Maternal Altitude-Corrected Hemoglobin and at Term Neonatal Anthropometry at 3400 m of Altitude

Abstract

Villamonte-Calanche, Wilfredo, Nelly Lam-Figueroa, Maria Jerí-Palomino, Cleto De-La-Torre, and Alexandra A. Villamonte-Jerí. Maternal altitude-corrected hemoglobin and at term neonatal anthropometry at 3400 m of altitude. High Alt Med Biol. 21:287–291, 2020.

Introduction:

Fetal growth is prominent in the last trimester of pregnancy. The development of the fetus depends on the nutrient consumption and oxygen delivery of the pregnant woman. Therefore, maternal anemia has an inverse relationship with fetal growth. Consequently, the newborn has lower anthropometric measurements. Residing in places of a high altitude increases the level of hemoglobin (Hb); as a result, the World Health Organization (WHO) recommends adjusting the value of Hb in maternal blood at 3400-m altitude by reducing 2.4 g/dL to obtain the corrected Hb (HbCorr).

Objective:

To determine if the relationship of maternal HbCorr for high altitude is related to term neonatal anthropometry at 3400-m altitude.

Material and Methods:

We performed a retrospective cohort study and evaluated the neonatal anthropometric variables (weight, ponderal index, head circumference [HC], and HC for birthweight index) in 308 exposed pregnant women (HbCorr <11 g/dL) and 600 unexposed pregnant women (HbCorr ≥11 g/dL). We obtained absolute relative frequencies and measures of central tendency. Besides, we compared the qualitative and quantitative variables using the chi-square and the Student t or the Mann–Whitney or Kruskal–Wallis U test, if applicable. We also performed linear regression.

Results:

Of anemic pregnant women, 68.2% were mild, while only 1% were severe. There was no relationship between HbCorr and neonatal anthropometry, and none of the anemic pregnant women showed a statistical difference in the neonatal anthropometric measures evaluated compared to the unexposed women.

Conclusion:

There is no relationship between HbCorr and neonatal anthropometry at 3400-m altitude.

Introduction

Fetal growth in hypobaric hypoxia (HH) conditions, such as living at high altitude, is lower compared to sea level; consequently, neonates at this level show lower birth weights (BWs) (Julian, 2011), which would be related to the lower accumulation of fetal fat (Galan et al., 2001). This situation is different in a population adapted to HH due to mutations produced in different maternal genes that regulate oxygen sensing, metabolic homeostasis, and vascular control that impact fetal growth and BW outcomes (Bigham et al., 2014). These modifications and other factors, such as proper maternal nutrition, have allowed observing better neonatal anthropometric measures such as those described for the city of Cusco (Villamonte-Calanche et al., 2017). The localization of Cusco is at 3400-m altitude in the southeast region of Peru, a country located in the central-western part of South America.

The anthropometric measurements of the newborn are weight, height, head circumference (HC), ponderal index (PI), which is the weight ratio on cube size, and the HC Index for birth weight (HCBW) defined as HC in cm × 1000/BW in grams. Recently, we published the reference cutoff of these neonatal anthropometric measurements for 3400-m altitude (Villamonte-Calanche et al., 2018).

Hemoglobin (Hb) is a molecule that transports oxygen from the maternal lungs to the placenta and then to the fetus, which uses oxygen to obtain energy to grow and develop. The iron found in Hb is essential for the neurocognitive and neurobehavioral development of the human being (Yusrawati et al., 2019). Anemia (maternal Hb <11 g/dL, cutoff made at sea level) is a condition that hurts fetal growth by lowering BW (Godoy Figueiredo et al., 2019); its effect is directly proportional to the severity of the problem (Gonzales, 2012a). The classification of anemia is mild (Hb 10–10.9 g/dL), moderate (Hb 7–9.9 g/dL), and severe (Hb <7 g/dL) anemia (Peruvian Ministry of Health, 2017a). In contrast, Gonzales et al. (2011) defined Erythrocytosis as a Hb >14.5 g/dL.

