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Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
Published in final edited form as:
Ann N Y Acad Sci. 2019 August ; 1450(1): 190–203. doi:10.1111/nyas.14167.

Reexamination of hemoglobin adjustments to define anemia:

altitude and smoking
Andrea J. Sharma1,2, O. Yaw Addo1,3, Zuguo Mei1, Parminder S. Suchdev1,3
1Divisionof Nutrition, Physical Activity, and Obesity, National Center for Chronic Disease
Prevention and Health Promotion, International Micronutrient Malnutrition Prevention and Control
Program (IMMPaCt), Centers for Disease Control and Prevention, Atlanta, Georgia.
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2The U.S. Public Health Service Commissioned Corps, Atlanta, Georgia.

3Hubert Department of Global Health, Emory University Rollins School of Public Health, Atlanta,
Georgia

Abstract
The correct interpretation of hemoglobin (Hb) to identify anemia requires adjusting for altitude
and smoking. Current adjustments were derived using data collected before 1985, from low-
income preschool-aged children (PSC) in the United States and indigenous men in Peru for
altitude, and from White women of reproductive age (WRA) in the United States for smoking.
Given the oldness and limited representativeness of these data, we reexamined associations
between Hb and altitude and/or smoking using 13 population-based surveys and 1 cohort study
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each conducted after 2000. All WHO regions except South-East Asia were represented. The
dataset included 68,193 observations among PSC (6−59 months) and nonpregnant WRA (15−49
years) with data on Hb and altitude (−28 to 4000 m), and 19,826 observations among WRA with
data on Hb and smoking (status or daily cigarette quantity). Generalized linear models were used
to assess the robustness of associations under varying conditions, including controlling for
inflammation-corrected iron and vitamin A deficiency. Our study confirms that Hb should be
adjusted for altitude and/or smoking; these adjustments are additive. However, recommendations
for Hb adjustment likely need updating. Notably, current recommendations may underadjust Hb

Address for correspondence: Andrea J. Sharma, Division of Nutrition, Physical Activity, and Obesity, National Center for Chronic
Disease Prevention and Health Promotion, International Micronutrient Malnutrition Prevention and Control Program (IMMPaCt),
Centers for Disease Control and Prevention, 4770 Buford Hwy NE, MS S107-5, Atlanta, GA 30341. [email protected].
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Author contributions
All authors (A.J.S., O.Y.A., Z.M., and P.S.S.) had substantial contributions to the conception or design of the work; or the acquisition,
analysis, or interpretation of data for the work; contributed to the drafting of the work or revising it critically for important intellectual
content; have given final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring
that questions related to the accuracy or the integrity of any part of the work are appropriately investigated and resolved.
Publisher's Disclaimer: Disclaimer
Publisher's Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.
This article has been contributed to by US Government employees and their work is in the public domain in the USA.
Competing interests
As part of their routine work duties, the authors provide technical assistance to countries in the design, training, implementation, data
management, analysis, and dissemination of public health population-based surveys, including collection of Hb and anemia.
Supporting information
Additional supporting information may be found in the online version of this article.
 Sharma et al. Page 2

for light smokers and for those residing at lower altitudes and overadjust Hb for those residing at
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higher altitudes.

Keywords
hemoglobin; altitude; smoking; anemia

Introduction
Hemoglobin (Hb) is the red, iron-containing chromoprotein within a circulating mature
erythrocyte that has the primary physiologic function of transporting oxygen to tissues and
plays a role in carbon dioxide transport. Anemia, a common global health problem,1 is
defined by having an Hb concentration lower than normal. It has been well established that
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normal Hb concentrations vary with age, sex, and at different stages of pregnancy. Hb
cutoffs to define anemia by age, sex, and trimester of pregnancy have remained relatively
unchanged since 1968.2

Exposure to chronic hypoxia is also known to increase erythropoiesis.3 The partial pressure
of oxygen in the atmosphere decreases with altitude (height above mean sea level, 0 m), thus
Hb concentration increases with altitude as an adaptive response to lower oxygen saturation
of the blood. Cigarette smoking is also known to cause an increase in Hb concentration,
likely mediated by exposure to carbon monoxide, which markedly reduces oxygen-carrying
capacity.4,5 To compensate for decreased oxygen delivery, smokers maintain higher Hb
concentrations relative to nonsmokers. The increase in Hb is positively associated with the
number of cigarettes smoked per day.6 Because of these adaptive increases in Hb, the correct
interpretation of Hb concentration to identify anemia requires adjusting for these factors. In
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2001, WHO UNICEF UNU established Hb concentration cutoffs to define anemia, which
also included adjustments needed to take into account altitude and smoking.7

Adjustments for altitude were published in 1989.8 Based on data from the Centers for
Disease Control and Prevention (CDC), Pediatric Nutrition Surveillance System (PedNSS),
and data from Hurtado et al.,9 the adjustment for altitude is based on the equation:

Hb−adjustment (g/dL) = − 0.032 × (altitude × 0.0032808) + 0.022 × (altitude × 0.0032808)2

where the adjustment is the value added to the Hb cutoff defining anemia, or subtracted from
an individual’s observed Hb concentration using standard cutoffs to define anemia.10,11
PedNSS data were from low-income children, aged 2−4 years (predominately White
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people), with little to no iron deficiency (ID), enrolled in public health programs from 1974
to the mid-1980s. Children resided at altitudes ranging from <900 to 2150 m above sea level.
8 Higher altitude adjustments were derived from Hurtado’s 1945 publication that assessed

healthy, indigenous men, 19−48 years of age, living at 3730–4540 m in Peru and men living
at sea level in Peru. Hurtado also included data from previous publications in the 1930s from
Denver (1500 m), Chile (5335 m), and the United Kingdom (sea level).9 A study of 469
children aged 6−59 months with no evidence of iron or zinc deficiency, residing at 0−3400

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m in Ecuador, confirmed similar adjustments.12 Refer to Figure 1 for a summary of

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equations for Hb adjustment for altitude based on these publications and the current WHO
recommended adjustments.

