Correcting haemoglobin cut-offs to define

anaemia in high-altitude pregnant women

in Peru reduces adverse perinatal outcomes
Gustavo F.Gonzales, Vilma Tapia &
Manuel Gasco

Archives of Gynecology and

Obstetrics
ISSN 0932-0067
Volume 290
Number 1
Arch Gynecol Obstet (2014) 290:65-74
DOI 10.1007/s00404-014-3182-z

1 23

Your article is protected by copyright and

all rights are held exclusively by SpringerVerlag Berlin Heidelberg. This e-offprint is
for personal use only and shall not be selfarchived in electronic repositories. If you wish
to self-archive your article, please use the
accepted manuscript version for posting on
your own website. You may further deposit
the accepted manuscript version in any
repository, provided it is only made publicly
available 12 months after official publication
or later and provided acknowledgement is
given to the original source of publication
and a link is inserted to the published article
on Springer's website. The link must be
accompanied by the following text: "The final
publication is available at link.springer.com.

1 23

Author's personal copy

Arch Gynecol Obstet (2014) 290:6574
DOI 10.1007/s00404-014-3182-z

Maternal-Fetal Medicine

Correcting haemoglobin cutoffs todefine anaemia

inhighaltitude pregnant women inPeru reduces adverse
perinatal outcomes
GustavoF.Gonzales VilmaTapia ManuelGasco

Received: 7 December 2013 / Accepted: 7 February 2014 / Published online: 27 February 2014
Springer-Verlag Berlin Heidelberg 2014

Abstract
PurposeTo determine if correction of cut-offs of haemoglobin levels to define anaemia at high altitudes affects
rates of adverse perinatal outcomes.
Methods Data were obtained from 161,909 mothers
and newborns whose births occurred between 1,000 and
4,500m above sea level (masl). Anaemia was defined with
or without correction of haemoglobin (Hb) for altitude as
Hb <11g/dL. Correction of haemoglobin per altitude was
performed according to guidelines from the World Health
Organization. Rates of stillbirths and preterm births were
also calculated.
Results Stillbirth and preterm rates were significantly
reduced in cases of anaemia calculated after correction of
haemoglobin for altitude compared to values obtained without Hb correction. At high altitudes (3,0004,500 masl),
after Hb correction, the rate of stillbirths was reduced
from 37.7 to 18.3 per 1,000 live births (p<0.01); similarly, preterm birth rates were reduced from 13.1 to 8.76%
(p<0.01). The odds ratios for stillbirths and for preterm
births were also reduced after haemoglobin correction.
Conclusion At high altitude, correction of maternal haemoglobin should not be performed to assess the risks for
preterm birth and stillbirth. In fact, using low altitude Hb
cut-off is associated with predicting those at risk.

G.F.Gonzales(*) M.Gasco
Department ofBiological andPhysiological Sciences,
Universidad Peruana Cayetano Heredia, Honorio Delgado 430,
Lima 31, Peru
e-mail: gustavo.gonzales@upch.pe
G.F.Gonzales V.Tapia M.Gasco
Instituto de Investigaciones de la Altura, Universidad Peruana
Cayetano Heredia, Honorio Delgado 430, Lima 31, Peru

Keywords Anaemia Altitude Perinatal adverse

outcomes Haemoglobin cut-off

Introduction
Most populations living at high altitude (HA) show an
increase in haemoglobin (Hb) concentration as the result of
increased erythropoietic activity as a mechanism to compensate an effect of tissue hypoxia consequence of low
barometric pressure [1]. For such reason, populations at
high altitudes have the distribution curve of haemoglobin
shifted to the right in relation to that observed at low altitudes [2]. Because of this, the World Health Organization
(WHO) has suggested that the Hb cut-off values to define
anaemia at high altitudes should be shifted accordingly [3,
4]. In populations of mothers living between sea level and
1,000m above sea level (masl), the cut-off point of Hb to
define anaemia is 11g/dL. Using adjustments for altitude,
the Hb cut-off value to define anaemia increases as altitude
increases [3, 4]. These cut-off values can be observed in
Table1. For instance, in Cerro de Pasco at 4,340 masl, the
Hb cut-off value to define anaemia is 14.5g/dL. At low levels, this value of Hb is considered high and it is used as the
threshold to define erythrocytosis [2].
These adjustments to the Hb cut-off value to define
anaemia are based on a mathematical distribution of normality rather than the use of any clinical parameter. In
the highlands, the use of Hb correction to define anaemia
results in an increase of the rate of anaemia and this rate
is higher to the one observed when anaemia was defined
by iron deficiency [5]. In fact, in 800 Bolivian mothers
living at altitudes between 150 and 3,750 masl, the prevalence of anaemia was 26.6% after correcting Hb for altitude, whereas body iron measurements indicated that only

13

Author's personal copy

66

Arch Gynecol Obstet (2014) 290:6574

Table1Haemoglobin cut-offs to define maternal anaemia at different altitudes according to guidelines from WHO
Altitude (m)

Haemoglobin cut-off to
define maternal anaemia
(g/dL)

Subtracting value
to obtain Hb at
each altitude

<1,000
1,000
1,500
2,000
2,500
3,000
3,500
4,000

11
11.2
11.5
11.8
12.3
12.9
13.7
14.5

0
0.2
0.5
0.8
1.3
1.9
2.7
3.5

4,500

15.5

4.5

The aim of the present study was to determine rates

of stillbirth and preterm birth before and after Hb cut-off
correction in maternal populations living at altitudes over
1,000 masl. The hypothesis is that correction will reduce
rates of stillbirths and preterm births in mothers who live
in the highlands and classified as moderate/severe anaemia.

