Download Renal and cerebral circularity reponses to hypoxemia in the ovine

University of Groningen
Renal and cerebral circularity reponses to hypoxemia in the ovine fetus
Braaksma, Margriethe Anna
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to
cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
1999
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Braaksma, M. A. (1999). Renal and cerebral circularity reponses to hypoxemia in the ovine fetus s.n.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 18-06-2017
Chapter
1
General Introduction
-VI-
2
Chapter 1
General Introduction
1.1 Intrauterine environment
1.2 Intrauterine growth retardation
1.3 Fetal adaptations to hypoxemia and the consequences
1.4 The fetal circulation
1.5 Fetal versus adult renal characteristics
1.6 Animal research on fetal hypoxemia
1.6.1 Renal and cerebral responses to hypoxemia
1.7 Blood flow measurement techniques
1.7.1 Microspheres
1.7.2 Electromagnetic flowprobes
1.7.3 Ultrasonic flowprobes
1.7.4 Doppler ultrasound
1.8 Aim and outline of the thesis
1.9 References
General Introduction
3
3
5
6
7
9
11
14
16
16
17
18
20
22
24
3
General Introduction
Undernutrition in utero is associated with cardiovascular and other diseases
in adult life. It has been suggested that abnormal programming in a critical
stage of fetal development is responsible for the adult disease, but the
mechanism has not been elucidated. Obviously, the placenta has a key role in
the transfer of nutrients and oxygen to the fetus and insufficient transfer by the
placenta is the most common cause of fetal undernutrition e.g. growth
retardation. The fetus, however, responds to undernutrition by a number of
short and long term adaptations. These adaptations include the cardiovascular
system, the central nervous system and the fluid regulation (kidneys). Many
of the fetal responses have been attributed to the hypoxemia which results
from the insufficient placental transfer. However, placental insufficiency not
only results in a reduced oxygen supply, but causes a reduction in the supply
and removal of a variety of substances from the fetus. Consequently, complex
changes occur in the ‘milieu interieur’of the fetus. This makes it practically
impossible to identify which factors are specifically responsible for the
adaptive changes in the various organ systems in the growth retarded fetus. In
the present study we aimed to unravel these mechanisms by studying the
effects of pure hypoxemia without all the accompanying disturbances resulting
from insufficient placental transfer. We focused on the circulatory adaptation
to sustained hypoxemia of the fetal kidney and the fetal brain, which are in
a critical stage of development in the near term ovine fetus.
1.1 Intrauterine environment
Growth and development of the mammalian fetus is a complicated
sequence of events. Fetal growth and development is mainly controlled by
genetic and environmental factors, the latter by altering the expression of fetal
genes.
The diversity of size and weight of babies born after normal pregnancies
is remarkable. Studies of the birthweight of relatives, together with evidence
from animal cross breeding experiments, have led to the conclusion that this
diversity is essentially determined by the intrauterine environment, and that
genetic factors play a relatively weak role (Desai and Hales 1997), as was
shown in the well-known experiments of Walton and Hammond (1938). In
4
Chapter 1
cross breeding between Shetland and Shire horses, foals were smaller at birth
when a Shetland pony was the mother than when a Shire horse was the
mother. Both crosses are genetically the same, which implied that the
Shetland mother had constrained the fetal growth. Studies of animals show
that the supply of nutrients and oxygen is one of the most relevant factors of
the intrauterine environment in determining the limits of fetal growth. In
humans, studies show that the degree of fetal growth constraint is actually set
when the mothers themselves are in utero, since low maternal birthweight was
the biological factor showing the highest risk associated with small babies
(Ounsted et al.1986).
Low birthweight for gestational age, disproportion between head and
abdominal circumference, disproportion between length and weight, and the
ratio between placental weight and birthweight, are markers for lack of
nutrients at particular stages of gestation (Barker 1997; Desai and Hales
1997). They reflect adaptations that the fetus made to sustain its development;
adaptations that, it seems, may permanently programme its physiology and
metabolism(King and Loke 1994; Barker 1997).
The process whereby disturbances at a critical or sensitive period can
modify early fetal development with possible long-term outcomes is called
programming. There are four essential principles which underlie the concept
of programming (Desai and Hales 1997):
1. Nutritional (or non-nutritional, such as hormonal signals during
critical periods) manipulations cause different effects at different times
in early life.
2. Rapidly growing fetuses and neonates are more vulnerable to these
manipulations.
3. Manipulation in early life has permanent effects.
4. The permanent effects include reduced cell numbers, altered organ
structure and resetting of hormonal axes.
Evidence for programming during critical periods of development in animals
dates back over 100 years ago (Spalding 1873). One of the classical examples
is the exposure of female rats at a critical period of fetal life to a single dose
of exogenous testosterone, which reorientates sexual behaviour of these
animals permanently (Ounsted et al. 1986).
Events that subtly retard intrauterine growth may determine common
disorders, such as hypertension (Dennison et al. 1997) and non-insulindependent diabetes (Seckl 1997), raised serum cholesterol, abnormal blood
clotting and autoimmune diseases in adult life (Kannisto et al. 1997).
General Introduction
5
Recently, it was found that asymmetrical growth retardation is associated
with a substantial reduction in the number of nephrons, and that there is no
postnatal compensation for this (Hinchcliffe et al. 1992). Furthermore, a
prospective study on preterm infants has shown that a brief period of early
dietary management (formula feed verses human milk) has a major impact
about 8 years later on brain growth, neurodevelopment and bone
mineralization, in that human milk promotes these processes (Desai and Hales
1997). It is not that surprising that especially neuronal and renal processes are
candidates for programming during fetal life, since at birth virtually all brain
neurons and renal glomeruli are already present (Hinchcliffe et al. 1991).
There is considerable evidence now that undernutrition during prenatal life
may have lifelong consequences (Gluckman 1993), indicating that lifespan is
at least partially determined before birth (Barker 1995). Therefore, fetal
growth retardation should be considered a major focus for those interested in
reducing morbidity in adult life.
1.2 Fetal growth retardation
Fetal growth depends on a stable supply of oxygen and other nutrients
from the mother. Impairment of the uteroplacental and/or the fetoplacental
circulation has been reported to cause chronic hypoxia in the fetus, which
results in fetal growth retardation (or intrauterine growth retardation (IUGR)),
fetal distress (Block et al. 1984; Mori et al. 1993), and possibly preterm labor
(Valenzuela et al. 1992).
IUGR occurs in ~3% of all human pregnancies and is associated with a
significant increase in both perinatal morbidity and mortality (Hooper et al.
1991; Kamitomo 1993). Although multiple etiologies of IUGR exist, many are
associated with limited nutrient and oxygen delivery to the fetus (Lueder et al.
1995). For example, umbilical cord occlusion, maternal cigarette smoking,
and reduced uteroplacental circulation all result into fetal hypoxia (Hooper et
al. 1990).
Oligohydramnios, a shortage of amniotic fluid, is often associated with
chronic fetal hypoxia as found in IUGR, suggesting that hypoxia affects the
fetal fluid balance (Wlodek et al. 1993).
Such a decrease in amniotic fluid is associated with an increase in fetal
morbidity and mortality (Veille et al. 1993). Animal research revealed that
oligohydramnios causes an increase in spinal flexion, leading to compression
6
General Introduction
Chapter 1
of abdominal content, upward displacement of the diaphragm, and loss of lung
liquid due to lung compression (Harding et al. 1990).This impairs fetal lung
development, and can result in permanent lung hypoplasia, in particular when
oligohydramnios is present in early pregnancy.