Smoking adjustments, published in 1990, were derived from data among White women aged
18−44 years in the United States participating in the Second National Health and Nutrition
Examination Survey (NHANES II, 1976−1980).6 Smokers, defined as having ever smoked
more than 100 cigarettes and being a current cigarette smoker at the time of the interview,
were compared with never smokers and adjustments categorized according to standard
cigarette pack size found in the United States (i.e., 20 cigarettes/pack). Smoking adjustments
are the same for all population groups (e.g., sex, age, and race). Note, adjustments for
altitude and smoking are additive such that a smoker living at a high altitude would have Hb
adjusted for both altitude and smoking.
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Given the oldness and limited representativeness of data (i.e., geographic, age, and race)
used to establish existing adjustments as well as the advancement of scientific understanding
of biological aspects affecting Hb,13 there is a need to reevaluate guidance on Hb
adjustments for altitude and smoking. Our objective was to examine the association between
Hb and altitude and/or smoking among diverse population groups using more recent (since
2000), multinational data in an effort to evaluate current WHO recommendations for
adjusting Hb for altitude and smoking.

Methods
Data source and study population
Data for this study were primarily drawn from the Biomarkers Reflecting Inflammation and
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Nutritional Determinants of Anemia (BRINDA) project (www.BRINDA-nutrition.org), a

multiagency, multi-country collaboration formed in 2012 as an effort to improve
micronutrient assessment and anemia characterization. BRINDA includes datasets from
nationally and/or regionally representative household nutrition surveys conducted after 2000
with similar sampling and data collection methodologies that have been described in detail
elsewhere.14,15 We used 12 out of 25 surveys (representing 11 countries) that reported data
on altitude and/or smoking behaviors. Two additional data sources were also included to
increase observations at altitudes >2500 m. This included data from the Guatemalan Sistema
de Vigilancia Epidemiológicade Salud y Nutrición (SIVESNU, 2013), nationally
representative integrated nutrition and maternal child health surveillance system with
altitudes up to 3000 m, and the Nutricion, Immunologia, y Diarrea Infantil study
(2013−2015) in El Alto, Bolivia (4000 m), a research study where the primary aim was to
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assess the effect of global nutritional status on rotavirus vaccine response.16 All data sources
included a measure of Hb, iron, and/or vitamin A (VA) status as well as biomarkers of
inflammation (C-reactive protein (CRP) and/or alpha-1 acid glycoprotein (AGP)). All
subjects with data on Hb, age, and either altitude or smoking status were eligible. Analyses
were restricted to preschool-aged children (PSC) aged 6−59 months for analysis of altitude,
and women of reproductive age (WRA) aged 15−49 years for analysis of altitude and
smoking. We did not examine infants <6 months of age because data were scarce in our
dataset, and there remains uncertainty around the appropriate cutoff to define anemia in this

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age group.17 Women known to be pregnant were excluded. A summary of the 15 surveys
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included in the analysis can be found in Table 1. In total, our multinational dataset included
68,193 observations among PSC and WRA with data on Hb and altitude, and 19,826
observations among WRA with data on Hb and smoking. All data were deidentified and
each survey had appropriate prior ethical approval, thus this study was considered nonhuman
subjects research and exempt from Institutional l Review Board review.

Variables
Hb concentrations were measured at the time of blood collection using point-of-care
photometers (HemoCue® all surveys, except in Georgia, which used HumaMeter) or by
Beckman Coulter MAXM hematology flow cytometer in the United States. Anemia was
considered present when Hb <110 g/L for PSC and Hb <120 g/L for WRA after adjusting
for altitude and smoking (subtracting indicated adjustment from measured Hb). Altitude, in
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meters (m), was reported as a continuous variable except for Laos (altitude coded as 999,
1125, and 1251 m), the United Kingdom (altitude coded as 80 m for all subjects based on
the average altitude of the 10 most populous areas18), and Georgia (altitude reported as
<1000, 1000−1249, 1250−1749, and 1750−2249 m, but recoded based on average altitude in
the cluster19). Method for determining altitude was typically at the cluster level using
topographic maps, GIS data, or handheld GIS devices (more common in surveys after 2010).
Smoking status was reported as smoker or nonsmoker. A number of cigarettes smoked per
day were coded as a continuous variable. Cigarettes represent combustible tobacco products,
not chewing tobacco or vaping products. Duration of smoking was not available in any
survey. Age was a continuous variable coded in months for PSC, and years for WRA. The
survey was a categorical variable.

