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Uterine artery blood flow during pregnancy in high-altitude Aymara women

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Uterine artery blood flow during pregnancy in high-altitude Aymara women
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Wilson, Megan
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English
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viii, 61 leaves : ; 28 cm

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Aymara women ( lcsh )
Uterine circulation ( lcsh )
Pregnancy ( lcsh )
Arteries ( lcsh )
Arteries ( fast )
Aymara women ( fast )
Pregnancy ( fast )
Uterine circulation ( fast )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

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Bibliography:
Includes bibliographical references (leaves 52-61).
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Department of Anthropology
Statement of Responsibility:
by Megan Wilson.

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|University of Colorado Denver
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ocm62879604
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Full Text
UTERINE ARTERY BLOOD FLOW DURING PREGNANCY IN HIGH-
ALTITUDE AYMARA WOMEN
B.A., University of Colorado- Boulder, 2000
A thesis submitted to the
University of Colorado at Denver
in partial fulfillment
of the requirements for the degree of
Masters of Arts
Anthropology
by
Megan Wilson
2005


This thesis for the Masters of Arts
degree by
Megan Jeannine Wilson
has been approved
by


Wilson, Megan Jeannine (M.A., Anthropology)
Uterine Artery Blood Flow During Pregnancy in High-Altitude Aymara Women
Thesis directed by Professor Loma G. Moore
ABSTRACT
Background: Birth weight falls with increasing altitude as the result of intrauterine
growth restriction (IUGR) likely due, in turn, to lower uterine artery (UA) blood
flow. The altitude-associated birth weight decline is least in the longest resident (in
generations) groups; suggesting that adaptations may have occurred that raise
uteroplacental blood flow to near sea-level values (Moore et al. 2001). Study
objective: Determine the factors responsible for raising UA blood flow in Andean
pregnant women, and whether the values near term resemble those of previously-
described high altitude and low-altitude residents. Methods: Measurements of the
vessel diameters and blood flow velocities (averaged throughout the cardiac cycle)
were made for the UA, common iliac (Cl), and external iliac (El) arteries at 23, 31,
and 37 weeks of pregnancy and 3 months postpartum to measure the nonpregnant
state, using Doppler ultrasound (ATL 3000 and an investigational Doppler
Velocimeter). Results: UA volumetric flow increased as a result of an early
enlargement of UA diameter with a continued, progressive rise in flow velocity.
There was a corresponding rise in Cl flow, which was increasingly directed to the
UA. The increase in Cl flow was due primarily to an increase in vessel diameter.
The near term UA volumetric flow appears similar to that of low-altitude residents
(wk 37 value = 353 mL/min, Palmer et al. 1992), consistent with our hypothesis.
This suggests that selection may have acted on the factors responsible for raising UA
diameter and flow velocity. (HL60131, TWO 1188)
This abstract accurately represents the content of the candidate^diesis^recommen^
its publication.
Signed


CONTENTS
Figures......................................................................vii
Tables .....................................................................viii
Glossary of Abbreviations.....................................................ix
CHAPTER
1. INTRODUCTION.................................................... 1
2. BACKGROUND..................................................... 5
Evolutionary Theory....................................5
Biological Demands of Pregnancy........................8
High Altitude.........................................15
Pregnancy Physiology..................................19
Physiology at Low Altitude......................19
Physiology at High Altitude.....................20
Social Factors........................................24
3. MATERIALS AND METHODS...........................................27
Study Advantages and Limitations......................32
4. RESULTS.........................................................35
Subject Characteristics...............................35
v


General Pregnancy Physiological Characteristics...........38
Uterine Artery............................................38
Common Iliac Artery.......................................41
External Iliac Artery.....................................41
Blood Flow Distribution...................................41
Fetal/Infant Characteristics..............................42
5. DISCUSSION..........................................................46
Comparison to Low Altitude................................47
Comparison to High Altitude...............................47
Fetal Growth..............................................50
Future Studies............................................50
REFERENCES.............................................................52
vi


FIGURES
Figure
2.1 Total atmospheric pressure and the partial pressure of oxygen decrease
with increasing altitude......................................................18
4.1 The rise in blood volume is accompanied by a rise in both uterine
artery and common iliac artery flow through pregnancy, while the external
iliac artery shows no significant change in flow during the course of
pregnancy......................................................................43
4.2 Changes in the relative flow of the uterine artery to common iliac
(UA/CI), the external to common iliac (EI/CI), and the uterine artery
to external iliac (UA/EI)......................................................44
4.3 Graph of fetal abdominal circumference in week 36 of gestation
versus uterine artery blood flow at week 20...................................45
5.1 Redistribution of common iliac flow to uterine artery flow in Andean
women in relation to birth weight is lower than previously reported values
for Tibetans and Coloradans, but higher than previously reported values for
Han migrants (modified from Moore et al. 2001).................................49


TABLES
Table
2.1 Previously reported comparisons of uterine artery flow characteristics
and birth weights at high altitude...................................................21
4.1 Maternal characteristics........................................................36
4.2 Infant characteristics..........................................................37
4.3 Hematological characteristics...................................................39
4.4 Vessel characteristics at all three gestational timepoints and in the
nonpregnant state....................................................................40
4.5 Uterine artery blood flow is significantly (but weakly) correlated with
fetal abdominal circumference at week 20.............................................45


GLOSSARY OF ABBREVIATIONS
Cl: Common iliac artery
CO: Carbon monoxide
EDV: End diastolic velocity
El: External iliac artery
Hb: Hemoglobin
IUGR: Intrauterine growth restriction
MDV: Minimum diastolic velocity
O2: Oxygen
PI: Pulsatility index
RI: Resistance index
S/D: Systolic/diastolic ratio
TAM: Time-averaged mean flow velocity
UA: Uterine artery


CHAPTER 1
INTRODUCTION
Pregnancy is a crucial time in the human life cycle, requiring a compromise
between maternal health and fetal demands in order to achieve maximal reproductive
success (Ellison, 2003; Rockwell et al., 2003). In order to meet the needs of the
fetus, systemic changes in maternal cardiovascular, renal, gastrointestinal,
respiratory, and metabolic physiology all take place. The remodeling of the
cardiovascular system is particularly crucial in pregnancy at high altitude. The
hypoxia of high altitude presents a challenge to the maternal cardiovascular system
to transport sufficient oxygen to the fetus for normal fetal growth (Jensen and
Moore, 1997). Often, the challenges of hypoxia exceed the capacity for alteration in
maternal physiology. Hence, birth weights have been shown to be inversely
correlated with altitude of pregnancy; above 2000 meters (Moore, 2003), for every
1000 meter increase in altitude, there is about a 100 gram decrease in average birth
weight due to intrauterine growth restriction (IUGR) (Jensen and Moore 1997).
Furthermore, babies bom with low birth weights (below 2500 grams) due to
intrauterine growth restriction (IUGR) have a significantly increased risk for
perinatal mortality (e.g. Mclntire et al., 1999; Lubchenco et al., 1963).
1