Materials andmethods
Study design
This is a retrospective cohort study based on data from the
Perinatal Information System in Peru that assess haemoglobin in pregnancy and perinatal outcomes.
Study population

5.7% had tissue iron deficiency severe enough to produce

anaemia [5]. Thus, there does not seem to be concordance
between the prevalence of anaemia at high altitude based
on adjusted haemoglobin levels and that defined by body
iron content measurements.
In addition, in the native Tibetan population resident for
more than 25,000years on the high Qinghai-Tibetan Plateau, 1012% of the population is anaemic; however, using
recommended cut-off values for their altitudes, the figures
increase to 4046% [7].
Global anaemia prevalence in 2010 was estimated in
32.9%, causing 68.36 (95% CI 40.98107.54) million
years lived with disability [8]. Globally, the main cause for
anaemia was iron deficiency [8]. Several studies find a relationship between severity of maternal anaemia (moderate
and severe anaemia) and adverse perinatal outcomes such
as increased rates of stillbirths and preterm births [2, 911].
If correction of Hb for populations at high altitudes would
increase the real prevalence of anaemia, then rates of stillbirths and preterm births should at least be maintained in
values similar to those obtained without Hb correction. In
addition, odds ratios (ORs) for stillbirths or preterm births
should remain the same or become higher in the anaemic
group after correction.
Correction of Hb at HA will result in more women being
defined as anaemic, rather than normal. On the other side,
increases in maternal haemoglobin values over 14.5g/dL
are associated with significantly higher relative risks of low
birth weight and premature delivery [12]. At high altitudes,
after correction, many women with uncorrected high Hb
levels will result as normal. For such reason, it is necessary to determine if the rate of anaemia after Hb correction is really true and if it is also associated with similar
perinatal adverse outcomes observed when it was assessed
without Hb correction.

13

Data were obtained from the Perinatal Information System

for the years between 2000 and 2010 and included mothers
attending Public Hospitals located in the mountains of the
Northern, Central and Southern regions (between 1,000 and
4,500 masl) of Peru, a South American country. These hospitals are supported by the Ministry of Health and attended
by population of scarce economic resources.
For the present study, all pregnant women whose data
on haemoglobin measurement during their pregnancy (first,
second or third trimester) and date of birth were available,
including gestational age, were included. The final sample
size included 161,909 mothers and their newborns (Fig.1).
This sample size is enough for a study power of 80% and a
confidence interval of 95%. Exclusion criteria were births
at altitudes below 1,000 masl, multiple pregnancies, congenital malformations, birth weight below 500g and lack
of maternal haemoglobin data.
Outcomes variables
The outcomes for the present study were preterm births and
stillbirths.
Stillbirth was defined as delivery of a dead foetus from
20weeks of gestation onwards or 500g. The stillbirth
rate was defined as number of late foetal deaths per 1,000
live births.
Preterm birth was defined as a delivery that occurred
before 37weeks of gestational age. Preterm birth rates were
calculated as percentages. Gestational age at delivery was
based on the first day of the last menstrual period and verified by a routine physical examination (Capurro). The gold
standard for age determination is the use of ultrasound. In
the database, gestational age was obtained by the date of
last menses, which is less reliable. However, this value was

Author's personal copy

Arch Gynecol Obstet (2014) 290:6574

67

Confounder variables
Potential confounders controlled for in the analysis were
age, body mass index (BMI), maternal education, antenatal
care, parity, preeclampsia, and urinary infection. These variables were correlated with exposure and with outcomes.
Quality control ofdata

Fig.1Flow diagram showing study sample size selection

compared with gestational age measured by physical examination and results (not shown) were also concordant.