Presence of ID was determined preferentially by serum ferritin (SF; <12 μg/L for PSC; <15
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μg/L for WRA).20 If SF was unavailable, the ID was determined using soluble transferrin
receptor (sTfR; >8.3 mg/L based on the Ramco method cutoff,21 for both PSC and WRA) of
those categorized with ID, <5% were based on sTfR. VA deficiency (VAD) was considered
present if either serum retinol (SR) or retinol binding protein (RBP) was low (SR or RBP
<0.70 μmol/L for PSC; SR or RBP <1.05 μmol/L for WRA).22 Indicators of iron and VA
status were assessed with and without correcting for inflammation as recommended23 and
described in detail elsewhere.24 Briefly, the corrected biomarker value was calculated by
subtracting out (e.g., SF) or adding back (e.g., RBP) the inflammation “influence” of CRP
and/or AGP using a linear regression approach. Specifically, we corrected SF for CRP
and/or AGP (depending on indicator availability) among PSC and WRA; sTfR was corrected
for AGP among PSC and WRA; and SR and RBP were corrected for CRP and/or AGP for
PSC only. BRINDA regression corrections for inflammation for each of the nutritional
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biomarkers were conducted separately for each survey. Assay methods used to measure SF,
sTfR, SR, RBP, CRP, and AGP have been reported elsewhere.14,16,25

Statistical analysis
We began by examining the association between Hb and altitude with a series of generalized
linear models (GLMs) to assess robustness of the association under varying conditions. First,
we assessed whether altitude (continuous) had a nonlinear association with Hb as well as

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effect modification by population group and sex (PSC only). Second, because Hb
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(uncorrected) and altitude were correlated with ID (PSC: r = −0.16, P < 0.0001 and r = 0.05,
P < 0.0001; WRA: r = −0.26, P < 0.001 and r = −0.02, P < 0.001, respectively) and VAD
(PSC: r = −0.06, P < 0.0001 and r = −0.04, P < 0.0001; WRA: r = −0.07, P < 0.0001 and r =
0.02, P = 0.03, respectively), we examined the independent association between Hb and
altitude by adjusting models for ID and VAD (biomarkers examined both uncorrected or
corrected for inflammation). Third, we restricted the study sample only to those with no ID
and no VAD (biomarkers corrected for inflammation). We refer to this group as “healthy”
and assumed that this group may be less likely to have another micronutrient deficiencies
that are correlated with ID or VAD. We considered other indicators of health status,
including wasting (weight-for-height Z-score <−2) among PSC or presence of malaria, but
after excluding those with ID or VAD, we found few additional cases of wasting (<100) and
only one survey (Malawi) with data on ID and VAD included data on malaria based on rapid
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test kit. Finally, we conducted several sensitivity analyses to assess the robustness of results.
We examined associations where (1) we excluded from the “healthy” group any observations
with evidence of wasting (PSC) or malaria; (2) we excluded surveys where altitude was
approximated (i.e., United Kingdom, Laos, and Georgia); (3) ID was defined using SF only;
and (4) we excluded Bolivia data as this was not a population-based survey. All models
included (1) age (in months for PSC and years for WRA) because Hb was correlated with
age (PSC: r = 0.29, P < 0.001; WRA: r = −0.05, P < 0.0001) and altitude (PSC: r = −0.06, P
< 0.001; WRA: r = −0.02, P < 0.0001) in these data due to the population selection criteria
(Bolivia at 4000 m, in particular, includes younger PSC and WRA) and(2) survey (i.e.,
country) to account for potential unmeasured confounding associated with each location and
to account for the underlying difference in mean Hb associated with each location. For each
model, we report the adjustment equation and proportion of Hb variance explained (R2). The
model adjusting for ID and VAD (biomarkers corrected for inflammation) was considered
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the best model to estimate the independent association between altitude and Hb and used as
the proposed equation for estimating cutoffs, which were calculated for each 500-m increase
in altitude. We additionally examined survey-specific adjustments among surveys that
covered a range of altitude by analyzing the model stratified by the survey.

Among surveys that included a marker of erythropoiesis (i.e., sTfR), we assessed whether
those identified as having anemia after applying the new proposed equations also had
evidence of increased erythropoiesis. We categorized Hb into five groups—severe, moderate
and mild anemia and two groups of normal Hb split to be approximately equal in sample
size. We determined whether mean sTfr was significantly elevated among those identified as
with anemia compared with the normal Hb groups. sTfR was examined both uncorrected
and corrected for inflammation.
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Mean Hb concentration for smokers and non-smokers was estimated for each survey. We
used GLM to estimate the overall means and adjusted mean difference in Hb between
smokers and non-smokers controlling for the survey, and without and with adjusting Hb for
altitude using the new equation for WRA. We examined the association between smoking
and Hb with smoking categorized as smoker or nonsmoker or with smoking assessed as the
number of cigarettes smoked per day. Similar to altitude, we used GLM to assess
nonlinearity (number of cigarettes smoked per day), effect modification by altitude

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(continuous), and the association between smoking and Hb, adjusted for ID. Hb
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(uncorrected) and smoking (number of cigarettes per day) were correlated with ID (WRA: r
= −0.19, P < 0.001 and r = 0.03, P = 0.006, respectively). We did not include VAD because
the availability of VAD data was limited among surveys that also included data on smoking;
furthermore, the prevalence of VAD was low (<2%) and was not associated with smoking (P
= 0.7). We additionally examined associations restricted to WRA considered “healthy” (no
ID). For sensitivity analysis, we examined associations where ID was defined using SF only.
All models included age, which was also correlated with cigarette number (r = 0.13, P <
0.0001) and survey to account for potential unmeasured confounding associated with each
location and to account for the underlying difference in mean Hb associated with each
location. For each model, we report the adjustment for smoking and the proportion of Hb
variance explained (R2). The model adjusting for ID (biomarkers corrected for
inflammation) was considered the best model to estimate the independent association
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between smoking and Hb and used as the proposed adjustments for smoking. Among
surveys that included a marker of erythropoiesis (i.e., sTfR), we assessed whether those
identified as having anemia, after applying the new proposed equations for smoking and
altitude, also had evidence of increased erythropoiesis.