1.3 Fetal adaptations to hypoxemia
and the consequences
The plasticity of the fetus enables it to adapt itself to life threatening
events. In case of acute hypoxemia, the fetal circulation is rearranged in such
a way that oxygenated blood is preferentially distributed to the cerebral
circulation, to the heart and to the adrenal glands (Block et al. 1984; Jensen
et al. 1987; Rudolph 1984; Jensen and Berger 1991), a phenomenon called
‘centralization’ or ‘brain sparing’. The influence of the mother and/or
placenta in this centralization is thought to be of minor importance, but
difficult to proof. Recently, Mulder et al. reported that fertilized eggs respond
to hypoxia in the same way as the mammalian fetus, in that the cardiac output
is redistributed to the most vital organs in the chick embryo. This all happens
without any influence of the mother (Mulder et al. 1998).
In the adult human the cardiovascular responses to hypoxia appear to be
caused largely through the activity of the sympathetic part of the autonomic
nervous system. In some species adrenal secretion of catecholamines
influences the response to hypoxia, and may be as important as enhanced
sympathetic nerve activity. Because sympathetic innervation in the fetus is
incomplete, tissues such as the heart have a supersensitivity to exogeneous
catecholamines (Jones et al. 1988). It is known that acute fetal hypoxemia
causes substantial changes in the fetal endocrine status: the plasma
concentrations of epinephrine, norepinephrine (Jones and Robinson 1975),
arginine vasopressin (AVP) (Wlodek et al. 1995), adrenocorticotropic
hormone (ACTH), and cortisol (Bocking et al. 1986) increase. All of these
responses presumably aid the fetus in surviving hypoxia (Hooper et al. 1990).
The growth-retarded fetus is thought to maintain a degree of redistribution
of oxygenated blood similar to that of a normal fetus exposed to acute
hypoxemia (Block et al. 1984). A consequence of this chronic redistribution
of blood flow is that other organs and tissues, that are less vital for intrauterine survival, such as the lungs, the skin and the carcass get a reduced
7
blood supply. Hence, growth and development of these organs is impaired.
The development of oligohydramnios in IUGR is explained by the presumed
decrease in renal blood flow leading to a decreased glomerular filtration rate
(GFR) and hence decreased fetal urine production rate (Chevalier 1996).
However, the precise mechanism leading to the decrease in amniotic fluid
during IUGR has not been clarified. Indeed, in the growth retarded human
fetus urine production rate is reduced, although overall data on fetal urine
production rate are not univocal (Nicolaides et al. 1990; Wladimiroff and
Campbell 1974; Oosterhof 1993). Doppler ultrasound studies on renal blood
flow in the human fetus, estimated by flow velocity waveforms of the renal
artery, show conflicting results (Arduini and Rizzo 1991; Vyas et al. 1989;
Oosterhof 1993).
It is becoming more and more apparent that survival of premature infants
weighing less than 1000g is related in part to a good understanding of the
limitations imposed by the immature kidney (Robillard et al. 1989). Since the
survival of these infants has increased dramatically over the past two decades,
knowledge of developmental renal physiology has assumed heightened clinical
relevance (Avner 1990).
1.4 The fetal circulation
In the fetus there are several vascular shunts to meet with the different
circulation of oxygenated blood compared with the adult situation: during
intrauterine life, the placenta serves as the site of gas exchange rather than the
lungs (Fig.1). The most important features of the fetal circulation are the
relatively large proportion of the combined output of both cardiac ventricles
distributed to the umbilical cord and the placenta and the small proportion
distributed to the lungs (Jensen and Berger 1991). This requires special
vascular channels: the ductus venosus, the foramen ovale and the ductus
arteriosus. The ductus venonus is a relatively large vessel through which a
large part of the umbilical venous return bypasses the liver tissue, and is
delivered straight to the fetal heart. In the heart itself, the foramen ovale is
shunting well-oxygenated inferior caval blood from the right to the left atrium,
without passing through the lungs. Blood from the right ventricle, flowing
towards the relatively high-resistance pulmonary circulation is bypassed into
the systemic arch via a short but large-diameter blood vessel, the ductus
arteriosus (Mott 1982).The fetal circulation is not only anatomically different,
8
Chapter 1
General Introduction
it also works under conditions very different from those found in adult
mammals. Arterial pressure is low and similar in all circuits, and systemic
arterial blood gas tensions are asphyxial compared to the adult standards.
9
small kidneys (about 1% of total body weight in humans) receive a remarkable
large amount of blood, carrying about 20-25% of the total cardiac output
(Eckert and Randall 1983), or about 1.2-1.3 l/min (Guyton and Hall 1996).
Kidney blood flow in the near term fetus is much less, estimated as 2 -4% of
the combined ventricular blood output in last trimester of gestation. In the
fetal sheep, renal blood flow is in the order of 1.5 to 2.0 ml·min-1·g-1 kidney
weight (Aperia et al. 1977; Robillard et al. 1981a) in this period of gestation.
1.5 Fetal versus adult renal characteristics
Figure 1. The fetal and placental
blood circu-lation (Silbernagl and
Despopoulos 1981).
Quantitative information about the fetal circulation has been acquired
almost entirely from the fetal lamb in the last one-third of gestation. About
60% of the combined cardiac output goes to the oxygen-consuming circuits of
the fetal body, and 40% to the umbilical circulation (Mott 1982). Under
control conditions, the umbilical vessels, which are widely patent in utero,
transport blood at 200 ml·kg-1·min-1 at an arterial blood pressure of 40-50
mmHg. The average cerebral blood flow is100-200 ml·100 g-1· min-1 at PO2
and CO2 values in the normal fetal range, which is 2 to 4 times higher than
in adult humans (53 ml·100 g-1· min-1). The pulmonary circulation receives
5-6% of the combined cardiac output (Mott 1982). In the adult, the relatively
Nephrogenesis begins at 8 weeks of gestational life and continues until 34
weeks in humans (Peters et al. 1992; McGory 1972). During nephrogenesis,
morphological and functional differentiation of nephrons happens
centrifugally. Nephrons at the inner cortex are perfused to a greater
proportion, and are more differentiated morphologically compared to the
nephrons located in the outermost region of the cortex (Kahane et al. 1995;
Lumbers 1995). Renal tubular maturation begins in the late first trimester, and
continues after birth (Peters et al. 1992).
As describe above, the blood flow to the adult kidney is much higher than
during fetal life. In the adult situation, the blood flow in the renal cortex (4-5
ml· g-1· min-1 kidney tissue) is much greater than in the medulla (0.3-2 ml·min1 -1
·g ). However, even the medullary flow is relatively large on a tissue weight
basis. For comparison, the normal blood flow to the adult brain is 0.5 ml· min1 -1
· g (Guyton and Hall 1996). In the fetal situation, this distribution of blood
flow per tissue weight between the brain and kidney is practically the same (12 ml/min/g ). Within 48 hours of delivery, renal blood flow increases by an
amount disproportionate to the rest of the body, primarily due to decreased
vascular resistance. This increase in RBF is critical to the emergence of the
kidney as the organ responsible for the maintenance of body fluid homeostasis
(Corey and Spitzer 1992).
The mature kidney is capable of maintaining a relatively constant renal
blood flow despite alterations in perfusion pressure over a range of 80-150
mmHg. This autoregulation is thought to be operable in the fetus also, despite
the much lower perfusion pressure to which the fetal kidney is exposed (40-60
mmHg) (Smith 1982).