Consequences of IUGR extend beyond immediate risk for the newborn infant. Low
birth weight due to IUGR has been shown to be associated with increased risk for
later life cardiovascular disease, non-insulin dependent diabetes, stroke, hypertension
(Barker, 1998), and possibly obesity (Ravelli et al., 1999). Since about 140 million
people live at high altitude worldwide (Moore et al., 1998), there is likely a
significant health burden due to the detrimental effects of hypoxia-induced IUGR on
both fetal and adult life.
Not all high altitude populations, though, are similarly affected by hypoxia.
Populations with longer residence at high altitude (such as Andean or Tibetan
populations) have a lesser reduction in birth weight compared with relatively new
immigrant populations (Zamudio et al., 1993; Moore et al., 2001), such as European
or Han people who have recently moved to high altitude. This suggests that
adaptations to hypoxia have been acquired in longer-resident populations, but
specific mechanisms, either maternal or fetal, through which these adaptations occur,
are unknown.
Maternal physiology is suspected to differ between populations in ways that
produce differences in oxygen delivery to the fetus. Oxygen transport to the
uteroplacental circulation and, subsequently, to the fetus, is determined both by the
oxygen content of the blood and the amount of uteroplacental blood flow, two thirds
of which is supplied by the uterine arteries (Thaler et al., 1990; Palmer et al., 1992).
The amount of blood that the uterine arteries can transport is contingent on both the
2


artery diameter, which increases with pregnancy due to vasodilation as well as its
growth and remodeling (Ni et al., 1997; Hollis et al., 2003), and the velocity of
blood flow through the artery. In normal pregnancy, the additional volume of blood
required by the fetus comes from both an increase in cardiac output (Stock and
Metcalfe, 1994), as evidenced by an increase in flow through the common iliac, and
redistribution (or stealing) from the external iliacs (Palmer et ah, 1992).
Whether these vasculature changes differ among populations is unknown.
Andeans, such as the Aymara of Bolivia, are long- term residents of high altitude, for
whom the vascular response to pregnancy has not been described. This study
specifically addresses the Andean pattern of maternal vasculature response to
pregnancy. Specifically, I aim to:
1. Describe the magnitude and time course of the rise in uterine artery (UA)
blood flow during pregnancy in Andean high-altitude residents
2. Determine the respective contributions of UA diameter, UA blood flow
velocity, and common iliac blood flow redistribution to favor the uterine
artery to the rise in UA blood flow.
3. Examine the relationship between blood flow and IUGR.
4. Compare this sample of Andeans with other studies to see if protection
from IUGR relates to UA blood flow at low as well as high altitude.
3


As described below, Andean patterns of vascular change differ from those of
European high altitude residents, and resemble those of normal women residing at
low altitude. This suggests that native Andeans have acquired genetic adaptations to
high altitude that protect fetal growth through mechanisms of oxygen transportation
to the fetus. Interpopulational comparisons that may be made from studies such as
this may provide an interesting foundation upon which to build further research in
identifying the genes involved in oxygen transport in pregnancy and IUGR.
4


CHAPTER 2
i
i
BACKGROUND
Evolutionary Theory
The theory of evolution, as proposed by Charles Darwin and Alfred Wallace
in 1858, provided an alternative framework to the widely accepted, and largely
unchallenged, divine creator-driven explanation in which species were created de
novo and remained static or fixed throughout time. Since Darwins time, the
definition of evolution has changed and is now generally defined as the change in
allelic frequency in a population over time. This can occur as the result of mutation,
gene flow of alleles between populations, genetic drift, or by means of natural
selection. Mutation, gene flow, genetic drift are all processes which are not
directional1, whereas natural selection is a process through which the fitness of the
individuals within a population will be maximized in future generations if the
environment stays constant, hence causing evolution of a population.
Evolution through natural selection occurs only when a certain set of criteria
is reached. For instance, there must be limited resources for which individuals must
1 Nondirectional in the sense that allelic change is random and should not change in a predictable
manner, whereas the directional process of natural selection causes changes in allelic frequencies to
favor the allele that increases reproductive fitness in a specific environment.
5
i


compete (e.g. food, habitat, or mates) or an alternative environmental stressor, such
as disease. Among these individuals there must also be variation, so that some
individuals are more successful in their competition for limited resources. Success in
competition depends heavily on the specific environment in which the population
exists; if the environment changes, then natural selection will select for different
traits, changing evolutionary trends.
Finally, in order for natural selection to act upon a species, the variation that
confers differential success must be heritable. Thus, through natural selection, those
alleles that confer better survival and reproductive success for the individual would
be expected to become more prevalent in the population over time.
A variable trait that confers increased fitness for the holo-organism is an
adaptation, but not all adaptations are heritable and, thus, subject to change through
biological evolution. An adaptation is any aspect of an organisms phenotype that
enhances the organisms overall fitness in some way (Mayr, 1988; Dobzhansky,
1956). Specific adaptations may vary in their mode of expression (physiological,
behavioral, developmental, etc.) and not all adaptations are produced through gene
expression (many are acquired or environmentally influenced). Only the frequency
of genetically heritable traits may be affected by biological evolution through natural 2
2 Holo- is a prefix used in science, such as that used to describe the movement of holism, to signify
whole or entire. Thus, holo-organism here refers to the observable tenet of evolutionary biology
that natural selection selects for an individuals total phenotype, not simply selecting for specific
alleles or systems, but the total constellation of all of these combined.
6


selection within a population. Therefore, it is important in discussions of adaptations
to distinguish both genetic and non-genetic aspects of individual phenotypes.
Some, such as Gould and Lewontin (1979), suggest that the search for
adaptive explanation for every phenotypic trait is reductionistic and overly optimistic
in assuming a purpose for every organismic characteristic. Indeed, it is true that
natural selection acts upon whole individuals, not each exclusive trait separately.
Additionally, some characteristics do not have adaptive explanations. Yet,
characteristics that have arisen or been sustained within a population attributable to
random processes such as genetic drift may not be scientifically proven as such, but
must be disproven as the result of other possible direction forces (i.e. natural
selection). Additionally, characteristics maintained within a population due to
chance tell us little about the biology of an organism, the environment, and the
interaction between the two. Thus, while it is important to remember that all traits
may not have an adaptive explanation, adaptation may still be a useful tool in the
consideration of a great many of traits.
An adaptation should add to an individuals fitness, or its differential
reproductive success within an environment. Several different factors impact
reproductive success, or the relative genetic contribution of an individual to
subsequent generations. Pregnancy, though, is the most crucial period for both
fertility (the ability to have children, evidenced by the birth of fit offspring) and risk
to maternal morbidity and mortality. Thus, the optimization of fitness includes
1
7


striking a balance between maternal (physiological self-maintenance) and fetal self-
interests, which often are complimentary, but may conflict at times.
Biological Demands of Pregnancy
In humans, reproductive fitness is profoundly affected by the extended period
of fetal gestation. The physical demands on the mother are great and the energetic
cost of pregnancy must be biologically balanced with an offsetting benefit to
reproductive fitness. A mother supplies a good deal to a fetus that lives to term; this
contribution is in the form of nourishment and protection from the external
environment during gestation. Maternal biology must balance the evolutionary
benefits of reproductive success with the requirements to maintain her own fitness
insofar as a pregnancy that is detrimental to her health might impair her future ability
to produce fit offspring, thereby reducing her overall reproductive success (Tracer,
2002; Ellison, 2003). Thus, the most adaptive phenotype would be one in which the
maternal and fetal self-interests overlapped the most. Indeed, most of the time,
benefits to either the mother or fetus benefit the other, and the relationship is
reciprocally beneficial. Unfortunately, there are some times when pregnancy creates
too much of a demand on maternal physiology.
Human mothers are particularly vulnerable during pregnancy because of our
unique biological commitment to bipedalism, big brains, and extended gestations.
With bipedalism, Homo sapiens shift about 25% of the typical mammalian
8


abdominal volume to the pelvic cavity, as the force of gravity and restriction of the
abdominal cavity (by the rectus abdominus and abdominal wall muscles) places the
support of abdominal organs onto the pelvis, as opposed to the anterior abdominal
wall which supports the organs of mammalian quadrupeds (Abitbol, 1993). With the
comparatively large fetal size at full gestation, the volume of the human uterus is
150% bigger than the abdominal cavity volume, while most mammals, including
chimpanzees, have a uterine volume of less than 100% of their abdominal cavity
volume (Abitbol, 1993). Additionally, the fossil record shows that the increased
encephalization of hominids was accompanied by an increase in size of the pelvic
outlet and reshaping towards a platypelloid shape (Lovejoy et al., 1973; Tague and
Lovejoy, 1986).
These factors, pelvic reshaping with the adoption of bipedalism, large uterine
volume compared with abdominal cavity volume, and the gravitational reorientation
of the uterus and abdominal organs over the pelvis, all combine to compress
abdominal organs and the lower vascular system, impeding blood flow to the lower
limbs through the abdominal aorta and venous blood return from the legs (Abitbol,
1993). Thus, when a fetus has nearly reached full gestation, the drastic restriction of
vena cava flow triggers a reduction in cardiac output requiring significant
compensation and, sometimes, overcompensation by uteroplactental vasculatory
remodeling and vasodilatation to supply the fetus (Rockwell et al. 2003). Thus,
Homo sapiens have a much higher risk for preeclampsia compared with other
9


