl Hear Lung, Blood Inst 2013.
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https://reds-iii.rti.org/.
[15] Matheson FI, Dunn JR, Smith KLW, Moineddin R, Glazier RH. Development of the Canadian
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2012;103:S12-6.
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Marginalization Index: a new tool for the study of inequality. Can J Public Health
[16] Peacock JL, Bland JM, Anderson HR. Preterm delivery: effects of socioeconomic factors,
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psychological stress, smoking, alcohol, and caffeine. BMJ 1995;311:531–5. [17] Srinivasjois RM, Shah S, Shah PS. Biracial couples and adverse birth outcomes: A systematic review and meta-analyses. Acta Obstet Gynecol Scand 2012;91:1134–46. https://doi.org/10.1111/j.1600-0412.2012.01501.x. [18] Sampson L, Dasgupta K, Ross NA. The association between socio-demographic marginalization and plasma glucose levels at diagnosis of gestational diabetes. Diabet Med 2014;31:1563–7. https://doi.org/10.1111/dme.12529. [19] To T, Stanojevic S, Feldman R, Moineddin R, Atenafu EG, Guan J, et al. Is asthma a vanishing 15
Journal Pre-proof disease? A study to forecast the burden of asthma in 2022. BMC Public Health 2013;13:254. https://doi.org/10.1186/1471-2458-13-254. [20] An Overview of BORN Ontario Reporting. BORN Ontario 2013. https://www.bornontario.ca/assets/documents/provincialrounds/Reporting Overview of BORN Ontario Reporting - March 2013.pdf (accessed December 14, 2018). [21] van der Heijden GJ, Donders AR, Stijnen T, Moons KG. Imputation of missing values is
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superior to complete case analysis and the missing-indicator method in multivariable diagnostic
https://doi.org/10.1016/j.jclinepi.2006.01.015.
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research: A clinical example. J Clin Epidemiol 2006;59:1102–9.
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[22] White IR, Carlin JB. Bias and efficiency of multiple imputation compared with complete-case
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analysis for missing covariate values. Stat Med 2010;29:2920–31.
[23] Born: Better Outcomes Registry & Network. Born Ontario 2013:4.
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2015).
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https://www.bornontario.ca/assets/documents/BORN Brochure_2013.pdf (accessed February 28,
[24] Rigas AS, Pedersen OB, Rostgaard K, Sørensen E, Erikstrup C, Hjalgrim H, et al. Frequent
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blood donation and offspring scholastic attainment: an assessment of long‐term consequences of prenatal iron deficiency. Transfusion 2019;59:1717–22. https://doi.org/10.1111/trf.15193. [25] Atsma F, Veldhuizen I, Verbeek A, de Kort W, de Vegt F. Healthy donor effect: its magnitude in health research among blood donors. Transfusion 2011;51:1820–8. https://doi.org/10.1111/j.1537-2995.2010.03055.x. [26] Sifakis S, Pharmakides G. Anemia in pregnancy. Ann N Y Acad Sci 2000;900:125–36. [27] Haider BA, Olofin I, Wang M, Spiegelman D, Ezzati M, Fawzi WW. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ 16
Journal Pre-proof 2013;346:f3443. https://doi.org/10.1136/bmj.f3443. [28] Goldman M, Uzicanin S, Osmond L, Scalia V, O’Brien SF. A large national study of ferritin testing in Canadian blood donors. Transfusion 2017;57:564–70.
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Figure 1. Flowchart of cohort creation.