Since the time of Hippocrates, it has been recognized that the fetus
produces urine (Needham 1931), which contributes substantially to the
10
Chapter 1
accumulation of amniotic fluid (Robillard et al. 1989; Ervin et al. 1986). Since
the maintenance of amniotic fluid volume within the normal range is
important for promoting fetal well-being (Brace and Wolf 1989), regulation
of the extracellular fluid volume by the immature kidney is of major
importance (Avner 1990). Without sufficient amniotic fluid, the development
of the fetal lung, limb and gut may be impaired, sometimes to the point where
life after birth is not possible (Lumbers 1995). So, in contrast to the adult
kidney, the fetal kidney plays an essential role in providing the environment
that surrounds the fetus (Lumbers 1983).
Research on the possible factors influencing the production of urine by the
fetal kidney were invesitgated in anesthetized fetal sheep more than 40 years
ago (Alexander et al. 1958). In fetal sheep, urine passes into the amniotic
cavity through the urethra and into the allantoic cavity through the urachus.
In the human, the allantois normally degenerates early in gestation so that
fetal urine flows only into the amniotic fluid cavity (Campbell et al. 1973).
During fetal life glomerular filtration rate (GFR) is low (1.4 ml min1 kg1)
compared to the mature kidney (2.4 ml min-1 kg-1) (Robillard et al. 1989;
Lumbers 1995), and urine is rather hypotonic to plasma (Ervin et al. 1986).
Furthermore, the regulation of the fluid balance in the fetus is substantially
different from that in the adult; the late-gestation fetus urinates and drinks a
volume equal to 20-30% of body weight per day, whereas comparable values
in the adult are 2-3 % of body weight per day (Brace 1989).
Despite the lower renal perfusion pressure and the higher renal vascular
resistance, the filtration fraction (FF) is not significantly different from the
adult (Lumbers 1995), although the total filtering capacity, as seen in the
mature kidney, is by far not yet reached. It is important to recognize that the
principal activity of the fetal kidney is growth and development, and that the
placenta is the chief homeostatic organ during intrauterine life (Aperia et al.
1977).
Since renal tubular maturation is a continuing process which goes on after
birth, it is not surprising that the fetal kidney is not yet capable of
concentrating urine, representing only 20-30% of the adult potential
(Robillard and Nakamura 1995). Furthermore, it is suggested that the
structural immaturity of the medulla, characterized by a short loop of Henle
and a the relatively high blood flow to the inner nephrons and medulla, may
limit the build-up of an osmotic gradient (Robillard and Nakamura 1995).
During development, certain functional characteristics become apparent
within a relatively short period of time, which are seen as “critical periods”
General Introduction
11
(Solomon 1982). Developmental changes of the kidney are associated with a
change in regulation rather than in renal function per se. For example, in the
sheep fetus, it has been shown that the capacity of the immature kidney to
secrete H+ is not a limiting factor in urinary acidification, but instead some
regulatory component is absent (Solomon 1982). Also, the antidiuretic
hormone, vasopressin (AVP) is present in fetal animals and as early as the 11th
week of gestation in the human, and is capable of concentrating the fetal
urine. However, vasopressin is shown to have less effect on the fetal nephron
compared to the adult kidney (Robillard et al. 1982).
1.6 Animal research on fetal hypoxemia
Through the years, much research has been done on the fetal responses to
asphyxia/hypoxemia. The early studies focused on short, acute and severe
forms of hypoxemia, in animals under general anaesthesia. In the late 1960s,
the first studies on fetuses in utero after recovery from surgery and anaesthesia
were performed, using chronic implantation of catheters and probes (Jensen
and Berger 1991). There are few species apart from the sheep in which it is
possible to perform the chronic instrumentation necessary to study the
development of fetal responses. Small laboratory animals such as the rat and
guinea pig are just too small, and other farm animals, such as the pig, have
large numbers of fetuses (Cheung and Brace 1988).
The results of the reported studies on fetal responses to hypoxemia are
difficult to compare, because of the great variety in methods used to apply
hypoxia: the severity, duration, mode of induction, and whether or not
concomitant changes in arterial pH and PCO2 occur, show considerable
variations (Robillard et al. 1981). Furthermore, the techniques used to
measure blood flow during fetal hypoxemia also differs.
Fetal hypoxia can be induced by reducing arterial oxygen content, by
restricting uterine blood flow, or by reducing umbilical blood flow by cord
compression. While maternal hypoxemia only reduces oxygen supply to the
fetus, reducing uterine or umbilical blood flow also interferes with fetal PCO2
elimination as well as with energy substrate supply to the fetus (Rudolph
1984).
Mat. O2
130-145
1979 Millard et al.
1979 Peeters et al.
1981 Robillard et al. 106-141
1985 Iwamoto et al. 124-133
40min
30 min
1h
10 min
24 h
132
128-135
124-132
125-130
125
110-113
late
gest.
127
115-129 RUBF
115-129
1990 Rurak et al.
1990a Rurak et al.
1990 Block et al.
1991 Arnold-Aldea
et al.
1993 Wlodek et al.
1994 Asano et al.
1994 Brace et al.
1994 Cock et al.
1995 Wlodek et al.
/
/
24 h
24 h
24 h
8h
24 h
/
/
/
/
microshperes
-
-
-
-
microspheres
-
microspheres
microspheres
microspheres
microspheres
microspheres
microspheres
microspheres
1997 Cock et al.
120-140 pl. embol. 20 days
CBF, cerebral blood flow; RBF, renal blood flow; UFR, urine flow rate; GFR, glomerular filtration rate; RVR, renal vascular
resistence; Technique, method used to measure blood flow.
122-138 RUBF
Mat. O2
RUBF
Mat. O2
Mat. O2
RUBF
20-25min
>20 min
Mat. O2
+ RUBF
Mat. O2
20 min
8h
8h
3h
Mat. O2
Mat. O2
Mat. O2
Mat. O2
/
microspheres
microspheres
pulsed Doppler
flowmeter
microshperes
Chapter 1
1996 Cock et al.
24 h
127-135
1989 Wlodek et al.
48 hrs
127 d
1988 Bocking et al.
RUBF
123-127 cord occl. 4-5 min
1987 Itskovitz et al.
arrest UBF 4 min
40 min
130
Mat. O2
1986 Robillard et al. 125-141
30 min
1987 Jensen et al.
Mat. O2
microspheres
microspheres
microspheres
microspheres
e.m. flowmeter /
Doppler Ultrasound
-
microspheres
b)
e.m. flowmeter
Technique
microspheres
/
pHa PaCO2 CBF RBF UFR GFR RV
R
4-44 min a)
arrest UBF 4 min
Mat. O2
Mat. O2
1985 Nakamura et al. 132-143
130
Mat. O2
125-140
1975 Daniel et al.
1985 Jensen et al.
109-130 cord occl. 60 min
Mat. O2
122-142
1974 Cohn et al.
cord occl. 15-45sec
138
1972 Dunne et al.
duration
fetal age method
(days)
Reference
Table I. Brief overvieuw of hypoxemia studies on fetal lambs, regarding renal blood flow and function and cerebral blood flow.
HYPOXEMIA
12
General Introduction
13
14
Chapter 1
1.6.1 Renal and cerebral responses to hypoxemia
Table I shows an (incomplete) overview of fetal studies on renal and
cerebral blood flow and urine flow rate, in response to hypoxemia, which have
been published over the last 25 years. In the first experiments on fetal sheep,
the hypoxemic condition lasted no longer than several minutes. Durations of
30 min were considered as a chronic situation. However, it became more and
more clear that in human pregnancy the most harmful effects were the result
of chronic fetal hypoxemia instead of acute hypoxemia. Therefore, chronic
hypoxemia studies with a duration of several hours, became more and more
in favour (Hooper et al. 1990).