The World Health Organization (WHO) has recommended correcting Hb according to the level of altitude where the pregnant woman lives (WHO, 2001). At 3400-m altitude, there is a correction factor of minus 2.4 g/dL to the Hb determined in the blood of the pregnant woman to obtain the corrected Hb (HbCorr). The prevalence of anemia in Cusco for 2011 was 37.7% (4.5% and 0.3% of pregnant women had moderate and severe anemia, respectively) (Peruvian Ministry of Health, 2017b). Iron deficiency as a cause of anemia varies from 30% to 70% during pregnancy (Munares-García et al., 2012). However, Gonzales et al. (2011) propose that it is not necessary to correct Hb in a population adapted to the altitude because there is no concordance in the frequency of anemia when it is based on the HbCorr or by body iron content (Cook et al., 2005).

In this study, we sought to determine if the HbCorr for a 3400-m altitude of pregnant women is related to changes in neonatal anthropometry at term through the evaluation of two groups: one with anemia and the other one without this condition.

Materials and Methods

We performed a retrospective cohort study and utilized the Epidat 4 program to obtain the sample using exposure risk of 37.7% and the risk of nonexposure of 62.3%. The power used was 90%, and the confidence level was 95%, obtaining a minimum sample size of 60 anemic and 120 nonanemic pregnant women. To improve the confidence of the results, we increased the sample size to 308 exposed and 600 unexposed. The anemic women were pregnant women with a single fetus without abnormalities, who were born between 37 and 42 weeks by last menstrual period and had the measurement of Hb level in the last trimester of pregnancy. The Hb value was <13.4 g/dL. Unexposed pregnant women had the same characteristics, but their Hb level was ≥13.4 g/dL.

From October 1, 2018, to June 30, 2019, we carried out this study. We searched the immediate postpartum women of the Obstetrics Service at Adolfo Guevara Velazco National Hospital of ESSALUD (AGVNH) in Cusco. The participants met the inclusion criteria if they were anemic or nonanemic according to the HbCorr level determined with the automated hematology analyzer Sysmex XN-1000™.

The medical records were the source of the necessary information of the selected pregnant women through a data collection form. Term neonatal anthropometric measurements, such as weight, HC, IP, and HCBW, were converted into multiples of the median (MoM) using the neonatal anthropometric table described for newborns at 3400-m altitude (Villamonte-Calanche et al., 2018). We used Statistical package R version 3.6.0 to perform analysis of the information, obtaining absolute relative frequencies and central trend measurements. We used t-tests and chi-square to compare the quantitative and qualitative variables, respectively, to be consistent with the normal distribution, and if not, we utilized the Mann–Whitney U test or Kruskal–Wallis. At the same time, we applied Levene's test and simple linear regression.

The ethics and research committee from AGVNH of ESSALUD, Cusco, has approved this trial. The medical records were the source of the data; thus, we did not require informed consent.

Results

After correcting the Hb level of pregnant women for 3400-m of altitude, we found an anemia frequency of 33.9%. Without correcting Hb for altitude, the frequency of anemic reduces to 1.7% (Table 1).

Table 1.

Pregnant Women With and Without Corrected Hemoglobin for 3400-m Above Sea Level

Condition	Hb corrected		Hb without correction
Condition	n	%	n	%
Normal (11–14.5)^a	600	66.1	685	75.4
Mild anemia (10–10.9)^a	210	23.1	12	1.3
Moderate anemia (7–9.9)^a	95	10.5	4	0.4
Severe Anemia (<7)^a	3	0.3	0	0.0
Erythrocytosis (>14.5)^a	0	0.0	207	22.8
Total	908	100.0	908	100.0

Levels of Hb in g/dL.

Hb, hemoglobin.

The maternal characteristics were: the average age of 31.9 and 31.8 years; gestational age of 39.4 weeks, weight before gestation 60.7 and 61 kg; body mass index of 25.8 and 25.9 for cases and controls, respectively (Table 2), showing no statistically significant difference. Similarly, there was no statistically significant difference in the level of altitude of maternal birth, occupation, and intercurrent disease (a simultaneous disease that can produce less growth of the fetus) of the pregnant woman (Table 3).

Table 2.