Data from the SIP were usually entered in each place by

trained personnel or midwives. Data were entered near to
real time.
Quality control was performed by examining clinical
records from a subsample in each maternity unit to address
potential sources of bias. Data were subjected by authors to
quality checks by reviewing at least 100 clinical records in
each study area and comparing them with data in the database. Discordant data were excluded, i.e. lower gestational
age with high birthweight. In the database, 546 data were
classified as discordant, representing 0.27% of the sample
size.
Some data in the perinatal record may not adequately
represent the residence characteristics of women in the
sample. For example, some women may have lived at sea
level and only travelled to high altitude (or vice versa) for
delivery, the timing of which the record might not reveal,
thus making it impossible to know the long-term effects
of altitude on the gestation. However, this number is likely
to be very small to significantly modify the results of the
study.
Statistical analyses

Exposure variables
Altitude was defined in three categories, 1,0001,999 masl,
2,0002,999 masl and 3,0004,500 masl.
In some cultures, married women migrate back to their
original birthplace to deliver. In the present study, 0.59%
of women have their pregnancy in a place different to the
hospital of delivery. This group was excluded from the
analysis.
Anaemia was also defined in three categories according to the WHO classification [4]: (1) Mild anaemia,
when maternal haemoglobin values were between 9 and
<11g/dL, (2) moderate anaemia for haemoglobin values
between 7 and <9g/dL, and (3) severe anaemia for haemoglobin values below 7g/dL.
From the available data, newborns whose mothers were
diagnosed with mild, moderate or severe anaemia before
and after correction of haemoglobin cut-off for altitude were
selected for further analyses. Correction of Hb cut-off point
to define anaemia was defined according to altitude of residence using the guidelines from WHO showed in Table1.

Statistical analysis was performed using STATA package

ver. 10 (Stata Corp, College Station, TX, USA).
The study population was categorized in two groups:
one defined as anaemic with maternal Hb <11g/dLfurther broken down into mild, moderate and severe anaemia according to the WHO definition [4], and the second
defined as anaemic after correction of the Hb for altitude
using the cut-offs as defined in Table1. In each group,
rates of stillbirths and of preterm births were calculated
and compared. These rates were assessed at each degree of
anaemia.
For multivariate analysis, bivariate comparisons were
first used to assess potential confounders or risk factors for
the outcome. Risk factors in the multivariable model that
had an association at a significance level of p<0.1 were
included. Thereafter, a multivariable model was created
with a backwards stepwise elimination strategy.
Rates of each adverse pregnancy outcome (preterm
births or stillbirths) were calculated for each group of
maternal haemoglobin levels or group of altitudinal

13

Author's personal copy

68

residence and estimates of crude odds ratio (OR) with

95% confidence interval (CI) were computed as measures
of association between the variables. Adjusted ORs were
derived through logistic regression models. Models were
adjusted for maternal age; maternal education; marital status; BMI; prenatal care; parity; preeclampsia and urinary
infection (in current pregnancy); and gestational age at
which haemoglobin was measured. All variables influencing the outcome were included in the final model.
The Chi-square test was used for categorical data. A
two-sided probability <0.05 was considered statistically
significant. A post hoc power analysis was performed
which showed greater than 80% power to detect an odds
ratio of 1.16 for the association between anaemia and preterm birth and, an odds ratio of 1.55 entre anaemia and
stillbirth.

Results
The rate of anaemia increased five times after Hb cut-off
was corrected to define maternal anaemia at high altitude (Fig.2). The rate of anaemia before Hb correction
decreased as altitude increased, whereas after Hb correction, the rate of anaemia was highest at the higher altitude
(3,000m) (Fig.2).
Table 2 shows the sociodemographic data according
to normal haemoglobin level or degree of anaemia (mild,
moderate or severe anaemia). Severe anaemia was associated with low and high maternal age, higher BMI, less education, less antenatal care, low and higher parity, higher
stillbirths and preterm births. Anaemia rates were decreased
as altitude of residence increases. Most of moderate/severe
anaemia was detected at third trimester of pregnancy.
The stillbirth rate in mothers with anaemia diagnosed
without correction of Hb was 28.0 per 1,000 live births,
a value significantly higher than that obtained when correction for altitude was performed, in which case the rate
was reduced to 18.2 per 1,000 live births (p<0.01). For

Fig.2Prevalence of maternal anaemia in Peruvian hospitals located

at different altitudes (1,0001,999m; 2,0002,999m; and >3,000m)
before (left column) and after (right column) Hb cut-off correction to
define anaemia

