Arch Obstet and Gynecol, 2014

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

Correcting haemoglobin cut-offs to defineanaemia in high-altitude pregnant womenin Peru reduces adverse perinatal outcomes

Gustavo F. Gonzales, Vilma Tapia &Manuel Gasco

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Arch Gynecol Obstet (2014) 290:65–74DOI 10.1007/s00404-014-3182-z

MAternAl-FetAl MeDIcIne

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

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

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 com-pensate 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 alti-tudes [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 1,000 m above sea level (masl), the cut-off point of Hb to define anaemia is 11 g/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 table 1. For instance, in cerro de Pasco at 4,340 masl, the Hb cut-off value to define anaemia is 14.5 g/dl. At low lev-els, 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 nor-mality 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 preva-lence of anaemia was 26.6 % after correcting Hb for alti-tude, whereas body iron measurements indicated that only

Abstract Purpose to determine if correction of cut-offs of hae-moglobin 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 4,500 m above sea level (masl). Anaemia was defined with or without correction of haemoglobin (Hb) for altitude as Hb <11 g/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 with-out Hb correction. At high altitudes (3,000–4,500 masl), after Hb correction, the rate of stillbirths was reduced from 37.7 to 18.3 per 1,000 live births (p < 0.01); simi-larly, 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 hae-moglobin 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 of Biological and Physiological Sciences, Universidad Peruana cayetano Heredia, Honorio Delgado 430, lima 31, Perue-mail: [email protected]

G. F. Gonzales · V. tapia · M. Gasco Instituto de Investigaciones de la Altura, Universidad Peruana cayetano Heredia, Honorio Delgado 430, lima 31, Peru

Author's personal copy

66 Arch Gynecol Obstet (2014) 290:65–74

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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 25,000 years on the high Qinghai-tibetan Pla-teau, 10–12 % of the population is anaemic; however, using recommended cut-off values for their altitudes, the figures increase to 40–46 % [7].

Global anaemia prevalence in 2010 was estimated in 32.9 %, causing 68.36 (95 % cI 40.98–107.54) million years lived with disability [8]. Globally, the main cause for anaemia was iron deficiency [8]. Several studies find a rela-tionship between severity of maternal anaemia (moderate and severe anaemia) and adverse perinatal outcomes such as increased rates of stillbirths and preterm births [2, 9–11]. If correction of Hb for populations at high altitudes would increase the real prevalence of anaemia, then rates of still-births 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 14.5 g/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 neces-sary to determine if the rate of anaemia after Hb correc-tion is really true and if it is also associated with similar perinatal adverse outcomes observed when it was assessed without Hb correction.

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 and methods

Study design

this is a retrospective cohort study based on data from the Perinatal Information System in Peru that assess haemoglo-bin in pregnancy and perinatal outcomes.

Study population

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 hos-pitals 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, con-genital malformations, birth weight below 500 g 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 20 weeks of gestation onwards or ≥500 g. 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 37 weeks 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 veri-fied 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

Table 1 Haemoglobin cut-offs to define maternal anaemia at differ-ent 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 11 0

1,000 11.2 0.2

1,500 11.5 0.5

2,000 11.8 0.8

2,500 12.3 1.3

3,000 12.9 1.9

3,500 13.7 2.7

4,000 14.5 3.5

4,500 15.5 4.5


67Arch Gynecol Obstet (2014) 290:65–74

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

exposure variables

Altitude was defined in three categories, 1,000–1,999 masl, 2,000–2,999 masl and 3,000–4,500 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 accord-ing to the WHO classification [4]: (1) Mild anaemia, when maternal haemoglobin values were between 9 and <11 g/dl, (2) moderate anaemia for haemoglobin values between 7 and <9 g/dl, and (3) severe anaemia for haemo-globin values below 7 g/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 resi-dence using the guidelines from WHO showed in table 1.

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 var-iables were correlated with exposure and with outcomes.