species, due to increased demands on maternal physiology and anatomy during
pregnancy (Rockwell et al. 2003).
Human pregnancy is additionally unique in the extensive invasion of
trophoblast cells into the maternal vessels in the placenta (Rockwell et al., 2003).
Human pregnancy depends on the hemochorial placenta to exchange nutrients
between the maternal and the fetal environments. With the incursion into the uterus
of the fetal trophoblast cells upon implantation, a series of maternal physiological
changes are triggered. These changes include fall of uteroplacental vascular
resistance through the loss of vasoreactivity, which triggers the vascular remodeling
of maternal vasculature (Rockwell et al., 2003).
This change in uteroplacental resistance is partly responsible for the increase
in uterine artery blood flow early in pregnancy, which continues to rise throughout
pregnancy (Stock and Metcalfe, 1994). Correspondingly, near term, a significant
portion, between 12 (Thaler et al., 1990) and 25% (Ueland, 1976), of the total
cardiac output flows through the uterine artery. Thereby, the uterine artery increases
its share of cardiac output drastically with pregnancy. Thus, the uterine artery
represents a significant part of physiologic changes with pregnancy, making it a good
indicator of both the healthy adaptation of the mother through physiologic change, as
well as the amount of nutrients supplied to the fetus, enabling its growth potential to
be fulfilled.
10


species, due to increased demands on maternal physiology and anatomy during
pregnancy (Rockwell et al. 2003).
Human pregnancy is additionally unique in the extensive invasion of
trophoblast cells into the maternal vessels in the placenta (Rockwell et al., 2003).
Human pregnancy depends on the hemochorial placenta to exchange nutrients
between the maternal and the fetal environments. With the incursion into the uterus
of the fetal trophoblast cells upon implantation, a series of maternal physiological
changes are triggered. These changes include fall of uteroplacental vascular
resistance through the loss of vasoreactivity, which triggers the vascular remodeling
of maternal vasculature (Rockwell et al., 2003).
This change in uteroplacental resistance is partly responsible for the increase
in uterine artery blood flow early in pregnancy, which continues to rise throughout
pregnancy (Stock and Metcalfe, 1994). Correspondingly, near term, a significant
portion, between 12 (Thaler et al., 1990) and 25% (Ueland, 1976), of the total
cardiac output flows through the uterine artery. Thereby, the uterine artery increases
its share of cardiac output drastically with pregnancy. Thus, the uterine artery
represents a significant part of physiologic changes with pregnancy, making it a good
indicator of both the healthy adaptation of the mother through physiologic change, as
well as the amount of nutrients supplied to the fetus, enabling its growth potential to
be fulfilled.
10


The maternal system is challenged globally by these pregnancy-initiated
vascular changes, which are required to support the fetus. Early in pregnancy, when
metabolic support of the placenta, uterus, and fetus are high, the principal demands
on the mother are primarily molecular, rather than mechanical (Ciliberto and Marx,
1998). Blood volume begins to increase in the first trimester primarily through an
increase in plasma volume that also continues to rise through pregnancy (Ciliberto
and Marx, 1998), rather than red cell mass, which increases primarily in the third
trimester (Stock and Metcalfe, 1994).
By the fifth week of gestation, cardiac output has already risen by about 10%,
and continues to rise until about week 32, after which it is maintained through the
rest of normal pregnancy (Robson et al., 1989). As mentioned above, the bipedal
posture of humans complicates cardiac output; in some cases because the venous
return of blood from the lower limbs is impeded by the pressure of the uterus (Kerr,
1965; Ikard et ah, 1971; Abitbol, 1993). This has been extensively shown in the
supine and seated posture (e.g. Bieniarz et ah, 1969; Ikard et ah, 1971; Abitbol,
1976), but the pressure is relieved in the left lateral decubitus posture3 (Ueland,
1976). Less often demonstrated4, but possibly more pertinent to humans context of
3 Left lateral decubitus posture is lying on down on the left side.
4 Erect, or standing posture, would be the optimal position of measurement as it is more indicative of
the predominant posture of the environment of evolutionary adaptedness, yet it is likely less used in
studies because of the difficulty involved in obtaining measurements from this posture. In the Ikert et
al. (1971) study, subjects were required to balance on the opposite limb so that the dependent limb did
not bear any weight and was relaxed while the measurements were obtained. In this study, similar
conclusions regarding the effects of pregnancy on venous blood flow and cardiac output, as
mentioned above.
11


evolutionary adaptedness, is the even more drastic venous occlusion in the standing
position, which obstructs femoral vein flow from the limbs about 3.5 times as much
as the considerable obstruction found in the supine position in the third trimester
(Ikard et al., 1971). Thus, the adoption of bipedal posture has complicated venous
return and, subsequently, cardiac output.
Hence, in order to maintain proper and sufficient development of the fetus,
pregnancy demands the extensive maternal physiological changes outlined above.
These drastic changes to typical female physiology illustrate the delicate balance
between fetal and maternal self-interests. Immediate maternal reproductive success
in the form of a healthy fetus must be balanced with her own fitness and future
reproductive possibilities (and overall reproductive fitness). If the demands of
pregnancy are too greatthe maternal ability to survive may be compromised, and,
thus, also compromise the fetus existence.
Adequate nourishment in the form of oxygen, glucose, lactate and amino
acids (McMillen et ah, 2001), as well as a propitious uterine environment, is
necessary for sufficient fetal growth. Without these, fetal growth will likely be
impaired and place the fetus at a higher risk for IUGR.
Growth restricted fetuses have increased risk for intrauterine and neonatal
mortality (Williams et ah 1982), as well as increased infant morbidity (Starfield et
ah, 1982). Additionally, low birth weight due to IUGR has been associated with
increased risk for noninsulin-dependent diabetes mellitus (e.g. Barker, 1998;
12


Godfrey and Barker, 2000; Harding, 2001; Ravelli et al., 1998), hypertension (e.g.
Barker, 2002; Barker et al., 2002; Roseboom et al., 1999, coronary heart disease (e.g.
Barker, 2001; Eriksson et al., 2001; Forsen et al., 1999; Huxley et al., 2000; Stein et
al., 1996), and obesity, which aggravates many of the above (e.g. Oken and Gillman,
2003). These later-in-life diseases have been found to be associated with IUGR
resulting from a myriad of causes, such as toxic chemical exposure (for instance, to
nicotine (Slotkin, 1998; Power and Jefferis, 2002), cocaine (Slotkin, 1998), and some
pesticides (Cory-Slechta et al., 2003)), twinning (Christensen et al., 2001; Ozanne
and Hales, 2002; Johansson-Kark et al., 2002), socioeconomic status (Kramer, 1998;
Giussani et al., 2001), and emotional stress (Mulder et al., 2002). Although, at this
time, the association between altitude-associated IUGR and adult disease has not
been studied, because of the similarities in fetal coping mechanisms when faced with
growth restriction triggered by one of multiple causes (such as stress or hypoxia), it
is reasonable to expect there may be an association between hypoxia-related IUGR
and adult health and illness. Thus, adequate nourishment of the fetus during
gestation profoundly affects its future health and fitness as a neonate and may affect
its health throughout the lifespan.
Besides fetal health, pregnancy may also affect maternal health. In order for
a mother to maximize her own fitness, she needs to produce a healthy offspring with
i
I
13
i