13

Arch Gynecol Obstet (2014) 290:6574

stillbirths, the ORs in anaemics defined before Hb correction were also significantly reduced from 1.69 (CI 1.48
1.94) to 1.17 (CI 1.071.27) in anaemics defined after Hb
correction for altitude (Fig.3a, b). The ORs for stillbirth
with variables as maternal age, BMI, maternal education,
number of visits of antenatal care, parity, trimester at Hb
measurement, preeclampsia, preterm births and altitude
were not different in the groups without or with Hb correction (data not shown).
The rate of preterm births in mothers with anaemia
without correction of Hb was 9.41%, which was reduced
to 8.24% (p<0.01) after Hb correction for altitude. For
preterm births, the OR in anaemics without Hb correction was 1.44 (CI 95% 1.341.55) and this value was
reduced to 1.20 (CI 95% 1.151.25) after Hb correction
for altitude (p<0.01) (Fig.3c, d). The ORs for variables
as maternal age, BMI, maternal education, number of visits of antenatal care, parity, trimester at Hb measurement,
preeclampsia, urinary infection and altitude were not different in the groups without or with Hb correction (data
not shown).
Results are similar if we break down the rates by different altitudes. Thus, the rate of stillbirths in mothers with
anaemia without Hb correction was higher than that after
Hb correction for altitude, both at 2,0002,999 masl (28.9
per 1,000 live births vs. 19.3 per 1,000 live births, p<0.01)
and at 3,0004,500 masl (37.7 per 1,000 live births vs. 18.3
per 1,000 live births, p<0.01) (Table3).
The rate of preterm births was also higher if anaemia
was diagnosed without Hb correction for altitude. This
was observed particularly at 2,0002,999 masl (9.20%
vs. 8.13%, p<0.01) and at 3,0004,500 masl (13.1 vs.
8.76%, p<0.01) (Table4). Similarly, ORs for both stillbirths and preterm births were reduced in anaemics after
Hb correction, particularly for altitudes over 2,000 masl
(Tables 3, 4). For stillbirths, the ORs calculated for the
variables age, BMI, maternal education, antenatal care,
parity, preeclampsia, preterm birth were not modified in
the groups of anaemics with or without Hb correction. For
preterm births, the ORs calculated for the variables age,
BMI, maternal education, antenatal care, parity, preeclampsia, and urinary infection were not modified after Hb
correction.
Stillbirths rates increased from 14 per 1,000 in mothers with normal haemoglobin to 161 per 1,000 in women
with severe anaemia. These values are significantly reduced
after Hb correction for altitude. For instance, in severe
anaemia, the rate of stillbirths was reduced from 161 per
1,000 to 94.5 per 1,000 (p<0.01) (Fig.4 upper). A similar pattern was observed with preterm births. The preterm
birth rate increased with magnitude of anaemia and it was
reduced if Hb cut-off to define anaemia is corrected for altitude (Fig.4 bottom).

Author's personal copy

Arch Gynecol Obstet (2014) 290:6574
Table2Sociodemographic
characteristics in the
Peruvian study population
attending public hospitals
in Peru according to normal
haemoglobin or different
degrees of anaemia during
pregnancy

Prim primary studies, Sec/

sup secondary/universitary
studies, m meters above sea
level, 2: p<0.01, except for
preeclampsia

Variable

69
Normal (151,485)
n

Age (years)
<20
28,947
2034
104,206
<34
18,332
2
BMI (kg/m )
<19
13,884
2025
97,544
>25
40,057
Study
None/prim
118,820
Sec/sup
32,665
Antenatal care
<6
76,381
6
75,104
Parity
None
73,963
13
66,227
>3
11,295
Preeclampsia
4,693
Stillbirth
2,116
Preterm
10,614
Urinary inf
27,381
Haemoglobin measurement
1st trim.
35,317
2nd trim.
62,646
3rd trim.
53,522
Altitude (m)
1,0001,999
11,371
2,0002,999
59,375
>3,000

80,739

ORs for stillbirths increased according to the magnitude

of anaemia. Highest ORs were observed with severe anaemia (OR=6.70). However, ORs were reduced if anaemia
was defined using Hb correction for altitude (OR=3.78).
Moreover, the OR for stillbirths after Hb correction was not
significant in mild anaemia (OR=1.04; CI=0.951.15)
but, it was significant in mild anaemia without haemoglobin correction (OR=1.43; CI=1.231.67) (Table5). ORs
for confounding variables assessed were not modified after
Hb correction for altitude.
Similarly, ORs for preterm births were increased as
anaemia worsened. The highest OR was observed with
severe anaemia without Hb correction (OR=4.27). This
OR value was reduced to 2.84 if Hb was corrected for altitude (Table6). Similarly, ORs for confounding variables
were not modified after Hb correction for altitude.

Mild anaemia (9,368) Moderate anaemia

(907)

Severe anaemia
(149)