Quality control of data

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 data-base. 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

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 <11 g/dl—fur-ther broken down into mild, moderate and severe anae-mia 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 table 1. 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

Fig. 1 Flow diagram showing study sample size selection



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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 sta-tus; BMI; prenatal care; parity; preeclampsia and urinary infection (in current pregnancy); and gestational age at which haemoglobin was measured. All variables influenc-ing 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 pre-term 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 alti-tude (Fig. 2). the rate of anaemia before Hb correction decreased as altitude increased, whereas after Hb correc-tion, the rate of anaemia was highest at the higher altitude (≥3,000 m) (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 associ-ated with low and high maternal age, higher BMI, less edu-cation, 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 cor-rection for altitude was performed, in which case the rate was reduced to 18.2 per 1,000 live births (p < 0.01). For

stillbirths, the Ors in anaemics defined before Hb correc-tion were also significantly reduced from 1.69 (cI 1.48–1.94) to 1.17 (cI 1.07–1.27) 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 correc-tion (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 correc-tion was 1.44 (cI 95 % 1.34–1.55) and this value was reduced to 1.20 (cI 95 % 1.15–1.25) after Hb correction for altitude (p < 0.01) (Fig. 3c, d). the Ors for variables as maternal age, BMI, maternal education, number of vis-its of antenatal care, parity, trimester at Hb measurement, preeclampsia, urinary infection and altitude were not dif-ferent in the groups without or with Hb correction (data not shown).

results are similar if we break down the rates by differ-ent altitudes. thus, the rate of stillbirths in mothers with anaemia without Hb correction was higher than that after Hb correction for altitude, both at 2,000–2,999 masl (28.9 per 1,000 live births vs. 19.3 per 1,000 live births, p < 0.01) and at 3,000–4,500 masl (37.7 per 1,000 live births vs. 18.3 per 1,000 live births, p < 0.01) (table 3).

the rate of preterm births was also higher if anaemia was diagnosed without Hb correction for altitude. this was observed particularly at 2,000–2,999 masl (9.20 % vs. 8.13 %, p < 0.01) and at 3,000–4,500 masl (13.1 vs. 8.76 %, p < 0.01) (table 4). Similarly, Ors for both still-births 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, preec-lampsia, and urinary infection were not modified after Hb correction.

Stillbirths rates increased from 14 per 1,000 in moth-ers 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 simi-lar 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 alti-tude (Fig. 4 bottom).

Fig. 2 Prevalence of maternal anaemia in Peruvian hospitals located at different altitudes (1,000–1,999 m; 2,000–2,999 m; and >3,000 m) before (left column) and after (right column) Hb cut-off correction to define anaemia



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Ors for stillbirths increased according to the magnitude of anaemia. Highest Ors were observed with severe anae-mia (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 = 0.95–1.15) but, it was significant in mild anaemia without haemoglo-bin correction (Or = 1.43; cI = 1.23–1.67) (table 5). 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 alti-tude (table 6). Similarly, Ors for confounding variables were not modified after Hb correction for altitude.

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 anae-mia. Anaemia was diagnosed when Hb cut-off to define anaemia was uncorrected (Hb <11 g/dl) and after correc-tion 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 haemoglo-bin 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 sug-gest 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

Table 2 Sociodemographic 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, χ2: p < 0.01, except for preeclampsia

Variable normal (151,485) Mild anaemia (9,368) Moderate anaemia (907)

Severe anaemia (149)

n % n % n % n %

Age (years)

<20 28,947 19.1 2,044 21.8 161 17.8 222 14.8

20–34 104,206 68.8 6,105 65.2 608 67.0 104 69.8

<34 18,332 12.1 1,219 13.0 138 15.2 23 15.4

BMI (kg/m2)

<19 13,884 9.2 983 10.5 83 9.2 15 10.1

20–25 97,544 64.4 6,222 66.4 609 67.1 91 61.1

>25 40,057 26.4 2,163 23.1 215 23.7 43 28.8

Study

none/prim 118,820 78.4 7,017 74.9 652 71.9 98 65.7

Sec/sup 32,665 21.6 2,351 25.1 255 28.1 51 34.2

Antenatal care

<6 76,381 50.4 4,323 46.1 275 30.3 53 35.6

≥6 75,104 49.6 5,045 53.9 632 69.7 96 64.4

Parity

none 73,963 48.8 4,507 48.1 364 40.1 57 38.3

1–3 66,227 43.7 3,974 42.4 412 45.4 68 45.6

>3 11,295 7.5 887 9.5 131 14.5 24 16.1

Preeclampsia 4,693 3.1 270 2.9 35 3.9 5 3.4

Stillbirth 2,116 1.4 210 2.2 58 6.4 24 16.1

Preterm 10,614 7.0 789 8.4 154 16.9 38 25.5

Urinary inf 27,381 18.1 1,604 17.8 143 15.8 15 10.1

Haemoglobin measurement

1st trim. 35,317 23.31 938 10.01 53 5.84 25 16.78

2nd trim. 62,646 41.35 4,420 47.18 305 33.63 52 34.90

3rd trim. 53,522 35.33 4,010 42.81 549 60.53 72 48.32

Altitude (m)