In a post-hoc analysis, we examined models that included weight-for-length/height Z-score

(WFH-Z) among children or body mass index (BMI) among women. While these measures
were weakly correlated with Hb (PSC, r = 0.07; WRA, r = 0.03; P < 0.0001 for both),
altitude (PSC, P = 0.74; WRA, r = −0.02, P < 0.0001), and cigarette number (WRA, r =
0.05, P < 0.0001), their inclusion had no change on total R2 or the Hb adjustments for
altitude or smoking. To maximize analytic sample size and model parsimony, we did not
include WFH-Z or BMI in final models.
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All analyses were conducted with SAS 9.4 with statistical significance considered at P <
0.05 for main effects and P < 0.15 for interactions. Bolivia included some subjects with
repeated measures of Hb (185 children and 231 WRA) collected at visits about 7 months
apart. Among the PSC, 78 also had indicators of both ID and VAD measured at the second
visit (no repeated ID or VAD measures among WRA). We retained repeated measures in our
analyses without controlling for correlated data because these subjects accounted for <0.7%
of all observations for any model. We did examine crude models using generalized
estimating equations, specifying an exchangeable working correlation matrix to account for
correlated data, and found no meaningful differences in effect estimates or statistical
significance. Survey weights were not applied to analyses examining associations between
Hb and altitude or smoking since the intent was to assess the biological association among
the study sample. Once the regression coefficients were calculated, we adjusted for complex
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survey design in later applications of the data. We assessed differences in the population
prevalence of anemia among the BRINDA surveys using the new proposed adjustments for
altitude (based on equations) and smoking (based on equation for number of cigarettes, if
number unknown then adjustment for a smoker, amount unknown applied) compared with
the use of existing adjustments (WHO cut-points and/or 1989 MMWR equation). When
estimating the population prevalence of anemia for each survey (except Bolivia, which was
not a population-based survey), we accounted for complex survey design by using the Taylor

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linearization method to obtain an unbiased estimate that incorporates the original sampling
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weights, strata, and cluster (as applicable).

Results
Hb and altitude
There were 31,967 observations (from 12 countries) for PSC and 36,226 observations (from
13 countries) for WRA with data to assess Hb and altitude. However, data were relatively
sparse at altitudes below sea level (0 m) and above 3000 m (Table S1, online only). We
tested and confirmed effect modification by population group (P < 0.0001) and a statistically
significant quadratic term for altitude among each population group (PSC, P = 0.0004;
WRA, P = 0.01). We found no effect modification by sex among PSC (P > 0.75). All
subsequent analyses included a quadratic term for altitude and examined PSC and WRA
separately.
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We report variation in sample size and in age for PSC and WRA and anemia prevalence for
each survey across select models assessing altitude in Table S2 (online only). Not all surveys
contribute data to every model. Mean age tended to be slightly older among PSC and WRA
with data on ID and VAD or who were categorized as healthy. Among PSC, 52% were males
(data not shown). Prevalence of anemia was generally lower among PSC with data on ID
and VAD or who were categorized as healthy but varied among WRA with data on ID and
VAD or who were categorized as healthy.

Adjustment equations and R2 for each model are reported in Table S3 (online only) and
visualized in Figure 2. Across all models, the proportion of Hb variance explained by
models was higher among WRA. All models, including sensitivity analyses, had a similar fit
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with slightly more variation among WRA. Results were similar when models 1−3 were
analyzed with the same subjects (n = 12,887 PSC; n = 13,889 WRA; data not shown). Hb
adjustments for each 500-m increase in altitude are reported in Table 2. Adjustment criteria
according to WHO cutoffs and the 1989 CDC equation are also provided for comparison.
Survey-specific associations are visualized in Figure S1 (online only) and adjustments are
provided in Table S4 (online only). Using the new proposed equations, we confirmed that
mean sTfR was highest among those categorized as having anemia (Fig. S2, online only).

Hb and smoking
Among WRA, there were 19,826 observations (from nine surveys) with data to assess Hb
and smoking status; 14.3% were smokers. Women who reported being a current smoker
were older than nonsmokers (31.8 (SD = 10.4) versus 29.6 (SD = 10.4) years old, P <
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0.0001). Eight surveys also included data on the number of cigarettes smoked per day (9724
observations; 22.0% categorized as smokers). Among smokers, women smoked 6.5 (SD =
7.9) cigarettes per day on average. The majority (63.9%) reported smoking 1−5 cigarettes
per day. Only 3.7% reported smoking more than 20 cigarettes per day. Detailed smoking
characteristics for each survey are reported in Table 3. We report variation in sample size
and anemia prevalence for each survey across select models assessing smoking in Table S5

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(online only). There were no meaningful differences in mean age. Prevalence of anemia was
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generally lower among WRA who were categorized as healthy (no ID).

Mean Hb concentration was generally higher among smokers compared with nonsmokers
across all surveys although the difference was not always statistically significant (Fig. S3,
online only). Overall, mean Hb was 3.3 g/L (95% CI 2.5−4.0) higher among smokers
compared with nonsmokers controlling for the survey, and 2.3 g/L (95% CI 1.6−2.9) higher
after additionally adjusting Hb for altitude.

We tested and confirmed a statistically significant quadratic term for cigarette quantity (P <
0.001). All subsequent analyses examining cigarette quantity as a continuous variable
included a quadratic term for cigarette quantity. There was no evidence of effect
modification between altitude and smoking quantity (P value for interaction >0.2).
Therefore, we used Hb adjusted for altitude (based on the proposed equation for WRA) so
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that any adjustments for smoking be considered independent of, and in addition to, altitude.