19.1
68.8
12.1

2,044
6,105
1,219

21.8
65.2
13.0

161
608
138

17.8
67.0
15.2

222
104
23

14.8
69.8
15.4

9.2
64.4
26.4

983
6,222
2,163

10.5
66.4
23.1

83
609
215

9.2
67.1
23.7

15
91
43

10.1
61.1
28.8

78.4
21.6

7,017
2,351

74.9
25.1

652
255

71.9
28.1

98
51

65.7
34.2

50.4
49.6

4,323
5,045

46.1
53.9

275
632

30.3
69.7

53
96

35.6
64.4

48.8
43.7
7.5
3.1
1.4
7.0
18.1

4,507
3,974
887
270
210
789
1,604

48.1
42.4
9.5
2.9
2.2
8.4
17.8

364
412
131
35
58
154
143

40.1
45.4
14.5
3.9
6.4
16.9
15.8

57
68
24
5
24
38
15

38.3
45.6
16.1
3.4
16.1
25.5
10.1

23.31
41.35
35.33

938
4,420
4,010

10.01
47.18
42.81

53
305
549

5.84
33.63
60.53

25
52
72

16.78
34.90
48.32

80.34
93.37

2,552
3,808

18.03
5.99

217
340

1.53
0.53

13
68

0.09
0.11

95.93

3,008

3.57

350

0.42

68

0.08

Discussion
In this large retrospective study on populations living
between 1,000 and 4,500 masl, we analyzed the rates of
stillbirths and preterm births associated with maternal anaemia. Anaemia was diagnosed when Hb cut-off to define
anaemia was uncorrected (Hb <11g/dL) and after correction for altitude [3, 4]. According to the results, stillbirth
and preterm birth rates were significantly reduced in those
cases of anaemia diagnosed after correction of haemoglobin for altitude. Since rates of anaemia increase after Hb
correction as observed in Fig.2 and anaemia is positively
correlated with stillbirths and prematurity, our results suggest that normal (non anaemic) women may have been
included as anaemic after correction of Hb for altitude. As
these cases correspond to women with low risk of stillbirths

13

Author's personal copy

70

30
25

20

OR for stillbirths

Stillbirth (per 1000 births)

Arch Gynecol Obstet (2014) 290:6574

15
10
5
0
Without Hb correction

2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0

Without Hb correction

With Hb correction

9.6

Preterm Births (%)

9.2

9.4

1.6

OR for preterm births

1.4

9
8.8

8.6
8.4
8.2
8
7.8
7.6

With Hb correction

Maternal Anaemia

Maternal Anemia

1.2
1

0.8
0.6
0.4
0.2
0

Without Hb correction

With Hb correction

Without Hb correction

Maternal Anemia

With Hb correction

Maternal Anaemia

Fig.3Stillbirth and preterm birth rates and their odds ratios with and
without Hb correction. a *p<0.001 with respect to the group without Hb correction; b *p<0.01. Logistic regression model adjusted
by age, BMI, maternal education, antenatal care, parity, trimester at
Hb measurement, preeclampsia, preterm birth and altitude of resi-

dence; c *p<0.001 with respect to the group without Hb correction;

d *p<0.01. Logistic regression model adjusted by age, BMI, maternal education, antenatal care, parity, trimester at Hb measurement,
preeclampsia, urinary infection and altitude of residence

Table3Logistic regression for the relationship between anaemia with and without a correction factor and stillbirth rates for each altitude
(1,0004,500m)
Altitude (m)

Stillbirth rates (per 1,000 live births) in anaemic mothers

without Hb correction

Stillbirth rates (per 1,000 live births) in anaemic mothers

with Hb correction for altitude

ORc

ORa

CI 95%

ORc

ORa

CI 95%

1,0001,999
2,0002,999

41
122

14.7
28.9

1.41
2.26*

1.22
1.74

0.831.77
1.412.15

59
286

13.8
19.3

1.36
1.56*

1.21
1.24

0.861.70
1.071.44

3,0004,500

129

37.7

2.53*

1.74

1.432.12

591

18.3

1.25*

1.12

1.011.26

Logistic regression model adjusted for age, BMI, maternal education, antenatal care, parity, preeclampsia, preterm birth. Each row represents a
model for each altitude range comparing the population of anemics with stillbirth and non anaemic with stillbirths (OR=1.0)
ORc crude odds ratio, ORa adjusted odds ratio
Per 1,000 live births
* p<0.01

and preterm births, the rates of perinatal adverse outcomes

were reduced after Hb correction for altitude.
This is an important finding since it is suggested that
due to Hb increase by effect of altitude [1], the Hb value
to define anaemia must be shifted to the right, [3, 4] and
in these conditions, many mothers with normal Hb values
at high altitude may become spuriously anaemic after
Hb correction. Our results demonstrate that the corrected

13

haemoglobin is not associated with adverse outcomes as

much as the uncorrected Hb.
Multivariable analyses confirmed that ORs for stillbirths
and preterm deliveries were lower after correction of Hb
for altitude particularly at the level of moderate and severe
anaemia. This suggests that the risks of perinatal adverse
outcomes were diluted as many pregnant women with
normal Hb were incorporated as anaemic.

Author's personal copy

Arch Gynecol Obstet (2014) 290:6574

71

Table4Logistic regression for the relationship between anaemia with and without a correction factor and preterm birth rates for each altitude
(1,0004,500m)
Altitude (m)

Preterm birth rates in anaemic mothers

without Hb correction
n

1,0001,999
2,0002,999

141
388

3,0004,500

452

%
5.07
9.20
13.1

Preterm birth rates in anaemic mothers with Hb correction

for altitude

ORc

ORa

CI 95%

ORc

ORa

CI 95%

1.25*
1.46*

1.04
1.34

0.851.27
1.201.50

201
1,203

4.72
8.13

1.15
1.34*

0.96
1.22

0.811.15
1.131.31

1.79*

1.57

1.411.75

2,827

8.76

1.16*

1.18

1.121.24

Logistic regression model adjusted for age, BMI, maternal education, antenatal care, parity, preeclampsia, and urinary infection. Each row represents a model for each altitude range comparing the population of anemics with preterm births and non anaemic with pre term births (OR=1.0)
ORc crude odds ratio, ORa adjusted odds ratio