BORN: Better Outcomes Registry and Network
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Journal Pre-proof Table 1. Maternal Baseline Characteristics
29.74 ± 4.94 1,523 (19.2%) 5,429 (68.6%) 964 (12.2%) 3 (0.0%)
26.29 ± 18.81 212,688 (84.4%) 1,679 (0.7%) 18,951 (7.5%) 10,227 (4.1%) 8,573 (3.4%)
27.62 ± 13.00 6,685 (84.4%) 14 (0.2%) 527 (6.7%) 363 (4.6%) 330 (4.2%)
2,360 (0.9%)
88 (1.1%)
2,559 (1.0%)
127,569 (50.6%)
3032 (38.3%)
3,500 (1.4%)
119 (1.5%)
229,591 (91.1%)
7,486 (94.5%)
19,027 (7.5%)
314 (4.0%)
0 (0-2) 159,503 (63.3%) 581 (0.2%) 23,144 (9.2%) 38,092 (15.1%) 20,888 (8.3%) 9,910 (3.9%)
0 (0-2) 5,589 (70.6%) 14 (0.2%) 586 (7.4%) 1,007 (12.7%) 492 (6.2%) 231 (2.9%)
42,481 (16.8%) 204,626 (81.2%) 5,011 (2.0%)
1,241 (15.7%) 6,496 (82.0%) 182 (2.3%)
245,505 (97.4%) 6,613 (2.6%)
7,713 (97.4%) 206 (2.6%)
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No Yes Time since previous delivery, years Median (IQR) <6 months 6 months – <1 year 1 – <2 years 2 – < 3 years 3 – <4 years ≥4 years Use of assisted reproductive therapy for current pregnancy Missing No Yes Hypertension No Yes
4,792 (60.5%)
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Missing
95 (1.2%)
121,990 (48.4%)
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No Yes Previous preterm delivery
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Missing
4,595 (58.0%) 3,236 (40.9%)
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108,923 (43.2%) 140,835 (55.9%)
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30.30 ± 5.38 48,460 (19.2%) 160,865 (63.8%) 42,522 (16.9%) 271 (0.1%)
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Missing Nulliparous Parous Previous term delivery
Donors n=7,919
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Age at Delivery, yrs Mean ± SD 18 - 25 26 - 35 36 - 45 45+ Pre-pregnancy BMI, kg/m2 Mean ± SD Missing <18.5 18.5-24.9 25.0-29.9 ≥30 Parity
Non-Donors n=252,118
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Journal Pre-proof 7,805 (98.6%) 114 (1.4%)
13,925 (5.5%) 211,992 (84.1%) 26,201 (10.4%)
426 (5.4%) 7,019 (88.6%) 474 (6.0%)
10,027 (4.0%) 241,839 (95.9%) 252 (0.1%)
480 (6.1%) 7,432 (93.9%) 7 (0.1%)
10,027 (4.0%) 229,584 (91.1%) 12,507 (5.0%)
480 (6.1%) 6,966 (88.0%) 473 (6.0%)
4,234 (1.7%) 59,778 (23.7%) 44,500 (17.7%) 44,609 (17.7%) 44,267 (17.6%) 54,730 (21.7%)
74 (0.9%) 2,102 (26.5%) 1,628 (20.6%) 1,591 (20.1%) 1,341 (16.9%) 1,183 (14.9%)
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246,918 (97.9%) 5,200 (2.1%)
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4,234 (1.7%) 30,392 (12.1%) 33,487 (13.3%) 40,415 (16.0%) 53,854 (21.4%) 89,736 (35.6%)
74 (0.9%) 1,500 (18.9%) 1,642 (20.7%) 1,638 (20.7%) 1,822 (23.0%) 1,243 (15.7%)
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Diabetes No Yes Smoking Missing No Yes Alcohol dependence syndrome Missing No Yes History of drug use (prescribed or illicit) Missing No Yes Deprivation Quintile Missing 1 (lowest) 2 3 4 5 (highest) Ethnic Concentration Quintile Missing 1 (lowest) 2 3 4 5 (highest)
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Journal Pre-proof Table 2. Neonatal and Maternal outcomes