Smoking adjustments based on mean difference in Hb between smokers and nonsmokers

and by cigarette quantity are reported in Table 4. Model R2 ranged from 0.09 to 0.20 with
models controlling for ID having the highest R2 (data not shown); however, the calculated
adjustments for smoking were the same regardless of model specification. We confirmed
that mean sTfR was highest among those categorized with anemia after adjusting for altitude
and smoking (Fig. S2, online only).

Comparison of proposed adjustments to current adjustments

We estimated the population prevalence of anemia for each survey applying the new
proposed adjustments for altitude and smoking and compared prevalence with that estimated
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when applying either current WHO cut-points or 1989 MMWR equation for altitude or the
WHO cut-points for smoking (PSC, Fig. 3; WRA, Fig. 4). Relative to current WHO cutoffs
and 1989 MMWR equation, the population prevalence of anemia was generally higher using
the proposed adjustments across all surveys for both PSC and WRA. Among population-
based surveys only adjusting for altitude (i.e., all PSC and WRA in Afghanistan, Azerbaijan,
Laos, and Malawi), the increase in anemia prevalence across adjustment criteria ranged from
3 to 22 (Laos) percentage points. Among population-based surveys only adjusting for
smoking (i.e., WRA in the United Kingdom and the United States), the increase in anemia
prevalence across adjustment criteria ranged from 1 to 2 (the United Kingdom) percentage
points. In Bolivia, a research study where participants all resided at 4000 m, prevalence of
anemia decreased with application of proposed adjustments by 15–25 percentage points.
Application of the WHO cutoffs consistently resulted in lower prevalence of anemia relative
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to the 1989 MMWR equation because the WHO cutoff is equivalent to the adjustment at
lowest altitude in the given altitude category range (e.g., an adjustment of 2 for 1000−1499
m, an adjustment of 5 for 1500−1999 m, etc.), whereas the equation adjusts for the exact
altitude reported.

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Discussion
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It has been well established that Hb concentrations increase as an adaptive response to

hypoxic conditions, such as residing at high altitudes and smoking cigarettes. The results of
this multinational study among approximately 32,000 PSC and 35,000 nonpregnant WRA
confirm the need to adjust Hb concentration for altitude and/or smoking for the correct
interpretation of Hb concentration to identify anemia. Further, these adjustments are
additive. However, our findings suggest that current WHO recommendations for the
adjustment of Hb for altitude and/or smoking likely need updating. Notably, current
recommendations may underadjust Hb for light smokers (<10 cigarettes per day) and for
those residing at lower altitudes (<2000 m) and overadjust Hb for those residing at higher
altitudes (>3000 m).

Our findings also demonstrate that the association between Hb and altitude is modified by
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population group (young children versus WRA), suggesting that adjustments to Hb may
need to be tailored to different population groups. Population-specific adjustments increase
the complexity of adjustments, particularly in the clinical context. The difference in the
adjustment made to Hb at a given altitude between PSC and WRA in our study was no more
than 3 g/L suggesting that common criteria for all population groups may be reasonable and
more practical, but this needs confirmation. It should be noted that population surveys often
sample participants from the same cluster and households, and some of the WRA could have
been mothers or related to the PSC. Thus, our population groups are not entirely
independent of each other. For Bolivia, women and children were enrolled as dyads.
Additional data confirming associations between Hb and altitude among other population
groups, including school-age children, pregnant women, men, and the elderly, as well as
additional modeling determining the degree of misclassification in anemia status using a
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combined population-group criteria would assist with determining the appropriateness of

one common criterion across all population groups.

We estimated the population prevalence of anemia using different criteria for adjusting Hb
and found differences in anemia prevalence between the currently recommended WHO
cutoffs and the direct equation (1989 MMWR). Thus, better guidance on the preferred
adjustment method is warranted. Guidance should specify the utility of using cutoffs versus
equations for clinical practice and for population-based surveys. Direct use of prediction
equations gives a more exact adjustment of Hb concentration for altitude and/or smoking,
but one has to balance this with ease of practical application and the technical capacity of the
setting. Further, the current WHO recommendation describes the cutoff for altitude at a
given altitude (e.g., 5 g/L at 1500 m).2 Clearer guidance is needed as to whether the
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adjustment is applied to all altitudes between cutoffs (e.g., Fig. 1: the 5 g/L adjustment is
applied to 1500−1999 m) or whether the adjustment represents the midpoint and is applied
to the surrounding altitudes (e.g., Fig. 1: the 5 g/L adjustment is applied to 1250−1749 m);
the latter approach more closely resembles the adjustment based on the 1989 MMWR
prediction equation.

Our study had several strengths. We were able to examine associations with Hb using
population-based data (with the exception of Bolivia) from multiple countries; all WHO

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Regions, except South East Asia, were represented. This enhanced our ability to examine Hb
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across a wide range of altitudes with data encompassing multiple racial and ethnic groups
and levels of socioeconomic status. Similarly, with multicountry data, we were able to
examine the additive effect of smoking across a wide range of altitudes and the associations
with smoking account for heterogeneity in the smoke delivery (e.g., carbon monoxide) of
local tobacco products.26 In addition, we were able to control for individual iron and VA
deficiency. Micronutrient deficiencies are associated with Hb and may vary by altitude due
to the context of location, including diet quality and composition. Controlling for
micronutrient status permits the assessment of the independent contribution of altitude and
smoking on Hb concentration. Our findings were robust across multiple model specifications
and sensitivity analyses. Furthermore, erythropoietic activity is known to increase in
response to low oxygen concentration due to low Hb and functional ID.27 We found that
classification of anemia independent of altitude and/or smoking (i.e., adjusted using the new
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proposed equations) was associated with significantly higher levels of sTfR (a marker of
erythropoiesis), indicating that those with anemia were correctly identified.