each pregnancy, but not at the cost of future offspring5. Thus, with each pregnancy
the mother would like to maintain the health and development of her fetus, but to the
extent that her longterm reproductive health would be jeopardized.
Pregnancies in which the fetal fitness requirements are discordant with
maternal fitness can trigger many different health problems for her, including
diabetes, edema, malnutrition, anemia, bleeding, puerperal endometritis, and
preeclampsia/eclampsia. Some of these pathologies may be attributed to excessive
demands of the fetus on the maternal resources, which must be shared by both the
mother and the fetus during pregnancy. For instance, preeclampsia has been
described as a result of maternal need/fetal demand imbalance, in which the
increased maternal peripheral vascular resistance which creates detrimental elevated
blood pressure for the mother results from the fetal demand for increased nutrients
(Haig, 1993; Odent, 2001). Thus, preeclampsia can be an example of an imbalance
in the conflicting interests of the mother and fetus.
As mentioned above, oxygen is one of the nutrients required by the fetus that
may trigger such a disparity between fetal demand for adequate nourishment and
maternal physiological limitations. Thus, environments low in oxygen, such as the
hypoxic environment found at high altitude, present a challenge for both maternal
health and fetal growth and health during pregnancy.
5 According to life history theory, as maternal age and parity increase, the mother should begin to
accept more risk to her health with each pregnancy to produce healthy offspring. Indeed, several
studies have shown that some populations exhibit a decline in maternal condition after pregnancy with
increasing parity (Tracer 2002).
14


High Altitude
Birth weights have been shown to be inversely correlated with altitude during
pregnancy; above 2000 meters (Moore, 2003); (Mortola et al., 2000), for every 1000-
meter increase in altitude, there is about a 100-gram decrease in average birth weight
(Jensen and Moore, 1997). This occurs because of the hypoxic (low oxygen)
environment found at high altitudes.
Atmospheric pressure decreases with altitude nonlinearly. At sea level, the
partial pressure of oxygen is 21.18 kPa (.209% O2 *101.325 kPa), and humans
generally have an arterial oxygen saturation of 98-100%. At 3000 meters, the partial
pressure of oxygen drops to 14.65 kPa, or about 2/3 the partial pressure of oxygen at
sea level (see Figure 2.1). Consequently, average, non-adapted human arterial
oxygen saturation at 3000 meters drops to 90-95%. At 3800 meters (the altitude of
La Paz, Bolivia), the partial pressure of atmospheric oxygen is 13.22 kPa, which is
about 62% that of sea level. But, it has been shown that arterial oxygen saturation
does not consistently drop with falling atmospheric oxygen partial pressure. Fro
instance, people of Andean descent at 3800 have been shown to have at least 1%
higher arterial oxygen saturation than people of European descent at the same
altitude and activity level (Brutsaert et al., 2000). Additionally, Tibetans maintain
their normal arterial oxygen saturation with exercise to a greater extent than do low
15


altitude natives at high altitude (Favier et ah, 1995), likely due to more efficient
delivery of inspired oxygen to the blood through greater lung diffusing capacity.
This population-based disparity suggests that adaptation has occurred among
Andeans and Tibetans to hypoxic conditions.
Unlike many other environmental stressors, hypoxia is not easily mediated by
human culture. At high altitudes, hypoxia may be avoided only by descending or
using new technologies such as oxygen supplementation. The effects of hypoxia
may be alleviated slightly by labor minimization or labor delegation to younger
children who require less oxygen compared with adults for a similar task (Thomas,
1976). Some people do utilize temporary emigration from high altitude, but both
emigration and labor adjustment are limited in scope and use. Because cultural
adaptation does relatively little to relieve chronic hypoxia, humans who have lived at
high altitude for multiple generations are likely to have genetic biological
adaptations to hypoxic environments.
The high altitude environment consists of other factors besides hypoxia. Due
to adiabatic lapse, air cools with increasing altitude, dropping in temperature at a rate
of about 10 degrees centigrade/ 1000 meters. Thus, at a certain point in its ascent,
the dew point is likely to be reached, causing water vapor to condense and precipitate
out, leaving the ascending air much dryer. Therefore, high altitude environments are
often cooler and dryer, which also allows for more diurnal temperature variation
(Niermeyer et al., 2001; Moore et al., 1998). Additionally, at high altitude less
16


atmosphere and, thus, ozone, shields the earths surface from the sun. Ozone absorbs
a fair amount of ultraviolet radiation that reaches the earth from the sun, therefore,
with decreasing ozone protection/ increasing altitude there an increase in ultraviolet
radiation (about a 4% increase in UVR per 300 meters).
These stressors may be relatively more easily mediated through cultural
adaptations, such as clothing and agricultural innovations, than is hypoxia. Thus, it
seems likely that the altitude-specific IUGR is likely most attributable to hypoxia
rather than other environmental factors of high altitude.
17


Atmospheric Pressure (kPa)
120
100
60
40
20
0
Atmospheric Pressure
Partial Pressure of Oxygen
mKTU"1
0 500 1 000 1 500 2000 2500 3000 3500 4000
Altitude (meters)
Figure 2.1 Total atmospheric pressure and the partial pressure of oxygen decrease
with increasing altitude.
18


Pregnancy Physiology
Physiology at Low Altitude
In general, in normal conditions at low altitude pregnancy provokes an early
and dramatic change in maternal physiology. In normal low-altitude pregnancies,
oxygen delivery to the fetus is facilitated by an early doubling of the uterine artery
diameter and consequent four-fold increase in cross-sectional area (by week 21) and
gradual increase in uterine artery flow velocity throughout gestation (Palmer et ah,
1992) . Similarly, Berstein et al. (2002) found that uterine artery blood flow
increases over seven-fold by week 12 of gestation.
Additionally, at low altitude, maternal vascular adjustments to pregnancy
enable an increase in uterine artery blood flow which, in turn, fuels fetal growth.
The correlation of uterine artery flow with fetal growth by week 36 is supported by
other studies of low altitude pregnancy. For instance, Konje (2003) found that a
group at higher risk for IUGR and, subsequently, had babies with lower birth
I
weights, had significantly smaller uterine artery diameters by at least week 24 and
lower volumetric flows by week 20 compared with a group with low risk for IUGR.
Interestingly, lower birth weights are correlated with lesser uterine artery flow
velocity at low but not high altitude among individuals in Colorado (Zamudio et ah,
1993) .
19


Therefore, at low altitude pregnancy has been shown to increase uterine
artery flow early in gestation through a rise in both velocity and vessel diameter.
Moreover, uterine artery flow and flow velocity have been shown to be associated
with IUGR at low altitude.
Physiology at High Altitude
At high altitude, where hypoxia presents a challenge for delivering sufficient
oxygen to the fetus during gestation, permanent Colorado residents showed that
uterine artery diameter, flow velocity, and, thus, volumetric flow also increase with
pregnancy (measured in Leadville, Colorado; Zamudio et al., 1995). This general
trend of increase in pregnancy is similar to that found at low altitude (see Table 2.1),
yet contrastingly, at high altitude compared with low altitude there is a lesser
increase in vessel diameter, greater increase in flow velocity, which results in a lesser
increase in volumetric flow (Zamudio et al., 1995). Pregnancies with hypertensive
complications at high altitude showed increased uterine artery flow velocity early,
with no further increase through the rest of gestation, which resulted in no increased
volumetric flow in the later stages of pregnancy (Zamudio et al., 1995).
i
20


Altitude (m) UA Diameter UA Flow velocity UA Volumetric Flow UA impedance to flow (Rl, PI, S/D) UA/CI Birth Weight Difference Citation
COMPARISONS BETWEEN ALTITUDES
USA: Low altitude residents compared with high altitude residents 1600 vs. 3100 Low alt. increase > High alt. increase Low alt. increase < High alt. increase Low alt. increase > High alt. increase not reported Volumetric Flow: Low alt. redistribution to UA > High alt. redistribution to UA 279g Zamudio et al. 1995a
Peruvian Andes: Low altitude mestizo residents compared with high altitude mestizo 4300 vs. 100 not reported not reported not reported Low alt. Rl and PI > High alt. Rl and PI not reported 371g Krampl et al. 2001
COMPARISONS BETWEEN HIGH ALTITUDE POPULATIONS
Tibetans compared with Han, both high altitude residents 3600 not reported Higher not reported not reported Velocity: Low alt. redistribution to UA > High alt. redistribution to UA likely 635g Moore et al. 2001
Table 2.1 Previously reported comparisons of uterine artery flow characteristics and birth weights at high altitude.