38.89 ± 1.77 39 (38-40) 236,910 (94.0%) 11,745 (4.7%) 1,611 (0.6%) 1,126 (0.4%) 726 (0.3%)
39.08 ± 1.78 39 (38-40) 7,469 (94.3%) 352 (4.4%) 43 (0.5%) 31 (0.4%) 24 (0.3%)
3,372.29 ± 544.62 3,384 (3,060-3,710) 193 (0.1%) 27,259 (10.8%) 212,643 (84.3%) 10,362 (4.1%) 941 (0.4%) 720 (0.3%)
3,456.24 ± 538.21 3,472 (3,158-3,787) 10 (0.1%) 1,081 (13.7%) 6,530 (82.5%) 248 (3.1%) 28 (0.4%) 22 (0.3%)
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Donors
42 (0.5%) 7,351 (92.8%) 526 (6.6%)
2,494 (1.0%) 248,968 (98.8%) 656 (0.3%)
100 (1.3%) 7,800 (98.5%) 19 (0.2%)
76,853 (30.5%) 174,247 (69.1%) 1,018 (0.4%)
2,400 (30.3%) 5,495 (69.4%) 24 (0.3%)
8 (0.0%) 246,961 (98.0%) 5,149 (2.0%)
1 (0.0%) 7,769 (98.1%) 149 (1.9%)
8 (0.0%) 228,927 (90.8%) 23,183 (9.2%)
1 (0.0%) 7,168 (90.5%) 750 (9.5%)
391 (0.2%) 251,485 (99.7%) 242 (0.1%)
21 (0.3%) 7,892 (99.7%) 6 (0.1%)
5,172 (2.1%) 241,878 (95.9%)
198 (2.5%) 7,532 (95.1%)
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834 (0.3%) 227,578 (90.3%) 23,706 (9.4%)
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Neonatal Outcomes Gestational age at birth, weeks Mean ± SD Median (IQR) Term, ≥37 Late Preterm, 34 - 37 Moderate Preterm, 32 - 33 Very Preterm, 28 - 32 Extremely Preterm, < 28 Birthweight Mean ± SD Median (IQR) Missing ≥4,000g ≥2,500-3999g ≥1500g - <2,499g ≥1000g - <1499g <1000g SGA (less than 10th centile) Missing No Yes APGAR <4 at 5 min Missing No Yes Arterial cord pH <7 Missing No Yes Hypoglycemia Missing No Yes Hyperbilirubinemia Missing No Yes Death at Birth Missing No Yes Maternal Outcomes Preeclampsia Missing No
Non-Donors
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Journal Pre-proof 189 (2.4%)
5,479 (2.2%) 245,245 (97.3%) 1,394 (0.6%)
210 (2.7%) 7,664 (96.8%) 45 (0.6%)
7,136 (2.8%) 236,548 (93.8%) 8,434 (3.3%)
270 (3.4%) 7,305 (92.2%) 344 (4.3%)
7,136 (2.8%) 232,556 (92.2%) 12,426 (4.9%)
270 (3.4%) 7,409 (93.6%) 240 (3.0%)
0 (0.0%) 250,725 (99.4%) 1,393 (0.6%)
0 (0.0%) 7,873 (99.4%) 46 (0.6%)
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0 (0.0%) 251,223 (99.6%) 895 (0.4%)
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5,068 (2.0%)
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Yes Placental Abruption Missing No Yes Gestational Hypertension Missing No Yes Gestational Diabetes Missing No Yes Transfusion Missing No Yes RBC transfusion Missing No Yes Infection during pregnancy Missing No Yes
225 (2.8%) 7,648 (96.6%) 46 (0.6%)
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5,818 (2.3%) 244,686 (97.1%) 1,614 (0.6%)
0 (0.0%) 7,896 (99.7%) 23 (0.3%)
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Journal Pre-proof Table 3. Association between number of donations and risk of Small for Gestational Age Unadjusted Odds Ratio (95%CI) 0.89 (0.86, 0.92) 1.04 (0.74, 1.46) 0.92 (0.81,1.04) 0.87 (0.76, 0.995) 0.87 (0.79, 0.94) 0.89 (0.82, 0.97)
Number of donations After Conception Conception-6months >6months-1yr >1yr-2yr >2yr-3yr
Adjusted Odds Ratio (95%CI)* 0.91 (0.88, 0.94) 1.14 (0.81, 1.61) 0.98 (0.86, 1.11) 0.91 (0.79, 1.04) 0.86 (0.79, 0.94) 0.91 (0.83, 0.99)
*