Fig.4Stillbirth rate (upper)

and preterm birth rate (bottom)
in pregnant women with normal
haemoglobin (Hb), mild,
moderate and severe anaemia
defined without (black) and
with (white) haemoglobin correction for altitude

Stillbirth rate (per 1000 live births

* p<0.01

180

Without Hb correction

160

With Hb correction

140
120

P<0.01

100
80
60

P<0.01

40

P<0.01

20
0

Normal Hb

Preterm births rate (%)

30

Mild anaemia

Moderate anaemia

Severe anaemia

Without Hb correction
With Hb correction

25

P<0.01

20
P<0.01

15
P<0.01

10
5
0
Normal Hb

Maternal anaemia rate is used as a marker for quality of

life of a population [10]. Our data indicate that a change
of the cut-off of Hb to define anaemia because of altitude
would increase unnecessarily and artificially the rates of
anaemia in populations living over 1,000 masl. In addition, the use of haemoglobin correction for altitude and
the increase in anaemia rates may result in treatment with
iron supplementation to mothers who otherwise would
not require it. In the literature, several papers have demonstrated that treatment with iron in non anaemic mothers could be more harmful than beneficial, increasing the
risk of adverse perinatal outcomes if maternal Hb increases
over 14.5g/dL [11, 12]. For example, higher Hb values in

Mild anaemia

Moderate anaemia

Severe anaemia

non anaemic women result in increased rates of newborn

small for gestational age [12]. Recent studies have also
demonstrated, in populations at low and high altitudes, that
uncorrected haemoglobin levels over 14.5g/dL were also
associated with increased rates of small for gestational age
[2, 13]. The finding that mothers with high haemoglobin
level is more common in populations located at altitudes
over 2,000 masl [13] is due to the reduction of low environmental pressure as altitude increases.
Worldwide, almost 140 million people live permanently
at altitudes >2,500 m in North, Central and South America, in East Africa, and Asia [14]. Moreover, 32% of the
total population of Peru lives at high altitudes, representing

13

Author's personal copy

72
Table5Relationship between
degree of anaemia (with and
without correction factor) and
stillbirth rate (per 1,000 live
births) in Peruvian populations
living at altitudes between 1,000
and 4,500 meters above sea
level (masl)

Arch Gynecol Obstet (2014) 290:6574

Stillbirths

Anaemia
Not
Mild
Moderate
Severe
Maternal age (years)
<20
2034
>34
BMI (kg/m2)
<19
1925
>25
None/low education
Secondary/superior
Antenatal care
<6
6
Parity
None
13
>3
Measure of Hb
1st trimester
2nd trimester
3rd trimester
Preeclampsia
Yes
Not
Preterm birth
<37weeks
37weeks
Altitude (m)
1,0001,999
2,0002,999
>3,000

Uncorrected haemoglobin

Corrected haemoglobin

OREE

OREE

95% CI

1.00
1.44
2.69
6.70

0.11
0.41
1.79

1.23
1.99
3.97

1.67
3.63
11.30

1.00
1.04
1.54
3.79

0.05
0.14
0.52

0.95
1.29
2.89

1.15
1.83
4.96

0.73
1.0
1.21

0.05
1.0
0.08

0.64

0.83

0.73

0.05

0.64

0.83

1.06

1.37

1.21

0.08

1.07

1.37

0.77
1.0
0.97
1.77
1

0.06
1.0
0.05
0.09

0.66

0.91

0.78

0.06

0.66

0.91

0.88
1.61

1.07
1.95

0.97
1.77
1.00

0.05
0.09

0.88
1.61

1.07
1.95

1.86
1.0

0.10
1.0

1.68

2.07

1.87

0.10

1.68

2.07

1.03
1.0
1.38

0.05
1.0
0.10

0.93

1.15

1.03

0.05

0.93

1.15

1.19

1.59

1.36

0.10

1.18

1.57

1.0
1.16
0.91

1.0
0.09
0.06

1.02
0.80

1.31
1.03

1.16
0.91

0.07
0.06

1.02
0.79

1.31
1.03

0.79
1.0

0.08
1.0

0.65

0.96

0.79

0.08

0.65

0.96

14.71
1.0

0.66

13.46

16.06

14.65

0.66

13.41

16.01

1.0
1.01

1.0
0.10

0.84

1.20

0.94

0.08

0.79

1.12

1.10

0.10

0.92

1.31

0.98

0.09

0.83

1.16

almost 9 million inhabitants [15]. For such reason, it is

important to know the relationship, if any, between haemoglobin levels, pregnancy and perinatal outcomes in these
populations. Particularly, it is necessary to know if Hb correction to define anaemia in the altitude is really needed.
Although it is a fact that Hb increases in populations living at high altitudes, studies conducted in the last few decades have demonstrated that populations adapted to high
altitudes over a long period of time have relatively lower
Hb levels than populations not yet adapted to high altitudes
[6]. In fact, populations with multigenerational residence