The studies discussed up to this point have consisted predominantly of
subjects of European descent residing in the United States. European populations
have lived at high altitude for an evolutionarily short period of time, probably no
more than 500 years. Thus, the phenotypes demonstrated by the Europeans have had
a relatively short period of time to show adaptive changes to the hypoxic
environment. Other populations have been studied, such as the Tibetans, who have
likely lived at high altitude for a longer period of time compared with Europeans or
Han Chinese, relative newcomers to high altitude with about 50 years in Tibet. The
Tibetan plateau is estimated to have been occupied as early as 25,000-50,000 years
ago (Sensui, 1981; Zhimin, 1982)). Thus, there has been ample time for adaptations
to high altitude to have accumulated in this population given the intense selective
pressure exerted by hypoxia.
Indeed, Tibetans, compared with Europeans or Han show less altitude-
associated decrease in birth weight (Moore et al., 2001; Zamudio, 1993). With
respect to vascular response, the Tibetans showed a greater increase in uterine artery
flow velocity, and a subsequent increase in the UA/CI flow velocity ratio (Table 5),
likely indicating a greater redistribution of blood flow to the uterine artery in
Tibetans (Moore et al., 2001). Unfortunately, these Tibetan studies were only able to
describe velocity, and not vessel diameter. Thus, volumetric flow data are not
available for the Tibetan studies.
22


Andeans have inhabited high altitude for an extended period of time
intermediate to long-resident Tibetans and the short-resident Han and Europeans.
Yet, similar to Tibetans, the extended length, spanning hundreds of generations, of
high altitude residence by the Andeans likely has been long enough for natural
selection to have affected this population. Evidence has shown human occupation
of South America at least 10,000 years ago (Denell et al., 1988), but cultural
innovations likely did not make the Andean Altiplano inhabitable until 4,000-6,000
years ago (Niermeyer et al. 2001; MacNeish and Berger, 1970; Lynch, 1978);
Nunez, 1983).
Prior to the present study, little work has been done to describe the vascular
changes with pregnancy in Andeans. Krampl et al. (2001) compared high altitude to
low altitude pregnant women and found that there was less uterine artery resistance
at high altitude compared with at low altitude. That study, though, lacked
explanatory power in that it did not collect any measure of fetal growth, uterine
artery flow (just resistance indices), measure of redistribution (only uterine arteries
were measured), had no serial measurements (cross-sectional data only), and had no
non-pregnant measurements. The present study, however, measures uterine artery
blood flow and redistribution indices serially at multiple time points in pregnancy
and at one point postpartum for a representation of the nonpregnant state in high
altitude natives in La Paz, Bolivia. These measurements, then, are examined for
23


correlations with indicators of fetal growth. Thus, much can be added by the present
study to what is known about Andean pregnancy at high altitude.
Social Factors
As mentioned above, Native Andeans, such as the Aymara or Quechua, have
been purported to have lived at high altitude on the Andean Altiplano (3,600 meters)
for about 10,000 years (Baker and Little, 1976). People of European descent have
lived at high altitude no longer than 500 years (in North or South America). Thus,
the Andean Altiplano provides an excellent opportunity to study modem human
adaptation to the physiological challenges of high altitude.
Bolivia is part of the periphery/developing world, which faces the forces of
globalization and Western modernization daily. Within the global context, Bolivia is
extremely poor, often causing major instability in economic, political, and health
arenas. Within the country, there is notable social and economic stratification and
power differentials, and these divisions often occur along ethnic lines (typically
between European, mestizo, and indigenous peoples) leaving indigenous Andeans
little agency. These factors all greatly impact the etiology of intrauterine growth
restriction (Kramer, 1998; Giussani et al., 2001; Mulder et al., 2002).
Bolivia is one of the poorest countries of Latin America with a gross national
income of $900 per capita in 2002, a health development index indicator of .548 (UN
2002), and the World Bank reporting 29.4% of the population lives in extreme
24


poverty (below $l/day, 1999 UN Human Development Report). The World Bank
report on Bolivia released in 2002 describe Bolivia with average rates of life
expectancy, primary school enrollment, and access to safe water compared with
other lower-middle income countries (the poorest category), but falls notably short of
the average in gross national income per capita. When income is broken down by
type of worker, the disparities between the rich and poor in Bolivia show that a great
many working Bolivians live on very little money6 (Thiele and Piazolo, 2002).
Consideration of ethnicity adds an extra dimension to this discouraging
picture. Fifty-seven percent of the population of Bolivia is of indigenous descent
(1992 census cited by WHO, 1996), with 36% of the urban population (EIH, 1993)
and, possibly, 92% of the rural population made up of indigenous Bolivians (WHO
1996). In La Paz, where this study was conducted, almost half (49.5%) of the
population is of indigenous descent (Censo Nacional Poblacion y Vivienda, 2001).
Indigenous people, though, carry much more of the burden of poverty in Bolivia,
with 68% in poverty, compared with nonindigenous population with 36% in poverty
(WHO 1996).
Socioeconomic status is a proven environmental and psychological stressor
which has been found to exacerbate IUGR (Kramer, 1998); (Giussani et al., 2001).
Thus, it could be expected that indigenous Bolivians may have a drastically
6 Smallholders, who make up about 40% of all Bolivian workers, averaged 244 Bolivianos or about
US$44 per month in 1998 (Thiele and Piazolo 2002). Urban informals (about 27% of all Bolivian
workers) averaged 415 Bolivianos or US$75 per month. Each of these types of workers were likely
the primary wage earners in their household (Thiele and Piazolo 2002).
25


increased risk for IUGR compared with their richer, more advantaged compatriots.
Intriguingly, however, the indigenous populations of Bolivia have less incidence of
IUGR compared with nonindigenous groups (Haas et al., 1987), despite their
increased rates of poverty and other non-hypoxia related risk factors. This protection
from IUGR despite the increase in other risk factors may be due to multi-
generational biological adaptation to the hypoxia of high altitude (e.g. Jensen and
Moore, 1997; Brutstaert et al., 2000). Thus, the likely confounding social factors for
this study are likely to be negative confounders, increasing the likelihood of seeing
less of the effect on IUGR in indigenous Andeans. Hence, this negative confounding
does decrease the risk of seeing a falsely significant difference in physiology in the
Andeans.
26


CHAPTER 3
MATERIALS AND METHODS
This study was conducted as a subsection of a larger project entitled
Interpopulational Differences in Intrauterine Growth Restriction (IUGR) at High
Altitude, principal investigator Dr. Loma G. Moore, and funded by National
Institutes of Health Fogarty International Research Collaborative Award, Award #
TW001188, and a National Science Foundation Graduate Research Fellowship.
Subjects included 45 pregnant women self-identified as of Andean
ancestry living in La Paz, Bolivia (3800 meters). The actual altitude of residence
was determined by questionnaire and ranged from about 3600 to 4000 meters (as
verified through matching neighborhood given with national geographical data).
Socioeconomic factors showed a wide range. Maternal education ranged from some
primary school education to university training and family income included a large
range from low to mid-range socioeconomic status. Subjects were recruited through
their prenatal care provider, thus, despite the poverty of some subjects, all subjects
received prenatal care during this pregnancy.
Informed consent was sought and study protocol was approved by the
Human Subjects Review Committees of the Colorado Multiple Institutions Review
27