Characteristics of Anemic and Nonanemic Pregnant Women

	Anemia		Normal		p
	Mean	CI 95%	Mean	CI 95%	p
Gestational age (weeks)	39.4	39.2–39.5	39.4	39.3–39.5	0.844^a
Age (years)	31.9	31.2–32.5	31.8	31.3–32.2	0.749^b
Pregnancies	2.2	2.1–2.3	2.2	2.1–2.3	0.969^a
Live births^c	0.8	0.7 0–0.89	0.75	0.68–0.83	0.308^a
Abortions^c	0.35	0.27–0.42	0.43	0.37–0.49	0.830^a
Prenatal care^d	7.1	6.8–7.3	7.3	7.2–7.5	0.076^a
Initial weight (kg)^e	60.7	59.6–61.9	61	60.3–61.8	0.117^a
Final weight (kg)^f	73.2	72.1–74.3	73.9	73.1–74.7	0.355^a
Weight gain (kg)	12.4	11.9–13	12.9	12.5–13.3	0.069^a
Height (m)	1.53	1.53–1.54	1.54	1.53–154	0.576^a
Body mass index	25.8	25.4–26.3	25.9	25.6–26.2	0.780^a
GA when Hb was measured^g (weeks)	37.9	37.5–38.4	38.1	37.9–38.4	0.099^a

U de Mann Whitney.

t-Test.

Background of the mothers.

Number of visits to the health center.

Maternal weight at the beginning of pregnancy.

Maternal weight at the end of pregnancy.

Gestational age when Hb was measured.

Table 3.

Qualitative Characteristics of Anemic and Nonanemic Pregnant Women

	Anemia		Normal		p
	N	%	n	%	p
Occupation					0.734^a
Dependent	70	22.7	143	23.8
Employee	73	23.7	152	25.3
Professional	165	53.6	305	50.8
Place of birth
Sea level	35	11.4	76	11.2	0.325^a
Altitude	273	88.6	600	88.8
Intercurrent disease^b
Present	13	4.2	27	4.5	0.497^a
Absent	295	95.8	573	95.5

Chi-square.

A simultaneous disease that can produce less growth of the fetus.

The regression model using HbCorr explains none of the variability of the neonatal anthropometric measurements. The neonatal anthropometric measurements expressed in MoM averages showed no difference in the groups studied (Table 4). Likewise, when we compared the cases according to the severity of the anemia and comparing them with the controls, there was no evidence of any significant statistical difference (Table 5). Levene's test did not show a difference in both cases.

Table 4.

Neonatal Anthropometric Measurements At 3400-m Altitude in Anemic and Nonanemic Pregnant Women

	Anemia		Normal		p	R²
	Media	CI 95%	Media	CI 95%	p	R²
MoM BW	1.02	1.006–1.035	1.011	1.002–1.020	0.27^a	0.001
MoM PI	1.033	1.022–1.044	1.021	1.013–1.028	0.149^b	0.001
MoM HC	1.026	1.021–1.031	1.024	1.020–1.027	0.591^b	0.002
MoM HC/BW Index	0.969	0.956–0.982	0.974	0.965–0.983	0.491^b	0.001

t-Test

U de Mann Whitney.

BW, birth weight; HC, head circumference; MoM, multiples of the median; PI, ponderal index.

Table 5.

Neonatal Anthropometric Measurements at 3400-m Altitude in Pregnant Women with Different Degrees Of Anemia And Nonanemia

	Severe anemia^a		Moderate anemia^b		Mild anemia^c		Normal		p
	Media	CI 95%	Media	CI 95%	Media	CI 95%	Media	CI 95%	p
MoM BW	1.144	0.808–1.441	1.114	0.990–1.038	1.021	1.003–1.039	1.011	1.002–1.020	0.190^d
MoM PI	1.122	1.045–1.199	1.025	1.008–1.043	1.035	1.021–1.049	1.021	1.013–1.028	0.071^e
MoM HC	1.074	0.975–1.174	1.022	1.014–1.030	1.027	1.021–1.033	1.024	1.020–1.027	0.216^e
MoM HCBW	0.834	0.655–1.013	0.97	0.948–0.993	0.97	0.954–0.986	0.974	0.965–0.983	0.153^e

Hb <7 g/dL.

Hb 7–9.9 g/dL.

Hb 10–10.9 g/dL.

Anova.

Kruskal-Wallis.

HCBW, HC Index for birth weight.