13

CI 95%

at high altitudes have lower levels of haemoglobin than

population with shorter residence at the highlands [16].
Heavier birth weights are generally seen in Tibetans in the
Himalayas Mountain, a population with multigenerational
residence, than among Andean (Peru and Bolivia) or Rocky
Mountain (USA) residents of the same altitude [14]. Tibetans have lived in the Himalayas for more than 25,000years,
whereas the Han Chinese ethnic group resides at the same
place for no longer than 70years. Tibetans experience less
altitude-associated intra-uterine growth restriction than
Hans living at the same altitudes and have lower levels of

Author's personal copy

Arch Gynecol Obstet (2014) 290:6574

73

Table6Relationship between degree of anaemia (with and without correction factor) and preterm birth (%) in Peruvian populations living at
altitudes between 1,000 and 4,500m
Degree of anaemia

Normal
Mild
Moderate
Severe

Preterm births without Hb correction

Preterm births with Hb correction for altitude

ORc

ORa

CI 95%

ORc

ORa

CI 95%

10,614
789
154

7.01
8.42
16.9

1.0
1.22*
2.71*

1.0
1.24
2.28

1.14 1.34
1.90 2.73

7,740
3,346
637

6.67
7.63
11.09

1.0
1.15*
1.74*

1.0
1.07
1.47

1.03 1.12
1.35 1.61

25.5

4.54*

4.07

2.77 5.99

172

20.3

3.56*

2.60

2.18 3.10

38

Logistic regression model adjusted for age, BMI, maternal education, antenatal care, parity, preeclampsia, altitude and urinary infection
ORc crude odds ratio, ORa adjusted odds ratio
* p<0.01

prenatal and postnatal mortality of babies [17]. Tibetans

also have lower haemoglobin levels than Hans residing at
a same altitude [16]. In Peruvian populations with generations living for longer periods at high altitude, such as those
from Cuzco and Puno in the Southern Andes, newborns
have higher birth weights [18] and lower stillbirth rates
than populations of generations living for shorter periods
at high altitude, such as those from the Central Andes [19].
Thus, data suggest that corrections based on a mathematical model of Hb increase by altitude [20] to correct
cut-offs of Hb for altitude [3, 4] should not be applied to
populations living at high altitude, at least in the outcomes
examined in the present study. This is based in the fact that
women at high altitude with Hb >11g/dL but diagnosed as
anaemic after correction of Hb for altitude do not have an
increased risk for preterm births or stillbirths and thus are
not seemingly anaemic.
A comparative study of iron metabolism conducted in
pregnant women at three Peruvian localities, Lima (sea
level), La Oroya (3,800 masl) and Puno (3,800 masl)
showed haemoglobin concentration values 2030% higher
in the women living in altitude, but the serum iron concentration was also higher in relation to women at sea level
(8590ug/dL vs. 49ug/dL) [21]. These data suggest that
populations at high altitude might not be considered as iron
deficient.
The change in blood volume at altitude is complex and
includes a reduction in plasma volume, increase in red cell
mass and a significant increase in the body/venous (B/V)
haematocrit ratio [22, 23]. The raised B/V haematocrit ratio
may well be a significant factor in the delivery of oxygen to
the developing foetus during pregnancy. The WHO recommendation to correct the haemoglobin value in regard to
the definition of anaemia in people resident at high altitude
seems to be simplistic and arbitrary.
The strength of this study is the size of the cohort
including measurements at different altitudes ranging from
1,000 to 4,500 masl. One potential limitation is the different methods of laboratory units that might have been used,

resulting in various haemoglobin values. However, the pattern of haemoglobin values varied harmoniously according to altitude, increasing haemoglobin values as altitude
increased (not shown), thus revealing that measurement
variation was probably small.
There is an underlying assumption that all stillbirths take
place in hospitals, when many take place at home. Hence,
a considerable number of stillbirths may have gone unrecorded. This is not a problem in the present study since we
compared rates of stillbirths at hospitals in situation when
Hb was corrected for altitude or not to define anaemia.
Another limitation could be that the study was retrospective. However, as we are comparing rates of adverse perinatal outcomes when anaemia was defined after correcting
or not Hb cut-off levels for altitudes, we can overcome this
limitation.
In conclusion, at high altitude, correction of maternal
haemoglobin should not be performed to assess the risks
for preterm birth and stillbirth. In fact, using low altitude
Hb cut-offs is associated with predicting those at risk.
AcknowledgmentsThe authors appreciate the collaboration of
the Ministry of Health and their representatives from different public hospitals in Peru. We acknowledge technical assistance from Dr.
Carlos Carrillo, MPH Leopoldo Bejarano and Lic. Vanessa Vasquez.
The study was supported by a grant from the UNDP/UNFPA/WHO/
WORLD BANK Special Programme of Research, Development
and Research Training in Human Reproduction at the World Health
Organization. The funding sources had no involvement in the design,
analysis or conclusions of this study.
Conflict of interestNone.