Board and the Colegio Medico, the institutional review counterpart at the Instituto
Boliviano de Biologia Altura in La Paz.
Women were studied serially at weeks 23 (23.4 .6), 31 (30.8 .2), and
week 37 (36.6 .6) of pregnancy, and three months postpartum for a measurement in
the nonpregnant state. Gestational age was determined using the first day of the last
menstrual period. If date of last menstrual period was unknown or if gestational age
determined by last menstrual period differed from estimated gestational age as
determined by ultrasound assessment of fetal biometry at week 20, then gestational
age at the time of study was back-calculated from the biometry-estimated value.
All measurements were taken in the afternoon at the same facility, with
the same machine and study personnel, so as to minimize interinstrumental and
interrater variability. At each time point, location and visualization of the common
iliac, external iliac, and the uterine arteries was done using the ATL3000 with 2D
color-imaging. The common iliac artery was measured just anterior to the external
iliac/ internal iliac bifurcation, while the external iliac artery was measured posterior
to this bifurcation. The uterine artery was identified by its low resistance waveform
and measured at the external iliac crossover.
The diameter of all vessels is optimally measured at an angle of
insonation of 90 degrees for best visualization of the vessel. The diameter of each of
the iliac arteries was measured in systole and in diastole first with and then without
color. The average diameter of the vessel without color was determined using the
28


equation (2*diastolic diameter + systolic diameter)/3, since, on average at rest, the
vessel is in diastole for two thirds of the cardiac cycle (Gauer, 1960); (Rogers and
Oosthuyse, 2000). Because of the difficulty in visualizing the uterine artery without
the Doppler color-imaging, it was necessary to use color imaging to obtain uterine
artery diameters. These diameters were subsequently adjusted to approximate
without color measurements (the more accurate method) using the difference
between with and without color measurements obtained in the common iliac vessel,
measured at a similar anatomical depth.
Flow velocity was determined using the ATL3000 High Q-Automatic
Doppler Measurement Mode, which was also used to ascertain peak systolic velocity
(PSV), minimum diastolic velocity (MDV) or end diastolic velocity (EDV),
pulsatility index (PI), resistance index (RI), and the systolic to diastolic ratio (S/D).
These measurements are optimally measured with an angle of insonation as close to
0 degrees as possible, so as to minimize error in the measurement (more thoroughly
described in Palmer et al., 1992). The time-averaged mean flow velocity (TAM) was
obtained in the volume flow mode after correcting for the angle of insonation. TAM
measurements of vessels measured at an angle of insonation greater than 45 degrees
were not used. At least three consecutive cardiac cycles of good quality were
averaged for the measurement of TAM, PSV, MDV or EDV, PI, RI, and S/D.
Volumetric flow of each vessel was subsequently calculated using the
equation 60 *(nr2)*(TAM), where r is the radius of the vessel, or half of the vessel
29


diameter, and the value is expressed in mL/min. The ratios of uterine artery to
common iliac flow and of external iliac to common iliac flow were calculated using
the volumetric flows of each respective vessel.
Blood volume was determined using a carbon monoxide rebreathing
technique which measures blood carboxyhemoglobin using a gas chromatograph
(model AD 2000, Dohrman Instruments) as described previously in Zamudio et al.
(1993). Subjects initially breathed 100% O2 into a rebreathing circuit with a CO2
absorber in place. After 5 minutes, a baseline blood sample was taken. Next, a
known volume of carbon monoxide was added to the rebreathing circuit and blood
samples were taken again at 5, 10, and 15 minutes. Carbon monoxide concentration
was measured in triplicate by gas chromatography in each sample. Total blood
volume was calculated using the equation
CO added * 1 * 100
ACO content Hb
where CO is the volume of carbon monoxide added to the rebreathing circuit, CICO
content is the difference in carbon monoxide content between the baseline and the
average of the 10- and 15- min samples. Hemoglobin concentration was measured
with a photometer (Aktiebolaget Leo Diagnostics HemoCue), which had been
previously calibrated using samples by the cyannethemoglobin techniques with a
spectrophotometer.
30


Red blood cell mass was calculated as total blood volume multiplied by
hematocrit. Hematocrit was measured by the microhematocrit technique. Plasma
volume was obtained by subtracting red blood cell mass from total blood volume
without correction for trapped plasma or whole body hematocrit.
At each time point during gestation, fetal measurements were taken as
growth indicators, including abdominal and head circumference, biparietal diameter,
femur length, and umbilical and cerebral blood vessel flow measurements. Birth
weights were not available for all babies, as some of the women delivered at home.
Thus, fetal abdominal circumference during pregnancy was used as a proxy
measurement for late fetal growth. Using abdominal circumference (measured at the
same time in gestation) as the primary growth indicator also controlled for variation
in gestational ages at birth.
Genetic admixture or the respective contributions of 22 highly
polymorphic short tandem repeat genetic markers (STR) characteristic of European,
African and Native American populations was determined. The STRs used were:
MID-575, TSC1102055, WI-11153, MID-52, SGC30610, WI-17163, WI-9231, WI-
4019, WI-11909, D11S429, TYR-192, DRD2 TaqD, DRD2 Bell, WI-14319, CYP19,
PV92, WI-7423, CKM, MID-161, MID-93, FY, and F13B. Of these, 20 markers had
highly divergent frequencies between European and Native American populations
(>30%) and two markers were unique to African populations. Each single nucleotide
polymorphism (SNP) was amplified using polymerase chain reaction (PCR),
31


digested using restriction enzymes to create restriction fragment length
polymorphisms (RFLP), which were scored using a melting-curve assay (Hybaid
DASH machine) (Brutsaert et al., 2004; Brutsaert et al., 2003).
Statistics were calculated using StatView, Version 5 (SAS Institute Inc.,
Cary, NC). Descriptive statistics are reported as mean standard error. Effects of
pregnancy were tested using 2-way analysis of variance with Student-Newman-
Keuls significant difference test. Multiple regression was used to test the
relationship of measures of fetal growth to the indices of blood flow. Significance is
defined as p<0.05, and the term trend is used when 0.05 Study Advantages and Limitations
The design of this study to describe change in blood flow with pregnancy is
limited in that all pregnant values are compared with postpartum values as an
approximation of prepregnancy values. The ATL 3000 used in this study has greater
ease of use and enables better visualization of vessels compared with previously used
technology (e.g. the Acuson 128 ultrasound coupled with a pulsed-wave, gated
Doppler flow meter used in studies such as Palmer et al. 1992; Zamudio et al. 1995).
Using the ATL3000 to assess vessel characteristics, though, still is complicated by
the difficulties in obtaining optimal angles of insonation for each measurement.
Vessel diameter is optimally measured at an angle of insonation of 90 degrees for the
best visualization of the vessel, while flow velocity is optimally measured at an angle
32


of insonation as close to 0 degrees as possible. Obtaining vessel measurements at
both 0 degrees and 90 degrees is difficult in subjects due to anatomical limitations,
but the curved linear array of the instrument provides a greater visible range,
allowing the best angle to be more easily obtained. Error was minimized by
measuring each variable (vessel diameter, flow indices, etc.) multiple times and
averaging the best measurements7. Additionally, anatomical landmarks were used to
ensure that each variable was measured at the same point in the vessel.
Part of the study design required that all women received prenatal care, which
some may suggest is unlikely representative of typical pregnancy in the developing
world. Yet, in Bolivia in 1998 63% of all pregnant women reported receiving
prenatal care, and in the Capital Department of La Paz, specifically, 84.6% of all
women received prenatal care (ENDSA, 1998).
Compared with a large-scale records review of high altitude residents in
Bolivia (Keyes et al., 2003), these women were on average 2 years younger but had
similar mean gravidities (Table 1), and their babies were bom with similar mean
birth weights and similar rates of IUGR (Table 2). Thus, this sample likely represents
the general population well.
This study was difficult to implement in a couple of respects. First of all, it
was difficult to obtain measurements at all time points for each woman. The varied
altitudes in the metropolitan area of La Paz resulted in a range in actual altitudes of
7 The best measurements were those that had well-defined waveforms, no interference, and the
strongest signal.
33