Acute hypoxemia, no matter how it is induced, is associated with
bradycardia and increased blood pressure, the latter being more pronounced
in case of severe hypoxemia (Cohn et al. 1974). Also, fetal body movements
and breathing movements are decreased during the hypoxemic insult. Acute
hypoxemia induces large increases in stress hormones such as catecholamines
which are known to rise 50-100 fold in the hypoxic ovine fetus, and 50 fold
increases in vasopressin (Jones et al. 1988). Increases in cortisol and
adrenocorticotropic hormone (ACTH) are also seen (Hooper et al. 1990).
During chronic hypoxemia (lasting several hours to days), fetal body
movements and heart rate gradually return to control levels, but the initial
redistribution of cardiac output is, in part, sustained. In addition, plasma
concentrations of ACTH decline to near control levels (Challis 1986; Hooper
et al. 1990), cortisol has either the tendency to decrease (Challis 1986) during
the course of hypoxemia, or, together with prostaglandin E2 concentrations,
remains elevated (Hooper et al. 1990). Norepinephrine remains elevated
throughout the hypoxic period, while epinephrine and AVP concentrations
return to control levels during course of hypoxemic period.
Studies in which a large decrease in fetal renal blood flow was found
during hypoxemia, concern situations with severe hypoxemia, lasting for
minutes to several hours, and were usually accompanied by progressive
acidemia. Other studies show that during hypoxic periods of 120 min to 24 h
in duration, no changes are seen in renal blood flow compared to control
values (Wlodek et al. 1989; McLellan et al. 1992). If the hypoxemia is severe,
a decrease in renal blood flow is reported (Daniel 1975), while in case of mild
hypoxemia with a duration of 48 h an increases in renal blood flow was seen
(Bocking et al. 1988).
General Introduction
15
It has been shown for various organ systems that the responses of the fetus to
acute and chronic hypoxemia are different (Jensen and Berger 1991; Iwamoto
and Rudolph 1985). Furthermore, it is important to distinguish hypoxemia
with and without acidemia: hypoxemia accompanied by acidemia causes a
decrease in fetal renal blood flow (Rudolph 1984; Cohn et al. 1974), whereas
fetal renal blood flow remains constant or increases when acidemia is absent
(Bocking 1988; Towell et al. 1987; McLellan et al. 1992). Another factor
influencing the fetal responses to hypoxemia is an elevated arterial PCO2
level. Hypercapnia itself is known to reduce fetal renal blood flow by
increasing resistance to flow (Beguin et al. 1974). The reduction in fetal renal
blood flow during acidosis and hypercapnia is essentially reflex mediated
(Beguin et al. 1974). This indicates that many factors concomitant with the
induced hypoxemia have their reflect on the renal response to decreased
arterial oxygen levels.
Data on fetal urine flow during hypoxemia are also inconsistent throughout
the literature, again probably due to differences in methods of inducing
hypoxia and the duration and severity of hypoxia. Acute fetal hypoxemia,
induced by lowering the inspired oxygen concentration of the ewe, caused
fetal urinary output to decrease (Nakamura 1985; Robillard 1981). During the
fall in urine flow found during acute or short periods (30 min) of hypoxemia,
fetal glomerular filtration rate (GFR), filtration fraction (FF) and free water
clearance (CH2O) decreased while urine osmolality and osmotic clearance
(Cosm) increased (Robillard et al. 1986; Nakamura 1985; Robillard 1981).
Fetal hypoxemia induced by reducing uterine blood flow resulted in an
increase in fetal urine production after an initial fall in urine flow (Cock et al.
1994; Wlodek et al. 1995). Chronic hypoxemia (a 3-h period) with progressive
acidemia produced a fetal diureses starting during the third hour of hypoxia.
A 24-h hypoxia period however, started with a 2-3 h antidiuresis followed by
a urine flow return to normal levels by 6 h hypoxia (Brace et al. 1994; Wlodek
et al. 1995).
Cerebral blood flow increases during acute and chronic hypoxemia, but the
mode of hypoxemia induction and the severity again influence the degree of
increase. Maternal hypoxemia leads to an increase in fetal cerebral blood flow
(76 % increase) (Cohn et al. 1974), and calculations of the oxygen delivery to
the brain during these circumstances shows a 40 % increase (Rudolph 1984).
16
Chapter 1
1.7 Blood flow measurement techniques
From Table I it is obvious that there is great variety in fetal blood flow
responses to hypoxemia. This can be partly explained by the way hypoxemia
was induced, the severity, and the duration of the hypoxic period. However,
yet another point of difference between the studies needs attention, that is the
way of measuring blood flows to the fetal organs of interest.
The most commonly used technique to study blood flow in fetal organs is
radiolabelled microspheres. This technique allows blood flow studies of many
fetal organs, but only intermittently at few time points during a study.
Electromagnetic and ultrasonic flowprobes have the advantage that
recordings can be made continuously, and for the entire duration of the study.
The disadvantage is that only the blood flow to a specific organ can be
measured, and that the probes have to be implanted.
Doppler-ultrasound is non-invasive, but has the disadvantage that not the
blood flow itself but the blood velocity in a particular vessel is measured. A
brief overview of the different techniques is described below.
1.7.1 Microspheres
Injections of indicators of different types into the intravascular
compartment has been applied for the study of the circulation for many years.
Solid foreign particles have been used as indicators to measure distribution of
organ blood flow, distribution of cardiac output, and the presence of shunting
through various organs. The ability to label these particles with radio nuclides
makes them therefore easily detectable or quantified.
The most commonly used nuclide-labelled microspheres are made of an
inert plastic. The nuclide is incorporated into the plastic, and therefore the
number of counts per minute determined will be related to sphere volume. The
micropheres are trapped in the arteriolar or capillary vascular system on the
first circulation after injection. In order to measure organ blood flow, the
microspheres must be well mixed at the site of the injection and their
concentration in all arteries downstream from the site of injection should be
similar. Distribution of the micropheres will then be similar to the distribution
of blood flow to the organs. It is essential that when measuring flow, the
number of micropheres injected be carefully calculated to satisfy the criteria
for the organ or portion of organ with the lowest flow that is to be measured.
General Introduction
17
A further prerequisite for the use of microsheres to measure distribution of
blood flow is that all microspheres are entrapped in the peripheral
microcirculation and that no significant number bypass the organs. To
quantitate the organ blood flow, the most common method used is that of a
surrogate organ flow known as the reference sample technique. Before,
during, and after injection of the micropheres, blood is collected from an
artery at a constant rate. The volume of the blood withdrawn is not critical as
long as more than 400 microspheres are present. Flow to any organ can now
be calculated using the relationship:
Unknown organ flow
(ml/min)
known organ flow (ml/min) * No. of microspheres in organ with unknown flow
=
---------------------------------------------------------No. of micropheres in organ with known flow
where the “known” organ is the reference sample (Heymann et al. 1977).
A disadvantage of the use of microspheres to measure blood flow is that
only a limited number of measurements can be made during a study period in
one and the same animal. The use of color “coded” micropheres instead of
radio-nuclide labeling is an attractive alternative which allows to take
measurements at more different time points during a study period.
1.7.2 Electromagnetic flowprobes
Electromagnetic flowprobes are one of the possibilities to measure blood
flow continuously.
When a magnetic field is applied at right angles to the direction of motion
of a conduction fluid, a potential difference is set up at right angles to both the
flow direction and the magnetic field. Fabre (1932) suggested that blood flow
could be measured using electromagnetic flowmeters and Kolin (1936)
showed results from in vitro measurement on an isolated carotid artery.
Wetterer (1937) developed a flowmeter independently of Kolin and published
results from in vivo measurements on the rabbit aorta (Woodcock 1975).