Discussion

The objective of this study was to determine if the HbCorr of pregnant women at 3400-m altitude has an impact on neonatal anthropometric measurements (weight, HC, IP, or HCBW) in singleton pregnancies. In this study, we did not observe a relationship between HbCorr and neonatal anthropometric measurements at term. Furthermore, we did not find any statistical difference in the group of pregnant women with anemia compared with the control group.

BW is a significant variable that is inversely related to perinatal morbidity and mortality. The decrease in Hb, which is characteristic of maternal anemia, determines a decrease in the transport of oxygen to the tissues and affects the production of energy in the fetus. Consequently, it generates a lower fetal growth expressed in lower BW (Godoy Figuereido et al., 2019). We have not found this result in newborns from mothers considered anemic (HbCorr <11 g/dL) at 3400-m altitude using the WHO's recommendations (WHO, 2001).

The population that has resided in high altitude for over 50 years (Hurtado et al., 1945) was a source of the mathematical procedure (Centers for Disease Control and Prevention, 1989) that originated HbCorr and has not been clinically validated until now (Gonzales, 2012b). In populations adapted to high altitudes such as the Tibetan and the Andean populations, the premise that as altitude levels rise, Hb levels should increase might not be correct. In contrast, fetal growth at high altitudes is adequate because of the adaptive changes, such as the increased blood flow and oxygen delivery through the uterine artery. An increase in diameter through pregnancy is an essential factor contributing to Andean protection from fetal growth reduction at high altitude (Julian et al., 2009). Larger uterine artery diameters are associated with PRKAA1 (Bigham et al., 2014).

The prevalence of anemia in the city of Cusco is above 30%. It is a condition that has a negative impact expressed in lower BW (Godoy Figueiredo et al., 2019). However, the BW at term is only lower by 121 g when comparing newborns at sea level (Villamonte et al., 2011a), unlike the phenomenon described in the United States (Jensen and Moore, 1997), where for every thousand meters that rise in altitude, the BW decreases by 102 g. Furthermore, there were no differences between the neonatal anthropometry at 3400-m altitude and sea level (Villamonte-Calanche et al., 2017). In addition, in Cusco, it was determined that BW was related to placental weight (R² = 0.39) and is not related to maternal Hb (Villamonte et al., 2011b). Moreover, considering the level of Hb and the deposits of iron in pregnant women, there are different anemia prevalences in the scientific literature. There is no correlation between both situations (Cook et al., 2005).

At sea level, severe or moderate anemia affects the anthropometric measurements in at-term neonates. At 3400-m altitude, 10.8% of pregnant women had this condition using HbCorr, but their neonates were healthy. Only 1.7% of pregnant women would be anemic if Hb did not correct for altitude, being mostly mild anemic. It has no impact on neonatal anthropometry (Gonzales, 2012b), probably due to changes in the neovascularization of the placenta (Charnock-Jones and Burton, 2000), as a result of increased growth factors such as VEGF and PIGF (Stangret et al., 2016).

Public health implications

The prevalence of anemia in Cusco is high. It represents a public health problem (WHO, 2011). Consequently, the government of Peru has implemented public policies to diminish the prevalence rate of anemia. However, up to date, those actions have not achieved the main objective at high altitude cities. Possibly HbCorr does not adequately assess the problem of anemia, which may lead to the artificial increase of anemia's prevalence. It could cause the possibility of supplementation of iron in pregnant women who may not need it. Otherwise, the increase of Hb levels above 14.5 g/dL in pregnancy increases the risk factor for prematurity and small for gestational age (Scanlon et al., 2000). Hence it is pertinent to develop more studies that clinically assess the WHO recommendation to define anemia at high altitudes better.

Conclusion

It seems that there was no relationship between HbCorr and neonatal anthropometry at 3400-m altitude. It is necessary to perform further studies on this topic.

Footnotes

Authors' Contributions

All authors participated in the writing of the article, critical review, and approval of the final version. W.V.-C., M.J.-P., C.D.-L.-T., and A.V.J. participated in the collection of data and result analysis.

Acknowledgments

The authors thank the staff and health professionals from AGVNH, specifically the Obstetrics Service, Cusco, Peru.

Disclosure Statement

The authors declare that they have no competing interests.

Funding Information

This study was supported by the Universidad Andina del Cusco. Resolución 640-CU-2018-UAC.

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