1,000–1,999 11,371 80.34 2,552 18.03 217 1.53 13 0.09

2,000–2,999 59,375 93.37 3,808 5.99 340 0.53 68 0.11

>3,000 80,739 95.93 3,008 3.57 350 0.42 68 0.08



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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

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”.

0

5

10

15

20

25

30

Without Hb correction With Hb correction

Sti

llbir

th (

per

100

0 b

irth

s)

Maternal Anemia

A

*

7.6

7.8

8

8.2

8.4

8.6

8.8

9

9.2

9.4

9.6


Pre

term

Bir

ths

(%)

Maternal Anemia

C

*

00.20.40.60.8

11.21.41.61.8

2


Maternal Anaemia

OR

fo

r st

illb

irth

s

B

*

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6


Maternal AnaemiaO

R f

or

pre

term

bir

ths

D

*

Fig. 3 Stillbirth and preterm birth rates and their odds ratios with and without Hb correction. a *p < 0.001 with respect to the group with-out 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, mater-nal education, antenatal care, parity, trimester at Hb measurement, preeclampsia, urinary infection and altitude of residence

Table 3 logistic regression for the relationship between anaemia with and without a correction factor and stillbirth rates for each altitude (1,000–4,500 m)

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

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

n ‰ Orc Ora cI 95 % n ‰ Orc Ora cI 95 %

1,000–1,999 41 14.7 1.41 1.22 0.83–1.77 59 13.8 1.36 1.21 0.86–1.70

2,000–2,999 122 28.9 2.26* 1.74 1.41–2.15 286 19.3 1.56* 1.24 1.07–1.44

3,000–4,500 129 37.7 2.53* 1.74 1.43–2.12 591 18.3 1.25* 1.12 1.01–1.26



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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 addi-tion, 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 dem-onstrated that treatment with iron in non anaemic moth-ers could be more harmful than beneficial, increasing the risk of adverse perinatal outcomes if maternal Hb increases over 14.5 g/dl [11, 12]. For example, higher Hb values in

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 14.5 g/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 environ-mental pressure as altitude increases.

Worldwide, almost 140 million people live permanently at altitudes >2,500 m in north, central and South Amer-ica, in east Africa, and Asia [14]. Moreover, 32 % of the total population of Peru lives at high altitudes, representing

Table 4 logistic regression for the relationship between anaemia with and without a correction factor and preterm birth rates for each altitude (1,000–4,500 m)

logistic regression model adjusted for age, BMI, maternal education, antenatal care, parity, preeclampsia, and urinary infection. each row repre-sents a model for each altitude range comparing the population of anemics with preterm births and non anaemic with pre term births (Or = 1.0)


* p < 0.01

Altitude (m) Preterm birth rates in anaemic mothers without Hb correction

Preterm birth rates in anaemic mothers with Hb correction for altitude

n % Orc Ora cI 95 % n % Orc Ora cI 95 %

1,000–1,999 141 5.07 1.25* 1.04 0.85–1.27 201 4.72 1.15 0.96 0.81–1.15

2,000–2,999 388 9.20 1.46* 1.34 1.20–1.50 1,203 8.13 1.34* 1.22 1.13–1.31

3,000–4,500 452 13.1 1.79* 1.57 1.41–1.75 2,827 8.76 1.16* 1.18 1.12–1.24

Fig. 4 Stillbirth 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 cor-rection for altitude

0

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40

60

80

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120

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180

Normal Hb Mild anaemia Moderate anaemia Severe anaemia

Sti

llb

irth

rat

e (p

er 1

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live

bir

ths

Without Hb correction

With Hb correction

P<0.01

P<0.01

P<0.01

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Normal Hb Mild anaemia Moderate anaemia Severe anaemia

Pre

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(%

)

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With Hb correction

P<0.01

P<0.01

P<0.01



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almost 9 million inhabitants [15]. For such reason, it is important to know the relationship, if any, between haemo-globin levels, pregnancy and perinatal outcomes in these populations. Particularly, it is necessary to know if Hb cor-rection to define anaemia in the altitude is really needed.