Our study has limitations. First, we were unable to explore whether the association between
Hb and altitude or smoking is modified by race/ethnicity or other population groups (e.g.,
adolescents, men, and pregnancy) as these data are not currently harmonized across datasets.
Second, data among individuals residing at altitudes above 3000 m were limited in our
study. However, our finding that current WHO recommendations may overadjust Hb for
those who reside at high altitudes has also been reported in a recent study of children 6−59
months residing in Peru.28 In this paper, the regression equation resulted in altitude
adjustments about 2−4 g/L lower than we report. Studies also report genetic or epigenetic
adaptions to high-altitude hypoxia that may differ among indigenous populations residing in
high-altitude Andean, Tibetan, and Ethiopian regions.29–31 The increase in Hb
Author Manuscript

concentrations due to altitude has been shown to be higher in high-altitude Andean

compared with high-altitude Tibetan and Ethiopian populations.30 Because ongoing debate
remains whether adaptation to high altitude hypoxia varies by genetic descent and duration
of residence, and our high-altitude data predominantly came from populations in the Andean
region (Bolivia and Ecuador), our findings warrant confirmation in other high-altitude
regions. In general, we observed the association between altitude and Hb to be similar across
surveys among the two population groups examined. There also remains debate as to
whether the threshold to define anemia (or polycythemia) based on health outcomes differs
between those who reside at low and high altitudes.32,33 Our study was not designed to
examine differences in Hb concentration and health outcomes by altitude. Third, smoking
status and cigarette quantity were self-reported and there was no information on the duration
of smoking. Self-reported smoking is known to be underreported,34,35 which may lead in an
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overestimate of adjustment at lower smoking levels of smoking. Less than 4% of women

reported being heavy smokers (>20 cigarettes per day), thus additional research is likely
needed to confirm the adjustment for this group. We also had no data on e-cigarette use.
Fourth, some study subjects were missing data on key variables, such as inflammation-
corrected ID and VAD reducing sample size for models. Subjects with complete data tended
to be older, and fewer children and more women were categorized with anemia, thus missing
data may have introduced selection bias. However, associations and adjustments were

Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
 Sharma et al. Page 11

similar across models indicating the impact of selection bias may be minimal. Finally, our
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models accounted for less than half of the variation in Hb. It is possible that we have not
controlled for all sources of confounding, including obstructive pulmonary diseases,
exposure to air pollution, or the status of other micronutrients. Folate and B12, in addition to
iron, are required for hematopoiesis and may be correlated with altitude due to diet quality
and composition.

Anemia is prevalent worldwide. Findings from this analysis will inform the current review
of global guidelines on the use of altitude and smoking−adjusted Hb concentrations for the
assessment of anemia.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Author Manuscript

Acknowledgments
This work was commissioned by the Evidence and Programme Guidance Unit, Department of Nutrition for Health
and Development of the World Health Organization (WHO), Geneva, Switzerland.

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 Sharma et al. Page 14

Statement
Author Manuscript

This manuscript was presented at the World Health Organization (WHO) technical
consultation “Use and Interpretation of Haemoglobin Concentrations for Assessing
Anaemia Status in Individuals and Populations,” held in Geneva, Switzerland on
November 29−30 and December 1, 2017. This paper is being published individually but
will be consolidated with other manuscripts as a special issue of Annals of the New York
Academy of Sciences, the coordinators of which were Drs. Maria Nieves Garcia-Casal
and Sant-Rayn Pasricha. The special issue is the responsibility of the editorial staff of
Annals of the New York Academy of Sciences, who delegated to the coordinators
preliminary supervision of both technical conformity to the publishing requirements of
Annals of the New York Academy of Sciences and general oversight of the scientific
merit of each article. The workshop was supported by WHO, the Centers for Disease
Control and Prevention (CDC); the United States Agency for International Development
Author Manuscript

(USAID); and the Bill & Melinda Gates Foundation. The authors alone are responsible
for the views expressed in this paper; they do not necessarily represent the views,
decisions, or policies of the WHO. The opinions expressed in this publication are those of
the authors and are not attributable to the sponsors, publisher, or editorial staff of Annals
of the New York Academy of Sciences.
Author Manuscript
Author Manuscript

Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
 Sharma et al. Page 15

••••••• Hurtado{1945) b - CDC{1989) c - - Diren{1994) d X WHO {2001(

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60

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·=
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0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000
Author Manuscript

Altitude (m)

Figure 1.
Summary of previously published equations to adjust hemoglobin for altitude and current
WHO adjustment valuesa.
aAdjustment is the amount added to the hemoglobin (Hb) cutoff defining anemia or

subtracted from an individual’s observed hemoglobin level.

bBased on the equation Hb_adjustment (g/L) = 6.83 × EXP(0.000445 × altitude) +113.3 and

reported as the difference between hemoglobin at a given altitude and hemoglobin at sea
level (0 m). Hemoglobin was assessed up to 4540 m.9,12
cBased on the equation Hb_adjustment (g/L) = [(−0.032 × (altitude × 0.0032808) + 0.022 ×

(altitude × 0.0032808)2) × 10]. Hemoglobin was assessed up to approximately 2150 m.8

dBased on the equation Hb_adjustment (g/L) = 3.44 × EXP(0.000633 × altitude) + 116.9 and
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reported as the difference between hemoglobin at a given altitude and hemoglobin at sea
level (0 m). Hb was assessed up to 3400 m.12
eWHO cutoffs shown with an X at each (altitude, Hb_adjustment) coordinate with the

recommended Hb adjustment value shown above each X.7

Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
 Sharma et al. Page 16

PSC WRA
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50

40

2
E) 30
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Q)
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Author Manuscript