There are several different types of electromagnetic flowmeter, differing
from each other in the way the magnetic field is produced. However, there are
basically two main types, namely, the direct current and the alternating
current flowmeters. Early electromagnetic flowmeters were all direct current
instruments. In general, the advantages of alternating current excitation of the
18
Chapter 1
magnet are, first, that electrode polarization is avoided, and second, it is easier
to amplify alternating current signals than direct current and consequently
they can be used to measure very low flows. Clark and Wyatt (1969) dicuss the
design of electromagnetic flow probes and distinguish three main categories:
1) perivascular, 2) cannular, and 3) intravascular probes (Woodcock 1975).
Although continuous measurement of blood flow is possible, there are
some factors that can disturb the blood flow measurement. First, for optimal
performance the diameter of the cuff- type probe should be 10 % smaller than
the outside diameter of the blood vessel, which reduces the vessel diameter
and moreover may result in vessel contractility. Second, the influence of
haemoglobin concentration on blood flow measurement can be relatively
large. Third, calibration of electromagnetic probes is preferably performed in
vivo, and fourth, the wall of a blood vessel can influence the measurement in
case the wall is pathologically thickened and in whether there is insulation
around the vessel.
1.7.3 Ultrasonic flowprobes
Another method to measure blood flow continuously and instantaneously
is by means of ultrasound flow probes. This technique for measuring fluid
velocity depends on the difference in phase between the emitted wave and a
wave traveling opposite to or in the same direction as the fluid. This phase
difference is proportional to flow.
Kalmus developed a more refined flow velocity meter which consisted of
two transducers switched alternately to emitter and receiver at a rate of 10 Hz
(Woodcock 1975).
These flowprobes use an ultrasonic transit-time principle to sense liquid
volume flow in vessels or tubing largely independent of flow velocity profile,
turbulence and hematocrit. The method and theory of operation of nowadays
used ultrasonic flowprobes is as follows:
The flowprobe consists of a probe body which houses two ultrasonic
transducers and a fixed acoustic reflector bracket. The ultrasonic transducers
are situated on one side of the vessel/tube under study and the reflector bracket
is situated equidistant between the two transducers on the opposite side of the
vessel or tube. Both transducers, transmit a plane wave of ultrasound of a
minimal level which intersects the flowing liquid in upstream and downstream
direction, bounces off the “acoustic reflector”, again intersects the vessel in
General Introduction
19
Figure 2.1. a) Schematic views of the perivascular Transonic© ultrasoni c
volume flowsensor. Two transducers pass ultrasonic signals back and forth ,
alternately intersecting the flowing liquid in upstream and downstrea m
direction. The difference in travel time of the upstream and downstream signals
is a measure of volume flow (Transonic manual 1991). b) Actual view of the type
of flowprobe used in our studies.
either the upstream or downstream direction and is received by the opposing
transducer where it is converted into electrical signals. The flowmeter then
analyzes and records the signals as an accurate measure of the “transit-time”
it took for both waves of ultrasound to travel from one transducer to the other.
The downstream transit time is then subtracted from the upstream transittime, and the difference is a measure of volume flow.
One ray of the ultrasonic beam records phase shift in transit time
proportional to the average velocity of the liquid and the path length over
which this velocity is encountered. With wide-beam ultrasonic illumination
, the receiving transducer integrates these velocity-vessel chord products over
the vessel’s full width and yields an average velocity time vessel inside area.
The rays of the ultrasonic beam which cross the acoustic window without
intersecting the vessel do not contribute to the volume flow integral. Volume
flow is therefore sensed even when the vessel is much smaller than the
acoustic window and is independent of the flow velocity profile. Misalignment
of the vessel within the probe, has little consequence for the flow measurement
because of the ultrasonic wave’s reflective pathway, whereby the sum of
vector components of the flow does not change. (Transonic flowmeters 1991).
20
Chapter 1
1.7.4 Doppler ultrasound
Blood-velocity waveforms can be transcutaneously recorded using the
ultrasonic doppler-shift (Woodcock 1975). Doppler ultrasound therefore offers
a noninvasive technology for investigating the circulatory system. Doppler
velocimetry has been extensively used to investigate fetal, fetoplacental, and
uteroplacental circulations vin the human. Doppler velocimetry requires a
comprehensive analysis of the Doppler signal involving applications of
advanced technology with varying degrees of complexity and sophistication
(Maulik,1995).
The method is based on the following principle: When a beam of energy
waves encounters a reflector smaller than its wavelength, the incident energy
waves are reflected in all directions, known as scattering. A portion of the
scattered energy will be reflected back to the source, known as backscattering.
This phenomenon is also observed when an ultrasound beam intersects blood
flow in a vessel (Shung 1976). In blood, the primary sources of ultrasonic
scattering are the circulating red blood cells. The moving red cells also cause
Doppler shift of the scattered ultrasound. The shift is proportional to the
velocity of red cell movement.
For flow quantification, instantaneous flow can be measured by integrating
the mean velocity across the vascular lumen with the vascular cross-sectional
area. However, the clinical usefulness of Doppler velocimetry for
quantification of flow is limited as it suffers from several sources of error
(Gill, 1985). One of the critical concerns is the accuracy of measuring the
vascular cross-sectional area, especially of the smaller fetal vessels. As
estimation of the cross-sectional area involves squaring the radius, any error
in measuring the vessel diameter is significantly amplified in the calculation
of volume flow. Another important source of inaccuracy is the error in
determining the angle of sonification.
Because of the problems related to volume flow measurement, there has
been a need to seek alternative ways for investigating vascular flow dynamics
using the Doppler method.
Techniques have therefore been developed for analysing the Doppler
frequency shift waveform in an angle-independent manner. Most of these
analytic techniques involve deriving Doppler ratios from the various
combinations of the peak systolic, end-diastolic and temporal mean values of
the maximum frequency shift envelope. Because these parameters are taken
from the same cardiac cycle, these ratios are virtually independent of the angle
General Introduction
21
of sonification (Maulik, 1995).
The maximum Doppler frequency shift waveform represents the temporal
changes in the peak velocity of the red cell movement during the cardiac
cycle, and is therefore under the influence of both upstream and downstream
circulatory factors (McDonald, 1974). The pulsatility of the flow velocity was
originally investigated using Doppler ultrasound in the peripheral vascular
system. Gosling and King were the first to develop the pulsatility index (PI)
as a measure of the systolic-diastolic differential of the velocity pulse (Gosling
1975). A simplification of the PI, namely the peak-to-peak PI was introduced
based on the peak systolic frequency shift, the end-diastolic frequency shift,
and the temporal mean frequency shift over one cardiac cycle. The PI is
presumed an index of vascular impedance downstream.
Vascular resistance is based on the Poisseuille equation:
vascular resistance = mean arterial pressure - mean venous pressure divided
by blood flow. However, the formula is applied for steady-flow resistance
calculations and may be unreliable in a pulsatile flow system (Milnor,1972).
Pulsatile flow and pressure are generated by cardiac contraction, and the
pulsatility at a given point in the vascular bed is determined by the elasticity
of the vessel walls, the distribution of the length and diameter of the vessels
throughout the vascular bed and the degree of wave reflection. Wave
reflections are created by the non-uniform elasticity of the vessels and by the
change of vessel diameter and the total cross-section of the bed at each point
of branching (McDonald, 1974).
Noninvasive Doppler is still the only option to the physician to monitor the
human fetal circulation, and although much information about fetal blood flow
characteristics can be obtained, the Doppler technique does not give
quantitative information on blood flow. Furthermore, Increased vascular
resistance indicates increased dissipation of the energy of blood flow within
the vascular bed, but it does not identify the nature, cause or exact site of this
increase (Maulik, 1995).