Although it is a fact that Hb increases in populations liv-ing at high altitudes, studies conducted in the last few dec-ades 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

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]. tibet-ans have lived in the Himalayas for more than 25,000 years, whereas the Han chinese ethnic group resides at the same place for no longer than 70 years. tibetans experience less altitude-associated intra-uterine growth restriction than Hans living at the same altitudes and have lower levels of

Table 5 relationship 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)

Stillbirths Uncorrected haemoglobin corrected haemoglobin

Or ± ee cI 95 % Or ± ee 95 % cI

Anaemia

not 1.00 1.00

Mild 1.44 0.11 1.23 1.67 1.04 0.05 0.95 1.15

Moderate 2.69 0.41 1.99 3.63 1.54 0.14 1.29 1.83

Severe 6.70 1.79 3.97 11.30 3.79 0.52 2.89 4.96

Maternal age (years)

<20 0.73 0.05 0.64 0.83 0.73 0.05 0.64 0.83

20–34 1.0 1.0

>34 1.21 0.08 1.06 1.37 1.21 0.08 1.07 1.37

BMI (kg/m2)

<19 0.77 0.06 0.66 0.91 0.78 0.06 0.66 0.91

19–25 1.0 1.0

>25 0.97 0.05 0.88 1.07 0.97 0.05 0.88 1.07

none/low education 1.77 0.09 1.61 1.95 1.77 0.09 1.61 1.95

Secondary/superior 1 1.00

Antenatal care

<6 1.86 0.10 1.68 2.07 1.87 0.10 1.68 2.07

≥6 1.0 1.0

Parity

none 1.03 0.05 0.93 1.15 1.03 0.05 0.93 1.15

1–3 1.0 1.0

>3 1.38 0.10 1.19 1.59 1.36 0.10 1.18 1.57

Measure of Hb

1st trimester 1.0 1.0

2nd trimester 1.16 0.09 1.02 1.31 1.16 0.07 1.02 1.31

3rd trimester 0.91 0.06 0.80 1.03 0.91 0.06 0.79 1.03

Preeclampsia

Yes 0.79 0.08 0.65 0.96 0.79 0.08 0.65 0.96

not 1.0 1.0

Preterm birth

<37 weeks 14.71 0.66 13.46 16.06 14.65 0.66 13.41 16.01

≥37 weeks 1.0

Altitude (m)

1,000–1,999 1.0 1.0

2,000–2,999 1.01 0.10 0.84 1.20 0.94 0.08 0.79 1.12

>3,000 1.10 0.10 0.92 1.31 0.98 0.09 0.83 1.16



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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 genera-tions 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 math-ematical 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 >11 g/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 20–30 % higher in the women living in altitude, but the serum iron concen-tration was also higher in relation to women at sea level (85–90 ug/dl vs. 49 ug/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 recom-mendation 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 differ-ent methods of laboratory units that might have been used,

resulting in various haemoglobin values. However, the pat-tern of haemoglobin values varied harmoniously accord-ing 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 unre-corded. 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 retrospec-tive. However, as we are comparing rates of adverse peri-natal 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.

Acknowledgments the authors appreciate the collaboration of the Ministry of Health and their representatives from different pub-lic 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 interest none.

References

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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:r1477–r1485

Table 6 relationship between degree of anaemia (with and without correction factor) and preterm birth (%) in Peruvian populations living at altitudes between 1,000 and 4,500 m

logistic regression model adjusted for age, BMI, maternal education, antenatal care, parity, preeclampsia, altitude and urinary infection


* p < 0.01

Degree of anaemia Preterm births without Hb correction Preterm births with Hb correction for altitude

n % Orc Ora cI 95 % n % Orc Ora cI 95 %

normal 10,614 7.01 1.0 1.0 7,740 6.67 1.0 1.0

Mild 789 8.42 1.22* 1.24 1.14 1.34 3,346 7.63 1.15* 1.07 1.03 1.12

Moderate 154 16.9 2.71* 2.28 1.90 2.73 637 11.09 1.74* 1.47 1.35 1.61

Severe 38 25.5 4.54* 4.07 2.77 5.99 172 20.3 3.56* 2.60 2.18 3.10



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