residence (from 3600 to, possibly, 4300 meters), but most of the women resided in El
Alto (n=34), generally at 4000 meters (predominantely in neighborhoods most
proximate to La Paz), but could have lived up to 4300 meters high. This variation
could cause more altitude-associated IUGR and vascular responses in some women
who live at higher altitudes. Socioeconomic status could also vary along with
altitude of residence in La Paz, but since there was no correlation of socioeconomic
factors with any variable in this study (see below), the range of altitudes probably
create more variation within the sample within the independent variable (altitude),
but probably does not introduce more confounders (e.g. SES). Socioeconomic
status, as inferred through education level (from partial primary education through
university training) and income, varied, but all women received prenatal care
(average 5 visits) and, in this study, no socioeconomic factor was significantly
related to birth weight or abdominal circumference in week 36.
34


CHAPTER 4
RESULTS
Subject Characteristics
The 45 women were self-identified as of Aymara descent. This was
confirmed both by examining the self-reported ancestry of their parents and
grandparents and by assessing ethnicity using 22 SNPs with frequencies known to
differ markedly in Native American, European, and African populations. Genetic
markers showed that these women were primarily of Aymara descent (92.5%), with
a small amount of European (3.2%) and African (2.0%) admixture. All women were
bom, raised, and live now at high altitude. The women ranged from 16-42 years of
age and had an average parity of 3.2 births including the current delivery (range
between 1 and 9) (Table 4.1). All of the women were nonsmokers. 84% delivered in
a hospital (Table 4.2). Three women developed preeclampsia but were excluded
from the present report, because measurements could not be completed at all time
points, including postpartum.
35


Table 4.1 Maternal characteristics
Variable Mean SEM or (95% Confidence Interval)
Age, yrs 27 1
Height, cm 150 1
Years in La Paz 22 1
Born at high altitude, % 100
Spent early childhood at high altitude, % 93 (86, 100
Monthly income, US$ 113 12
Maternal education
None (0 years), % 2 (0, 7)
Primary School (up until age 12), % 16 (5, 27)
Secondary School (between ages 12 and 18), % 66 (52, 80)
University or Technical school (overage 18), % 16 (5, 27)
Nonsmokers, % 100
Ancestry % Aymara 92.5 2.6
Ancestry % European 3.2 1.1
Ancestry % African 2.0 0.7
Parity 3.2 0.3
Primigravid, % 20 6
Weight in week 20, kg 61 2
Weight gain with third trimester of pregnancy, kg 6.3 0.5


Table 4.2. Infant characteristics
Variable Mean SEM or (95% Confidence Interval)
Birth Characteristics:
% Born in hospital 84 (73, 96)
Delivery Type
Spontaneous vaginal, % 82 (70, 95)
Cesarean section, % 15(3,27)
Other, % 3 (0, 9)
Male, % 45.7 (31,61)
Birthweight, g 3100 61
Gestational age, weeks 38.9 0.3
Preterm, % 6(0, 15)
Postterm, % 3 (0, 8)
IUGR, % 15 (0, 26)
Biometry characteristics in week 37:
Gestational age, weeks 36.6 0.6
Head circumference, cm 31.6 0.2
Biparietal diameter, cm 8.8 0.1
Abdominal circumference, cm 31.2 0.3
Femoral length, cm 6.9 0.1


General Pregnancy Physiological Characteristics
Subjects gained weight steadily through pregnancy (Table 4.1). Mean arterial
pressure increased with pregnancy by week 20 (p=0.0186), and then decreased by
week 30 (Table 4.3). Total blood and plasma volume increased and hematocrit
decreased at week 36 of pregnancy relative to the nonpregnant value. Hemoglobin
did not change significantly with pregnancy, but red blood cell mass showed a trend
toward higher values at week 36 compared with week 20 (p=0.0883).
Uterine Artery
Uterine artery diameter more than doubled and, thus, the cross-sectional area
of the vessel quadrupled by week 20 of pregnancy relative to the nonpregnant state
(Table 4.4). Flow velocity also increased with pregnancy, raising volumetric flow
nearly 20-fold (Table 4.4). The increase in TAM was especially due to increased
diastolic flow, as shown by the rise in end diastolic velocity and the fall in the
systolic/diastolic velocity ratio, pulsatility index, and resistance index. As a result of
both the increased cross-sectional area and flow velocity, the volumetric flow in the
uterine artery increased with pregnancy.
38


Table 4.3 Hematological characteristics
Nonpregnant Week 20 Week 30 Week 36
Mean arterial pressure, mmHg 72.1 1.0 76.1 1.4* 71.9 1.6 74.4 1.3
Total blood volume, mL/kg 74.8 3.1 76.4 3.1 83.8 3.0*
Plasma volume, mL/kg 41.9 1.8 46.0 1.7 49.4 1.9*
Red blood cell mass, mL/kg 33.3 1.4 31.3 1.3 34.2 1.3$
Hemoglobin, g/dL 15.3 0.9 14.2 0.9 13.4 0.2
Hematocrit 44.4 0.5 40.2 0.3* 40.3 0.5*
Data are presented as mean SEM
* p<.05 when compared with nonpregnant value.
Student newman keuls
$.05

Table 4.4 Vessel characteristics at all three gestational timepoints and in the nonpregnant state
Nonpregnant Week 20 Week 30 Week 36
Uterine Artery
diameter, mm 2.25 0.33 4.70 0.14* 4.85 0.15* 4.86 0.16*
flow velocity, cm/s 7.3 8.0 30.2 2.8* 32.6 2.5* 35.2 2.5*
volumetric flow, mL/min 23 116 300 53 380 47* 427 47*
end diastolic velocity 11 1 29 3* 37 3* 36 3*
Systolic/diastolic ratio 2.55 0.15 2.140.15$ 2.36 0.15
pulsatility index 1.01 0.05 0.89 0.05$ 0.88 0.05$
resistance index 0.59 0.02 0.56 0.02 0.54 0.02$
Common Iliac Artery
diameter, mm 6.71 0.20 8.90 0.21* 9.02 0.20* 8.91 0.24*
flow velocity, cm/s 11.2 0.9 12.2 1.0 12.2 1.0 11.2 0.9
volumetric flow, mL/min 256 43 462 48* 437 39* 526 42*
External Iliac Artery
diameter, mm 5.67 0.09 6.29 0.09* 6.21 0.09* 6.31 0.10*
flow velocity, cm/s 14.1 0.7 10.4 0.8* 10.1 0.7* 10.8 0.7*
volumetric flow, mL/min 218 15 192 16 191 14 196 15
Data are presented as mean SEM
* p<.05 when compared with nonpregnant value.
Student newman keuls
$.05