22
Chapter 1
1.8 Aim and outline of the thesis
Since there is a close relationship between the degree of growth retardation
and perinatal morbidity and mortality, fetal growth retardation (FGR) is of
major clinical concern. One of the causes of FGR is placental insufficiency,
leading to a situation of chronic fetal hypoxemia, which is often accompanied
by a decreasing amount of amniotic fluid, resulting in oligohydramnios. This
shortage in amniotic fluid is ascribed to a reduction in fetal urine flow as a
consequence of reduced renal blood flow. The presumed reduction in renal
blood flow is thought to be the result of the redistribution of the cardiac output
due to hypoxemia. However, experimental and clinical data on renal blood
flow in the hypoxemic fetus do not show conclusive evidence. Therefore, the
aim of the thesis was to study the responses of the renal physiology to chronic
fetal hypoxemia without acidemia and hypercapnia.
Since urine production rate in the human fetus was found to be dependent
on behavioral states, we first studied whether in the ovine fetus this was also
the case (Chapter 1). During hypoxemia, fetal behavioral states change
towards a higher percentage of high-voltage electrocortical activity (HVECoG). Changes in fetal urine production rate during hypoxemia could
therefore be the consequence of behavioral state changes, rather than changes
in fetal renal blood flow and physiology. Secondly, we studied the daily
rhythm of fetal urine production rate and fetal renal blood flow (Chapter 2)
to exclude the possibility to measure normal variances, in stead of changes due
to chronic fetal hypoxemia. With this information in mind we studied fetal
renal blood flow and renal function during 48 hours of isocapnic moderate
hypoxemia (Chapter 3). These were strictly time dated studies in order to
diminish the effects of daily rhythms. Finding a very quick response of the
fetal renal blood flow to hypoxemia, we studied the fetal renal and cerebral
blood flow responses during contractures, the latter representing spontaneous
short periods of mild to moderate fetal hypoxemia (Chapter 4). The finding
that during these short periods of hypoxemia the cerebral blood flow showed
a decrease instead of a maintenance or increase in blood flow for
compensation of decreased oxygen saturation and increased carbon dioxide,
prompted us to study the response time of renal blood flow and cerebral blood
flow during the onset of hypoxemia (Chapter 4). The possible influence of
chronic moderate hypoxemia on the developing fetal brain was studied in
Chapter 5. Most studies on hypoxemic influences on the fetal sheep brain
General Introduction
23
concern conditions of severe and acute hypoxemia, and consequently brain
lesions. We looked for more subtle changes during chronic moderate
hypoxemia without acidemia in the developing ovine brain using
immunochemical staining technique for protein kinase C (PKC ), known
for its multifunctional role in neurons. We studied one of the most vulnerable
brain areas to hypoxemia, namely the hippocampus, for changes in PKC
staining.
The gestational age of the fetuses during these studies (123-128 days) is
known as a period in which both cerebral and renal development and function
undergo major maturational changes.
24
Chapter 1
1.9 References
Alexander, D. P. and et al. Renal function in the sheep foetus. J Physiol
(London) 140: 141958.
Aperia, A., O. Broberger, P. Herin, and I. Joelsson. Renal hemodynamics
in the perinatal period. A study in lambs. Acta Physiol Scand 99: 261-269,
1977.
Arduini, D. and G. Rizzo. Fetal renal artery velocity waveforms and amniotic
fluid volume in growth-retarded and post-term fetuses. Obstet Gynecol
370: 370-373, 1991.
Arnold-Aldea, S. A., R. A. Auslender, and J. T. Parer. The effect of the
inhibition of prostaglandin synthesis on renal blood flow in fetal sheep.
Am J Obstet Gynecol 165: 185-190, 1991.
Asano, H., J. Homan, L. Carmichael, S. Korkola, and B. Richardson.
Cerebral Metabolism During Sustained Hypoxemia in Preterm Fetal
Sheep. Am J Obstet Gynecol 170: 939-944, 1994.
Avner, E. D. Polypeptide growth factors and the kidney: A developmental
perspective. Pedriatr Nephrol 4: 345, 1990.
Barker, D. J. P. The fetal and infant origins of disease. Eur J Clin Invest 25:
457-463, 1995.
Barker, D. J. P. Fetal nutrition and cardiovascular disease in later life. Br
Med Bull 53: 96-108, 1997.
Beguin, F., D. R. Dunnihoo, and E. J. Quilligan. Effect of carbon dioxide
elevation on renal blood flow in the fetal lamb in utero. Am J Obstet
Gynecol 119: 630-637, 1974.
Block, B. S. B., A. J. Llanos, and R. K. Creasy. Responses of the
growth-retarded fetus to acute hypoxemia. Am J Obstet Gynecol 148:
878-885, 1984.
Block, B. S., D. H. Schlafer, R. A. Wentworth, L. A. Kreitzer, and P. W.
Nathanielsz. Intrauterine asphyxia and the breakdown of physiologic
circulatory compensation in fetal sheep. Am J Obstet Gynecol 162:
1325-1331, 1990.
Bocking, A. D., I. C. McMillen, R. Harding, and G. D. Thorburn. Effect
of reduced uterine blood flow on fetal and maternal cortisol. J Dev Physiol
8: 237-245, 1986.
Bocking, A. D., R. Gagnon, S. E. White, J. Homan, K. M. Milne, and B.
S. Richardson. Circulatory responses to prolonged hypoxemia in fetal
General Introduction
25
sheep. Am J Obstet Gynecol 159: 1418-1424, 1988.
Brace, R. A. Fetal blood volume, urine flow, swallowing, and amniotic fluid
volume responses to long-term intravascular infusions of saline. Am J
Obstet Gynecol 161: 1049-1054, 1989.
Brace, R. A., M. E. Wlodek, G. J. Mccrabb, and R. Harding. Swallowing
and urine flow responses of ovine fetuses to 24 h of hypoxia. Am J Physiol
266: R1345-R1352, 1994.
Brace, R. A. and E. J. Wolf. Normal amniotic fluid volume changes
throughout pregnancy. Am J Obstet Gynecol 161: 382-388, 1989.
Campbell, S., J.W. Wladimiroff, and C.J. Dewhurst. The antenatal
measurement of fetal urine production. Br J Obstet Gynaecol 80: 680,
1973.
Challis, J. R. G., B. S. Richardson, D. Rurak, M. E. Wlodek, and J. E.
Patrick. Plasma adrenocorticotropic hormone and cortisol and adrenal
blood flow during sustained hypoxemia in fetal sheep. Am J Obstet
Gynecol 155: 1332-1336, 1986.
Cheung, C. Y. and R. A. Brace. Fetal hypoxia elevates plasma atrial
natriuretic factor concentration. Am J Obstet Gynecol 159: 1263-1368,
1988.
Chevalier, R. L. Developmental renal physiology of the low birth weight preterm newborn. J Urol 156: 714-719, 1996.
Cock, M. L. and R. Harding. Renal and amniotic fluid responses to
umbilicoplacental embolization for 20 days in fetal sheep. Am J
Physiol-Regul Integr C. 42: R1094-R1102, 1997.
Cock, M. L., M. E. Wlodek, S. B. Hooper, G. J. Mccrabb, and R.
Harding. The effects of twenty-four hours of reduced uterine blood flow
on fetal fluid balance in sheep. Am J Obstet Gynecol 170: 1442-1451,
1994.
Cock, M. L., M. E. Wlodek, G. J. Mccrabb, and R. Harding. Alterations
in fetal urine production during prolonged hypoxaemia induced by
reduced uterine blood flow in sheep: Mechanisms. Clin Exp Pharmacol
Physiol 23: 57-63, 1996.
Cohn, H. E., E. J. Sacks, M. A. Heymann, and A. M. Rudolph.