Adjusted for maternal age at delivery, maternal BMI, maternal alcohol dependence syndrome and drug use, pre-existing maternal diabetes and hypertension, use of assisted reproduction technologies, maternal deprivation quintile, ethnic concentration quintile, parity, time since previous delivery. Table 4. Association between number of donations and risk of secondary outcomes After Conception
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Adjusted Odds Ratio (95%CI)* Conception- >6months>1yr-2yr >2yr-3yr 6months 1yr
Neonatal outcomes
Cord pH <7 Hypoglycemia Hyperbilirubinemia Maternal outcomes Gestational hypertension Gestational Diabetes Pre-eclampsia
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APGAR <4 at 5 minutes
0.83 (0.49, 1.41) 0.67 (0.09, 5.01) 0.52(0.07, 3.84) 1.12 (0.59, 2.13) 1.14 (0.84, 1.55) 1.35 (0.89, 2.07) 1.33 (0.83, 2.13) 0.81 (0.41, 1.60)
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Birthweight <2,500
Placental Abruption
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Infection during pregnancy Maternal Transfusion Maternal RBC transfusion
0.96 (0.30, 3.09) 2.19 (0.95, 5.04) 2.22 (0.69, 7.12)
0.98 (0.90, 1.18) 1.14 (0.61, 2.12) 0.97 (0.88, 1.08) 1.02 (0.72, 1.45) 0.58 (0.34, 0.97) 0.94 (0.81, 1.10) 1.04 (0.97, 1.11)
1.01 (0.93, 1.10) 0.83 (0.38, 1.81) 0.95 (0.85, 1.06) 1.06 (0.75, 1.50) 0.65 (0.39, 1.09) 0.93 (0.79, 1.08) 0.99 (0.92, 1.06)
0.99 (0.96, 1.02) 0.98 (0.77, 1.25) 0.95 (0.91, 0.98) 1.03 (0.91, 1.16) 0.88 (0.75, 1.02) 0.97 (0.92, 1.03) 0.99 (0.97, 1.01)
1.05 (0.89, 1.23) 0.80 (0.65, 0.98) 1.00 (0.81, 1.24) 1.27 (0.84, 1.92) 0.89 (0.58, 1.37) 1.59 (1.15, 2.21) 1.32 (0.73, 1.48)
1.05 (0.95, 1.15) 0.95 (0.84, 1.07) 0.99 (0.88, 1.12) 1.17 (0.90, 1.50) 1.02 (0.80, 1.32) 1.04 (0.82, 1.33) 1.04 (0.73, 1.48)
0.99 (0.89, 1.09) 0.91 (0.80, 1.03) 1.05 (0.93, 1.19) 0.79 (0.56, 1.11) 0.89 (0.67, 1.17) 0.76 (0.55, 1.05) 0.57 (0.31, 1.02)
1.03 (1.001, 1.07) 0.91 (0.87, 0.95) 1.01 (0.97, 1.06) 0.96 (0.86, 1.07) 0.99 (0.91, 1.09) 1.01 (0.93, 1.10) 0.93 (0.81, 1.08)
-p
-
1.03 (0.90, 1.18) 0.65 (0.17, 2.50) 0.88 (0.73, 1.05) 0.89 (0.47, 1.68) 1.65 (1.07, 2.55) 1.25 (1.01, 1.55) 0.96 (0.86, 1.08)
re
Infant Death
0.96 (0.83, 1.10) 1.54 (0.67, 3.56) 0.98 (0.83, 1.16) 1.21 (0.71, 2.07) 1.08 (0.66, 1.77) 0.82 (0.64, 1.06) 0.90 (0.80, 1.00)
lP
0.90 (0.60, 1.37)
na
Preterm Birth
1.05 (0.90, 1.22) 0.88 (0.72, 1.06) 1.04 (0.85, 1.28) 0.66 (0.37, 1.16) 1.24 (0.87, 1.77) 0.68 (0.43, 1.09) 0.74 (0.39, 1.42)
Overall
*
Adjusted for maternal age at delivery, maternal BMI, maternal alcohol dependence syndrome and drug use, pre-existing maternal diabetes and hypertension, use of assisted reproduction technologies, maternal deprivation quintile, ethnic concentration quintile, parity, time since previous delivery. 23
Journal Pre-proof Highlights
1. We observed a reduction in the risk of small for gestational age birth with increasing number of lifetime whole blood donations.
2. We observed no other association between repeated blood donation and other neonatal and maternal outcomes.
3. Our findings are reassuring to female donors and their children as well as to clinicians and blood
Jo
ur
na
lP
re
-p
ro
of
system stakeholders seeking to inform policy decisions.
24