References
1. Gonzales GF (2011) Hemoglobin and testosterone: importance
on high altitude acclimatization and adaptation. Rev Peru Med
Exp Salud Publica 28:92100 Spanish
2. Gonzales GF, Steenland K, Tapia V (2009) Maternal hemoglobin
level and fetal outcome at low and high altitudes. Am J Physiol
Regul Integr Comp Physiol 297:R1477R1485

13

Author's personal copy

74
3. World Health Organization (2006) 11 Prevalence of anaemia in
women. In: Reproductive health indicators. Guidelines for their
generation, interpretation and analysis for global monitoring.
WHO Press, France, p 4143
4. World Health Organization/NHD (2001) Iron deficiency anaemia: assessment, prevention and control. A Guide for Programme
Managers. 99
5. Cook JD, Boy E, Flowers C, del Daroca MC (2005) The influence of high-altitude living on body iron. Blood 106:14411446
6. Miller S, Tudor C, Thorsten V, Wright L, Varner M (2008)
Comparison of maternal and newborn outcomes of Tibetan and
Han Chinese delivering in Lhasa Tibet. J Obstet Gynaecol Res
34:986993
7. Moore LG, Zamudio S, Zhuang J, Sun S, Droma T (2001) Oxygen transport in Tibetan women during pregnancy at 3,658m.
Am J Phys Anthropol 114:4253
8. Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N,
Lozano R, Regan M, Weatherall D, Chou DP, Eisele TP, Flaxman
SR, Pullan RL, Brooker SJ, Murray CJ (2013) A systematic analysis of global anemia burden from 1990 to 2010. Blood. (Epub
ahead of print)
9. Ali AA, Rayis DA, Abdallah TM, Elbashir MI, Adam I (2011)
Severe anaemia is associated with a higher risk for preeclampsia
and poor perinatal outcomes in Kassala hospital, eastern Sudan.
BMC Res Notes 4:311
10. Sanghvi TG, Harvey PW, Wainwright E (2010) Maternal ironfolic acid supplementation programs: evidence of impact and
implementation. Food Nutr Bull 31(2 Suppl):S100S107 Review
11. Pea-Rosas JP, De-Regil LM, Dowswell T, Viteri FE (2012)

Intermittent oral iron supplementation during pregnancy.
Cochrane Database Syst Rev 7:CD009997. Review
12. Casanueva E, Viteri FE, Mares-Galindo M, Meza-Camacho C,
Lora A, Schnaas L, Valdes-Ramos R (2006) Weekly iron as a
safe alternative to daily supplementation for non-anemic pregnant
women. Arch Med Res 37:674682

13

Arch Gynecol Obstet (2014) 290:6574

13. Gonzales GF, Tapia V, Gasco M, Carrillo CE (2012) Maternal
haemoglobin concentration and adverse pregnancy outcomes at
low and moderate altitudes in Peru. J Matern Fetal Neon Med
25:11051110
14. Moore LG (2001) Human genetic adaptation to high altitude.
High Alt Med Biol Summer 2(2):257279 Review
15. INEI (2008) Peruvian National Census 2007. XI of Population
and VI of Housing. Peruvian Sociodemographic profile. 2nd edn.
Lima, p 474
16. Wu T, Wang X, Wei C, Cheng H, Wang X, Li Y, Dong G, Zhao
H, Young P, Li G, Wang Z (2005) Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs Han. J Appl
Physiol 98:598604
17. Moore LG, Young DY, McCullough RE, Droma TS, Zamudio
S (2001) Tibetan protection from intrauterine growth restriction
(IUGR) and reproductive loss at high altitude. Am J Hum Biol
13:635644
18. Hartinger S, Tapia V, Carrillo C, Bejarano L, Gonzales GF (2006)
Birth weight at high altitudes in Peru. Int J Gynecol Obstet
93:275281
19. Gonzales GF, Tapia V, Carrillo CE (2008) Stillbirth rates in

Peruvian populations at high altitude. Int J Gynecol Obstet
100:221227
20. Hurtado A, Merino C, Delgado E (1945) Influence of anoxemia
on haematopoietic activities. Arch Intern Med 75:284323
21. Reynafarje Hurtado C (1987) Iron metabolism during pregnancy
at high altitudes. Arch Biol Med Exp 20:3137
22. Metz J, Levin NW, Hart D (1962) Effect of altitude on the body/
venous haematocrit ratio. Nature 194:483
23. Sanchez C, Merino C, Figallo M (1970) Simultaneous measurement of plasma volume and cell mass in polycythemia of high
altitude. J Appl Physiol 28:775778