Cardiovascular responses to hypoxemia and acidemia in fetal lambs. Am
J Obstet Gynecol 129(6): 817-824, 1974.
Corey, H. E. and A. Spitzer. Renal blood flow and glomerular filtration rate
during development. In: Pediatric Kidney Disease. Volume 1.The Kidney
26
Chapter 1
and Urinary Tract: Development, Morphology, and Physiology in Health
and Disease, (C. M. Edelmann Jr., J. Bernstein, S. R. Meadow, A.
Spitzer, and L. B. Travis, eds.), Little, Brown and Company, , Boston,
1992, pp. 49-77.
Daniel, S. S., M. Yeh, E. T. Bowe, A. Fukunaga, and L. S. James. Renal
response of the lamb fetus to partial occlusion of the umbilical cord. J
Pediatr 87: 788-794, 1975.
Dennison, E., C. Fall, C. Cooper, and D. Barker. Prenatal factors
influencing long-term outcome. Horm Res 48: 25-29, 1997.
Desai, M. and C. N. Hales. Role of fetal and infant growth in programming
metabolism in later life. Biol Rev Cambridge Phil Soc 72: 329-348, 1997.
Dunne, J. T., J. E. Milligan, and B. W. Thomas. Control of renal
circulation in the fetus. Am J Obstet Gynecol 112(3): 323-329, 1972.
Eckert, R. Osmoregulation and excretion. In: Animal Physiology,
mechanisms and adaptations, W.H. Freeman and company, New York,
1983, pp 483-544.
Ervin, M. G., M. G. Ross, A. Youssef, R. D. Leake, and D. A. Fisher.
Renal effects of ovine fetal arginine vasopressin secretion in response to
maternal hyperosmolality. Am J Obstet Gynecol 155: 1341-1347, 1986.
Gill, R.W. Measurement of blood flow by ultrasound: Accuracy and sources
of error. Ultrasound Med Biol 11: 625-641, 1985.
Gluckman, P. D. Intrauterine Growth Retardation - Future Research
Directions. Acta Paediatrica 82: 96-99, 1993.
Gosling, R.G., and D.H. King. Ultrasound angiology. In: Arteries and
Veins, ( A.W. Harcus and J. Adamson, eds.) Churchill-Livingstone,
Edinburgh, 1975.
Harding, R., S. B. Hooper, and K. A. Dickson. A mechanism leading to
reduced lung expansion and lung hypoplasia in fetal sheep during
oligohydramnios. Am J Obstet Gynecol 163: 1904-1913, 1990.
Heymann, M. A., B. D. Payne, J. I. E. Hoffman, and A. M. Rudolph.
Blood flow measurements with radionuclide-labeled particles. Prog Card
Dis 20: 55-79, 1977.
Hinchcliffe, S. A., P. H. Sargent, C. V. Howard, Y. F. Chan, and D. v.
Velzen. Human intrauterine renal growth expressed in absolute number
of glomeruli assessed by the 'Disector' method and Cavalieri principle.
Laboratory Investigations 64: 777-784, 1991.
Hinchcliffe, S. A., M. R. J. Lynch, P. H. Sargent, C. V. Howard, and D.
General Introduction
27
v. Velzen. The effect of intrauterine growth retardation on the
development of renal nephrons. Br J Obstet Gynaecol 99: 296-301, 1992.
Hooper, S. B., C. L. Coulter, J. M. Deayton, R. Harding, and G. D.
Thorburn. Fetal endocrine responses to prolonged hypoxemia in sheep.
Am J Physiol 259: R703-R708, 1990.
Hooper, S. B., A. D. Bocking, S. White, J. R. G. Challis, and V. K. M.
Han. DNA synthesis is reduced in selected fetal tissues during prolonged
hypoxemia. Am J Physiol 261: R508-R514, 1991.
Itskovitz, J., E. F. LaGamma, and A. M. Rudolph. Effects of cord
compression on fetal blood flow distribution and O2 delivery. Am J
Physiol 252: H100-H109, 1987.
Iwamoto, H. S. and A. M. Rudolph. Metabolic responses of the kidney in
fetal sheep: effect of acute and spontaneous hypoxemia. Am J Physiol 249:
F836-F841, 1985.
Jensen, A., W. Künzel, and M. Hohmann. Dynamics of fetal organ blood
flow redistribution and catecholamine release during acute asphyxia. In:
Proceedings of the International Symposium: Physiological Development
of the Fetus and Newborn (C. Jones and P. Nathanielsz, eds.) Academic
Press, New York, 1985, pp 405-410.
Jensen, A., M. Hohmann, and W. Künzel. Dynamic changes in organ blood
flow and oxygen consumption during acute asphyxia in fetal sheep. J Dev
Physiol 9: 543-559, 1987.
Jensen, A. and R. Berger. Fetal circulatory responses to oxygen lack. J Dev
Physiol 16: 181-207, 1991.
Jones, C. T. and R. O. Robinson. Plasma catecholamines in foetal and adult
sheep. J Physiol 248: 15-33, 1975.
Jones, C. T., M. M. Roebuck, D. W. Walker, and B. M. Johnston. The role
of the adrenal medulla and peripheral sympathetic nerves in the
physiological responses of the fetal sheep to hypoxia. J Dev Physiol 10:
17-36, 1988.
Kahane, V. L., J. C. Cutrin, C. P. Setton, M. D. Fernandez, S. D. Catz,
and N. B. Sterinspeziale. Biochemical and morphological changes in the
developing kidney. Biol Neonate 68: 141-152, 1995.
Kamitomo, M., J. G. Alonso, T. Okai, L. D. Longo, and R. D. Gilbert.
Effects of long-term, high-altitude hypoxemia on ovine fetal cardiac
output and blood flow distribution. Am J Obstet Gynecol 169: 701-707,
1993.
Kannisto, V., K. Christensen, and J. W. Vaupel. No increased mortality
28
Chapter 1
in later life for cohorts born during famine. Am J Epidemiol 145: 987-994,
1997.
King, A. and Y. W. Loke. Unexplained fetal growth retardation: What is the
cause? Arch Dis Child 70: F225-F227, 1994.
Lueder, F. L., S. B. Kim, C. A. Buroker, S. A. Bangalore, and E. S.
Ogata. Chronic maternal hypoxia retards fetal growth and increases
glucose utilization of select fetal tissues in the rat. Metabolism 44:
532-537, 1995.
Lumbers, E. R. A brief review of fetal renal function. J Dev Physiol 6: 1-10,
1983.
Lumbers, E. R. Development of renal function in the fetus: A review. Reprod
Fertil Dev 7: 415-426, 1995.
Maulik, D. Principles of Doppler signal processing and hemodynamic
analysis. In: Doppler Ultrasound in Obstetrics and Gynecology, (J.A.
Copel and K.L. Reed, eds.) Raven Press, New York, 1995.
McDonald, D.A. Blood flow in arteries, (E. Arnould, ed.), Publishes Ltd.,
London, 1974,
McGory, W.W. Developmental Nephrology. Harvard University Press,
Cambridge, pp 1-50, 1972.
McLellan, K., S. Hooper, A. Bocking, P. D. Delhanty, I. Phillips, D. Hill,
and V. M. Han. Prolonged hypoxia induced by the reduction of maternal
uterine blood flow alters insulin-like growth factor-binding protein-1
(IGFBP-1) and IGFBP-2 gene expression in the ovine fetus.
Endocrinology 131: 1619-1628, 1992.
Millard, R. W., H. Baig, and S. F. Vatner. Prostaglandin control of the
renal circulation in response to hypoxemia in the fetal lamb in utero. Circ
Res 45: 172-179, 1979.
Milnor, W.R. Pulsatile blood flow. N Engl J Med 287:27-34, 1972.