.0
20
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0 1000 2000 3000 4000 0 1000 2000 3000 4000

Altitude (m)
Model 1 : Crude
Model 2: Adjusted for ID and VAD (no correction for inflammation)
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Model 3: Adjusted for ID and VAD (correction for inflammation)

Model 4: Restricted to healthy (No ID and No VAD, inflammation corrected)
- -- - Sensitivity: Model 3 excluding countries reporting altitude in categories
-- Sensitivity: Model 3 with ID defined using serum ferritin only
- -- - Sensitivity: Model 3 excluding Bolivia
- - - - Sensitivity: Model 4 also excluding cases with WHZ<-2 (PSC) or malaria (PSC, WRA)
11111111 MMWR 1989 - representing current WHO guidance

Figure 2.
Hemoglobin adjustment for altitude for preschool-age children (PSC) and women of
reproductive age (WRA) by model. Note: All models adjusted for age and the survey. ID and
VAD biomarkers corrected for inflammation using BRINDA method.23,24
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Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
 Sharma et al. Page 17

a b C
■ WHO (2001) D MMWR (1989) !ill Proposed adjustments
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100

90

80

70

~ 60
1lC:
2 50
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•:~ n n1~11~l1nl I 1~11~1

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Afghanistan Azerbaijan Bolivia•• Colombia Ecuador Georgia Guatemala Laos Malawi Mexico Mexico Papua New
(2006) (2012) Guinea

Figure 3.
Prevalence of anemia among preschool-aged children (6−59 months) based on different
criteria to adjust for hemoglobin for altitude.* Note: *All adjustments subtracted from
individual’s Hb concentration. Anemia defined as Hb < 110 g/L. **Prevalence weighted to
be nationally representative, except for Bolivia, as it was not sampled to be a representative
survey.
aWHO (2001) based on WHO recommended cutoffs.2
bMMWR (1989) based on the equation Hb_adjust_altitude (g/L) = [(−0.032 ×(altitude ×

0.0032808) + 0.022 (altitude × 0.0032808)2) ×10].8

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cProposed adjustment, Hb_adjust_altitude (g/L) = (0.0048108 × altitude) + (0.0000004 ×

altitude2).
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Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
 Sharma et al. Page 18

■ WHO (2001) 8 □ MMWR (1989) b l§ll Proposed adjustmentsc

60
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50

40

l
1j
~30
-;;;
i
..
~20

Ii dd
(U
C:

10

Afghanistan Azerbaijan Bolivia•• Colombia Ecuador Georgia Guatemala Laos Malawi Mexico Mexico Papua New United United States
(2006) (2012) Guinea Kindgom
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Figure 4.
Prevalence of anemia among women of reproductive age (15−49 years) based on different
criteria to adjust for hemoglobin for altitude and smoking.* Note: *The United Kingdom
and the United States adjusted for smoking only; Afghanistan, Azerbaijan, Bolivia, Laos,
and Malawi adjusted for altitude only. All adjustments subtracted from the individual’s Hb
concentration. Anemia defined as Hb < 120 g/L. **Prevalence weighted to be nationally
representative, except for Bolivia, as it was not sampled to be a representative survey.
aWHO (2001) based on WHO recommended cutoffs for altitude and smoking.2
bMMWR (1989) based on the equation Hb_adjust_altitude (g/L) = [(−0.032 (altitude

×0.0032808) + 0.022 × (altitude × 0.0032808)2) × 10] and the WHO recommended cutoffs
for smoking.2,10
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cProposed adjustments, Hb_adjust_altitude (g/L) (0. 0052792 × altitude2); Smoker, cigarette

quantity known Hb_adjust_smoking (g/L) = (0.4459 ×cigarette_number)+(−0.007×

cigarette_number2); Smoker, cigarette quantity unknown Hb_adjust_smoking (g/L) = 2.
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Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Table 1.

Data source location, altitude range, and data availability, sorted by maximum altitude

Altitude Biomarker data available

Sharma et al.

Country Year Min Max Group Hb SF sTfR SR RBP CRP AGP Smoking data available
a 2008–2014 80 80 PSC: NA -
The United Kingdom
WRA: X X X X X Yes/No # cigarettes/day
a 2006 999 1251 PSC: X X X X X -
Laos
WRA: X X X X X NA
Malawi 2016 52 1626 PSC: X X X X X X X -
WRA: X X X X X X X NA
Azerbaijan 2013 −27 1662 PSC: X X X X X -
WRA: X X X X X X NA
a 2009 3 1944 PSC: X X X -
Georgia
WRA: X X X Yes/No # cigarettes/day
Papua New Guinea 2005 10 2400 PSC: X X X X X -
WRA: X X X X X Yes/No
Mexico 2012 0 2985 PSC: X X X -
WRA: X X X Yes/No # cigarettes/day
Guatemala 2013 0 3034 PSC: X X X X X X -
WRA: X X X X X X Yes/No # cigarettes/day
Mexico 2006 1 3110 PSC: X X X X -
WRA: X X X X Yes/No # cigarettes/day
Colombia 2010 −15 3204 PSC: X X X X -

Ann N Y Acad Sci. Author manuscript; available in PMC 2020 February 01.
WRA: X X X Yes/No
Afghanistan 2014 325 3360 PSC: X X X X X -
WRA: X X X X X NA
Ecuador 2012 0 3931 PSC: X X X X -
WRA: X X X X Yes/No
Bolivia 2013–2015 4000 4000 PSC: X X X X X X X -