Common Iliac Flow
Pregnancy increased common iliac diameter by a third; due to both greater
diameter during systole (p<0.001) and diastole (p<0.001) (Table 4.4). Flow velocity
did not change between the nonpregnant state and pregnancy, nor during pregnancy.
Common iliac blood flow rose by week 20 (see Table 4.4) and maintained the
increased flow throughout pregnancy, doubling nonpregnancy flow by week 36.
Thus, this rise in common iliac flow in pregnancy accompanies the increase in blood
(and plasma volume) mentioned above (Figure 4.1).
External Iliac Artery
The external iliac artery showed a slight (relative to other vessels), but
significant, 11 % increase in vessel diameter with pregnancy. Contrastingly, the
flow velocity of the external iliac decreased by 16%. Thus, there was no significant
change in volumetric flow in the external iliac with pregnancy (Table 4.5).
Blood Flow Distribution
During pregnancy, the proportion of the common iliac flow distributed to the
uterine artery (Figure 4.2) tended to rise (difference between nonpregnant state and
week 36, p=0.095). The uterine artery flow compared with external iliac flow
(Figure 4.2) increased progressively through pregnancy to a significant difference at
week 36 with the nonpregnant state. Reciprocally, the proportion of the common
41


iliac flow distributed to the external iliac (Figure 4.2) significantly decreased early in
pregnancy.
Fetal/Infant Characteristics
Births weights averaged 3100 grams with 18% of babies bom prematurely
(Table 4.2). Among term births, birth weights were 3200 grams, which is within the
sea-level range (Lubchenco et al., 1972). In this study, no significant association
was found between birth weight (or abdominal circumference) and SES indicators
(such as monthly income or educational status of either parent). Due to the births of
several babies occurring outside of the hospital setting where birth weights could be
obtained, abdominal circumference at week 36 of gestation was used for assessing
fetal growth. UA blood flow at week 20 was positively associated with fetal
abdominal circumference at week 36 (Table 4.5 and Figure 4.3) but not at later time
points during pregnancy. Other flow parameters, including UA resistance indices,
were not associated with fetal abdominal circumference.
42


Non-Pregnant Week 23 Week 31 Week 37
Figure 4.1 The rise in blood volume is accompanied by a rise in both uterine artery and common
iliac artery flow through pregnancy, while the external iliac artery shows no significant change in
flow during the course of pregnancy. The bars show the standard error of the mean.
*** : p<0.001 compared with non-pregnant state
** : p<0.01 compared with non-pregnant state
* : p<0.05 compared with non-pregnant state
43


0.4 -
0 *
UA/EI
Figure 4.2 Changes in the relative flow of the uterine artery to common iliac
(UA/CI), the external to common iliac (EI/CI), and the uterine artery to external
iliac (UA/EI). The bars show the standard error of the mean.
* : p<0.05 compared with non-pregnant state, : 0.05 44


Table 4.5 Uterine artery blood flow is significantly (but weakly) correlated with
fetal abdominal circumference at week 20.
Correlation coefficient (r-value) of uterine artery blood flow with:
Week 20 Week 30 Week 36
Birth weight 0.322 0.298 0.167
Week 36 abdominal circumference 0.480* 0.105 -0.002
week jjt> nead circumference 0.207 0.165 0.443*
Figure 4.3 Graph of fetal abdominal circumference in week 36 of gestation versus
uterine artery blood flow at week 20.
(D
o
c=
(D
£
E
Z3
O
O
ro
c
E
o
"O
<
UA Flow in Week 20 (mL7min)
45


CHAPTER 5
DISCUSSION
This study is the first to examine multiple vessels in a large number of
women serially throughout pregnancy, thereby developing a more accurate,
comprehensive picture of maternal vasculature at different stages of pregnancy.
Primarily, there is increased common iliac and uterine artery blood flow early in
pregnancy, and maintenance of this increased flow throughout gestation (Figure 4.4),
accompanied by a rise in blood volume. Reciprocally, blood flow in the external
iliac showed no significant change with pregnancy (Figure 4.2), but, rather, fell in
relation to UA flow (Figure 4.4, p=0.05 trend for all time points, p=0.02 between
nonpregnant and week 36).
An increase in blood volume helps to raise cardiac output and common iliac
flow (Stock and Metcalfe, 1994; Palmer et al., 1992). The increased common iliac
flow is distributed to favor the UA and not the external iliac. Thus, in addition to
describing basic trends in pregnancy, this study shows that Andean women at high
altitude show changes with pregnancy closely resembling those of normal pregnancy
in women residing at low altitude. Finally, among individuals, fetal growth as
shown by abdominal circumference in late gestation, is directly correlated with
46


uterine artery blood flow in week 20 of gestation, suggesting that patterns of growth
are established early in pregnancy.
Comparison to Low Altitude
In general, in normal conditions at low altitude pregnancy provokes an early
and dramatic change in maternal physiology. The Andeans in this study increased
uterine artery diameter early (by week 20), along with an early increase in flow,
followed by a steady rise in flow through the rest of pregnancy. This is similar to the
early (week 21) doubling of uterine diameter and gradual increase in uterine artery
flow velocity throughout gestation found by Palmer et al. (1992) and the seven-fold
increase in uterine artery blood flow by week 12 of gestation reported by Bernstein
et al. (2002).
Comparison to High Altitude
Although the Andeans of this study reside at high altitude, previously studied
populations at high altitude (predominantly of European descent) demonstrate
contrasting trends in pregnancy physiology. As mentioned above, at high altitude
compared with low altitude there is a lesser increase in vessel diameter, greater
increase in flow velocity, which results in a lesser increase in volumetric flow
(Zamudio et al., 1995a). Pregnancies with hypertensive complications at high
altitude showed increased uterine artery flow velocity early, with no further increase
47


through the rest of gestation, which resulted in no increased volumetric flow in the
later stages of pregnancy (Zamudio et al. 1995b). Thus, the large increase in uterine
artery diameter and flow presented here suggest that Andean patterns of vasculature
change during pregnancy more closely resemble those of low altitude, rather than
high altitude, Colorado residents.
Whereas European populations have lived at high altitude for an
evolutionarily short period of time, other populations such as Andeans and Tibetans,
have likely lived at high altitude for a longer period of time and are more likely to
have accumulated adaptations to the hypoxic environment. Compared with
Europeans, Tibetans showed a greater increase in uterine artery flow velocity, and a
subsequent increase in the UA/CI flow velocity ratio (Moore et al., 2001) (see Table
2.1), likely indicating a greater redistribution to the uterine artery in Tibetans. The
Andeans of this study, who have also lived at high altitude for a long period of time
(though likely shorter than that of Tibetans), seem to have a UA/CI flow velocity
ratio intermediate to Tibetan and normotensive Coloradan values and Han and pre-
eclamptic Coloradan values (see Figure 5.1, Colorado values combined in graph).
48


Birth weight, gm
3400
3300
3200
3100
3000
2900
2800
2700
2600
2500 -
3
Han Migrant,
3658 m
3.5 4 4.5 5
UA flow velocity/ Cl flow velocity
Figure 5.1 Redistribution of common iliac flow to uterine artery flow in Andean women in relation to birth
weight is lower than previously reported values for Tibetans and Coloradans, but higher than previously
reported values for Han migrants (modified from Moore et al. 2001).


Fetal Growth
Fetal abdominal circumference is correlated with uterine artery flow at week
20 but not at any other time point studied (Table 4.5), which suggests growth
restriction is established early in gestation. Both whole blood and plasma volume
peak around week 24 (e.g. Zamudio et al. 1993), which supports this idea.
Additionally, NOx levels peak and the ratio of endothelin to NOx reaches its lowest
level at about week 20 (Julian et al., 2004); and both of these variables correlate
significantly with birth weight (Moore et al., 2004).
Future Studies
While this study suggests that increased uterine artery blood flow leads to
greater oxygen delivery to the fetus, and may help to explain the greater birth
weights of Andean babies, a systematic comparison with non-high altitude native
groups living at a similar altitude needs to be performed. Additionally,
interpopulational comparisons such as these may lead to the discovery of population-
specific alleles that comprise the source of protection for IUGR in longer-resident
high altitude populations. Interpopulational comparisons have presented a new and
exciting avenue for genetic mapping that is cheaper and requires smaller sample
sizes than previously practiced methods, that also provides insight into selection at
the genomic level. This current study combined with these comparative
50


physiological and genetic studies can improve our understanding of human
evolution, modem human variation, and modem human physiology.
51


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