Guyton, A.C. and J.E. Hall. The kidney and body fluids. In: Textbook of
medical physiology 9th edition, Chapters 17, 26-31, pp 199-208, 315-421,
W.B. Saunders Company, Philadelphia, 1996
Mori, A., M. Iwashita, and Y. Takeda. Haemodynamic changes in IUGR
fetus with chronic hypoxia evaluated by fetal heart-rate monitoring of
blood flow velocity. MBEC 31: S49-S58, 1993.
Mott, J. C. Control of the foetal circulation. J Exp Biol 100: 129-146, 1982.
Mulder, A.L., J.C. van Golde, F.W. Prinzen, and C.E. Blanco. Cardiac
output distribution in response to hypoxia in the chick embryo in the
General Introduction
29
second half of the incubation time. J Physiol Lond. 508:281-287, 1998.
Nakamura, K. T., N. A. Ayres, R. A. Gomez, and J. E. Robillard. Renal
responses to hypoxemia during renin-angiotensin system inhibition in fetal
lambs. Am J Physiol 249: R116-R124, 1985.
Needham, J. Chemical Embryology, Vol 1., Cambridge University Press,
London, 1931.
Nicolaides, K. H., M. T. Peters, S. Vyas, R. Rabinowitz, D. J. D. Rosen,
and S. Campbell. Relation of rate of urine production to oxygen tension
in small-for-gestational-age fetuses. Am J Obstet Gynecol 162: 387-391,
1990.
Oosterhof, H. Maternal and fetal circulatory changes in normal and
complicated pregnancy. A Doppler ultrasound study. Thesis, University
Groningen, pp 1-131, 1993.
Ounsted, M., A. Scott, and C. Ounsted. Transmission through the female
line of a mechanism constraining human fetal growth. Ann Human Biol
13: 143-151, 1986.
Peeters, L. L. H., R. E. Sheldon, M. D. Jones jr., E. L. Makowski, and G.
Meschia. Blood flow to fetal organs as a function of arterial oxygen
content. Am J Obstet Gynecol 135: 637-646, 1979.
Peters, C. A., M. C. Carr, A. Lais, A. B. Retik, and J. Mandell. The
response of the fetal kidney to obstruction. J Urology 148: 503-509, 1992.
Robillard, J. E., R. E. Weitzman, D. A. Fisher, and F. G. Smith.
Developmental aspects of renal tubular reabsorption of water and fetal
renal response to arginine vasopressin. In: The kidney during
development. Morphology and Function, edited by A. Spitzer. New York:
Masson Publishing USA, 1982, p. 205-213.
Robillard, J. E., F. G. Smith, K. T. Nakamura, and G. P. Matherne. Fetal
renal function regulation of water and electrolyte excretion. In: Fetal &
neonatal body fluids, edited by R. A. Brace, M. G. Ross, and J. E.
Robillard. perinatology press, 1989, pp. 65-83.
Robillard, J. E. and K. T. Nakamura. Hormonal regulation of renal
function during development. Perinatal Nephrology Biol Neonate 53:
201-211, 1995.
Robillard, J. E., R. E. Weitzman, L. Burmeister, and F. G. Smith.
Developmental aspects of the renal response to hypoxemia in the lamb
fetus. Circ Res 48: 128-138, 1981.
Robillard, J. E., D. N. Weismann, and P. Herin. Ontogeny of single
30
Chapter 1
glomerular perfusion rate in fetal and newborn lambs. Pediatr Res 15:
1248-1255, 1981a.
Robillard, J. E., K. T. Nakamura, and G. F. Bibona. Effects of renal
denervation on renal responses to hypoxemia in fetal lambs. Am J Physiol
250: F294-F301, 1986.
Rudolph, A. M. The fetal circulation and its response to stress. J Dev Physiol
6: 11-19, 1984.
Rurak, D. W., B. S. Richardson, J. E. Patrick, L. Carmichael, and J.
Homan. Blood flow and oxygen delivery to fetal organs and tissues during
sustained hypoxemia. Am J Physiol 258: R1116-R1122, 1990.
Rurak, D. W., B. S. Richardson, J. E. Patrick, L. Carmichael, and J.
Homan. Oxygen consumption in the fetal lamb during sustained
hypoxemia with progressive acidemia. Am J Physiol 258: R1108-R1115,
1990a.
Seckl, J. R. Glucocorticoids, feto-placental 11beta-hydroxysteroid
dehydrogenase type 2, and the early life origins of adult disease. Steroids
62: 89-94, 1997.
Shung, K.K., Sigelman, R.A., and J.M. Reid. Scattering of ultrasound by
blood. JEEE Trans Biomed Eng 23: 460- , 1976.
Silbernagl S. and A. Despopoulos. Sesam atlas van de fysiologie, Bosch &
Keuning NV, Baarn, 1981.
Smith, F.G. The growth and functional development of the fetal kidney.
Thesis, Bachelor of Science. University of New South Wales, Sydney,
Australia, 1982.
Solomon, S. Critical periods in the development of renal regulatory
mechanisms. In: The kidney during development. Morphology and
Function, edited by A. Spitzer. New York: Masson Publishing USA, 1982,
pp. 283-289.
Spalding, D. A. Instinct with original observations on young animals.
Macmillan's Magazine 27: 282-293, 1873.
Towell, M., J. Figueroa, S. Markowitz, B. Elias, and P. Nathanielsz. The
effect of mild hypoxemia maintained for twenty-four hours on maternal
and fetal glucose, lactate, cortisol, and arginine vasopressin in pregnant
sheep at 122 to 139 days' gestation. Am J Obstet Gynecol 157: 1550-1557,
1987.
Transonic T106/T206 Small Animal Flowmeter Operator’s manual 6/91.
Transonic System Inc. 1991
Valenzuela, G. J., M. Norburg, and C. A. Ducsay. Acute intrauterine
General Introduction
31
hypoxia increases amniotic fluid prostaglandin F metabolites in the
pregnant sheep. Am J Obstet Gynecol 167: 1459-1464, 1992.
Veille, J. C., M. Penry, and E. Muellerheubach. Fetal Renal Pulsed
Doppler Waveform in Prolonged Pregnancies. Am J Obstet Gynecol 169:
882-884, 1993.
Vyas, S., K. H. Nicolaides, and S. Campbell. Renal artery flow-velocity
waveforms in normal and hypoxemic fetuses. Am J Obstet Gynecol 161:
168-172, 1989.
Walton, A. and J. Hammond. The maternal effects on growth and
conformation in Shire horse-Shetland pony crosses. Proc Royal Soc
London 125: 311-315, 1938.
Wladimiroff, J. W. and S. Campbell. Fetal urine-production rates in normal
and complicated pregnancy. The Lancet 2: 151-154, 1974.
Wlodek, M. E., R. A. Brace, M. L. Cock, S. B. Hooper, and R. Harding.
Endocrine responses of fetal sheep to prolonged hypoxemia with and
without acidemia: Relation to urine production. Am J Physiol-Renal Fl
Elect 37: F868-F875, 1995.
Wlodek, M. E., M. L. Cock, S. B. Hooper, G. D. Thorburn, and R.
Harding. The effects of prolonged hypoxia on fetal urine production and
composition and on the composition of fetal and maternal plasma in sheep.
Physiol Rev S216: 1993.(Abstract)
Wlodek, M., J. Challis, B. Richardson, and J. Patrick. The effects of
hypoxemia with progressive acidemia on fetal renal function in sheep. J
Dev Physiol 12: 323-328, 1989.
Woodcock, J. P. Measurement of blood flow in major vessels. In: Theory and
Practice of Blood Flow Measurement, Butterworths, London, 1975, p.
1-141.