WRA: X X X X X X X b
NA
Page 19
 Author Manuscript Author Manuscript Author Manuscript Author Manuscript

Altitude Biomarker data available

Country Year Min Max Group Hb SF sTfR SR RBP CRP AGP Smoking data available

The United States 2003–2006 c NA PSC: -

NA
WRA: X X X X X Yes/No # cigarettes/day
Sharma et al.

a
Altitude reported as categories (the United Kingdom, all assumed to be 80 m based on average altitude of the 10 most populous areas; Georgia, altitude recoded based on an average altitude within the
cluster. Laos reported altitude in three categories).
b
Smoking data not included in the analysis because only two women reported smoking.
c
Altitude data collected, but not available in the public use dataset.

AGP, alpha-1 acid glycoprotein; CRP, C-reactive protein; NA, data not available; PSC, preschool-aged children; RBP, retinol binding protein; SF, serum ferritin; SR, serum retinol; sTfR, serum transferrin
receptor; WRA, women of reproductive age.

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 Sharma et al. Page 21

Table 2.
a
Proposed adjustments to hemoglobin (g/L) by 500-m increments of altitude by population group
Author Manuscript

WHO MMWR 1989

Altitude (m) b c d e
cutoffs equation PSC WRA
−50 to −1 0 0 0 0
0 0 0 0 0
1–499 0 0 1 1
500–999 0 1 4 4
1000–1499 2 2 7 7
1500–1999 5 5 10 10
2000–2499 8 10 13 13
2500–2999 13 15 16 17
3000–3499 19 22 20 20
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3500–3999 27 29 24 24
4000–4499 35 38 28 28

a
Adjustment is amount (g/L) added to the hemoglobin cutoff defining anemia, or subtracted from an individual’s observed hemoglobin level.
b
WHO cutoffs published as the lowest altitude value in range (e.g., 1500 m for the 1500−1999 range).2
c
MMWR cutoffs calculated using Hb_adjustment (g/L) = [(−0.032 × (altitude × 0.0032808) + 0.022 × (altitude × 0.0032808)2) × 10], where
altitude is based on the midpoint of altitude range (e.g., 1750 m for the 1500−1999 range).8,10
d
Proposed cutoffs calculated using Hb_adjust_altitude (g/L) = (0.0048108 × altitude) + (0.0000004 × altitude2), where altitude is based on the
midpoint of altitude range (e.g., 250 m for the 1−499 range).
e
Proposed cutoffs calculated using Hb_adjust_altitude (g/L) = (0.0052792 × altitude) + (0.0000003 × altitude2), where altitude is based on the
midpoint of altitude range (e.g., 250 m for the 1−499 range).

Note: Current WHO recommendations and adjustments based on the MMWR 1989 equation provided for comparison.
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PSC, preschool-aged children (6−59 months); WRA, women of reproductive age (15−49 years).
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Table 3.

Smoking characteristics among women of reproductive age for each country

Observations Observations
with data on with data on
Sharma et al.

smoking a cigarette
(yes/no) Smoker quantity Among smokers, distribution of the number of cigarettes smoked per day
(n) (% yes) (n) Mean (SD) 1–5 (%) 6–10 (%) 11–15 (%) 16–20 (%) >20 (%)
Colombia 9674 4.1 0 - - - - - -
Ecuador 2225 21.5 2002 1.9 (2.2) 94.8 4.4 0.3 0.5 0.0
Georgia 1710 3.3 1710 12.9 (6.9) 12.3 43.9 10.5 29.8 3.5
Guatemala 1616 6.8 1616 2.3 (2.5) 97.3 0.9 0.0 1.8 0.0
Mexico (2006) 939 31.8 846 3.5 (6.2) 81.1 13.1 2.4 1.9 1.5
Mexico (2012) 1110 42.6 1018 2.2 (3.4) 90.6 7.1 0.8 1.6 0.0
Papua New Guinea 759 21.5 755 5.0 (5.9) 81.1 8.8 1.3 6.9 1.9
The United Kingdom 896 25.8 886 12.9 (7.6) 16.7 30.3 21.7 19.9 11.3
The United States 897 69.8 891 11.3 (9.3) 33.9 30.2 9.8 18.6 7.6
Total 19,826 14.3 9724 6.5 (7.9) 63.9 17.1 5.9 9.4 3.7

a
Unweighted prevalence represents the proportion of smokers in the data and not population prevalence.

NA, data not available.

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 Sharma et al. Page 23

Table 4.
a
Proposed adjustments to hemoglobin for smoking status and cigarettes per day
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b c
WHO adjustments (g/L) Proposed Hb adjustment (g/L)
Smoker, quantity unknown 3 Smoker, quantity unknown 2
Cigarettes (packs) per day Cigarettes per day

< 10 2(-)1 0 1–5 2

6–10 4
1
(- )
10 − 19 2 to 1 3 11–15 5

16–20 6
20–39 (1–2) 5 >20 7
≥40 (>2) 7
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a
Adjustment is the amount added to the hemoglobin cutoff defining anemia, or subtracted from an individual’s observed hemoglobin level.
b
WHO cutoffs published as packs per day.2
c
Adjustments based on Hb adjustment (g/L) = (0.4565 × cigarette_number) + (−0.0078 × cigarette_number2), solved for the upper end of each
interval (e.g., 5 for the 1−5 range). >20 solved using 30 cigarettes/day.

Note: Current WHO recommendations provided for comparison.

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